Evidence Report/Technology Assessment 

Number 116 

Effects of Omega-3 Fatty Acids on Mental Health 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0021 

Prepared by: 

University of Ottawa Evidence-based Practice Center at 

The University of Ottawa, Ottawa, Canada

Investigators

Howard M Schachter, PhD 

Kader Kourad, MD, PhD 

Zul Merali, PhD 

Andrew Lumb, BA 

Khai Tran, PhD 

Maia Miguelez, PhD 

Gabriela Lewin, MD 

Margaret Sampson, MLIS 

Nick Barrowman, PhD 

Hope Senechal, BSc 

Candice McGahern, HRA 

Li Zhang, BSc 

Andra Morrison, BSc 

Jakov Shlik MD, PhD 

Yi Pan, MSc 

Elizabeth C Lowcock, BScH 

Isabelle Gaboury, MSc 

Jacques Bradwejn, MD 

Anne Duffy, MD 

AHRQ Publication No. 05-E022-2 

July 2005 
 

This report is based on research conducted by the University of Ottawa Evidence-based 

Practice Center (EPC), under contract to the Agency for Healthcare Research and Quality 

(AHRQ), Rockville, MD (Contract No. 290-02-0021). The findings and conclusions in this 

document are those of the authors, who are responsible for its contents; the findings and 

conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this 

report should be construed as an official position of AHRQ or of the U.S. Department of 

Health and Human Services. 

The information in this report is intended to help health care decisionmakers, patients and 

clinicians, health system leaders, and policymakers make well-informed decisions and thereby 

improve the quality of health care services. This report is not intended to be a substitute for 

the application of clinical judgment. Anyone who makes decisions concerning the provision 

of clinical care should consider this report as they would any medical reference and in 

conjunction with all other pertinent information, i.e., in the context of available resources and 

circumstances presented by individual patients. 

This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. Neither AHRQ’s nor the U.S. Department of Health and Human Services’ 

endorsement of such derivative products may be stated or implied. 
 ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Schachter H, Kourad K, Merali Z, Lumb A, Tran K, Miguelez M, et al. Effects of Omega-3 

Fatty Acids on Mental Health. Evidence Report/Technology Assessment No. 116. (Prepared by 

the University of Ottawa Evidence-based Practice Center, Under Contract No. 290-02-0021.) 

AHRQ Publication No. 05-E022-2. Rockville, MD: Agency for Healthcare Research and 

Quality. July 2005. 
 iii

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. This report was requested and funded by the Office of 

Dietary Supplements, National Institutes of Health. The reports and assessments provide 

organizations with comprehensive, science-based information on common, costly medical 

conditions and new health care technologies. The EPCs systematically review the relevant 

scientific literature on topics assigned to them by AHRQ and conduct additional analyses when 

appropriate prior to developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

 We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by email to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

 

Paul M. Coates, Ph.D. 

Director 

Office of Dietary Supplements 

National Institutes of Health 

Jean Slutsky, P.A., M.S.P.H.

Director 

Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Kenneth S. Fink, M.D., M.G.A., M.P.H. 

Director, EPC Program 

Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, R.N., Ph.D. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 
iv

Acknowledgments 

 The authors would like to thank numerous individuals for their support of the present project: 

Isabella Steffensen and Christine Murray for their ability to clarify the meaning of our words, 

figures and tables; Pieter Oosthuizen and Robin Emsley for responding affirmatively to our 

request for data; Malcolm Peet for trying to facilitate the sharing of data he collected yet which 

are now held by one of his studies’ funding sources; Bill Hodge for arranging timely help with 

assessors of study quality; Samantha Fulton for helping check some of our work; Vladimir Fox 

for arranging the expert and timely translation of non-English language articles; Herb Woolf for 

responding with substance to our request of industry for evidence; Peter O’Blenis for assuring 

that the Internet-based software we used for all aspects of the review process was adapted to our 

needs; our collaborators at SC-RAND and Tufts-NEMC EPCs; Beth Collins-Sharp, Rosaly 

Correa-de-Araujo and Jacqueline Besteman who, as our Task Order Officers, provided steady 

support and guidance on behalf of AHRQ; and, Anne Thurn of the Office of Dietary 

Supplements for her thoughtful direction on behalf of the Federal Partners. Sections of Chapter 

1 were developed in collaboration with Tufts-NEMC EPC, and with contributions from SCRAND EPC. 
v

Structured Abstract 

Context: One popular view holds that psychiatric problems reflect disorders of brain 

functioning. Fifty percent to 60% of the adult brain is composed of lipids (dry weight), of which 

35% are phospholipids comprised of unsaturated fatty acids. Of these, the polyunsaturated fatty 

acids docosahexaenoic acid (an omega-3 fatty acid) and arachidonic acid (an omega-6 fatty acid) 

are found in the highest concentrations. Thus, it has been proposed that omega-3 fatty acids 

could play an important role in mental health.

Objectives: The purpose of this study was to conduct a systematic review of the scientificmedical literature to identify, appraise and synthesize the evidence for the effects of omega-3 

fatty acids in mental health. Evidence was sought to permit the investigation of three basic 

questions: the efficacy and safety of omega-3 fatty acids as (primary or supplemental) treatment 

of psychiatric disorders or conditions (e.g., symptoms alone); the association between intake of 

omega-3 fatty acids and the onset, continuation or recurrence of psychiatric disorders or 

conditions; and, the association between the fatty acid content of biomarkers and the onset, 

continuation or recurrence of psychiatric disorders or conditions. The latter two questions 

examined the protective value of omega-3 fatty acid content in the diet and/or blood lipid 

biomarkers. The impact of effect modifiers was examined as well. The results will be used 

largely to inform a research agenda. 

Data Sources: A comprehensive search for citations was conducted using five databases 

(Medline, Embase, Cochrane Central Register of Controlled Trials, PsycInfo, and CAB Health). 

Searches were not restricted by language of publication, publication type, or study design, except 

with respect to the MeSH term “dietary fats,” which was limited by study design to increase its 

specificity. Search elements included: scientific terms, with acronyms, as well as generic and 

trade names relating to the exposure and its sources (e.g., eicosapentaenoic acid [EPA]; fish oil); 

and, relevant population terms (e.g., mental disorders). Additional published or unpublished 

literature was sought through manual searches of references lists of included studies and key 

review articles, and from the files of content experts. 

Study Selection: Studies were considered relevant if they described live human populations 

of any age, investigated the use of any foods or supplements known to contain omega-3 fatty 

acids, and utilized mental health outcomes. Studies examining the questions concerning 

treatment efficacy or the fatty acid content of biomarkers had to employ a controlled research 

design, whereas any type of design other than a case series or case study was permitted to 

address the possible association of the intake of omega-3 fatty acids and clinical outcomes. 

Three levels of screening for relevance, and two reviewers per level, were employed. 

Disagreements were resolved by forced consensus and, if necessary, third party intervention. 

Data Extraction: All data were abstracted by one reviewer, then verified by another. Data 

included characteristics of the report, study, population, intervention/exposure, comparator(s), 

cointerventions, discontinuations (and reasons), and outcomes (i.e., clinical, biomarkers, safety). 

Study quality (internal validity) and applicability (external validity) were appraised. 
vi

Data Synthesis: Question-specific qualitative syntheses of the evidence were derived. Metaanalysis was conducted with data concerning the supplemental treatment of schizophrenia. 

Limited numbers of studies addressing the other research questions precluded further metaanalysis. Eighty-six reports, describing 79 studies, were deemed relevant for the systematic 

review, with each of 6 studies described by more than one report. 

Conclusions: A notable safety profile for any type or dose of omega-3 fatty acid 

supplementation was not observed. Overall, other than for the topics of schizophrenia and 

depression, few studies were identified. Only with respect to the supplemental treatment of 

schizophrenia is the evidence even somewhat suggestive of omega-3 fatty acids’ potential as 

short-term intervention. However, these meta-analytic results exclusively pertaining to 2 g/d 

EPA require replication using design and methods refinements. Additional research might reveal 

the short-term or longterm therapeutic value of omega-3 fatty acids. One study demonstrating a 

significant placebo-controlled clinical effect related to 1 g/d E-EPA given, over 12 weeks, to 17 

patients with depressive symptoms—rather than depressive disorders—cannot be taken to 

support the view of the utility of this exposure as a supplemental treatment for depressive 

symptomatology or disorders. Nothing can yet be concluded concerning the clinical utility of 

omega-3 fatty acids as supplemental treatment for any other psychiatric disorder or condition, or 

as a primary treatment for all psychiatric disorders or conditions, examined in our review. 

Primary treatment studies were rare. Much more research, implementing design and methods 

improvements, is needed before we can begin to ascertain the possible utility of (foods or 

supplements containing) omega-3 fatty acids as primary prevention for psychiatric disorders or 

conditions. Overall, almost nothing is known about the therapeutic or preventive potential of 

each source, type, dose or combination of omega-3 fatty acids. Studies of their primary 

protective potential in mental health could be “piggybacked” onto longitudinal studies of their 

impact on general health and development. Because of limited study designs, little is known 

about the relationship between PUFA biomarker profiles and the onset of any psychiatric 

disorder or condition. Studies examining the possible association between the intake of omega-3 

fatty acids, or the PUFA content of biomarkers, and the continuation or recurrence of psychiatric 

disorders or conditions were virtually nonexistent. If future research is going to produce data 

that are unequivocally applicable to North Americans, it will likely need to enroll either North 

American populations or populations exhibiting a high omega-6/omega-3 fatty acid intake ratio 

similar to what has been observed in the diet of North Americans. Furthermore, if a reasonable 

view is that omega-3 fatty acids may play a role in mental health, then given the observed or 

proposed inter-relationships between omega-3 and omega-6 fatty acid contents both in the 

regular diet and in the human biosystem, it may behoove researchers to investigate the possible 

therapeutic or preventive value of the dietary omega-6/omega-3 fatty acid intake ratio. 
vii

Contents 

Evidence Report 

Chapter 1. Introduction ..........................................................................................................3 

 Metabolism and Biological Effects of Essential Fatty Acids ...........................................3 

 Metabolic Pathways of Omega-3 and Omega-6 Fatty Acids............................................4 

 U.S. Population Intake of Omega-3 Fatty Acids ..............................................................8 

 Dietary Sources of Omega-3 Fatty Acids .........................................................................9 

 Disorders of Mental Health: an Overview........................................................................11 

 Affective Disorders...........................................................................................................11 

 Treatment Options .......................................................................................................12 

 Anxiety Disorders .............................................................................................................13 

 Treatment Options .......................................................................................................13 

 Anorexia Nervosa .............................................................................................................13

 Treatment Options .......................................................................................................14 

 Attention Deficit/Hyperactivity Disorder .........................................................................14 

 Treatment Options .......................................................................................................14 

 Tendencies or Behaviors With the Potential to Harm Others: the Spectrum of 

Anger/Hostility, Aggression and Violence .......................................................................14 

 Treatment Options .......................................................................................................15 

 Alcoholism........................................................................................................................15 

 Treatment Options .......................................................................................................15 

 Borderline Personality Disorder .......................................................................................15 

 Treatment Options .......................................................................................................16 

 Schizophrenia....................................................................................................................16 

 Treatment Options .......................................................................................................16 

 Autism...............................................................................................................................16 

 Treatment Options .......................................................................................................17 

 Omega-3 Fatty Acids and Mental Health .........................................................................17 

Chapter 2. Methods...............................................................................................................19 

 Overview...........................................................................................................................19 

 Key Questions Addressed In This Report.........................................................................19 

 Analytic Framework .........................................................................................................21 

 Study Identification...........................................................................................................24 

 Search Strategy ............................................................................................................24 

 Eligibility Criteria ........................................................................................................25 

 Study Selection Process ...............................................................................................27 

 Data Abstraction ...............................................................................................................28 

 Summarizing the Evidence ...............................................................................................29 

 Overview......................................................................................................................29 

 Study Quality ...............................................................................................................29 

 Study Applicability ......................................................................................................31 
viii

 Summary Matrix ..........................................................................................................33 

 Qualitative Data Synthesis...........................................................................................33 

 Quantitative Data Synthesis.........................................................................................34 

Chapter 3. Results ..................................................................................................................37 

 Results of Literature Search..............................................................................................37 

 Report and Study Design Characteristics of Included Studies .........................................38 

 Are Omega-3 Fatty Acids Efficacious as Primary Treatment for Depression?................40 

 Overview of Relevant Study’s Characteristics and Results.........................................40 

 Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for Depression?.......42 

 Overview of Relevant Studies .....................................................................................42 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................44 

 Qualitative Synthesis of Individual Study Results.......................................................47 

 Quantitative Synthesis .................................................................................................49 

 Impact of Covariates and Confounders........................................................................51 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Depression? ...........................................51 

 Overview of Relevant Studies .....................................................................................52 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................58 

 Qualitative Synthesis of Individual Study Results.......................................................64 

 Quantitative Synthesis .................................................................................................66 

 Impact of Covariates and Confounders........................................................................66 

 Is the Onset, Continuation or Recurrence of Depression Associated With Omega-3 

or Omega-6/Omega-3 Fatty Acid Content of Biomarkers? ..............................................67 

 Overview of Relevant Studies .....................................................................................67 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................72 

 Qualitative Synthesis of Individual Study Results.......................................................76 

 Quantitative Synthesis .................................................................................................78 

 Impact of Covariates and Confounders........................................................................78 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Suicidal Ideation or Behavior? ..............78 

 Overview of Relevant Studies’ Characteristics and Results........................................79 

 Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for Bipolar 

Disorder? ...........................................................................................................................80 

 Overview of Relevant Studies’ Characteristics and Results........................................80 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Bipolar Disorder? ..................................83 

 Overview of Relevant Study’s Characteristics and Results.........................................83 

 Is the Onset, Continuation or Recurrence of Bipolar Disorder Associated With 

Omega-3 or Omega-6/Omega-3 Fatty Acid Content of Biomarkers? ..............................84 

 Overview of Relevant Studies’ Characteristics and Results........................................85 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Anxiety? ................................................87 

 Overview of Relevant Studies’ Characteristics and Results........................................87 

 Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for 

Obsessive-Compulsive Disorder? .....................................................................................89 
ix

 Overview of Relevant Study’s Characteristics and Results.........................................89 

 Is the Onset, Continuation or Recurrence of Anorexia Nervosa Associated With 

Omega-3 or Omega-6/Omega-3 Fatty Acid Content of Biomarkers? ..............................90 

 Overview of Relevant Studies’ Characteristics and Results........................................90 

 Are Omega-3 Fatty Acids Efficacious as Primary Treatment for Attention 

Deficit/Hyperactivity Disorder? ........................................................................................92 

 Overview of Relevant Studies .....................................................................................92 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................94 

 Qualitative Synthesis of Individual Study Results.......................................................97 

 Quantitative Synthesis .................................................................................................97 

 Impact of Covariates and Confounders........................................................................97 

 Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for Attention 

Deficit/Hyperactivity Disorder? ........................................................................................98 

 Overview of Relevant Studies .....................................................................................98 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................100 

 Qualitative Synthesis of Individual Study Results.......................................................102 

 Quantitative Synthesis .................................................................................................102 

 Impact of Covariates and Confounders........................................................................103 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Attention Deficit/Hyperactivity 

Disorder? ...........................................................................................................................103 

 Overview of Relevant Study’s Characteristics and Results.........................................103 

 Is the Onset, Continuation or Recurrence of Attention Deficit/Hyperactivity Disorder 

Associated With Omega-3 or Omega-6/Omega-3 Fatty Acid Content of Biomarkers?...104 

 Overview of Relevant Studies’ Characteristics and Results........................................105 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Mental Health Status Difficulties? ........107 

 Overview of Relevant Study’s Characteristics and Results.........................................107 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Tendencies or Behaviors With the 

Potential to Harm Others? .................................................................................................108 

 Overview of Relevant Studies .....................................................................................109 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................114 

 Qualitative Synthesis of Individual Study Results.......................................................117 

 Quantitative Synthesis .................................................................................................119 

 Impact of Covariates and Confounders........................................................................119 

 Is the Onset, Continuation or Recurrence of Tendencies or Behaviors With the 

Potential to Harm Others Associated With Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers?............................................................................................120 

 Overview of Relevant Studies’ Characteristics and Results........................................120 

 Quantitative Synthesis .................................................................................................122 

 Impact of Covariates and Confounders........................................................................123 

 Is the Onset, Continuation or Recurrence of Alcoholism Associated With Omega-3 

or Omega-6/Omega-3 Fatty Acid Content of Biomarkers? ..............................................123 

 Overview of Relevant Studies’ Characteristics and Results........................................123 

 Quantitative Synthesis .................................................................................................125 
x

 Impact of Covariates and Confounders........................................................................125 

 Are Omega-3 Fatty Acids Efficacious as Primary Treatment for Borderline 

Personality Disorder? ........................................................................................................125 

 Overview of Relevant Study’s Characteristics and Results.........................................125 

 Are Omega-3 Fatty Acids Efficacious as Primary Treatment for Schizophrenia?...........126 

 Overview of Relevant Study’s Characteristics and Results.........................................127 

 Are Omega-3 Fatty Acids Efficacious as Supplemental Treatment for Schizophrenia?..128 

 Overview of Relevant Studies .....................................................................................128 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................132 

 Qualitative Synthesis of Individual Study Results.......................................................136 

 Quantitative Synthesis .................................................................................................139 

 Impact of Covariates and Confounders........................................................................142 

 Is Omega-3 Fatty Acid Intake, Including Diet and/or Supplementation, Associated 

With the Onset, Continuation or Recurrence of Schizophrenia? ......................................143 

 Overview of Relevant Studies .....................................................................................143 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................147 

 Qualitative Synthesis of Individual Study Results.......................................................149 

 Quantitative Synthesis .................................................................................................151 

 Impact of Covariates and Confounders........................................................................151 

 Is the Onset, Continuation or Recurrence of Schizophrenia Associated With 

Omega-3 or Omega-6/Omega-3 Fatty Acid Content of Biomarkers? ..............................151 

 Overview of Relevant Studies .....................................................................................151 

 Qualitative Synthesis of Relevant Studies’ Key Characteristics .................................156 

 Qualitative Synthesis of Individual Study Results.......................................................159 

 Quantitative Synthesis .................................................................................................161 

 Impact of Covariates and Confounders........................................................................161 

 Is the Onset, Continuation or Recurrence of Autism Associated With Omega-3 or 

Omega-6/Omega-3 Fatty Acid Content of Biomarkers?...................................................162 

 Overview of Relevant Study’s Characteristics and Results.........................................162 

 What is the Evidence That, in Review-Relevant Studies Concerning Mental Health, 

Adverse Events (e.g., Side Effects) or Contraindications are Associated With 

the Intake of Omega-3 Fatty Acids?..................................................................................163 

Chapter 4. Discussion ............................................................................................................169 

 Overview...........................................................................................................................169 

 Evidence Synthesis and Appraisal....................................................................................170 

 Clinical Implications.........................................................................................................182 

 Research Implications and Directions ..............................................................................185 

 Limitations of the Review.................................................................................................197 

 Conclusion ........................................................................................................................198 

References and Included Studies ...........................................................................................201 

Listing of Excluded Studies at Level 2 Screening.................................................................210 

Listing of Excluded Studies at Level 3 Screening.................................................................216 
xi

Table of Studies Investigating Each Question: organized by the order of presentation 

in the text................................................................................................................................219 

Abbreviations.........................................................................................................................225

Figures 

Figure 1. Classical Omega-3 and Omega-6 Fatty Acid Synthesis Pathways and the 

Role of Omega-3 Fatty Acids in Regulating Health/Disease Markers ..............7 

Figure 2. Analytic Framework for Omega-3 Fatty Acids in Mental Health......................22 

Figure 3. Estimates of the Change in HDRS Score Between Omega-3 Fatty Acid 

and Placebo Groups From Studies Evaluating the Supplemental Treatment 

of Depression......................................................................................................50 

Figure 4. Estimates of the Difference in Mean Total PANSS Score Between EPA 

and Placebo Groups, by Study Evaluating the Supplemental Treatment of 

Schizophrenia .....................................................................................................140 

Figure 5. Estimates of the Difference in Mean Total PANSS Score Between Low 

Dose (<3 g/day) EPA and Placebo Groups. Percentage Weights 

Contributed by Each Study to the Pooled Estimate are Shown on the 

Right-hand Side..................................................................................................141 

Figure 6. Estimates of the Difference in Total PANSS Score Between High Dose 

(3 g/day or greater) EPA and Placebo Groups. Percentage Weights 

Contributed by Each Study to the Pooled Estimate are Shown on the 

Right-hand Side..................................................................................................142 

Tables 

Table 1. Estimates of the Mean± Standard Error of the Mean (SEM) Intake of 

Linoleic Acid (LA), Alpha-Linolenic Acid (ALA), eicosapentaenoic Acid 

(EPA), and Docosahexaenoic Acid (DHA) in the US Population, Based on 

Analyses of a Single 24-hour Dietary Recall of NHANES III Data....................8 

Table 2. Mean, Range, Median, and Standard Error of the Mean (SEM) of Usual 

Daily Intakes of Linoleic Acid (LA), Total Omega-3 Fatty Acids (n-3 FA), 

Alpha-linolenic (ALA), Eicosapentaenoic Acid (EPA), Docosapentaenoic 

Acid (DPA) and Docosahexaenoic Acid (DHA) in the US Population, 

based on CSFII Data (1994-1996, 1998) .............................................................9 

Table 3. The Omega-3 Fatty Acid Content, in Grams per 100g Food Serving, of a 

Representative Sample of Commonly Consumed Fish, Shellfish, Fish Oils, 

Nuts and Seeds, and Plant Oils that Contain at Least 5g Omega-3 Fatty 

Acids per 100g .....................................................................................................10 
xii

Summary Tables 

Summary Table 1. Omega-3 Fatty Acids as Primary Treatment for Depression ..............41 

Summary Table 2. Omega-3 Fatty Acids as Supplemental Treatment for Depression.....43 

Summary Table 3. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Depression (RCTs) ............................53 

Summary Table 4. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Depression (observational studies)....55 

Summary Table 5. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Depression (observational studies)....56 

Summary Table 6. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Depression (cross-national 

ecological analyses).............................................................................57 

Summary Table 7. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Depression ...................................................................68 

Summary Table 8. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Depression ...................................................................69 

Summary Table 9. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Depression ...................................................................70 

Summary Table 10. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Depression ...................................................................71 

Summary Table 11. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Depression ...................................................................72 

Summary Table 12. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Suicidal Ideation or Behavior............79 

Summary Table 13. Omega-3 Fatty Acids as Supplemental Treatment for Bipolar 

Disorder...............................................................................................81 

Summary Table 14. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Bipolar Disorder ................................84 

Summary Table 15. Association Between Omega-3 or Omega-6/Omega-3 Fatty Acid 

Content of Biomarkers and Onset, Continuation or Recurrence 

of Bipolar Disorder..............................................................................85 

Summary Table 16. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Anxiety ..............................................88 

Summary Table 17. Omega-3 Fatty Acids as Supplemental Treatment for ObsessiveCompulsive Disorder...........................................................................90 

Summary Table 18. Association Between Omega-3 or Omega-6/Omega-3 Fatty Acid 

Content of Biomarkers and Onset, Continuation or Recurrence of 

Anorexia Nervosa................................................................................91 
xiii

Summary Table 19. Omega-3 Fatty Acids as Primary Treatment for Attention 

Deficit/hyperactivity Disorder.............................................................93 

Summary Table 20. Omega-3 Fatty Acids as Supplemental Treatment for Attention 

Deficit/hyperactivity Disorder.............................................................99 

Summary Table 21. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Attention Deficit/hyperactivity 

Disorder...............................................................................................104 

Summary Table 22. Association Between Omega-3 or Omega-6/Omega-3 Content of 

Biomarkers and Onset, Continuation or Recurrence of AD/HD.........105 

Summary Table 23. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Mental Health Difficulties.................108 

Summary Table 24. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Tendencies or Behavior with the 

Potential to Harm Others (RCTs)........................................................110 

Summary Table 25. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Tendencies or Behavior with the 

Potential to Harm Others (RCT) .........................................................111 

Summary Table 26. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Tendencies or Behavior with the 

Potential to Harm Others (cross-sectional study)................................112 

Summary Table 27. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Tendencies or Behavior with the 

Potential to Harm Others (RCT) .........................................................113 

Summary Table 28. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Tendencies or Behavior with the 

Potential to Harm Others (cross-national ecological analysis) ...........114 

Summary Table 29. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Tendencies or Behaviors with the Potential to 

Harm Others ........................................................................................121 

Summary Table 30. Association Between Omega-3 and Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Alcoholism...................................................................124 

Summary Table 31. Omega-3 Fatty Acids as Primary Treatment for Borderline 

Personality Disorder............................................................................126 

Summary Table 32. Omega-3 Fatty Acids as Primary Treatment for Schizophrenia .........127 

Summary Table 33. Omega-3 Fatty Acids as Supplemental Treatment for 

Schizophrenia ......................................................................................129 

Summary Table 34. Omega-3 Fatty Acids as Supplemental Treatment for 

Schizophrenia ......................................................................................130 

Summary Table 35. Omega-3 Fatty Acids as Supplemental Treatment for 

Schizophrenia ......................................................................................131 

Summary Table 36. Omega-3 Fatty Acids as Supplemental Treatment for 

Schizophrenia ......................................................................................132 
xiv

Summary Table 37. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Schizophrenia (observational 

studies).................................................................................................144 

Summary Table 38. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Schizophrenia (observational 

studies).................................................................................................145 

Summary Table 39. Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Schizophrenia (cross-national 

ecological analyses).............................................................................146 

Summary Table 40. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Schizophrenia...............................................................152 

Summary Table 41. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Schizophrenia...............................................................153 

Summary Table 42. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Schizophrenia...............................................................154 

Summary Table 43. Association Between Omega-3 or Omega-6/Omega-3 Fatty Acid 

 Content of Biomarkers and Onset, Continuation or Recurrence of 

Schizophrenia ......................................................................................155 

Summary Table 44. Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Schizophrenia...............................................................156 

Summary Table 45. Association Between Omega-3 and Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Autism..........................................................................163 

Summary Table 46. Studies Reporting Adverse Events (e.g., side effects) or 

Contraindications.................................................................................164 

Summary Table 47. Studies Reporting Adverse Events (e.g., side effects) or 

Contraindications.................................................................................166 

Summary Table 48. Studies Reporting Adverse Events (e.g., side effects) or 

Contraindications.................................................................................167 

Summary Matrix 

Summary Matrix 1. Study Quality and Applicability of Evidence Regarding the 

Supplemental Treatment of Depression.............................................47 

Summary Matrix 2. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Depression (all designs) ...................63 

Summary Matrix 3. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 or Omega-6/Omega-3 Fatty 
xv

Acid content of Biomarkers and Onset, Continuation or 

Recurrence of Depression (all designs) .............................................75 

Summary Matrix 4. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Suicidal Ideation or Behavior 

(all designs)........................................................................................80 

Summary Matrix 5. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Bipolar Disorder.........................................................86 

Summary Matrix 6. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Anxiety.............................................89 

Summary Matrix 7. Study Quality and Applicablility of Evidence Regarding the 

Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Anorexia Nervosa.......................................................92 

Summary Matrix 8. Study Quality and Applicability of Evidence Regarding the 

Primary Treatment of Attention Deficit/hyperactivity Disorders 

(all designs)........................................................................................96 

Summary Matrix 9. Study Quality and Applicability of Evidence Regarding the 

Supplemental Treatment of Attention Deficit/hyperactivity 

Disorder..............................................................................................101 

Summary Matrix 10. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Contnuation or 

Recurrence of Attention Deficit/hyperactivity Disorder....................106 

Summary Matrix 11. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Tendencies of Behavior with the 

Potential to Harm Others ...................................................................117 

Summary Matrix 12. Study Quality and Applicability of Evidence Regarding the 

Association Between the Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Tendencies or Behavior with the Potential to 

Harm Others.......................................................................................122 

Summary Matrix 13. Study Quality and Applicability of Evidence Regarding the 

Association Between the Omega-3 or Omega-6/Omega-3 

Fatty Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Alcoholism .................................................................124 

Summary Matrix 14. Study Quality and applicability of Evidence Regarding the 

Supplemental Treatment of Schizophrenia........................................136 

Summary Matrix 15. Study Quality and Applicability of Evidence Regarding the 

Association Between Omega-3 Fatty Acid Intake and Onset, 

Continuation or Recurrence of Schizophrenia...................................149 
xvi

Summary Matrix 16. Study Quality and Applicability of Evidence Regarding the 

Association Between the Omega-3 or Omega-6/Omega-3 Fatty 

Acid Content of Biomarkers and Onset, Continuation or 

Recurrence of Schizophrenia .............................................................158 

Appendixes 

Appendix A: Search Strategies 

Appendix B: Letter to Industry Representatives 

Appendix C: Data Assessment and Data Abstraction Forms 

Appendix D: Modified QUOROM Flow Chart 

Appendix E: Evidence Tables 

Appendix F: Additional Acknowledgements 

Appendixes and Evidence Tables are provided electronically at 

http://www.ahrq.goc/clinic/tp/o3menttp.htm. 
Introduction

The purpose of this study was to conduct a

systematic review of the scientific-medical

literature to identify, appraise, and synthesize the

human evidence for the effects of omega-3 fatty

acids on mental health. The review was requested

and funded by the Office of Dietary

Supplements, National Institutes of Health. It was

undertaken as part of a consortium involving

three Evidence-based Practice Centers (EPCs),

which investigated the value of omega-3 fatty acid

supplementation across 11 health/disease areas.

The three EPCs are Southern California-RAND,

Tufts-New England Medical Center, and the

University of Ottawa. To ensure consistency of

approach, the three EPCs collaborated on selected

methodologic elements, including literature

search strategies, rating of evidence, and data table

design.

While the intention was to evaluate the

spectrum of psychiatric disorders or conditions

(i.e., behavior or symptoms which, while their

consequences could be serious, do not warrant

receipt of a formal psychiatric diagnosis), certain

foci were beyond the scope of the review (see

Methods). At the same time, a mental health

disorder or condition did not require extant

animal or basic science data or models to justify

the investigation of their evidence. Nevertheless,

justification for the study of two disorders exists

in the literature: depression and schizophrenia. 

The mechanism by which diet may affect

health, including depression or cardiovascular

disease, has been thought to involve low levels of

omega-3 fatty acid content in biomarkers (e.g.,

red blood cells [RBCs]).1,2 An omega-3 fatty acid

deficiency hypothesis of depression has been put

forward, which has helped justify treatment with

omega-3 fatty acid supplementation.3 The

membrane phospholipid hypothesis of

schizophrenia has been proposed in an attempt to

develop a model explaining its etiology.4 It

describes the presumed biochemical dynamics

underpinning a neurodevelopmental theory.

Some of the evidence used to support this

perspective suggests the existence of phospholipid

and polyunsaturated fatty acid (PUFA) metabolic

abnormalities in schizophrenia.4-6 It has been

posited that modifications to diet could mitigate

or even aggravate an underlying abnormality of

phospholipid metabolism.4

However, the present review was not

conducted to test these hypotheses. Rather, the

rationale for this 2-year project investigating the

possible health benefits of omega-3 fatty acids was

to systematically review the evidence to aid in the

development of a research agenda. Nevertheless,

these emerging models regarding depression and

schizophrenia do suggest plausible bases for the

use of omega-3 fatty acids to treat or prevent

these psychiatric disorders. 

Evidence Report/Technology Assessment

Number 116

Effects of Omega-3 Fatty Acids on Mental Health

Summary

Authors: Schachter HM, Kourad K, Merali Z, Lumb A, Tran K, Miguelez M, et al. 

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

Key Questions

Four basic questions were investigated with respect to each

psychiatric disorder or condition for which evidence meeting

eligibility criteria could be identified. To illustrate, the questions

pertaining to depression were:

• Are omega-3 fatty acids efficacious as (primary or

supplemental) treatment for depression? 

• Is omega-3 fatty acid intake, including diet and/or

supplementation, associated with the onset, continuation,

or recurrence of depression (i.e., primary or secondary

prevention)? 

• Is the onset, continuation, or recurrence of depression

associated with omega-3 or omega-6/omega-3 fatty acid

content of biomarkers (i.e., primary or secondary

prevention)?

• What is the evidence in review-relevant studies concerning

mental health that adverse events (e.g., side effects) or

contraindications are associated with the intake of omega3 fatty acids?

Where data permitted, the impact of effect modifiers (e.g.,

covariates) was investigated with respect to the following study

characteristics:

• Population (e.g., primary diagnosis, disorder severity,

smoker status, alcohol consumption).

• Intervention/exposure (e.g., source, type, dose or serving

size, and method to deliver the omega-3 fatty acids;

intervention length; dietary omega-6/omega-3 fatty acid

content).

• Comparator/control (e.g., type of placebo material, a

“gold standard” medication).

• Cointerventions (e.g., concurrent psychotropic

medication, other supplement use).

Methods

A Technical Expert Panel (TEP) consisting of nine members

was convened to provide advisory support to the project,

including refining the questions and highlighting key variables

requiring consideration in the evidence synthesis. 

Study Identification

Several electronic databases were searched: MEDLINE®,

EMBASE®, the Cochrane Library including the Cochrane

Central Register of Controlled Trials, PsycINFO, and CAB

Health®. Searches were not restricted by language of

publication, publication type, or study design, except with

respect to the MeSH® term “dietary fats,” which was limited

by study design to increase its specificity. Search elements

included: scientific terms, with acronyms, as well as generic and

trade names relating to the exposure and its sources (e.g.,

eicosapentaenoic acid (EPA), omega-3 fatty acids, MaxEPA®);

and relevant population terms (e.g., depression). Additional

published or unpublished literature was sought through manual

searches of reference lists of included studies and key review

articles, and from the files of content experts. A final set of

1,212 unique references was identified and posted to an

Internet-based software system for review.

Studies were considered relevant if they described live human

populations of any age with any or no comorbidity, exhibiting

a psychiatric status consistent with one of the above-noted

research questions concerning treatment or prevention (i.e.,

with or without [a known elevated risk to develop] a psychiatric

diagnosis or condition). Studies also had to investigate at least

one pertinent clinical outcome (e.g., symptom improvement,

incidence of a disorder). 

As markers of omega-3 fatty acid metabolism, the following

fatty acid compositions or concentrations, from any source

(e.g., plasma phospholipids), were considered relevant as

possible predictors of the onset, continuation, or recurrence of

psychiatric disorders or conditions: EPA, docosahexaenoic acid

(DHA), arachidonic acid (AA)/EPA, AA/DHA, and

AA/EPA+DHA. Studies exclusively evaluating the role of other

biomarkers (e.g., cytokine production, eicosanoid levels) were

not included. Populations with degenerative (e.g., Alzheimer’s)

and peroxisomal (e.g., Zellweger’s) disorders were excluded

since each was addressed in Southern California-RAND’s year2 review of the evidence concerning omega-3 fatty acids in

neurology. 

Treatment studies, as well as those investigating the possible

association between omega-3 fatty acid intake and the onset,

continuation, or recurrence of psychiatric disorders or

conditions, had to investigate foods or supplements known to

contain omega-3 fatty acids of any type (e.g., EPA), from any

source (e.g., walnuts), any serving size or dose, delivered in any
fashion (e.g., capsules, PUFA-rich diet), and for any length of

time. In all studies, some method had to have been employed

to suggest the presence of omega-3 fatty acid content in the

exposure, if not its actual amount (e.g., g/d). Studies

investigating “PUFAs” or “ long-chain PUFAs,” or even types

of diet one might presume would contain marine or land

sources of omega-3 fatty acids (e.g., “Mediterranean diet”) at

minimum had to highlight at least one source of the omega-3

fatty acid content (e.g., oily fish servings). No restrictions were

placed on the types or doses of pre- or on-study cointerventions

(e.g., psychotropic medication, omega-6 fatty acid intake). 

Controlled studies employing any control were required to

address questions of intervention efficacy (or effectiveness),

with randomized controlled trials (RCTs) being the gold

standard method to investigate these questions.7 Any type of

research design other than noncomparative case series or case

studies was deemed appropriate for questions concerning the

possible association between the intake of omega-3 fatty acids

and the onset, continuation, or recurrence of psychiatric

disorders or conditions. A special interpretative emphasis was

placed on results from prevention RCTs and other controlled

prospective designs. Controlled studies involving any control

were required to address the questions of the possible

association between the fatty acid content of biomarkers and

the onset, continuation, or recurrence of psychiatric disorders

or conditions. These decisions were made with the assistance of

our TEP. 

Two initial levels of screening for relevance, and two

reviewers per level, were directed at bibliographic records and

then full articles. A third dual-assessor relevance screening

identified and thereby excluded uncontrolled studies with

respect to questions of intervention efficacy or the possible

protective role of lipid biomarker content. Calibration exercises

preceded each step of the screening process. Excluded studies

were noted as to the reason for their ineligibility using a

modified QUOROM format.8 Disagreements were resolved by

forced consensus and, if necessary, third party intervention. 

Data Abstraction 

Following a calibration exercise, seven reviewers

independently abstracted the contents of each included study

using an electronic data abstraction form. A second reviewer

verified these data. Data included the characteristics of the

report (e.g., publication status), study (e.g., research design),

population (e.g., diagnosis), intervention/exposure (e.g., omega3 fatty acid type), comparator group(s), cointerventions (e.g.,

medications), withdrawals or dropouts, and outcomes (i.e.,

symptom improvement, biomarker status, adverse events). 

After calibration exercises, each study’s quality (internal

validity) and applicability (external validity) were formally

assessed. Dual-review appraised RCTs’ quality while only

single-assessor evaluations could be conducted for other

research designs. For the RCTs, disagreements were resolved by

forced consensus and, if necessary, third party intervention.

RCTs’ reporting of randomization, double blinding,

withdrawals and dropouts, and the concealment of allocation,

were evaluated using Jadad’s9 and Schulz’s validated

instruments.10 The validated Newcastle-Ottawa Scale (NOS)

assessed case-control and cohort study designs, while all other

designs were evaluated using modifications of the NOS,11

Jadad’s instrument,9 or items from Downs and Black’s validated

27-item tool.12 Applicability was defined as the extent to which

a given study’s sample population was representative of a

“typical” North American population. The method of diagnosis

and the omega-6/omega-3 fatty acid ratio in the background

diet were the key variables defining the reference population of

North Americans identified with a psychiatric disorder. The

omega-6/omega-3 fatty acid ratio in the background diet

defined the reference population of North Americans who did

not exhibit a psychiatric disorder.

Data Synthesis

A summary table provided a question-specific overview of

included studies’ relevant data presented in greater detail in

evidence tables. A question-specific summary matrix situated

each study in terms of its quality and applicability ratings.

Question-specific qualitative syntheses of the evidence were

derived. A dearth of studies best suited to address a particular

kind of question (i.e., RCTs, prospective and controlled

observational studies), as well as limitations on, or the strong

clinical heterogeneity of, available studies (e.g., divergent

intervention-comparator contrasts, use of complex

interventions where it was impossible to tease out the possible

specific benefit of omega-3 fatty acids, failure to control for key

confounders), made it impossible to perform meta-analysis for

any question other than the supplemental treatment for

schizophrenia.

3
4

Results

Literature Search

Of 1,212 records entered into the initial screening for

relevance, 955 were excluded. All but seven of the remaining

257 reports were then retrieved and subjected to a more

detailed relevance assessment.13-21 A second relevance screening

then excluded 137 reports. A third screening excluded 27

reports of uncontrolled studies. In total, 86 reports, describing

79 unique studies, were deemed relevant for the systematic

review, with six studies each described by more than one report.

To simplify matters, only one report per study is referred to in

this summary. Yet, data from all of a study’s documents were

included in qualitative and quantitative syntheses. Some studies

addressed more than one question.

Of the included studies, only one failed to be described by at

least one published report.22 It was reported in abstract format.

Sixteen relevant studies were identified by manual search. One

report required translation from Chinese.23 All the other

included reports were written in English. 

Overall, depression (n=22 studies) and schizophrenia (n=28)

were the most frequently studied disorders. Only the 10 studies

investigating attention-deficit/hyperactivity disorder (AD/HD)

enrolled pediatric populations. Many of the studies exhibited

poor quality or weak applicability to North American

populations. Synopses of evidence are presented according to

seven cross-cutting topics:

Adverse Events 

A number of study reports explicitly stated that no exposurerelated adverse events had been observed.24-32 Ten RCTs

described at least one mild adverse event associated with an

omega-3 fatty acid intervention/exposure.2,33-41 Results from

these studies suggest that the exposures were well tolerated. In

spite of a small number of discontinuations presumed to have

been instigated by an adverse event, it is unlikely that moderate

or severe side effects were ever observed in relation to an

omega-3 fatty acid exposure. Reported difficulties tended to be

mild and transient, often involving gastrointestinal upset or

nausea. Occasionally, adverse events were linked to the intake

of oily substances, rather than to the omega-3 fatty acid

contents in the oils. Aside from the mild adverse effects

associated with Stoll et al.’s very high dose of 9.6 g/d

EPA+DHA (i.e., three patients had to decrease the number of

capsules swallowed per day, yet none were required to

discontinue),38 no other patterns were discerned regarding the

impact of dose, type (e.g., DHA, EPA) or source (e.g., marine,

plant) of omega-3 fatty acids on safety. In one study, a child

with AD/HD in the active treatment group had to leave the

study due to problems swallowing the capsules.41 Few of the

events described in two trials by Hamazaki et al., which

enrolled healthy volunteers, suggested that the adverse effects

had been directly related to the exposure.39,40

Primary Treatment

One RCT examined omega-3 fatty acids as primary

treatment for depression.34 It found no benefit for 2 g/d DHA

as primary treatment despite an increase in the absolute RBC

levels of DHA in the active treatment group.34 Reasons for this

null result could include the use of too small a dose, too short

an intervention period, the “wrong” omega-3 fatty acid, broken

blinding, low power, or failure to modify the on-study

background intake of omega-6 fatty acids. 

Notwithstanding the noncomparability of interventions,

comparators, and populations (i.e., with32,42,43 or without a

formal diagnosis of AD/HD,41 with32 or without significant

comorbidity41,43), the complex definitions of the intervention

where it was impossible to tease out the possible specific benefit

of omega-3 fatty acids,41 evidence for selection bias,43 or the

failure to specify study enrollees’ specific diagnostic subtype of

AD/HD (e.g., inattentive),44 the results of the three RCTs32,41,42

and the comparative before-after study43 addressing the

question about the primary treatment of AD/HD were

inconsistent. Thus, no definitive conclusions can be drawn

about the value of omega-3 fatty acids as primary treatment for

AD/HD. 

One RCT examined ethyl (E)-EPA as primary treatment for

borderline personality disorder and observed significant clinical

effects, as the E-EPA group had, at study end, significantly

lower mean scores on both clinical outcomes compared with

the placebo group.31 Despite its strong applicability to the

North American population, this is a small study requiring

replication.

While the results of Peet et al.’s trial37 indicate placebocontrolled benefits accruing to omega-3 fatty acids as primary

treatment for schizophrenia, this was a small, albeit

methodologically adequate, pilot trial with little applicability to

a North American population. More work is required before we

can determine omega-3 fatty acids’ promise in this context. 
Supplemental Treatment

Peet et al.’s dose-ranging RCT of E-EPA as supplemental

treatment for depression found that only 1 g/d for 12 weeks

had a significant impact on various clinical outcomes.2 Two

RCTs of shorter duration also showed significant benefits

associated with 2 g/d E-EPA and 6.6 g/d of EPA+DHA,

respectively;27,33 the significant clinical effect reported by Su et

al. was associated with a significant increase in RBC EPA

exclusively in the active treatment group.33 However, we

decided to forego meta-analysis due to study differences on the

basis of the intervention (i.e., type, dose, followup length) and

comparator (i.e., placebo source). Also, unlike the other two

trials, Peet et al.’s did not formally identify patients with a

depressive disorder.2 This may account for their finding that 1

g/d E-EPA had a beneficial effect on depressive

symptomatology.2 A low dose might not have helped the

treatment-resistant depressive disorders investigated in the other

RCTs. Yet, this likely cannot explain why Peet et al.’s higher

doses (2 g/d, 4 g/d) did not likewise ameliorate depressive

symptoms, or why more responders (i.e., 50 percent

improvement) were found in the placebo group than in the 2

g/d E-EPA group. Su et al.’s trial may have been confounded by

uncontrolled combinations of medication.33 The question of

omega-3 fatty acids as supplemental treatment for depression

requires additional investigation.

Two studies, one a RCT38 and one defined merely as

“controlled,”45 evaluated the supplemental treatment of bipolar

disorder. Only the RCT report gave us an opportunity to assess

its study parameters and results.38 While it had to be stopped

prematurely, their very high dose of 9.6 g/d EPA+DHA

produced a significantly longer period of remission in the active

treatment group compared with controls. This study’s

limitations (i.e., loss of power due to its stoppage, broken

blind) require its replication. Therefore, the evidence base is too

limited to allow us to conclude anything about the value of

omega-3 fatty acids as supplemental therapy for bipolar

disorder. Likewise, one underpowered and flawed crossover

RCT, which failed to show that E-EPA is effective as

supplemental treatment for obsessive-compulsive disorder, is

insufficient to permit drawing a definitive conclusion.25

Inconsistencies in the results produced by three RCTs, the

occasional use of a complex intervention making it impossible

to tease out the possible specific benefit of omega-3 fatty

acids,46 the confirmation by parents—but not by

professionals—of an AD/HD diagnosis,46 interventions that did

not last long enough,30,42,46 and failures to weight-adjust doses of

omega-3 fatty acids prevent us from identifying clear

conclusions about their value as supplemental treatment for

AD/HD.30,42,46

Three of four good quality placebo-controlled RCTs

investigating the supplemental treatment of schizophrenia26,35-37

reported significant clinical effects in favor of EPA using total

Positive and Negative Syndrome Scale (PANSS) scores,26,36,37

although Peet et al.’s study observed this effect only for those

receiving clozapine as primary treatment.36 Yet, the Emsley et al.

study found a nonsignificant trend towards greater reduction in

total PANSS scores in participants taking typical antipsychotic

medication, compared with those receiving clozapine.26 Results

of our meta-analysis of two studies’ PANSS total data revealed

that dose influenced outcome. A or significant placebocontrolled effect was identified for 2 g/d EPA yet not for doses

of at least 3g/d EPA.36,37 However, these results might have been

different had we been able to analyze data by type of

psychotropic medication, had both studies used either the

purified or unpurified form of EPA as well as the same placebo

oils, had their intervention periods lasted longer, or had both

trials employed capsules to deliver the omega-3 fatty acids.

While the findings are suggestive, they remain inconclusive

given that the data subjected to meta-analysis were derived

from two small trials exhibiting certain limitations. 

Primary Prevention (i.e., Onset) Via Omega-3

Fatty Acid Intake

Inconsistent results, in addition to too few studies exhibiting

sound methodologies or research designs that are ideally suited

to investigate this question (e.g., prospective, controlled, with

subject-level data), suggest that it is too early to conclude

whether or not the intake of omega-3 fatty acids protects

against the onset of depressive disorders or

symptomatology.1,24,28,47-55 The same issues prevent us from

concluding whether or not the intake of omega-3 fatty acids

protects against the onset of suicidal ideation or behavior.51,55

Given the inability of any cross-national ecological analysis to

provide meaningful subject-level data, and the failure to control

for key confounders (i.e., socioeconomic status, urban/rural

ratio, educational level, marital status, alcohol consumption,

smoker status, or family history), we cannot conclude anything

about the value of seafood consumption as protection against

the onset of bipolar disorder.

56

5
Two RCTs failed to clarify the protective value of omega-3

fatty acid intake with respect to the onset of symptoms, not

disorders, of anxiety.28,47 However, these small studies do not

constitute optimal tests of this potential. Based on one crosssectional study, which controlled for age, income, smoking,

alcohol consumption, and eating patterns, mental health

difficulties were more prevalent in those consuming no fish.57

However, this design precludes inferring a causal link between

fish consumption and the onset of mental health difficulties.

Four RCTs,28,39,40,58 three of which enrolled healthy volunteers,

one single population cross-sectional survey59 and one crossnational ecological analysis60 studied the possible association

between omega-3 fatty acid intake and the onset of tendencies

or behavior with the potential to harm others. Overall, their

findings are too inconsistent and involve too few research

designs permitting the drawing of causal inferences or too

many different definitions of the exposure, population, or

outcome to permit us to draw a consistent, individual/patientlevel conclusion regarding the value of omega-3 fatty acid

intake to protect against tendencies or behavior with the

potential to harm others. 

We could not identify the research designs which, due to

their prospective and controlled nature, are most appropriate

for addressing the question of the possible relationship between

intake of omega-3 fatty acids (e.g., via breastfeeding) and the

onset of schizophrenia. Five case-control designs,22,61-64 one

single prospective cohort,65 and three cross-national ecological

analyses50,56,66 were found. The only prospective study was not

controlled, and its followup was very short.65 Moreover, failure

to control for confounders was common (e.g., maternal feeding

patterns, sex of children, maternal age, socioeconomic status,

early mother-infant contact). Thus, nothing definitive can be

asserted about a reliable association between omega-3 fatty acid

intake and the onset of schizophrenia. 

Secondary Prevention (i.e., Continuation,

Recurrence) Via Omega-3 Fatty Acid Intake

One small, multiple-group cross-sectional study revealing

that, relative to healthy controls, AD/HD children consumed

significantly lesser amounts of linoleic acid and alpha linolenic

acid (ALA) is insufficient to permit us to conclude anything

definitive regarding the potential of these PUFAs to alter the

course, or continuation, of AD/HD.23 Likewise, a single RCT

demonstrating that a complex intervention including omega-3

fatty acids—whose independent effect could not be

ascertained—provided young adult prisoners with some

protection against committing new offences29 is insufficient to

determine its capacity to prevent the recurrence of tendencies

or behavior with the potential to harm others (i.e., antisocial

behavior).29

Primary Prevention (i.e., Onset) Via Lipid

Biomarker Content

Inconsistent results as well as too few studies exhibiting

sound methodologies (e.g., protection against selection bias;

control for smoking, alcohol use, and psychotropic medication)

or research designs (e.g., prospective, controlled) that are ideally

suited to investigate this question suggest that it is too early to

conclude whether or not omega-3 fatty or omega-6/omega-3

acid content in biomarkers protects against the onset of

depressive disorders or symptomatology. One RCT24 and seven

multiple-group cross-sectional studies1,67-72 were included. 

The inconsistency in findings across two multiple-group

cross-sectional studies,73,74 which is potentially attributable to

the fact that the studies obtained their PUFA samples from

different biomarker sources, in addition to the recognition that

this type of research design is less than an ideal test of the

research question, and the observation that the studies failed to

control for different key confounders together indicate that

nothing definitive can be concluded about the ability of specific

lipid biomarker content to protect against the onset of bipolar

disorder. Irrespective of the limited agreement in observing that

both ALA and total omega-6 fatty acid levels in plasma

phospholipids were significantly lower in anorexic patients

compared with controls, the use of cross-sectional designs in

two small studies prevent the drawing of causal inferences

regarding the role of lipid biomarker content in the onset of

anorexia nervosa.75,76 Inconsistent findings from three multiplegroup cross-sectional studies whose designs are of limited use in

investigating the research question,77-79 the failures to control for

dietary intake,77 to formally rule out the presence of

psychopathology in the control subjects, or to employ formal

diagnostic criteria (i.e., DSM-III) to identify their hyperactive

subjects,78 made it impossible to draw causal inferences about

the role of omega-3 or omega-6/omega-3 fatty acid content in

biomarkers to prevent the onset of AD/HD. 

Three multiple-group cross-sectional studies examined the

possible association of the onset of tendencies or behavior with

the potential to harm others with the omega-3 or omega6/omega-3 fatty acid content of biomarkers.80-82 Inconsistent

results, small sample sizes, and the exclusive use of crosssectional designs preclude deriving clear inferences regarding

6
etiology. Two multiple-group cross-sectional studies investigated

the possible association of the onset of alcoholism with the

omega-3 or omega-6/omega-3 fatty acid content of

biomarkers.83,84 However, conflicting results and the use of

cross-sectional designs do not allow us to draw conclusions

regarding this possible etiology of alcoholism.

Medication status may have had somewhat of an influence

on between-group differences in RBC or plasma phospholipid

fatty acid content when the comparison group was healthy

controls. However, because these data were obtained exclusively

from twelve multiple-group cross-sectional studies74,85-95 or two

single prospective cohort studies with methodologic flaws,96,97

no meaningful possibility exists to permit drawing causal

inferences regarding patterns of lipid biomarker content and

the onset of schizophrenia. The same criticism relating to crosssectional designs applies to the single study examining

biomarkers data with respect to the onset of autism.98

Secondary Prevention (i.e., Continuation,

Recurrence) Via Lipid Biomarker Content

This question could not be evaluated since studies meeting

eligibility criteria were not identified. 

Discussion

A notable safety profile (i.e., beyond occasional and mild

discomfort) for any type or dose of omega-3 fatty acid

supplementation was not observed. Overall, other than for the

topics of schizophrenia and depression, few efficacy or safety

studies were identified. 

Only with respect to the supplemental treatment of

schizophrenia is the evidence even somewhat suggestive of

omega-3 fatty acids’ potential as short-term intervention.

However, these meta-analytic results exclusively pertaining to 2

g/d EPA require replication using design and method

refinements. Additional research might reveal the short-term or

long-term therapeutic value of omega-3 fatty acids. 

One study demonstrating a significant placebo-controlled

clinical effect related to 1 g/d E-EPA given over 12 weeks to 17

patients with depressive symptoms—rather than depressive

disorders—cannot be taken to support the view of the utility of

this exposure as a supplemental treatment for depressive

symptomatology or disorders. Nothing can yet be concluded

concerning the clinical utility of omega-3 fatty acids as

supplemental treatment for any other psychiatric disorder or

condition, or as a primary treatment for all psychiatric disorders

or conditions examined in our review. Primary treatment

studies were rare. 

Much more research, implementing design and methods

improvements, is needed before we can begin to ascertain the

possible utility of (foods or supplements containing) omega-3

fatty acids as primary prevention for psychiatric disorders or

conditions. Studies of omega-3 fatty acids’ primary protective

potential in mental health could be “piggybacked” onto

longitudinal studies of their impact on general health and

development. 

Overall, almost nothing is known about the therapeutic or

preventive potential of each source, type, dose, or combination

of omega-3 fatty acids. Likewise, limitations within the

evidence base prevented us from identifying the influence of

key covariables (e.g., smoking, alcohol use, psychotropic

medication) on the relationship between omega-3 fatty acid

content and clinical outcomes.

Because of limited study designs, little is known about the

relationship between PUFA biomarker profiles and the onset of

any psychiatric disorder or condition. Studies examining the

possible association between the intake of omega-3 fatty acids,

or the PUFA content of biomarkers, and the continuation or

recurrence of psychiatric disorders or conditions were virtually

nonexistent. 

If future research is going to produce data that are

unequivocally applicable to North Americans, it will need to

enroll either North American populations or populations

exhibiting a high omega-6/omega-3 fatty acid intake ratio

similar to what has been observed in the diet of North

Americans. Furthermore, if a reasonable view is that omega-3

fatty acids may play a role in mental health, then given the

observed or proposed inter-relationships among omega-3 and

omega-6 fatty acid contents both in the human diet and

metabolism, researchers should likely consider taking into

account the possible therapeutic or preventive influence of the

dietary omega-6/omega-3 fatty acid intake ratio. 

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the University of Ottawa Evidence-based

Practice Center under Contract No. 290-02-0021. It is

expected to be available in July 2005. At that time, printed

7
copies may be obtained free of charge from the AHRQ

Publications Clearinghouse by calling 800-358-9295.

Requesters should ask for Evidence Report/Technology

Assessment No. 116, Effects of Omega-3 Fatty Acids on Mental

Health. In addition, Internet users will be able to access the

report and this summary online through AHRQ’s Web site at

www.ahrq.gov.

Suggested Citation

Schachter HM, Kourad K, Merali Z, Lumb A, Tran K,

Miguelez M, et al. Effects of Omega-3 Fatty Acids on Mental

Health. Summary, Evidence Report/Technology Assessment

No. 116. (Prepared by the University of Ottawa Evidence-based

Practice Center under Contract No. 290-02-0021.) AHRQ

Publication No. 05-E022-1. Rockville, MD: Agency for

Healthcare Research and Quality. July 2005.

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www.ahrq.gov

AHRQ Pub. No. 05-E022-1

July 2005

ISSN 1530-440X
 

Evidence Report 

 3 

Chapter 1. Introduction 

 This evidence report by the University of Ottawa’s Evidence-Based Practice Center (EPC) 

concerning the effects of omega-3 fatty acids on mental health is one among several that address 

topics related to omega-3 fatty acids that were requested and funded by the Office of Dietary 

Supplements (ODS), National Institutes of Health (NIH), through the EPC program at the 

Agency for Healthcare Research and Quality (AHRQ). Three EPCs—the Tufts-New England 

Medical Center (Tufts-NEMC) EPC, the Southern California-RAND (SC-RAND) EPC, and the 

University of Ottawa EPC (UO-EPC)—each produced evidence reports. To ensure consistency 

of approach, the three EPCs collaborated on selected methodological elements, including 

literature search strategies, rating of evidence, and data table design. 

The aim of these reports is to summarize the current evidence concerning the health effects 

of omega-3 fatty acids on the following: cardiovascular diseases, cancer, child and maternal 

health, eye health, gastrointestinal/renal diseases, asthma, autoimmune diseases, immunemediated diseases, transplantation, mental health, and, neurological diseases and conditions. In 

addition to informing the research community and the public on the effects of omega-3 fatty 

acids on various health conditions, it is anticipated that the findings of the reports will also be 

used to help define the agenda for future research. 

The focus of this report is on mental health outcomes in humans. In this chapter, the 

metabolism, physiological functions, and sources of omega-3 fatty acids are briefly discussed. 

This constitutes background material, placing in context the data presented in the evidence 

report. As well, the description of the U.S. population’s intake of omega-3 fatty acids is 

provided in response to a general question posed within the task order (i.e., project). This 

introductory material is then complemented by a brief review of the epidemiology and 

descriptions of mental health disorders or conditions, in addition to some of their treatment 

options. The brief review is intended as an overview rather than a comprehensive description. 

The terms “mental health” and “psychiatric” are used interchangeably, as in “psychiatric” or 

“mental health” disorders or conditions. “Conditions” refer to behavior or symptoms (e.g., 

dysphoric feelings, suicidal ideation, anger, aggressiveness), which are necessary yet insufficient 

to warrant a formal diagnosis of psychiatric disorder despite their potentially serious 

consequences. 

Chapter 2 describes the methods used to identify, review and synthesize the results from 

studies concerning omega-3 fatty acids in mental health. Chapter 3 presents the findings of 

studies meeting eligibility criteria, with discussion points, including recommendations for future 

research, completing the report in Chapter 4. 

Metabolism and Biological Effects of Essential Fatty Acids 

Dietary fat is an important source of energy for biological activities in human beings. It 

encompasses saturated fatty acids (SFAs), which are usually solid at room temperature, and 

unsaturated fatty acids (UFAs), which are liquid at room temperature. UFAs can be further 

divided into monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs). PUFAs can 
4

be classified, on the basis of their chemical structure, into two groups: omega-3 (n-3) fatty acids 

and omega-6 (n-6) fatty acids. The omega-3 or n-3 notation means that the first double bond in 

this family of PUFAs is 3 carbons from the methyl end of the molecule. The same principle 

applies to the omega-6 or n-6 notation. Despite their differences in structure, all fats contain the 

same amount of energy (i.e., 9 kcal/g or 37 kJ/g). 

Of all fats found in food, two—alpha-linolenic acid (chemical abbreviation: ALA; 18:3 n-3) 

and linoleic acid (LA; 18:2 n-6)—cannot be synthesized in the human body, yet these are 

necessary for proper physiological functioning. These two fats are thus called “essential fatty 

acids” (EFAs). The EFAs can be converted in the liver to long-chain PUFAs (LC PUFAs), 

which have a higher number of carbon atoms and double bonds. These LC PUFAs retain the 

omega type (n-3 or n-6) of the parent essential fatty acids. 

ALA and LA comprise the bulk of the total PUFAs consumed in a typical North American 

diet. Typically, LA comprises 89 percent of the total PUFAs consumed, while ALA comprises 9 

percent. Smaller amounts of other PUFAs make up the remainder.1

 Both ALA and LA are 

present in a variety of foods. For example, LA is present in high concentrations in many 

commonly used oils, including safflower, sunflower, soy, and corn oil. ALA, which is consumed 

in smaller quantities, is present in leafy green vegetables and in some commonly used oils, 

including canola and soybean oil. Some novelty oils, such as flaxseed oil, contain relatively high 

concentrations of ALA, but these oils are not commonly found in the food supply. 

The Institute of Medicine (IOM) suggests that, for adults 19 and older, an adequate intake 

(AI) of ALA is 1.1-1.6 grams/day (g/d), and 11-17 g/d for LA.2

 Recommendations regarding AI 

differ by age and gender groups, and for special conditions such as pregnancy and lactation. 

As shown in Figure 1, eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid 

(DHA; 22:6 n-3) can act as competitors for the same metabolic pathways as arachidonic acid 

(AA; 20:4 n-6). In human studies, the analyses of fatty-acid compositions in both blood 

phospholipids and adipose tissue have shown a similar competitive relationship between omega3 LC PUFAs and AA. General scientific agreement supports an increased consumption of 

omega-3 fatty acids and reduced intake of omega-6 fatty acids to promote good health. 

However, for omega-3 fatty acid intake, the specific quantitative recommendations vary widely 

among countries not only in terms of different units — ratio, grams, total energy intake — but 

also in quantity.3

 Furthermore, there remain numerous questions relating to the inherent 

complexities concerning omega-3 and omega-6 fatty acid metabolism, in particular the 

relationships between the two fatty acids. For example, it remains unclear to what extent ALA is 

converted to EPA and DHA in humans, and to what extent the high intake of omega-6 fatty acids 

compromises any benefits of omega-3 fatty acid consumption. Without the resolution of these 

two fundamental questions, it remains difficult to study the importance of the omega-6/omega-3 

fatty acid ratio. 

Metabolic Pathways of Omega-3 and Omega-6 Fatty Acids 

Omega-3 and omega-6 fatty acids share the same pools of enzymes and go through the same 

oxidation pathways while being metabolized (Figure 1). Once ingested, the parent of the omega3 fatty acids, ALA, and the parent of the omega-6 fatty acids, LA, can be elongated and 

desaturated into LC PUFAs. LA is converted into gamma-linolenic acid (GLA; 18:3 n-6), an 
5

omega-6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the 

long-chain omega-6 fatty acid, AA, while ALA can be converted, to a lesser extent, to the longchain omega-3 fatty acids, EPA and DHA. However, the conversion from parent fatty acids into 

LC PUFAs occurs slowly in humans, and conversion rates are not well understood. Because of 

the slow rate of conversion, and the importance of LC PUFAs to many physiological processes, 

humans must augment their level of LC PUFAs by consuming foods rich in these important 

compounds. Meat is the primary food source of AA, and fish is the primary food source of EPA. 

The specific biological functions of fatty acids depend on the number and position of double 

bonds and the length of the acyl chain. Both EPA and AA are 20-carbon fatty acids and are 

precursors for the formation of prostaglandins (PGs), thromboxane (Tx), and leukotrienes 

(LTs)—hormone-like agents that are members of a larger family of substances called 

eicosanoids. Eicosanoids are localized tissue hormones that seem to be one of the fundamental 

regulatory classes of molecule in most higher forms of life. They do not travel in the blood, but 

are created in the cells to regulate a large number of processes, including the movement of 

calcium and other substances into and out of cells, dilation and contraction of muscles, inhibition 

and promotion of clotting, regulation of secretions including digestive juices and hormones, and, 

the control of fertility, cell division and growth.4

 

As shown in Figure 1, the long-chain omega-6 fatty acid, AA, is the precursor of a group of 

eicosanoids including series-2 prostaglandins (PG2) and series-4 leukotrienes (LT4). The omega3 fatty acid, EPA, is the precursor to a group of eicosanoids including series-3 prostaglandins 

(PG3) and series-5 leukotrienes (LT5). The series-2 prostaglandins and series-4 leukotrienes 

derived from AA are involved in intense actions (such as accelerating platelet aggregation, and 

enhancing vasoconstriction and the synthesis of mediators of inflammation) in response to 

physiological stressors. The series-3 prostaglandins and series-5 leukotrienes derived from EPA 

are less physiologically potent than those derived from AA. More specifically, the series-3 

prostaglandins are formed at a slower rate and work to attenuate excessive series-2 

prostaglandins. Thus, adequate production of the series-3 prostaglandins, which are derived 

from the omega-3 fatty acid, EPA, may protect against heart attack and stroke as well as certain 

inflammatory diseases like arthritis, lupus and asthma.4

 In addition, animal studies have 

demonstrated that omega-3 LC PUFAs, such as EPA and DHA, engage in multiple 

cytoprotective activities that may contribute to antiarrhythmic mechanisms.5

 Arrhythmias are 

thought to be the cause of “sudden death” in heart disease. 

In addition to affecting eicosanoid production as described above, EPA also affects 

lipoprotein metabolism and decreases the production of other compounds—including cytokines, 

interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α)—which have pro-inflammatory 

effects. These compounds exert pro-inflammatory cellular actions that include stimulating the 

production of collagenase and increasing the expression of adhesion molecules necessary for 

leukocyte extravasation.6

 The mechanism responsible for the suppression of cytokine production 

by omega-3 LC PUFAs remains unknown, although suppression of eicosanoid production by 

omega-3 fatty acids may be involved. EPA can also be converted into the longer chain omega-3 

form of docosapentaenoic acid (DPA, 22:5 n-3), and then further elongated and oxygenated into 

DHA. EPA and DHA are frequently referred to as VLN-3FA—very long chain n-3 fatty acids. 

DHA, which is thought to be important for brain development and functioning, is present in 

significant amounts in a variety of food products, including fish, fish liver oils, fish eggs, and 

organ meats. Similarly, AA can convert into an omega-6 form of DPA. 
6

Studies have reported that omega-3 fatty acids decrease triglycerides (Tg) and very low 

density lipoprotein (VLDL) in hypertriglyceridemic subjects, concomitant with an increase in 

high density lipoprotein (HDL). However, they appear to increase or have no effect on low 

density lipoprotein (LDL). Omega-3 fatty acids apparently lower Tg by inhibiting VLDL and 

apolipoprotein B-100 synthesis, and decreasing post-prandial lipemia.7

 Omega-3 fatty acids, in 

conjunction with transcription factors (small proteins that bind to the regulatory domains of 

genes), target the genes governing cellular Tg production and those activating oxidation of 

excess fatty acids in the liver. Inhibition of fatty acid synthesis and increased fatty acid 

catabolism reduce the amount of substrate available for Tg production.8 

As noted earlier, omega-6 fatty acids are consumed in larger quantities (> 10 times) than 

omega-3 fatty acids. Maintaining a sufficient intake of omega-3 fatty acids is particularly 

important since many of the body’s physiologic properties depend upon their availability and 

metabolism. 
7

Figure 1. Classical omega-3 and omega-6 fatty acid synthesis pathways and the role of omega-3 fatty acids 

in regulating health/disease markers 

Docosahexaenoic acid

(DHA)

22:6 n-3

(Human milk, egg yolks,

fish liver oils, fish eggs, liver,

brain, other organ meats)

Omega-6

Eicosanoids

Linoleic acid (LA)

18:2 n-6

(Sunflower, soy, cottonseed,

safflower oils)

Alpha-Linolenic acid (ALA)

18:3 n-3

(Canola, Soybean, and

Flaxseed oils, grains, green

vegetables)

Octadecatetranenoic acid

18:4 n-3

Delta-6 Desaturase (D6D)

Delta-6 Desaturase (D6D)

Gamma-linolenic acid

(GLA)

18:3 n-6

(Evening primrose, borage,

black currant oils)

Eicosatetraenoic acid

20:4 n-3

Elongase

Elongase

Dihomo-gamma-linolenic

acid (DGLA)

20:3 n-6

(Liver & other organ meats)

Arachidonic acid (AA)

20:4 n-6

(Animal fats, brain, organ

meats, egg yolk)

Eicosapentaenoic acid

(EPA)

20:5 n-3

(Fish liver oils, fish eggs)

Adrenic acid

22:4 n-6

Docosapentaenoic acid

(DPA)

22:5 n-3

Docosapentaenoic acid

(DPA)

22:5 n-6

24:4 n-6 24:5 n-3

24:5 n-6 24:6 n-3

Polyunsaturated Fatty Acids (PUFAs)

Omega-3

 Minor intake

(0.3-0.4% dietary energy)*

*The dietary intake levels

are based on approximate

current levels in North

American diets Series-1

Prostaglandins:

TXA1

 PGE1 PGF1a

PGD1

Series-2

Prostaglandins:

TXA2

 PGE2 PGF2a

PGD2 PGH2 PGL2

Series-4 Leukotrienes

Series-3

Prostaglandins:

PGE3 PGH3

 PGI3 TXA3

Series-5 Leukotrienes

Thromboxanes (TX)

are important for:

- blood clotting

- constricting blood

vessels

- inflammatory

function of white

blood cells

Leukotrienes are

important for:

- inflammation

- lung function

Prostaglandins (PG)

are important for:

- pregnancy, birth

- stomach function

- kidney function

- maintaining blood

vessel patency

- preventing blood clots

- inflammation,

response to infection

suppress

Beta-oxidation

Cell

membrane

Adrenoceptors Endothelial and

smooth muscle cells

Extracellular

Ca2+

endoplasmic

reticulum

Intracellular

Ca2+

Delta-5 desaturase (D5D)

Elongase

Elongase

D6D

Beta-oxidation

DNA

Energy metabolic pathway Beta-oxidation

TNF-alpha

IL-1 beta

amino

acids

Lower VLDL,

Apo B-100, Tg

 Large intake

(7-8% dietary energy)*
8

U.S. Population Intake of Omega-3 Fatty Acids 

The major source of omega-3 fatty acids is dietary intake of fish, fish oil, vegetable oils 

(principally canola and soybean), some nuts such as walnuts, and, dietary supplements. Two 

population-based surveys, the third National Health and Nutrition Examination (NHANES III) 

1988-94, and the Continuing Survey of Food Intakes by Individuals 1994-98 (CSFII), are the 

main sources of dietary intake data for the U.S. population. NHANES III collected information 

on the U.S. population aged ≥2 months. Mexican Americans and non-Hispanic AfricanAmericans, children ≤5 years old, and adults ≥ 60 years old were over-sampled to produce more 

precise estimates for these population groups. There were no imputations for missing 24-hour 

dietary recall data. A total of 29,105 participants had complete and reliable dietary recall. 

The CSFII 1994-96, popularly known as the “What We Eat in America” survey, addressed 

the requirements of the National Nutrition Monitoring and Related Research Act of 1990 (Public 

Law 101-445) for continuous monitoring of the dietary status of the American population. The 

CSFII 1994-96 utilized an improved data-collection method for 24-hour recall known as the 

multiple-pass approach. Given the large variation in intake from day-to-day, multiple 24-hour 

recalls are considered to be best suited for most nutrition monitoring and will produce stable 

estimates of mean nutrient intake from groups of individuals.9

 In 1998, the Supplemental 

Children’s Survey, a survey of food and nutrient intake by children under the age of 10 years, 

was conducted as a supplement to the CSFII 1994-96. The CSFII 1994-96, 1998 surveyed 

20,607 people of all ages with over-sampling of low-income population (<130% of the poverty 

threshold). Dietary intake data from individuals of all ages were collected over two 

nonconsecutive days via two one-day dietary recalls. 

Table 1 reports the NHANES III survey mean intake ± the standard error of the mean (SEM), 

in addition to the median and range for each omega-3 fatty acid. Distributions of EPA, DPA, 

and DHA were very skewed; therefore, the means and standard errors of the means should be 

used and interpreted with caution. Table 2 reports the CSFII survey mean and median intakes 

for each omega-3 fatty acid, along with SEMs, as reported in the Dietary Reference Intakes from 

the Institute of Medicine.2 

Table 1: Estimates of the mean±standard error of the mean (SEM) intake of linoleic acid (LA), alpha-linolenic 

acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) in the US population, based on 

analyses of a single 24-hour dietary recall of NHANES III data

Grams/day % Kcal/day

Mean±SEM Median (range)1

 Mean±SEM Median (range)1

LA (18:2 n-6) 14.1±0.2 9.9 (0 - 168) 5.79±0.05 5.30 (0 - 39.4) 

ALA (18:3 n-3) 1.33±0.02 0.90 (0 - 17) 0.55±0.004 0.48 (0 - 4.98) 

EPA (20:5 n-3) 0.04±0.003 0.00 (0 - 4.1) 0.02±0.001 0.00 (0 - 0.61) 

DHA (22:6 n-3) 0.07±0.004 0.00 (0 - 7.8) 0.03±0.002 0.00 (0 - 2.86) 1

The distributions are not adjusted for the over-sampling of Mexican-Americans, non-Hispanic African-Americans, children ≤5 

years old, and adults ≥ 60 years old in the NHANES III dataset. 
9

Table 2: Mean, range, median, and standard error of the mean 

(SEM) of usual daily intakes of linoleic acid (LA), total omega-3 

fatty acids (n-3 FA), alpha-linolenic acid (ALA), eicosapentaenoic 

acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic 

acid (DHA) in the US population, based on CSFII data (1994-1996, 

1998) 

Grams/day

Mean±SEM Median±SEM 

LA (18:2 n-6) 13.0±0.1 12.0±0.1 

Total n-3 FA 1.40±0.01 1.30±0.01 

ALA (18:3 n-3) 1.30±0.01 1.21±0.01 

EPA (20:5 n-3) 0.028 0.004 

DPA (22:5 n-3) 0.013 0.005 

DHA (22:6 n-3) 0.057±0.018 0.046±0.013 

Dietary Sources of Omega-3 Fatty Acids 

Omega-3 fatty acids can be found in many different sources of food, including fish, 

shellfish, some nuts, and various plant oils. Selected from the USDA website, Table 3 lists the 

amount of omega-3 fatty acids in some commonly consumed fish, shellfish, nuts, and edible 

oils.10 
10

Table 3: The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample of 

commonly consumed fish, shellfish, fish oils, nuts and seeds, and plant oils that contain at least 5 g omega-3 

fatty acids per 100 g 

Food item EPA DHA ALA Food item EPA DHA ALA 

Fish (Rawa) Fish, continued 

Anchovy, European 0.6 0.9 - Tuna, Fresh, Yellowfin trace 0.2 trace 

Bass, Freshwater, Mixed Sp. 0.2 0.4 0.1 Tuna, Light, Canned in Oile trace 0.1 trace 

Bass, Striped 0.2 0.6 trace Tuna, Light, Canned in Watere trace 0.2 trace 

Bluefish 0.2 0.5 - Tuna, White, Canned in Oile trace 0.2 0.2 

Carp 0.2 0.1 0.3 Tuna, White, Canned in Watere 0.2 0.6 trace 

Catfish, Channel trace 0.2 0.1 Whitefish, Mixed Sp. 0.3 0.9 0.2 

Cod, Atlantic trace 0.1 trace Whitefish, Mixed Sp., Smoked trace 0.2 - 

Cod, Pacific trace 0.1 trace Wolffish, Atlantic 0.4 0.3 trace 

Eel, Mixed Sp. trace trace 0.4 

Flounder & Sole Sp. trace 0.1 trace 

Grouper, Mixed Sp. trace 0.2 trace Shellfish (Raw) 

Haddock trace 0.1 trace Abalone, Mixed Sp. trace - - 

Halibut, Atlantic and Pacific trace 0.3 trace Clam, Mixed Sp. trace trace trace 

Halibut, Greenland 0.5 0.4 trace Crab, Blue 0.2 0.2 - 

Herring, Atlantic 0.7 0.9 0.1 Crayfish, Mixed Sp., Farmed trace 0.1 trace 

Herring, Pacific 1.0 0.7 trace Lobster, Northern - - - 

Mackerel, Atlantic 0.9 1.4 0.2 Mussel, Blue 0.2 0.3 trace 

Mackerel, Pacific and Jack 0.6 0.9 trace Oyster, Eastern, Farmed 0.2 0.2 trace 

Mullet, Striped 0.2 0.1 trace Oyster, Eastern, Wild 0.3 0.3 trace 

Ocean Perch, Atlantic trace 0.2 trace Oyster, Pacific 0.4 0.3 trace 

Pike, Northern trace trace trace Scallop, Mixed Sp. trace 0.1 - 

Pike, Walleye trace 0.2 trace Shrimp, Mixed Sp. 0.3 0.2 trace 

Pollock, Atlantic trace 0.4 - Squid, Mixed Sp. 0.1 0.3 trace 

Pompano, Florida 0.2 0.4 - 

Roughy, Orange trace - trace 

Salmon, Atlantic, Farmed 0.6 1.3 trace Fish Oils 

Salmon, Atlantic, Wild 0.3 1.1 0.3 Cod Liver Oil 6.9 11.0 0.9 

Salmon, Chinook 1.0 0.9 trace Herring Oil 6.3 4.2 0.8 

Salmon, Chinook, Smokedb 0.2 0.3 - Menhaden Oil 13.2 8.6 1.5 

Salmon, Chum 0.2 0.4 trace Salmon Oil 13.0 18.2 1.1 

Salmon, Coho, Farmed 0.4 0.8 trace Sardine Oil 10.1 10.7 1.3 

Salmon, Coho, Wild 0.4 0.7 0.2 

Salmon, Pink 0.4 0.6 trace 

Salmon, Pink, Cannedc 0.9 0.8 trace Nuts and Seeds 

Salmon, Sockeye 0.6 0.7 trace Butternuts, Dried - - 8.7 

Sardine, Atlantic, Canned in Oild 0.5 0.5 0.5 Flaxseed 18.1 

Seabass, Mixed Sp. 0.2 0.4 - Walnuts, English - - 9.1 

Seatrout, Mixed Sp. 0.2 0.2 trace 

Shad, American 1.1 1.3 0.2 

Shark, Mixed Sp. 0.3 0.5 trace Plant Oils 

Snapper, Mixed Sp. trace 0.3 trace Canola (Rapeseed) - - 9.3 

Swordfish 0.1 0.5 0.2 Flaxseed Oil - - 53.3 

Trout, Mixed Sp. 0.2 0.5 0.2 Soybean Lecithin Oil - - 5.1 

Trout, Rainbow, Farmed 0.3 0.7 trace Soybean Oil - - 6.8 

Trout, Rainbow, Wild 0.2 0.4 0.1 Walnut Oil - - 10.4 

Tuna, Fresh, Bluefin 0.3 0.9 - Wheatgerm Oil - - 6.9 

Tuna, Fresh, Skipjack trace 0.2 - 

Trace = <0.1; - = 0 or no data; Sp. = species; aExcept as indicated; bLox.; cSolids with bone and liquid; dDrained solids with 

bone; eDrained solids. 
11

Disorders of Mental Health: an Overview 

Disorders of mental health are becoming increasingly common in the US. It is estimated that 

in a given year, 22%, or one in five American adults, suffers from a diagnosable mental health 

disorder.11 These disorders, including major depression, bipolar disorder, schizophrenia, and 

obsessive-compulsive disorder, account for four of the ten leading causes of disability in the US 

and other developed countries.12 Many people suffer from more than one mental disorder at a 

given time. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSMIV), published by the American Psychiatric Association, is the reference guide currently used 

particularly in North America to diagnosis psychiatric disorders. 

The DSM approach, with its diagnostic criteria often embodied as various methods (e.g., 

structured interviews), has been updated several times over the past decades, an observation 

suggesting the need to recognize that individuals diagnosed using the different versions of DSM 

may actually be exhibiting varying clusters or intensities of clinical features (e.g., 

symptoms/behaviors).13 Other classification systems (e.g., ICD-10), employing diagnostic 

criteria which are potentially different from the DSM approach, have also been used to identify 

psychiatric disorders. Together, these two observations highlight the importance of considering 

how the ways in which psychiatric populations are identified may account for varying responses 

to the same interventions within clinical or research contexts.13 The following sections introduce 

the psychiatric disorders or conditions for which evidence pertinent to this systematic review was 

identified. 

Affective Disorders 

Affective, or mood, disorders include depression (major and dysthymic) and bipolar disorder 

(manic depression). In a given year, it is estimated that 18.8 million American adults, or 9.5% of 

the population aged 18 years and older, exhibit the characteristics of a depressive disorder.11 

Twice as many women (12%) as men (6.6%) are affected.(National Institute of Mental Health, 

2001) The World Health Organization (WHO) has estimated that major depressive disorder may 

become the second leading cause of diability by 2020, positioning it second only to ischemic 

heart disease, and making it the leading cause in developing regions.14

The mainstay of depressive symptoms are feelings of unhappiness, loss of energy and 

interest, fatigue, poor concentration, altered appetite, sleep disturbances, diminished cognitive 

function, weight gain/loss, anxiety, agitation or irritability, chronic indecisiveness, and often, 

suicidal ideation.15,16 Individuals with dysthymic disorder (chronic, mild depression) have 

depressive symptoms of lesser severity than what is seen in individuals with major depression. 

Dysthymic disorder can begin in childhood, adolescence or early adulthood. Symptoms must 

persist for a minimum of two years in adults, or one year in children, in order to meet criteria for 

a DSM-IV diagnosis. Individuals with dysthymic disorder are usually able to manage their life, 

although symptoms may be severe enough to cause distress and interfere with important life 

responsibilities. In a given year, approximately 40 percent of adults with dysthymic disorder 

may end up meeting the criteria for major depressive disorder or bipolar disorder.11
12

Major depression (clinical depression, unipolar depression) is characterized by severe 

symptoms of depression. WHO has determined that major depression is the third leading cause 

of vocational disability worldwide.12 According to DSM-IV, major depression is defined as two 

or more weeks of low mood or diminished interest in usual activities, combined with four or 

more of the following symptoms: sleep alteration (increased or decreased); inappropriate guilt or 

loss of self-esteem; altered appetite (increased or decreased); diminished energy; diminished 

concentration; psychomotor symptoms (either agitation or retardation); or suicidal ideation. The 

average age of onset is the mid-twenties, and for most people, episodes of major depression last 

from six to nine months.11 

Bipolar disorder (manic depression) is characterised by extreme mood swings, that is, 

alternating between periods of mania and periods of depression. According to DSM-IV, mania is 

defined as a distinct change in mood and functioning, lasting at least one week, and is 

characterized by a euphoric or irritable mood accompanied by symptoms such as increased 

energy, decreased need for sleep, rapid thinking and speech, grandiosity, poor judgement and 

impulsivity, and in some cases, psychosis (i.e., delusions and/or hallucinations). For patients 

with bipolar disorder, episodes of mania are followed by periods of major depression. Patients 

may also have “mixed” mood states in which the symptoms of mania and depression occur 

simultaneously, or “rapid cycling,” where continuous or frequently shifting mood states occur.16 

Unlike dysthymia and major depression, where the incidence is higher in women, bipolar 

disorder tends to affect men and women equally. The average age of a first manic episode is the 

early twenties.11 It has been estimated that 20% to 30% of individuals with bipolar disorder will 

die as a direct consequence of their illness, usually by suicide.17

Treatment Options 

Treatment options for patients diagnosed with depression include psychotherapy, 

pharmacotherapy, and in some instances, electroconvulsive therapy. For individuals with severe 

depression, antidepressant medication is the treatment of choice, whereas psychotherapy alone 

may be sufficient to treat individuals with mild to moderate depression. 

The most commonly used antidepressant medications include the selective serotonin reuptake 

inhibitors (SSRIs) and tricyclic antidepressants. The monoamine oxidase inhibitors (MAOIs) are 

used less frequently. Herbal therapy, including St. John’s wort, has also been suggested as being 

helpful in the treatment of depression. The treatment of choice for bipolar disorder remains 

lithium or divalproex. The SSRIs and tricyclics act by slowing the reuptake of neurotransmitters, 

thus making them more available. The SSRIs work specifically on the neurotransmitter 

serotonin, whereas the tricyclics and MAOIs work on both serotonin and norepinephrine. In 

general, the SSRIs appear to demonstrate fewer side effects than do the tricyclics or MAOIs. 

In spite of the availability of these medications, it has been estimated that 29% to 46% of 

patients are treatment-resistant, that is, they show no clinical response or only a partial response 

to the antidepressant medications. One approach to dealing with treatment-resistant depression 

is the use of combination therapy or the addition of a “booster drug” to augment the effects of the 

primary medication(s). Natural compounds, including omega-3 fatty acids, have recently been 

touted as potential augmentors of antidepressants’ effects in treatment-resistant depression.18,19
13

Anxiety Disorders 

Anxiety disorders typically include panic disorder, generalized anxiety disorder, obsessivecompulsive disorder, post-traumatic stress disorder, and phobias (social phobia, agoraphobia). 

Anxiety disorders often coexist with other disorders (e.g., depressive disorders), with an 

estimated 75% of individuals with an anxiety disorder also meeting criteria for at least one other 

psychiatric illness. The NIMH estimates that within a given year, 19 million American adults 

between the ages of 18 and 54 years exhibit evidence of an anxiety disorder. Although equal 

numbers of men and women suffer from obsessive-compulsive disorder and social phobia, 

approximately twice as many women than men suffer from panic disorder, post-traumatic stress 

disorder, generalized anxiety disorder, and agoraphobia.11

Obsessive-compulsive disorder is estimated to afflict 2% to 3% of the world’s population,20

including approximately 3.3 million American adults or 2.3% of the population.11 It is 

characterized by obsessive thoughts and compulsive actions (e.g., cleaning, ordering, counting) 

that are associated with, and often are behavioral attempts to deal with, marked anxiety or 

distress (DSM-IV). While it can range from mild to severe in intensity, severe obsessivecompulsive disorder can interfere with a person’s ability to function. 

Treatment Options 

As with other mental health disorders, treatment for anxiety disorders, including obsessivecompulsive disorder, typically involves pharmacologic and psychotherapy treatment approaches. 

Pharmacologic treatment options have included benzodiazepines, tricyclic antidepressants and 

MAOIs, but more recently include antidepressant medications such as the SSRIs. 

Psychotherapeutic strategies that help patients cope with their anxiety include the cognitivebehavioural therapies. For individuals with obsessive-compulsive disorder, complete remission 

is rare, with most people requiring longterm medication. 

Anorexia Nervosa 

Anorexia nervosa is an eating disorder that more commonly afflicts females. An estimated 

0.5% to 3.7% of American females suffer from anorexia during their lifetime.21 According to 

DSM-IV, criteria for the diagnosis of anorexia nervosa include an individual’s refusal to 

maintain their body weight at or above a minimally normal weight for their age and height, an 

intense fear of gaining weight or becoming fat, and a refusal to acknowledge weight loss. 

Amenorrhea is a common concomitant because of the impact of weight loss on the endocrine 

system. Other potential problems include heart rhythm disturbances, abdominal abnormalities 

and anemia. The mortality rate for individuals with anorexia has been estimated to be 0.56% per 

year.22
14

Treatment Options 

The goal of treatment of individuals with anorexia is weight gain. To achieve this, 

physicians must restore healthy eating patterns and to address thoughts and feelings concerning 

body image. This usually requires individual and/or family psychotherapy, and in some 

instances the use of antidepressant medications. 

Attention Deficit/Hyperactivity Disorder 

Attention deficit/hyperactivity disorder (AD/HD) is the most commonly diagnosed mental 

health disorder in children and adolescents. According to the American Academy of Pediatrics, 

4% to 12% of all school-age children are estimated to be affected by AD/HD. Although 

traditionally associated with school-age children, its prevalence in adults and in preschoolers is 

being increasingly recognized. Individuals with AD/HD are often unable to focus on assigned 

tasks, are easily distracted, and are often impulsive and/or hyperactive (DSM-IV). AD/HD is two 

to three times more common in boys than in girls. DSM-IV recognizes three main subtypes, that 

is, where clinical features indicate AD/HD predominantly characterized by problems of 

inattention, hyperactivity/impulsivity, or both. 

Treatment Options 

According to the American Academy of Pediatrics, children with AD/HD should be treated 

with a stimulant medication such as methylphenidate (Ritalin®), dextroamphetamine and/or 

behavior therapy.23 A relatively recent complementary or alternative approach, called EEGcentered biofeedback, aims to teach the child to modulate their own attentional states so that they 

may adapt more readily to varying environmental expectations regarding behavior. 

Tendencies or Behaviors With the Potential to Harm Others: 

the Spectrum of Anger/Hostility, Aggression and Violence 

Numerous forms of behavior have the potential to harm others. While not always correlated 

with or culminating in physical action, verbally manifested anger and hostility can be quite 

disruptive to others. Aggression—any action that causes injury to oneself, others, or objects—is 

a common feature of many psychiatric disorders. According to the NIMH, more than 90% of 

individuals who commit suicide have a diagnosable mental health disorder, most commonly a 

depressive disorder or a substance abuse disorder. In a review of 28 studies, Flannery found that 

patients who were found to be repetitively violent more frequently than not had received a 

diagnosis of schizophrenia or a personality disorder; both males and females were equally 

represented and patients tended to be younger.24 Underlying factors that relate to aggression 

include genetics, environment (i.e., childhood experiences of aggression, parental dysfunction), 

structural brain abnormalities, and neurotransmitter dysfunction. The focus here is on the broad 
15

spectrum of externalizing tendencies (e.g., angry outbursts) or behaviors (e.g., physical 

aggression) with the potential to harm others. 

Treatment Options 

Pharmacological treatment for aggression includes the full spectrum of psychotropic 

medications including antidepressant medications, neuroleptics, and mood stabilizers. Although 

these agents have been used successfully in the clinic or in clinical trials, the Food and Drug 

Administration (FDA) has yet to approve any agent specifically for the treatment of aggression. 

Approaches to dealing with anger, hostility or violence have also ranged from psychotherapy to 

incarceration. 

Alcoholism 

According to DSM-IV, alcoholism is defined as a destructive pattern of alcohol use leading 

to significant social, occupational or medical impairment. Alcohol dependence and alcohol 

abuse are among the most common psychiatric disorders in the general population, with an 

estimated 8% of adults suffering from alcohol dependence and 5% from alcohol abuse. There 

appears to be a strong genetic predisposition toward alcoholism—the risk is three to four times 

higher in a close relative of individuals with alcohol dependence. Alcoholism is sometimes seen 

as a component of general maladaptive functioning that may include tendencies or behavior with 

the potential to harm others. 

Treatment Options 

Treatment options for individuals with alcoholism include self-help programs and 

psychosocial therapy. Pharmacotherapy is often used as an adjunct to psychosocial therapy, with 

the former including medications such as naltrexone that block the alcohol-brain interaction(s). 

Borderline Personality Disorder 

Borderline Personality Disorder, according to DSM-IV, is characterized by a pervasive 

pattern of unstable interpersonal relationships, self-image, and behavior. This instability often 

interferes with family, work and long-term planning. Although less well known than bipolar 

disorder or schizophrenia, borderline personality disorder is actually more common, affecting an 

estimated 2% of adults, including mostly young women. Unlike depression or bipolar disorder 

where a person can experience the same mood for weeks, a person with borderline personality 

disorder can exhibit intense periods of anger, depression and anxiety that each last only hours, or 

maybe a day. The risks of self-injury without suicidal intent or of suicide are both elevated for 

individuals with this disorder.25
16

Treatment Options 

Borderline personality disorder does not appear to respond well to existing pharmacotherapy 

approaches. In general, antidepressants and mood stabilizers are used to treat some of the 

defining symptoms, such as depression or psychosis. A new form of psychotherapy called 

dialectical behavior therapy, developed specifically to treat patients with borderline personality 

disorder, has shown promising results.26

Schizophrenia 

Schizophrenia is a debilitating condition characterized by perceptual and behavioral 

disturbances, conceptual disturbances, impaired ability to communicate, and social/occupational 

dysfunction. According to the NIMH, approximately 2.2 million American adults experience 

schizophrenia in a given year. Although it afflicts men and women with equal frequency, 

symptoms usually appear earlier in men (late teens to early twenties) than in women (twenties or 

early thirties). In general, diagnostic criteria for schizophrenia include at least two of the 

following “active phase” symptoms that persist for a significant portion of time during a onemonth period: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, 

or negative symptoms (i.e., affective flattening, alogia, or avolition). Only one of these 

symptoms is required if it is accompanied with a voice that keeps a running commentary on the 

person’s behavior or thoughts, or if two or more voices are talking with each other. 

Treatment Options 

The hallmark of schizophrenia treatment remains antipsychotic medications. These help to 

reduce symptoms, thus allowing patients to function better and improve their quality of life. 

Although these medications have been available since the mid-1950’s, many have demonstrated 

significant side effects. A new class of antipsychotic, the atypical antipsychotics, have been 

available since the late 1980’s. These medications, which include clozapine, risperidone, 

olozapine, quetiapine, ziprasidone and aripiprazole, may be somewhat more effective while 

producing fewer side effects than the earlier neuroleptic mediations. However, side effects with 

these medications still occur and often it is necessary to alter dosages or add additional drugs to 

find the most effective approach. 

Autism 

Autism is one of a spectrum of Pervasive Developmental Disorders. It is characterized by 

severe and pervasive impairment in thinking, feeling, language, and the ability to relate to others. 

Autism affects an estimated one to two per 1000 individuals, and is generally apparent by the age 

of three. Although autism is four times more likely to affect boys than girls, girls with autism 

tend to have more severe symptoms and greater cognitive impairment.11
17

Treatment Options 

There is currently no single treatment approach for individuals with autism. Most healthcare 

professionals agree that early intervention is important. Pharmacotherapy is sometimes used to 

treat associated behavioral problems (e.g., aggression, self-injurious behaviour) so that the 

individual can function more smoothly at home and school. The possible importance of nutrition 

has also been speculated upon. 

Omega-3 Fatty Acids and Mental Health 

Approximately 50% to 60% of the adult brain is composed of lipids (dry weight), of which 

roughly 35% are phospholipids comprised of UFAs.27 Of the UFAs, AA and DHA are found in 

the highest concentrations. These components of phospholipids have important functions in 

maintaining nerve cell membrane integrity and fluidity, as well as contributing to neuronal signal 

transduction. DHA has been shown to be especially important in prenatal brain development, 

where it appears to play a key role in synaptogenesis.28,29 DHA deficiency has been linked to a 

number of neurophysiological deficits including cognitive impairment,30 decreased visual 

acuity,31 and decreased cerebellar function.32

In the adult biosystem, an optimal balance between omega-3 and omega-6 fatty acids is 

likely essential for normal neuronal function, and it has been suggested that the current 

imbalance in the omega-6 to omega-3 fatty acid ratio in the North American diet may be in small 

or large part responsible for the observed increases in disorders of all kinds.33-45 This imbalance 

has likewise suggested an etiologic mechanism by which psychiatric disorders may develop (i.e., 

abnormalities in PUFA metabolism), and in turn, a rationale for ways to treat them (e.g., PUFA 

supplementation). In both of these regards, depression and schizophrenia have been the two 

most investigated and speculated upon psychiatric disorders. 

The strong variability in the annual prevalence rates for major depressive disorder, expressed 

as an almost 60-fold variation across countries,46 parallels the wide cross-national differences in 

mortality rates from coronary artery disease, suggesting that similar risk factors could be 

involved in both scenarios.47 In the 20th century the increasing lifetime risk of depression has coemerged with a shift in diet involving an increase in omega-6 fatty acid intake and a decrease in 

the intake of omega-3 fatty acids;48 and, this change in the dietary omega-6/omega-3 fatty acid 

intake ratio has been proposed as being responsible for the increased risk of depression.49 At the 

same time, it has been suggested that these recent changes in the especially Western diet are 

responsible for the increase in cardiovascular and inflammatory disorders.49 To add to this 

picture, there is some empirical evidence suggesting that major depression is strongly predictive 

of both coronary heart disease and myocardial infarction;50,51 and, some physical illnesses, such 

as coronary heart disease or diabetes, appear to occur with increased frequency in patients with 

major depression and schizophrenia.52 

The mechanism by which diet may affect health, including depression or cardiovascular 

disease, is thought to involve low levels of omega-3 fatty acid content in biomarkers (e.g., red 

blood cells [RBCs]).48,53 An omega-3 fatty acid deficiency hypothesis of depression has been 

put forward, which has helped justify treatment with omega-3 fatty acid supplementation.54 
18

These treatment-related data, as well as those reflecting the possible association of the fatty acid 

content of biomarkers with the risk of depression, are systematically reviewed in this report. 

The membrane phospholipid hypothesis of schizophrenia has been proposed in an attempt to 

develop a model explaining schizophrenia’s etiology.55 It describes the presumed biochemical 

dynamics underpinning a neurodevelopmental theory. Some of the evidence used to support this 

perspective is systematically reviewed in this review, and so these data are not presented here. 

Nevertheless, by way of introducing the topic, at least some of the empirical evidence suggests 

the existence of phospholipid and PUFA metabolic abnormalities in schizophrenia. 

Experimental investigations have focused on peripheral tissues, including RBCs and skin 

fibroblasts. Certain data pertaining to phospholipids, which are not systematically reviewed 

here, have shown that there are reduced levels of phospholipid subtypes (e.g., 

phosphatidylcholine, phosphatidylethanolamine) in schizophrenic patients.56 Since other work 

has shown increased levels of phosphodiesters (i.e., phospholipid breakdown products) and 

decreased levels of phosphomonoesters (i.e., used in phsopholipid synthesis) in prefrontal and 

temporal brain tissue of drug-naïve schizophrenic patients,57 it has been proposed that there 

exists increased phospholipid turnover in the brains of schizophrenic patients.55 

Numerous studies have assessed the PUFA content of membrane phospholipids in 

schizophrenia, with controlled studies eligible for inclusion in the present review (see Chapter 2). 

The ensuing discussions in the literature have centered on whether there is evidence for a 

depletion of omega-6 and omega-3 fatty acid content in the RBCs and the brain tissue of patients 

with schizophrenia.58 At the same time, some animal studies have shown that essential and nonessential fatty acids in the diet can have a significant impact on neuronal membrane phospholipid 

composition.59 Thus, it has been posited that modifications to diet could mitigate or aggravate 

an underlying abnormality of phospholipid metabolism.55 

However, the present review was not conducted specifically to test either of these 

hypotheses. Rather, the rationale for this two-year project investigating the possible health 

benefits of omega-3 fatty acids is to systematically review the evidence to aid in the development 

of a research agenda. Nevertheless, these emerging models regarding depression and 

schizophrenia do suggest plausible bases for the use of omega-3 fatty acids to treat these two 

psychiatric disorders. As with depression, treatment-related data, as well as those reflecting the 

possible association of the fatty acid content of biomarkers with the risk of schizophrenia, are 

systematically reviewed in this report. Evidence concerning psychiatric disorders and conditions 

for which there are poorly developed, or no, animal or human models suggesting the use of 

omega-3 fatty acids as treatment or prevention are also systematically reviewed.
 19 

Chapter 2. Methods 

Overview 

The UO-EPC’s evidence report on omega-3 fatty acids in mental health is based on a 

systematic review of the scientific-medical literature to identify, and synthesize the results from, 

studies addressing key questions. Together with content experts, UO-EPC staff identified 

specific issues integral to the review. A Technical Expert Panel (TEP) helped refine the research 

questions as well as highlighted key variables requiring consideration in the evidence synthesis. 

Evidence tables presenting key study-related characteristics were developed and are found in the 

Appendices. In-text summary tables were derived from the evidence tables. The methodological 

quality and generalizability of the included studies was appraised, and individual study results 

were summarized. 

Key Questions Addressed In This Report 

The purpose of this evidence report was to synthesize information from relevant studies to 

address the following basic questions: 

• Are omega-3 fatty acids efficacious as primary or supplemental treatment for (some 

psychiatric disorder or condition)? (Question 1) 

• Is omega-3 fatty acid intake, including diet and/or supplementation, associated with the 

onset, continuation or recurrence of (some psychiatric disorder or condition)? (Question 

2) 

• Is the onset, continuation or recurrence of (some psychiatric disorder or condition) 

associated with omega-3 or omega-6/omega-3 fatty acid content of biomarkers? 

(Question 3) 

• What is the evidence that, in review-relevant studies concerning mental health, adverse 

events (e.g., side effects) or contraindications are associated with the intake of omega-3 

fatty acids? (Question 4) 

The overarching goal was to identify and systematically review whatever evidence exists 

within the eligibility boundaries established for this review in consultation with our TEP and in 

light of the topics being addressed by SC-RAND and Tufts-NEMC EPCs. These boundaries are 

delineated in the Eligibility Criteria section (below). More details concerning the four basic 

questions are provided in conjunction with the description of the Analytic Framework (below). 

We were also guided collectively by ODS, our TEP and our UO-EPC review team content 
20

experts to examine, where data permitted, the possible influence on efficacy, association or 

safety evidence of the following potential effect modifiers: 

• intervention/exposure length; 

• type(s) of omega-3 fatty acid (e.g., ALA, EPA, DHA); 

• source of the omega-3 fatty acids (e.g., marine, plant, nut), including the specific source 

(e.g., mackerel as an oily fish); 

• delivery format (e.g., whole food servings, capsules, pourable or spreadable oils); 

• dose/serving size, including the precision/control of its delivery (e.g., per-day specific, 

minimum, maximum or range of numbers of capsules, whole food servings or bottlepourable litres); 

• type of processing used to purify the intervention/exposure and/or to maintain the 

experimental blind (e.g., ethyl esterification; adding an anti-oxidant to stabilize/preserve 

oils; adding flavor to oils; [vacuum] deodorization); 

• amount/dose of omega-6 fatty acid intake either added as a separate cointervention or 

identified as being present in the background diet, thereby establishing a specific, 

minimum, maximum or range of allowable or mandated on-study omega-6/omega-3 fatty 

acid intake; 

• the identity of the manufacturer and/or certain characteristics of their product(s) (i.e., 

purity; presence of other potentially active agents that have not been added intentionally: 

e.g., methylmercury content); 

• for questions relating to efficacy or association, the prestudy/baseline or on-study omega3 or omega-6/omega-3 fatty acid content of blood lipid biomarkers; 

• absolute or relative omega-3 fatty acid content of the prestudy/baseline diet; 

• omega-6/omega-3 fatty acid content in the prestudy/baseline diet, with the study 

population’s country of origin as a possible surrogate measure of the omega-6/omega-3 

fatty acid content of the background diet; and, 

• any study subpopulations (e.g., minority; ethnic; genetic, including diabetics). 

Furthermore, where data permitted, the following factors with the potential to influence (i.e.., 

aggravate, control) mental health outcomes (e.g., intensity of symptoms/behaviors) were also 

investigated: 

• severity of the psychiatric disorder or condition; 
21

• psychotropic medication type and dose; 

• comorbid conditions and their treatments; 

• diagnostic classification system/criteria employed to identify study population; 

• age and other sociodemographic factors (e.g., marital status, education, income, 

employment status); 

• general health status; 

• stressors; 

• other cointerventions (e.g., licit drug use, other supplement use, psychological 

interventions, use of complementary/alternative [CAM] medicine/products); 

• social support; 

• current smoker status; 

• current alcohol consumption; and, 

• influences on vegetative functioning (e.g., exercise, quality of sleep). 

Psychotropic medication, current smoker status, and alcohol consumption are especially 

important effect modifiers in that they have been observed to influence both mental health status 

and essential fatty acid status, with levels of the latter potentially affecting the former.60 

Analytic Framework 

An analytic framework was developed to make explicit the review’s specific links relating 

the populations and settings of interest (i.e., the study participants and the disorders or conditions 

of interest), the focal exposure or intervention (i.e., omega-3 fatty acids ingested as 

supplementation and/or from food sources), potential effect-modifying factors, key mental health 

outcomes, and the possible role played by the omega-3 or omega-6/omega-3 fatty acid content of 

biomarkers in mediating the intake-outcome relationship (Figure 2). The possibilities of adverse 

events (e.g., side effects) and contraindications are recognized. In short, the framework outlines 

the various lines of logic defining the review’s research questions. However, not all linkages 

were investigated. 

One criterion established in this review is that each researchable question had to be clinically 

relevant. That is, each question had to involve the investigation of at least one relevant clinical 

outcome. Likewise, to be eligible for inclusion in the review each study had to entail an 

investigation of at least one pertinent clinical outcome. Considering the purpose of the two-year 
22

task order is to afford a clinically-relevant research agenda, this decision was judged to be 

appropriate by both our TEP and our review team. Thus, excluded were studies whose sole 

focus was to examine the impact of omega-3 fatty acid interventions or exposures on the omega3 or omega-6/omega-3 fatty acid content of biomarkers, even if the study populations met the 

other eligibility criteria set for the present review. Each of the four basic questions outlined 

above is now seen in light of the links identified in the framework. 

Figure 2. Analytic Framework for omega-3 fatty acids in mental health. Populations of interest in rectangles. 

Exposure in oval. Outcomes in rounded rectangles. Effect modifiers in hexagons. Solid connecting arrows indicate 

associations and effects reviewed in this report. 

ADDITIONAL EFFECT

MODIFIERS

y Populations formally diagnosed with a psychiatric disorder

y Populations at elevated risk for a psychiatric disorder given a past diagnosis,

currently exhibiting a subset of a disorder's defining symptoms/behaviors albeit

insufficient to merit a formal diagnosis, or having a first order relative with a

psychiatric diagnosis

y Populations not necessarily at elevated risk for a psychiatric disorder despite

exhibiting a subset of its defining symptoms/behaviors (e.g., dysphoric mood)

y Healthy populations (i.e., not at elevated risk for a psychiatric disorder/diagnosis)

y Specific subpopulations (minority, ethnic, genetic: e.g., diabetic)

FATTY ACID CONTENT OF BIOMARKERS

INTAKE OF OMEGA-3 FATTY ACIDS

y Severity

y Response/remission (e.g., length of remission)

y Onset (prevalence, incidence)

y Continuation

y Recurrence

y Via diet &/or supplementation

y Source: e.g., marine, plant, nut, seed

y Type: ALA, EPA, DHA or combinations

y Dosage/serving size

y Duration of exposure

y Omega-6 or omega-6/

omega-3 fatty acid content

of background diet

y Concurrent treatment (e.g.,

medication)

y Comorbidity

POPULATIONS OF INTEREST

y Source: e.g., red blood cell membranes

y Content: EPA, DHA, AA, AA/EPA,

 AA/DHA, AA/EPA+DHA

y Composition (%) or concentration

CLINICAL OUTCOMES

ADVERSE EVENTS

y Side effects

y Contraindications
23

The populations of interest include those: 

• with a current psychiatric diagnosis (Population 1); 

• at elevated risk to develop a psychiatric disorder or condition by virtue of certain past or 

present events (i.e., a past psychiatric diagnosis; currently experiencing a subset of 

symptoms/behaviors with the potential [e.g., intensity] to develop into a full-fledged 

disorder; having a first order relative with a psychiatric diagnosis) (Population 2); 

• who are not necessarily at risk to develop a psychiatric disorder despite currently 

experiencing a subset of its symptoms/behaviors (Population 3); 

• “healthy” individuals who, under certain circumstances (e.g., stress) may exhibit a subset 

of symptoms/behaviors necessary yet insufficient to indicate a psychiatric disorder (e.g., 

aggression) (Population 4); and, 

• specific subpopulations, some of whose characteristics may predispose them to develop 

or avoid developing psychiatric difficulties (Population 5). 

Our TEP requested that studies investigating the fourth population category be included in the 

review. As the four basic questions are introduced, and their important linkages are highlighted 

within the framework, the relevant populations are identified. The fifth category of population, 

or specific subpopulations, could be examined with respect to each of the four basic questions. 

Questions pertaining to the efficacy of omega-3 fatty acids as primary or supplemental 

treatment (i.e., Question 1) entail a direct investigation of their potentially beneficial influence on 

clinical outcomes. Pertinent populations include the first three delineated above, that is, those 

individuals with a psychiatric diagnosis or a psychiatric condition at the time of the study, the 

latter including symptoms/behaviors insufficient to merit a formal diagnosis (e.g., dysphoric 

mood). Outcomes could involve changes in symptom severity, time to a treatment failure, or 

remission of the disorder. 

The question regarding the possible association between the intake of omega-3 fatty acids 

and the onset, continuation or recurrence of a psychiatric disorder or condition (i.e., Question 2) 

examines whether intake protects individuals from developing, or perhaps predisposes them to 

develop, a psychiatric disorder or a subset of its symptoms/behaviors (i.e. onset). The question 

also examines whether omega-3 fatty acid intake influences the clinical course or outcome of a 

psychiatric disorder or condition insofar as it could facilitate or prevent its continuation (e.g., 

progression of a condition so that it becomes a disorder; progression of a disorder) or recurrence. 

Relevant populations for the “onset” subquestion include those in Population 4 (i.e., “healthy” 

individuals), those belonging to “at risk” Population 2 with a psychiatrically diagnosed first order 

relative, or those in either Populations 2 or 3 who might be exhibiting a psychiatric condition that 

could develop into a full-fledged disorder. For the “continuation” subquestion, pertinent 

populations include Populations 1 (i.e., a current psychiatric disorder), 2 or 3 (i.e., a current 

psychiatric condition). The “recurrence” focus includes Population 2 (i.e., past diagnosis). 

Outcomes could include prevalence and incidence, as well as indices of secondary prevention. 

The latter could be observed where amounts or types of fatty acid intake prevent the intensity of 
24

a psychiatric condition (e.g., dysphoric mood) from increasing and contributing to the 

development of a full-fledged disorder (e.g., major depression). 

Results from relevant studies (see Eligibility Criteria) with respect to Questions 1 and 2, 

which reflect the possible influence of interventions/exposures on the omega-3 or omega6/omega-3 fatty acid content of biomarkers (see their definition in Eligibility Criteria section), 

are highlighted briefly and exclusively with an exploratory intention since reliable associations 

between biological and clinical effects could suggest a mechanism by which omega-3 fatty acid 

interventions/exposures bring about improved clinical outcomes. 

The question regarding the possible association between the omega-3 or omega-6/omega-3 

fatty acid content of biomarkers and the onset, continuation or recurrence of a psychiatric 

disorder or condition (i.e., Question 3) investigates whether certain levels of fatty acid content 

(i.e., composition, or concentration) in blood lipid biomarkers (e.g., RBCs, plasma 

phospholipids) protect individuals from developing, or perhaps predispose them to develop, 

psychiatric disorders or subsets of their symptoms/behaviors (i.e. onset). The question also 

examines whether certain levels of fatty acid content in blood lipid biomarkers can influence the 

clinical course or outcome of a psychiatric disorder or condition by facilitating or preventing 

their continuation (e.g., progression of a condition so that it becomes a disorder; progression of a 

disorder) or recurrence. Relevant populations for the “onset” subquestion include those in 

Population 4 (i.e., “healthy” individuals), those belonging to “at risk” Population 2 with a 

diagnosed first order relative, or those in either Populations 2 or 3 who might have a psychiatric 

condition that could develop into a full-fledged disorder. For the “continuation” subquestion, 

pertinent populations are Populations 1 (i.e., a current psychiatric disorder), 2 or 3 (i.e., a current 

psychiatric condition). The “recurrence” focus includes Population 2 (i.e., a past diagnosis). 

Outcomes could include prevalence and incidence, although observing that a certain fatty acid 

composition in biomarkers prevents the intensity of a psychiatric condition (e.g., dysphoric 

mood) from increasing and contributing to the development of a full-fledged disorder (e.g., 

major depression) could indicate secondary prevention. Question 4 is addressed using safety 

data from studies meeting eligibility criteria. 

The possible influence of predefined effect modifiers is evaluated in relation to each of the 

basic questions. Where possible, question-specific sections titled “Impact of Covariates and 

Confounders” elucidate a) those variables (e.g., omega-3 fatty acid type; comorbid conditions; 

psychotropic medication) that were consistently observed, across reviewed studies, to influence 

study outcomes as well as b) those variables (e.g., age, sex), which having been controlled for 

either experimentally or analytically in reviewed studies, were observed to consistently 

influence, or consistently fail to influence, study outcomes. 

Study Identification 

Search Strategy 

The search strategy for this project was designed to be comprehensive and achieve the 

highest possible recall of relevant clinical studies. The electronic search strategy was developed 

by an information specialist in consultation with clinical content experts in mental health. 

Because of the number of conditions falling under the rubric of mental health, the mental health 
25

subject tree and index terms for suicidal, aggressive and impulsive behavior was used, rather 

than terms appearing in free text. For those with less robust subject indexing in the area of 

mental health, supplemental free text terms were added to the electronic search strategy (CDSR, 

CAB Health). The mental health search concept was combined with the core omega-3 fatty 

acids search strategy established in collaboration with the project librarians, biochemists, 

nutritionists, and clinicians from the three EPCs involved in the 2-year, Health Benefits of 

Omega-3 Fatty Acids task order. Consultation among these sources provided the biochemical 

names and abbreviations of omega-3 fatty acids, names of commercial omega-3 fatty acids 

products, and food sources of omega-3 fatty acids. 

The following electronic databases were searched: Medline (1966 – November Week 2 2003 

and updated to April Week 3 2004), Embase (1980 to 2003 Week 48 and updated to 2004 Week 

18), the Cochrane Library including the Cochrane Central Register of Controlled Trials (3rd

Quarter 2003), PsycInfo (1982 to December Week 1, 2003) and CAB Health (1973-Sept 2003). 

All databases were searched via the Ovid interface using Search Strategy 1 (Appendix A*

), 

except CDSR where we used Search Strategy 2 (Appendix A*) and CAB Health, which was 

searched through SilverPlatter using Search Strategy 3 (Appendix A*). Searches were not 

restricted by language of publication, publication type, or study design, except with respect to the 

MeSH term “dietary fats,” which was limited by study design to increase its specificity. A total 

of 1606 bibliographic records were downloaded, with 410 duplicate records identified and 

removed using citation management software (Reference Manager®). 

Reference lists of included studies, book chapters, and narrative or systematic reviews 

retrieved after having passed the first level of relevance screening, were manually searched to 

identify additional unique references. Through contact with content experts, attempts were made 

to identify both published and unpublished studies. On behalf of the three EPCs investigating 

the evidence concerning the health benefits of omega-3 fatty acids, a letter was written to 

industry representatives to obtain additional evidence (Appendix B*). Unsuccessful attempts 

were made to contact the lead author of a recent Cochrane Collaboration systematic review of 

PUFA supplementation for schizophrenia to obtain unpublished data they claimed to have 

received from investigators.61 These supplementary efforts identified an additional 16 records 

that were added to the collection for review. A final set of 1,212 unique references was 

identified. 

Eligibility Criteria 

Published and unpublished studies, written in any language, were eligible for inclusion. 

Excluding grey literature from systematic reviews of interventions can lead to the overestimation 

of effect sizes.62 Substantial bias in the results of a systematic review pertaining to a 

complementary/alternative medical (CAM) intervention can ensue from the exclusion of data 

from reports written in languages other than English.63 AHRQ and ODS consider omega-3 fatty 

acids to be a CAM exposure. 

Data from live human study populations or subpopulations (e.g., genetic, minority, ethnic: 

e.g., diabetic) of any age were required to maximize generalizability. Study populations in 

treatment studies, as well as in those investigating the possible association of the onset, 

continuation or recurrence of psychiatric disorders or conditions with either the intake of omega-

 

* Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm. 
26

3 fatty acids or the fatty acid content of biomarkers had to have been assessed using any formal 

psychiatric diagnostic criteria (e.g., DSM-IV) or established psychiatric research instruments 

(e.g., Hamilton Depression Rating Scale). Our TEP requested that we investigate both 

psychiatric disorders and psychiatric conditions (i.e., behaviors, symptoms: e.g., dysphoric 

mood), recognizing that while the latter are necessary to identify a psychiatric disorder, alone 

they are insufficient to signal the presence of one (e.g., major depression). Any and all types of 

comorbid condition were eligible. Studies conducted in any era of psychiatric practice were 

considered candidates for inclusion. 

The specific types of population required to address each of the basic research questions are 

described with reference to the analytic framework and those details are not repeated here. As 

one point of clarification, our TEP asked that, within the context of assessing the possible 

association between omega-3 fatty acid intake and psychiatric disorders or conditions (Question 

2) we should review studies examining the possible protective effects of omega-3 fatty acid 

intake on the development of maladaptive behavior in populations presumed to be “healthy” 

(e.g., college volunteers), yet who might, for example, develop evidence of disrupted well-being 

when subjected to stressful circumstances. Excluded populations were those with degenerative 

(e.g., Alzheimer’s) and peroxisomal (e.g., Zellweger’s) disorders since each was addressed in 

SC-RAND’s year-2 review of the evidence concerning omega-3 fatty acids in neurology. 

Treatment studies, as well as those investigating the possible association between omega-3 

fatty acid intake and the onset, continuation or recurrence of specific psychiatric disorders or 

conditions, had to specifically investigate foods or supplements known to contain omega-3 fatty 

acids of any type (e.g., EPA, ALA), from any source (e.g., fish, walnuts, seed oil), any serving 

size or dose, delivered in any fashion (e.g., capsules, liquid, PUFA-rich diet), and for any length 

of time. In all studies, some method had to have been employed to suggest the presence of 

omega-3 fatty acid content in the exposure, if not its actual amount (e.g., g/d). Studies 

investigating “PUFAs” or “ LC PUFAs,” or even types of diet one might presume would contain 

marine or land sources of omega-3 fatty acids (e.g., “Mediterranean diet”) at minimum had to 

highlight at least one source of the omega-3 fatty acid content (e.g., oily fish servings). No 

restrictions were placed on the types or doses of pre- or on-study cointerventions (e.g., 

medication, omega-6 fatty acid intake, other dietary supplements). 

Controlled studies were required to address questions of intervention efficacy or 

effectiveness, with randomized controlled trials (RCTs) being the gold standard method to 

investigate these questions (Question 1).64 Any definition of control, or comparator, was 

permitted. RCTs exhibit a greater inherent potential to deal with potentially serious biasing 

influences (e.g., selection bias) although a poorly designed or conducted RCT can produce 

results whose interpretability is no less complicated by the presence of confounding influences, 

for example, than observations derived from a well-constructed and conducted study employing 

a design with a lesser intrinsic capacity to control for these biases (e.g., non-RCT; prospective 

cohort study). For example, not all RCTs succeed, either through an explicit experimental plan 

or the process of randomization per se, to equally distribute known confounding influences (e.g., 

background diet; energy/caloric intake from the intervention; types and doses of psychotropic 

medication) across study arms in intervention studies. That said, our TEP asked that we identify 

all excluded uncontrolled studies with respect to questions of intervention efficacy/effectiveness 

so that future synthesis work could begin with these data. We achieved this by adding a third 

level of screening, which yielded a listing of citations for these excluded studies (see Study 

Selection Process section for details). 
27

Any type of research design other than noncomparative case series or case studies was 

deemed appropriate for questions concerning the possible association between the intake of 

omega-3 fatty acids and the onset, continuation or recurrence of psychiatric disorders or 

conditions (Question 2). Often, but not exclusively, relevant data were generated by crosssectional surveys involving a single sample. A special interpretative emphasis was placed on 

results from prevention RCTs and other controlled prospective designs. 

Controlled studies were required to address the questions of the possible association between 

the fatty acid content of biomarkers and the onset, continuation or recurrence of psychiatric 

disorders or conditions (Question 3). Evidence of the possible role played by the fatty acid 

content of biomarkers in the etiology of schizophrenia, for example, requires derivation from 

controlled designs although not all of these designs are equal in their capacity to generate data 

directly pertinent to Question 3. A special interpretative emphasis was thus placed on results 

from prospective controlled designs, with cross-sectional studies yielding the least direct 

evidence. 

Overall, any and all clinical outcomes were considered relevant, including symptom severity 

or control, response rate, incidence, prevalence or diagnostic status (e.g., case-control or crosssectional studies). As markers of omega-3 fatty acid metabolism, the following fatty acid 

compositions or concentrations, from any source (e.g., red blood cell [RBC] membranes, plasma 

phospholipids), were considered relevant in intervention studies (i.e., exclusively as an 

exploratory focus on the possible covariation of clinical and biomarker effects, or correlations 

between these factors) or as possible predictors of the onset, continuation or recurrence of 

psychiatric disorders or conditions: EPA, DHA, AA/EPA, AA/DHA, AA/EPA+DHA. Studies 

exclusively evaluating the role of other biomarkers (e.g., cytokine production, eicosanoid levels) 

were not included. These decisions were made with the assistance of our TEP. 

Study Selection Process 

The present review employed specific electronic functionality in the form of an internetbased software system, housed on a secure web site. It brings appreciable efficiencies to the 

systematic review process and the management of a systematic review team. Electronic yields of 

literature searches are posted to the system for review. Reviewers then submit all of their results 

of relevance screening, data appraisal or data abstraction directly to the system. The software 

system automatically conducts an internal comparison of multiple reviewers’ responses to 

screening questions, to determine the eligibility/relevance of a bibliographic record or a full 

report. As well, the software captures responses to specific requests to abstract pre-specified 

data (e.g., mean age of study participants; the assessment of a study’s internal validity) from 

pertinent reports. One large advantage associated with using this software is that review team 

members are able to complete their work from wherever they have internet access. 

Following a calibration exercise, which involved screening five sample records using an 

electronic form developed and tested especially for this review (Appendix C*

), two reviewers 

independently screened the title, abstract, and key words from each bibliographic record for 

relevance by liberally applying the eligibility criteria. A record was retained if it appeared to 

contain pertinent study information. If the reviewers did not agree in finding at least one 

unequivocal reason for excluding it, it was entered into the next phase of the review. The 

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
28

reasons for exclusion were noted using a modified QUOROM format (Appendix D*).65 The 

screening process also aimed to identify the exact mental health question a record addressed, in 

addition to determining whether it might also or instead pertain to any of the other topics being 

systematically reviewed by the three EPCs in year 2 of the omega-3 fatty acids project. 

Print or electronic copies of the full reports for those citations having passed level one 

screening were then retrieved. After completing a calibration exercise which involved 

evaluating five sample reports using the same eligibility criteria (Appendix C*), the rest of the 

reports were independently assessed by two reviewers. Reports were not masked given the 

equivocal evidence regarding the benefits of this practice.66 To be considered relevant at this 

second level of screening, all eligibility criteria had to be met. Implementing the 

recommendations of our TEP, a third level of dual-reviewer screening was used to exclude, yet 

at the same time to identify, studies addressing questions of intervention efficacy/effectiveness 

employing uncontrolled research designs. 

Disagreements arising at either screening levels 2 or 3 were resolved by forced consensus 

and, if necessary, third party intervention. Excluded studies at each of these levels are noted as 

to the reason for their ineligibility in listings found at the end of this report. 

Data Abstraction 

Following a calibration exercise involving two studies, seven reviewers independently 

abstracted the contents of included studies using an electronic Data Abstraction form developed 

especially for this review (Appendix C*). A second reviewer then verified those data. Data 

abstracted included the characteristics of the: 

• report (e.g., publication status, language of publication, year of publication); 

• study (e.g., sample size; research design; number of study arms/groups, cohorts, or 

phases; funding source); 

• population (e.g., age; percent males; diagnosis description, including severity, duration, 

and comorbid conditions); 

• intervention/exposure (e.g., omega-3 fatty acid types, sources, doses, and 

intervention/exposure length), and comparator(s); 

• cointerventions (e.g., concurrent medications, omega-6 fatty acid use); 

• withdrawals and dropouts, including reasons; 

• clinical outcomes; 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
29

• fatty acid content of biomarkers; and, 

• adverse events (e.g., side effects). 

Summarizing the Evidence 

Overview 

The evidence is presented in three ways. Evidence tables in the Appendices offer a detailed 

description of the included studies (e.g., study design, population characteristics [e.g., diagnosis], 

intervention/exposure characteristics [e.g., omega-3 fatty acid types and doses], cointervention 

[e.g., background diet, concurrent medication]), with a study represented only once. These 

tables are organized by research design (Table 1: experimental studies [e.g., treatment RCTs]; 

Table 2: observational studies [e.g., cross-sectional studies examining the possible association of 

the omega-3 or omega-6/omega-3 fatty acid content of biomarkers with the onset, continuation 

or recurrence of a specific psychiatric disorder or condition]; Table 3: cross-national ecological 

analyses [e.g., studies addressing the possible association of omega-3 fatty acid intake with the 

onset, continuation or recurrence of a specific psychiatric disorder or condition), with studies 

arranged alphabetically within each of the three table/design categories. 

Question-specific summary tables embedded in the text describe each study addressing a 

given question in abbreviated fashion, highlighting some key characteristics, including sample 

size (as measure of the “weight” of the evidence and possible precision of the results), dose and 

type of omega-3 fatty acids, and comparators’ (i.e., comparison groups’) specifications. This 

affords a comparison of all studies addressing a given question. A study can appear in more than 

one summary table since it can address more than one research question. Also question-specific 

is each summary matrix, situating each study in terms of its study quality and its applicability. 

Study Quality 

Study quality refers to the internal validity, or methodological soundness, of a study. A 

systematic review can be faced with great variability in the quality of its included studies. Our 

approach is not to use a minimal level of quality as an inclusion criterion since this precludes 

assessing the possible impact of study quality on study results. 

A study with low quality can make it difficult to clearly and meaningfully interpret its results, 

that is, to unequivocally attribute a significant observed benefit exclusively to an 

intervention/exposure (as opposed to other factors). Since definitions, or standards, of study 

quality can depend on the type of research design, different constructs were selected to evaluate, 

from study reports, the quality of RCTs and studies employing other types of research design. 

After a calibration exercise involving two studies with an RCT design, two assessors 

independently evaluated study quality. Disagreements were resolved via forced consensus. In 

the case of designs other than RCTs, a single experienced quality assessor performed the 

evaluations. Time did not permit their dual assessment. 

Four fundamental quality constructs from two instruments were used to rate the internal 

validity of RCTs. These tools were chosen collectively by the three EPCs involved in the 2-year 
30

task order because they have been validated. The Jadad items67 assess the reporting of 

randomization, double blinding, and, withdrawals and dropouts (Appendix C*

). Total scores 

range from 0 to 5, with a score less than 3 indicating low quality. The reporting of the 

concealment of a trial’s allocation to treatment68 yields three grades (A = adequate; B = unclear; 

C = inadequate) (Appendix C*). 

The assessment of the quality of studies using designs other than RCTs is complicated by the 

dearth of validated instruments and the variety of such designs (e.g., non-randomized controlled 

trials; uncontrolled studies). Nevertheless, a recent systematic review by Deeks et al. identified 

a number of “best tools” for use with these designs.69 Among them was a published instrument 

developed by Downs and Black70 and an unpublished one derived by experts in Newcastle and 

Ottawa (NOS).71 The former validated both design-specific and design-neutral items. 

Where case-control and cohort studies were included in the review, the validated NOS was 

employed. Items applicable to other designs such as non-RCTs, cross-sectional designs, crosssectional surveys and others were taken from the Downs and Black instrument; or, if the required 

constructs were not operationalized in this instrument, they were developed as modifications of 

existing Downs and Black items (e.g., for multiple-group cross-sectional designs), NOS items 

(e.g., single prospective cohort studies), borrowed from Jadad’s assessment tool (e.g., description 

of withdrawals/dropouts), or developed outright. For example, items needed to be created to 

evaluate cross-national ecological analyses (Appendix C*). 

It should be noted that the items defining the case-control and cohort study assessment tools 

from the NOS were each used as a whole, although specific guidelines as to which designspecific total scores indicate low or sound quality are unavailable. Likewise, no guidelines exist 

to mark low or sound study quality based on any subset of Downs and Black’s 27-item 

instrument. As already asserted, an Jadad total quality score of less than 3 indicates low quality. 

To permit the entry of these quality data into a summary matrix, cutpoints for each type of design 

were set somewhat arbitrarily to establish three levels of internal validity (see Summary Matrix). 

It was decided by our review team that, given the limitations of space, especially in printbased study reports, and the amount of detail that would likely be required to provide all of the 

details we needed to fully establish that only appropriate methods had been used to extract, 

prepare, store and analyze lipid content, it was reasonable to appraise these methods by focusing 

instead on identifying extant descriptions of inappropriate methods. On occasion, the 

inappropriateness of methods had to be determined by reference to standard protocols. 

Pilot-tested exclusively for their ease of use within the data abstraction form were questions 

designed to informally assess the successful control of study confounding from variables 

identified by content experts as potential threats to the internal validity of studies pertinent to the 

review. In their view, these variables required experimental or statistical control to permit an 

uncomplicated interpretation of study results (Appendix C*). The two major categories of threat 

in controlled designs came from having study groups vary in terms of key prestudy or baseline 

characteristics (e.g., background diet; psychotropic medication; severity of a disorder), or from 

having certain on-study changes (e.g., unexpected stressors; changes in medication type or dose) 

unrelated to the exposure or intervention, occur unequally across study groups to produce 

confounding. Even RCTs are not immune from being affected by these threats to internal 

validity. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
31

For example, if in a placebo-controlled RCT test of the supplemental treatment efficacy of 

omega-3 fatty acids, only certain treatment group members’ background diets changed 

appreciably from what was observed at baseline (e.g., decreased fish intake and thus an increased 

omega-6/omega-3 ratio in the background diet), at which point the two study groups’ baseline 

diets had been deemed comparable, then this on-study inequality could influence study 

outcomes. Because of this change in background diet, one study group might all of a sudden be 

receiving a different ratio of omega-6/omega-3 fatty acid intake than what had been set in the 

study protocol. This would amount to a change in the planned, on-study between-group 

difference in omega-6/omega-3 fatty acid intake; and, it is this intake ratio which could have the 

greatest influence on clinical outcomes. In general, contraventions of planned on-study betweengroup equivalences (e.g., caloric/energy intake; background diet; medication types and doses; 

severity of disorder; current smoker status; alcohol consumption) or of planned, on-study 

between-group differences (e.g., amount of omega-3 fatty acid intake) related to events other 

than the intervention/exposure (e.g., stressors, which can alter the severity of the disorder in 

addition to the patterns of eating, smoking and alcohol consumption), that is, in variables with 

the potential to affect mental health outcomes (and biomarker levels), could either “mask” or 

incorrectly “reveal” clinical benefits of the intervention depending on the groups in which these 

unexpected changes occurred. Then, unless statistical adjustments are made, such a scenario will 

complicate the meaningful interpretation of outcomes. 

These informal assessment items were modified to assess single group studies since on-study 

changes involving the same key variables can also complicate the interpretation of their study 

results. However, no quality scores were derived from the data abstractors’ responses to these 

questions pertaining to controlled or uncontrolled studies. 

Study Applicability 

As specified in the scope of work for this series of evidence reports on the health benefits of 

omega-3 fatty acids, the primary focus is on the US population. Given the geographical location 

of the UO-EPC, however, the definition of study applicability was expanded slightly to include 

Canada as part of a larger North American context. This study’s reference point became the 

“typical” North American. 

Also known as external validity, or generalizability, the construct of applicability refers to 

the degree to which a given study’s sample population is sufficiently representative of the 

population to which one wishes to generalize its results. In the present review, two schemes 

operationally defined applicability (Appendix C*

). One assessed studies involving at least one 

target population identified with a psychiatric disorder or condition, with the other evaluating 

studies involving a target population with or without a known elevated risk for a psychiatric 

disorder or condition. 

With regards to the highest level of applicability (Level I) in the first scheme, the broadest 

definition of the population of interest is the otherwise “healthy” North American (or similar 

individual) identified with a psychiatric disorder or condition, diagnosed using a standard North 

American strategy and methodology/nomenclature (e.g., DSM-IV) or identified using at least 

one established psychiatric instrument, presenting with or without comorbid psychiatric 

conditions while possibly receiving “typical” North American medications for the primary 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
32

diagnosis, is drawn from a somewhat broad socio-demographic spectrum (i.e., gender, race), and 

eats a diet “typical” of a broad spectrum North American population (e.g., with an estimated 

omega-6/omega-3 intake ratio of at least 15: see below for references). For Level I applicability 

in the second scheme, the broadest definition of the population of interest is the otherwise 

“healthy” North American (or similar) individual, presenting with or without a known elevated 

risk for onset of a psychiatric disorder or condition, representing a somewhat broad sociodemographic spectrum (i.e., gender, race), and eating a diet “typical” of a broad spectrum North 

American population (e.g., with an estimated omega-6/omega-3 intake ratio of at least 15). 

Together, these level I definitions represent the respective reference points, with applicability 

decreasing as the definition of the sample study population narrows in terms of the factors 

represented in the two schemes. With respect to the scheme applied to studies with diagnosed 

participants, we identified what are likely the two most important variables as being the method 

of diagnosis and the background diet of participants leading up to the study, if not also during the 

study. Each defines the study population. When the second scheme is applied to studies where 

the participants have not yet been diagnosed with a psychiatric disorder or condition, background 

diet is the key variable. 

The method of diagnosis is an important factor since not all countries employ the diagnostic 

methods or nomenclatures used most frequently in North America (e.g., DSM). Psychiatric 

populations identified using different approaches, even when diagnostic labels are the same, can 

vary in terms of what these labels refer to.13 At the same time, different labels (e.g., “AD/HD” in 

North America versus “hyperactivity” in the UK) can refer to the same clinical entity. That said, 

the most frequently employed approaches employed in North America are considered the 

reference point. 

Operationalized ideally in this review as the omega-6/omega-3 fatty acid ratio, background 

diet is an important factor in assessing both types of study population (i.e., diagnosed vs 

undiagnosed participants). Given the competitive relationship between omega-3 and omega-6 

fatty acids, both for enzymes to yield key metabolites with specific effects in the human 

biosystem (see Chapter 1) and for positions in cell membranes from which to have these and 

other possible influences (e.g., clinical improvement or prevention), the absolute and relative 

intake of omega-3 and omega-6 fatty acids from all sources, and not just from the identified 

exposure, likely need to be taken into account when deciding whether populations assessed in 

different studies are comparable. The likelihood of biological and/or clinical effects in studies 

may turn out to vary depending on these absolute or relative intake values. A high background 

dietary omega-6/omega-3 fatty acid intake ratio—potentially reflected in a corresponding 

differential in these contents in cell membranes—may make it harder for omega-3 fatty acid 

supplementation to make a clinically meaningful difference,72 although already having 

considerable omega-3 fatty acid content in the background diet and in cell membranes because of 

a low omega-6/omega-3 fatty acid intake ratio may make it difficult for typically small amounts 

of omega-3 fatty acid supplementation to make a clinically meaningful difference (see 

Discussion). 

Irrespective of which of these hypotheses may be eventually confirmed elsewhere, the fact 

that national, and sometimes regional, populations can vary in terms of their diet’s omega6/omega-3 fatty acid intake ratio strongly suggests that this potential confounding influence on 

study outcomes needs to be represented in the applicability schemes whereby the North 

American value is the reference point. The typical North American diet contains an omega-
33

6/omega-3 fatty acid intake ratio of at least 15, while urban India and Japan’s corresponding 

values are 38-50 and 4, respectively.33-45 

UK populations represent somewhat of a special case in that, while they often use the same 

diagnostic methods and research instruments to identify psychiatric disorders and conditions in 

populations, respectively, and while they can exhibit socio-demographic pictures similarly broad 

to the ones seen in North American study populations, their somewhat different lifestyle and 

background diet recommended an applicability value of “II.” However, if participants were 

drawn from a narrower UK population, then a “III” was assigned. Given their inclusion of multinational populations, with or without representation from the U.S. or Canada, cross-national 

ecological analyses necessarily received a “III.” One experienced assessor evaluated study 

applicability. 

Summary Matrix 

For a given research question, and where possible (e.g., more than one study addressing the 

question), a summary matrix situates the pertinent studies in terms of their respective study 

quality (internal validity) and applicability (external validity) values. The Jadad total quality 

score defined RCTs’ internal validity in summary matrices. A three-level format was derived 

from the range of possible RCT quality scores (A = Jadad total score of 4 or 5; B = Jadad total 

score of 3; C = Jadad total score of 0, 1 or 2). Given that allocation concealment scores have in 

the past tended to vary less widely than Jadad total scores, allocation concealment values were 

entered as superscripts in the summary matrices.72 A similar approach was taken for the studies 

employing other research designs. The following cutpoints were established, albeit without 

benefit of a validational exercise: 

• comparative before-after study: A = total quality score of 8-11; B = 5-7; C = 1-4; 

• case-control study (NOS): A = 8-10; B = 4-7; C = 1-3; 

• (multiple-group) cross-sectional study: A = 8-10; B = 4-7; C = 1-3; 

• single prospective cohort study (Modified NOS): A = 8-10; B = 4-7; C = 1-3; 

• cross-sectional survey: A = 8-10; B = 4-7; C = 1-3; and, 

• cross-national ecological analysis: A = 7-9; B = 4-6; C = 1-3. 

The three-level applicability format was established by the 3 EPCs involved in the 2-year 

project for practical reasons, to permit the incorporation of quality scores within a summary 

matrix. Studies assigned an “X” (i.e., insufficient information to establish applicability) were 

excluded from summary matrices. 

Qualitative Data Synthesis 

An overarching qualitative synthesis describes the progress of each citation, then report, 

through the stages of the systematic review. It also highlights certain report and study design 
34

characteristics of included studies (e.g., distributions of research design by research question). 

Then, for each question, a separate qualitative synthesis is derived for included evidence, 

organized by broad categories of research design (i.e., experimental studies vs observational 

studies vs cross-national analyses). A brief study-by-study overview typically introduces the 

synthesis, followed by a narrative summary of the key defining features of relevant studies (e.g., 

inclusion/exclusion criteria), including their populations (e.g., diagnosis-related), 

intervention/exposures (e.g., types of omega-3 fatty acid), cointerventions (e.g., psychotropic 

medication), outcomes, study quality, applicability and results. Whether or not data can be 

organized according to these subheadings depends on the number of studies addressing a given 

question and the amount or variety of detail available in the study reports. For example, having 

identified too few studies per research question that do and do not exhibit significant effects for a 

given clinical outcome can preclude determining the impact of covariables with the potential to 

modify or confound study results (e.g., type or dose of omega-3 fatty acids). 

Juxtaposing, in turn, all pertinent studies’ parameters for a given research question has two 

key consequences. It allows us to identify the “gaps” in knowledge deemed crucial by content 

experts to understand the clinical phenomenon (e.g., efficacy of omega-3 fatty acids). That is, 

data regarding possible confounders may be lacking, making it difficult to interpret study results 

with unfettered confidence. These gaps point to those variables requiring measurement and 

experimental or statistical control in future research. Second, it affords an understanding of the 

definition and extent of the included studies’ clinical homogeneity (i.e., population, intervention, 

cointervention, outcome), which can then inform decisions regarding the appropriateness of 

meta-analysis. Where strong clinical heterogeneity is observed, it may be important to forego 

meta-analysis because the “population” to which any point estimate, and measure of precision, 

might be extrapolated may not exist per se; it, too, is synthetic (e.g., the “average” 

schizophrenic). Subject to scrutiny in the evaluation of cross-study clinical homogeneity is the 

ability of each study to control for confounding influences and yield results that can be 

interpreted without serious question marks. The existence of statistical heterogeneity also plays 

a role in the decision to do without a quantitative synthesis. Whether or not meta-analysis is 

considered appropriate, an attempt is made to make sense of the possible influence of covariates 

and confounders within the context of the qualitative synthesis. 

Where eligibility criteria permit, evidence from research designs with a lesser inherent 

potential to control for biasing influences are used to see whether, collectively, they confirm the 

picture of efficacy, or association, derived from designs with a greater inherent potential to 

achieve this goal (see Eligibility Criteria). For the purposes of interpreting results, greater 

emphasis is placed on the latter, with “greater emphasis” meaning that we assign greater 

interpretative, not numerical or statistical, weight to these intrinsically stronger designs. Factors 

other than study design also taken into account in interpreting results include study quality, the 

number of studies, and whether studies were sufficiently powered. 

Quantitative Data Synthesis 

Given its greater potential to control for possible confounding factors, only RCT evidence 

regarding the question of interventions’ efficaciousness was considered for inclusion in metaanalysis. All things being equal, it was also assumed that priority in meta-analysis might be 

given to clinical outcomes pertinent to the present day practice of psychiatry and psychology. 
35

Providing the result would have a clearly defined population to which to generalize a 

synthetic result, and that sufficient numbers of prospective controlled studies exist (e.g., RCT; 

cohort study), meta-analysis was considered with respect to data investigating questions of the 

possible association of the onset, continuation or recurrence of a psychiatric disorder or condition 

with either the intake of omega-3 fatty acids or the PUFA content of biomarkers. Prospective 

controlled designs constitute the most appropriate way to establish these risk-relationships 

among variables. Decisions regarding statistical models are provided where results of metaanalysis are reported. Reasons to forego meta-analysis are likewise described. 

 37 

Chapter 3. Results 

Results of Literature Search 

Regardless of its source, the progress of each bibliographic record through the stages of the 

systematic review is illustrated in the modified QUOROM flow chart (Appendix D*). Ideally, a 

record included an abstract and key words, in addition to a citation. When a citation was 

discovered, for example through a manual search of a reference list, its complete bibliographic 

record was sought (e.g., Pubmed) and then entered into the first level of relevance screening. 

Of 1,212 records entered into the initial screening for relevance, 955 were excluded. 

Reflecting the specific eligibility criteria, the reasons for exclusion were: a. not a first publication 

of empirical evidence (e.g., a review; n = 500); b. not involving human participants (n = 216); c. 

no omega-3 fatty acid focus (i.e., intervention/exposure or biomarkers) (n = 167); and, d. not 

related to predefined mental health outcomes (n = 72). All but 773-79 of the remaining 257 

reports were then retrieved and subjected to a more detailed relevance assessment. Of those 7 

reports which were not retrieved, one was an abstract77 whose study results may have been 

published subsequently as a journal article included in the review. 

 A second relevance screening then excluded 137 reports for the following reasons: a. not a 

first publication of empirical evidence (e.g., a review; n = 91); b. not involving human 

participants (n = 7); c. no omega-3 fatty acid focus (i.e., intervention/exposure or biomarkers) (n 

= 23); and, d. not related to predefined mental health outcomes (n = 16). Finally, a third 

relevance screening level excluded 27 uncontrolled studies failing to meet eligibility criteria 

regarding the questions of the efficacious nature of omega-3 fatty acid interventions or the 

possible assocation of the fatty acid content of biomarkers with the onset, continuation or 

recurrence of psychiatric disorders or conditions. 

In total, 86 reports, describing 79 unique studies, were deemed relevant for the systematic 

review, with 6 studies each described by more than one report. The specific relationships 

between studies and reports are identified in the next paragraph. As stated earlier, the two 

listings of studies excluded as a result of appraisals of full reports are presented at the end of this 

document. 

When the lead author of the Tanskanen et al. studies was contacted because their two studies 

appeared to be similar,80,81 he clarified that the studies, and their study populations, were nonoverlapping. As introduced above, on occasion multiple reports published or presented in 

different places did describe the same study. To afford transparency for those considering 

replicating or updating our work, we identify these relationships at this time. Hibbeln47 included 

Weissman et al.’s46 data as part of their cross-national ecological analysis. Edwards et al.’s 

data48 were first disseminated in an abstract.82 Likewise, Peet et al.’s publication, describing 

their study of the primary treatment of schizophrenia,58 was preceded by an abstract.83 Peet and 

Mellor’s abstract84 became available before their data, concerning the supplemental treatment of 

schizophrenia, were published.58 Two abstracts85,86 also reported Peet and Horrobin’s data 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
38 

regarding the supplemental treatment of schizophrenia.87 Two additional analyses60,88 extended 

Fenton et al.’s initial work.89 To avoid confusion in the text, evidence tables, summary tables 

and figures, only one report is used to refer to a given study and its data. It is typically the first, 

or “parent,” publication. Peet et al.’s report, describing two relevant studies (primary vs 

supplemental treatment of schizophrenia),58 is represented twice in Evidence Table 1 (see 

Appendices*

). 

Some studies provided data addressing more than one research question. For example, 

Noaghiul and Hibbeln’s cross-national ecological analysis evaluated the possible association of 

seafood consumption with bipolar disorder and with schizophrenia.90 Mellor et al.’s study 

investigated the possible associations of schizophrenia outcomes with the dietary intake of 

omega-3 fatty acids as well as with the omega-3 and omega-6/omega-3 fatty acid content of 

biomarkers.91 However, Mellor et al.’s subsequent intervention study, described in the same 

report, was not eligible for the present review because it employed an uncontrolled design. 

To help guide the reader, a table appears at the end of this report, which lists the studies 

addressing each question. The questions are organized by the order in which they are addressed 

in the text. Only the first, or “parent,” report is represented in the table.

Report and Study Design Characteristics of Included Studies 

Of the included studies, only one failed to be described by at least one published report.92 It 

was reported in abstract form. Another included report was a published letter to the editor, 

which while reporting the use of omega-3 fatty acids for a problem outside the scope of the 

present review (i.e., lithium-induced psoriasis), it referred to the source of these data as being a 

placebo-controlled trial investigating the supplemental treatment of bipolar disorder.93 Of the 16 

relevant studies identified by manual search, only one was disseminated in a format other than a 

journal publication.92 All but one of the included reports (all published), which required 

translation from Chinese,94 were written in English. 

As an overview, the number of included studies investigating each of the three basic 

questions are described, distinguished by psychiatric disorder, or condition, and by research 

design. A given study may have addressed more than one basic question. 

Twenty-two unique studies investigated the first three basic questions concerning depression. 

Of these, seven were RCTs,53,95-100 seven were multiple-group cross-sectional studies,48,101-106

three were single population cross-sectional surveys,80,81,107 three were cross-national ecological 

analyses47,108,109 and two were single prospective cohorts.110,111 Four RCTs examined omega-3 

fatty acids as either a primary95 or supplemental treatment.53,96,97 Three RCTs,98-100 three crossnational ecological analyses,47,108,109 three single population cross-sectional surveys,80,81,107 one 

multiple-group cross-sectional study48 and two single prospective cohorts110,111 comprised the 

twelve studies investigating the possible association of omega-3 fatty acid intake with the onset, 

continuation or recurrence of depression. One RCT98 and seven multiple-group cross-sectional 

studies48,101-106 looked at the possible association of the onset, continuation or recurrence of 

depression with the omega-3 or omega-6/omega-3 fatty acid content of biomarkers. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
39 

Two studies, one a single prospective cohort111 and the other a single population crosssectional survey,80 investigated the possible association of omega-3 fatty acid intake with the 

onset, continuation or recurrence of suicidal ideation or behavior. Five unique studies 

investigated three basic questions concerning bipolar disorder. Two studies, one RCT112 and one 

defined merely as “controlled,”93 evaluated the supplemental treatment of bipolar disorder. One 

cross-national ecological analysis90 examined the possible association of omega-3 fatty acid 

intake with the onset, continuation or recurrence of bipolar disorder. Two multiple-group crosssectional studies looked at the possible association of the onset, continuation or recurrence of 

bipolar disorder with the omega-3 or omega-6/omega-3 fatty acid content of biomarkers.113,114 

Two RCTs investigated the possible association of omega-3 fatty acid intake with the onset, 

continuation or recurrence of anxiety.99,100 One crossover RCT studied the supplemental 

treatment of obsessive-compulsive disorder.115 Two multiple-group cross-sectional studies 

examined the possible association of the onset, continuation or recurrence of anorexia nervosa 

with the omega-3 or omega-6/omega-3 fatty acid content of biomarkers.116,117 

Ten unique studies assessed the first three basic questions pertaining to AD/HD. These 

studies were the only ones in the review that investigated children. Three RCTs,118-120 with one 

facet of one of them118 centered on children not receiving medication, and one comparative 

before-after study,121 investigated the primary treatment of AD/HD. One of the same RCTs,118

this time looking exclusively at children receiving medication, and two other RCTs,122,123

evaluated the supplemental treatment of AD/HD. One multiple-group cross-sectional study 

investigated the possible association of omega-3 fatty acid intake with the onset, continuation or 

recurrence of AD/HD.94 Three multiple-group cross-sectional studies examined the possible 

association of the onset, continuation or recurrence of AD/HD with the omega-3 or omega6/omega-3 fatty acid content of biomarkers.124-126 One single population cross-sectional survey 

assessed the possible association of omega-3 fatty acid intake with the onset, continuation or 

recurrence of mental health difficulties.127

Ten unique studies investigated two of the three basic questions regarding tendencies or 

behavior with the potential to harm others. Five RCTs,99,128-131 one single population crosssectional survey132 and one cross-national ecological analysis,133 studied the possible association 

of omega-3 fatty acid intake with the onset, continuation or recurrence of these tendencies or 

behavior. Three multiple-group cross-sectional studies examined the possible association of the 

onset, continuation or recurrence of these tendencies or behavior with the omega-3 or omega6/omega-3 fatty acid content of biomarkers.134-136 Two multiple-group cross-sectional studies 

investigated the possible association of the onset, continuation or recurrence of alcoholism with 

the omega-3 or omega-6/omega-3 fatty acid content of biomarkers.137,138 One RCT studied the 

primary treatment of borderline personality disorder.139 

Twenty-eight unique studies investigated the first three basic questions concerning 

schizophrenia. One RCT58 studied the primary treatment of schizophrenia and four 

RCTs58,87,89,140 investigated the supplemental treatment of schizophrenia. Five case-control 

designs,92,141-144 one single prospective cohort91 and three cross-national ecological 

analyses90,109,145 assessed the possible association of omega-3 fatty acid intake with the onset, 

continuation or recurrence of schizophrenia. Twelve multiple-group cross-sectional 

studies114,146-156 and two single prospective cohort studies157,158 investigated the possible 

association of the onset, continuation or recurrence of schizophrenia with the omega-3 or omega6/omega-3 fatty acid content of biomarkers. 
40 

One multiple-group cross-sectional study159 examined the possible association of the onset, 

continuation or recurrence of autism with the omega-3 or omega-6/omega-3 fatty acid content of 

biomarkers. Ten RCTs described adverse event (e.g., side effects) data associated with an 

omega-3 fatty acid intervention/exposure (Question 4),53,58,87,89,95,96,112,119,129,130 with two of these 

trials involving healthy volunteers.129,130

The remainder of this chapter is organized by disorder or condition, with the evidence 

addressing each of its first three basic questions presented in turn. If a question is not 

represented in the report, there was no evidence that met eligibility criteria. Safety data are 

presented last. We begin with mood disorders. 

Are Omega-3 Fatty Acids Efficacious as Primary Treatment 

for Depression? 

As observed in Summary Table 1 (below), derived from Evidence Table 1 (Appendix E*), 

only one controlled study (2003) employing an RCT design met eligibility criteria in 

investigating the question of omega-3 fatty acids’ possible efficaciousness as a primary treatment 

for depression. 

Overview of Relevant Study’s Characteristics and Results 

Likely at one US site, Marangell et al. randomized 36 adult outpatients (18-65 years; 

racial/ethnic background unreported) meeting DSM-IV criteria for major depressive disorder 

(duration unreported), without psychotic features, to receive either 2 grams per day (2 g/d) DHA 

or placebo (source undefined) in a 6-week parallel design (followups at 2 and 6 weeks).95 

Inclusion criteria were a score of at least 12 on the Montgomery-Asberg Depression Rating Scale 

(MADRS), a score of at least 17 on the Hamilton Depression Rating Scale (HDRS), no 

psychotropic medication for at least 2 weeks, and dietary intake of no more than one fish serving 

per week. Exclusion criteria included any significant comorbid psychiatric or medical 

conditions, and a lifetime failure of at least two adequate antidepressant trials. Clinical response 

was the primary outcome, and was defined as a mimimum 50% reduction, from baseline to 6 

weeks, on the MADRS. Funding was provided by way of an investigator-initiated grant from 

Martek Biosciences Corporation. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
41 

Summary Table 1: Omega-3 fatty acids as primary treatment for depression 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Notable clinical 

effects

Notable 

biomarker 

effects2,3

Internal 

validity Applicability 

Marangell, 

2003, 

US: 

6 wk 

parallel 

RCT95

2g/d 

DHA 

(n=18) 

pb 

(source 

undefined) 

(n=18) 

NS MADRS response 

rate; NS after 

adjusting for baseline 

HDRS score 

Ï absolute RBC 

DHA only in 

DHA grp;++++ 

RBC DHA (% wt 

of total FAs) Ï

only in DHA grp 

Jadad 

total: 2 

[Grade: 

C]; 

Schulz: 

Unclear 

X 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = 

study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; MADRS = Montgomery-Asberg Depression 

Rating Scale; HDRS = Hamilton Depression Rating Scale; RBC = red blood cells; Jadad total = Jadad total quality score: 

reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation concealment 

(adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower 

Response rates were 27.8% and 23.5% in the DHA (n=18 with at least one followup) and 

placebo groups (n=17), respectively, with the difference failing to reach statistical significance in 

an intention-to-treat analysis (ITT). This null finding held after an adjustment for baseline 

HDRS score. The two groups did not vary in terms of age, percent male participants, alcohol 

intake, or education. The placebo group comprised a significantly greater number of smokers 

and a lower weight. Both at baseline and at study endpoint the placebo group exhibited a 

significantly higher HDRS score. Only in the DHA group did the absolute level of RBC DHA 

content increase in statistically significant fashion from baseline to endpoint, whereas a report of 

a similar difference in the change in DHA’s percent weight of total fatty acids was not 

accompanied by results of a statistical test of significance. No information was provided 

regarding the reason one participant in the placebo group did not reach final followup. 

A summary matrix is not required for a single study. Study quality assessed via the Jadad 

total score was low, with insufficient clear information preventing us from concluding that the 

allocation to study groups had likely been adequately concealed. There were insufficient details 

reported by Marengell et al. to permit the determination of a level of applicability even though 

the trial appeared to have been conducted in the US. 

This was a single study with a limited sample size and a limited complexity to its design 

(e.g., no stratification for covariates). Thus, other than the observation that the possible 

confounding impacts of certain factors (e.g., between-group differences or on-study changes in 

psychotropic medication type or dose; alcohol intake; education, age, sex) were likely controlled 

in this primary treatment study, little can be said about the possible impact of additional factors 

with the potential to influence mental health outcomes. Yet, one factor with the potential to 

influence these outcomes, current smoker status, was not distributed equally across study groups 

although the observation that more placebo group members were smokers makes it difficult to 

see how this may have contributed to a null between-group difference in the primary clinical 

outcome. This between-group difference could have influenced the observations of a betweengroup difference in changes in RBC DHA content, however, given the effects of smoking on 
42 

EFA status.60 The restriction on weekly fish intake likely made study groups somewhat more 

comparable. Meta-analysis was considered unnecessary. 

Are Omega-3 Fatty Acids Efficacious as Supplemental 

Treatment for Depression? 

As observed in Summary Table 2 (below), derived from Evidence Table 1 (Appendix E*

), 

three RCTs met eligibility criteria in investigating omega-3 fatty acids’ possible efficaciousness 

as supplemental treatment for depression. Studies were published in 2002 or 2003. 

Overview of Relevant Studies 

Peet and Horrobin conducted a dose-ranging study of the effects of ethyl eicosapentaenoate 

(E-EPA: i.e., a pure ethyl ester derivative of EPA) in adult outpatients (n=70; 18-70 years) 

identified with persistent depressive symptomatology despite ongoing treatment with an 

adequate dose (undefined) of a standard antidepressant (Summary Table 2).53 Recruited by 

family physicians, study participants were randomized into a 12-week parallel RCT (followups 

at 4, 8 and 12 weeks) on a double-blind basis to receive either placebo (liquid paraffin) or total 

doses of 1 g/d, 2 g/d or 4 g/d E-EPA via 500 mg soft gelatin capsules (taken morning and 

evening). The primary outcome was HDRS score, with the MADRS and the patient-completed 

Beck Depression Inventory (BDI) serving as secondary outcome measures. 

 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
43 

Summary Table 2: Omega-3 fatty acids as supplemental treatment for depression 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Notable clinical 

effects

Notable 

biomarker 

effects2,3

Internal 

validity Applicability 

Peet, 2002, 

England & 

Scotland: 

12 wk 

parallel 

RCT53

4g/d 

E-EPA 

(n=17)/ 

liquid 

paraffin 

pb 

(n=18) 

2g/d E-EPA 

(n=18)/ 

1g/d E-EPA 

(n=17) 

All ITT & PP 

analyses of HDRS, 

MADRS & BDI 

showed Ï Ð’s only 

for 1g/d grp at 12 

wk+ - +++ 

n/a Jadad 

total: 4 

[Grade: 

A]; 

Schulz: 

Adequate 

II 

Nemets, 

2002, Israel: 

4 wk 

parallel 

RCT97

2g/d 

E-EPA 

(n=10) 

pb 

(source 

undefined) 

(n=10) 

2g/d E-EPA showed 

Ï HDRS Ð’s at 2,+++

3+++ & 4 wk+++ 

n/a Jadad 

total: 4 

[Grade: 

A]; 

Schulz: 

Unclear 

III 

Su, 2003, 

China: 

8 wk 

parallel 

RCT96

4.4g/d 

EPA + 

2.2g/d 

DHA 

(n=14) 

olive oil 

ethyl ester 

pb 

(n=14) 

6.6g/d showed Ï

HDRS Ð’s at 4,+++

6,+++ & 8 wk;+++ rate 

of Ð in HDRS Ï in 

EPA grp++ 

Ï RBC DHA for 

EPA grp only;+

 

NS Ï in RBC 

EPA for both grps 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; 

grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; MADRS = Montgomery-Asberg Depression Rating Scale; 

HDRS = Hamilton Depression Rating Scale; BDI = Beck Depression Inventory; RBC = red blood cells; Jadad total = Jadad 

total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; ITT = intention-to-treat analysis; PP = per-protocol analysis (e.g., completers); Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower

Nemets et al. randomized 20 Israeli outpatients (mean age: 53.4 [28-73] years), meeting 

DSM-IV criteria for a current diagnosis of major depressive disorder, to receive either 2 g/d EEPA derived from 96% pure fish oil (stabilized with 0.2% vitamin E) or matching placebo 

(undefined) given in 1 g doses twice daily (via 50 0mg soft gelatin capsules) for 4 weeks.97 Only 

one patient did not continue receiving the antidepressant treatment they had been taking for at 

least 3 months, making this male’s trial an evaluation of the impact of E-EPA as a primary 

treatment. He was exhibiting a 4-month severe depressive disorder that had been resistant to 

treatment with two different SSRIs. All other study participants had, in the past, suffered 

relapses when antidepressant doses were reduced or discontinued altogether. The primary 

outcome measure was the HDRS, with ratings conducted at baseline and weekly thereafter in this 

double-blind trial. 

Su et al. conducted an eight-week, double-blind, placebo-controlled parallel RCT.96 They 

compared the impact, on HDRS scores, of 6.6 g/d of omega-3 fatty acids (i.e., 4.4 g/d EPA and 

2.2 g/d DHA from menhaden fish) against placebo (i.e., olive oil ethyl ester) in 28 physically 

healthy outpatients diagnosed with DSM-IV major depressive disorder. Five identical gelatin 

capsules containing 440 mg EPA and 220 mg DHA were taken twice daily. Inclusion criteria 

were an HDRS score of at least 18, and no change in medication or psychotherapy 4 weeks prior 

to enrolment. Participants could not exhibit comorbid Axis I or Axis II psychiatric disorders, or 
44 

be receiving antipsychotics or mood stabilizers. Placebo responders (i.e., mimimum 20% 

decrease in HDRS score) during a pre-randomization, one-week run-in were excluded. One 

participant in each group was free of medication, indicating that their trials assessed the primary 

treatment of depression. Followups using the HDRS occurred every 2 weeks. Dietary frequency 

ratings, recorded food diary data, and blood samples to assess the fatty acid content of RBC 

membranes were assessed during the run-in and at 8 weeks. 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. Three parallel RCTs involving adults addressed the question 

(Summary Table 2; Evidence Table 1: Appendix E).53,96,97 Only Su et al.96 and Nemets et al.97

provided detailed descriptions of both inclusion and exclusion criteria. Only Peet and Horrobin53

employed a design having more than two study groups (i.e., 4). A total of 118 adult outpatients 

were randomized. The mean sample size for the three studies was 39.3 (range: 20-70) 

participants, with the Peet and Horrobin trial being much larger than either of the other two. The 

studies’ participants received the intervention for an average of eight (range: 4-12) weeks, with 

Peet and Horrobin’s intervention period lasting the longest. The RCTs were conducted in three 

countries outside North America: the UK,53 Israel,97 and China.96 The UK RCT was funded by 

industry (Laxdale Research Ltd),53 the study from China was funded by government (National 

Science Council) and industry (China Chemical & Pharmaceutical Company),96 and the Israeli 

trial’s funding source was not reported.97 

Population characteristics. The mean age of study participants across the three trials was 

impossible to determine given that full sample means were not given for two trials.53,96 

Participants’ ages ranged from 18-73 years when two studies’ data were combined.53,97 

Participants in the Su et al. study tended to be younger (mean for omega-3 group=35.2 years; 

placebo group: 42.3 years), on average, than participants in the Peet et al. (means of four groups: 

43-48 years)53 or Nemets et al. studies (omega-3 group mean: 54.2 years; placebo mean: 52.1).97 

Females were consistently more strongly represented in the three trials (82-85%). Racial/ethnic 

backgrounds included Asian96 and Middle Eastern,97 yet no data were provided for a potentially 

diverse UK population.53 

Only the Peet and Horrobin RCT53 did not report having employed any formal diagnostic 

criteria. The other two studies used DSM-IV to identify populations with major depressive 

disorder. Rather, the UK study required a score of at least 15 on the HDRS, and thus likely 

identified their participants as merely experiencing persistent depressive symptomatology. 

Nemets et al.’s participants had had relapses in the past when medication dosages were reduced 

or discontinued.97 All three studies employed the HDRS score to establish the severity of the 

psychiatric condition. While Peet and Horrobin required a score over 15, Su et al. required a 

score above 18.96 Nemets et al. only reported mean actual HDRS scores of 22.3 (placebo group) 

and 24.0 (EPA group).97 Based only on completer data subjected to a statistical test, Su et al. 

noted that HDRS-defined severity was equivalent for study groups.96 Peet and Horrobin did not 

present baseline HDRS severity data for study groups. 

Peet and Horrobin53 did not identify or exclude any comorbidity while Nemets et al. required 

that there be no unstable medical disease, no alcohol or drug abuse, no psychotic features, no 

history of hypomania or mania, and no comorbid psychiatric diagnosis other than panic disorder 

(n=2, one per study group), dysthymic disorder (n=2, one per study group), and obsessive 
45 

compulsive disorder (n=1, E-EPA group).97 Su et al. asserted that no one in their sample 

received any other Axis I or any Axis II psychiatric diagnosis.96 

Likely because their study participants did not receive a formal diagnosis, Peet and Horrobin 

did not report data concerning the duration of the current depressive episode, age of onset, the 

number of previous episodes, or the time since diagnosis.53 Su et al. reported the study groups’ 

mean current episode duration (omega-3 group: 21.5 weeks; placebo group: 22.8 weeks), age of 

onset (omega-3 group: 30.6 years; placebo group: 35.1 years), number of previous episodes 

(omega-3 group: 2.5; placebo group: 2.3), but not the time since diagnosis.96 Statistical tests of 

the possible significance of between-group baseline differences exclusively for completers 

revealed that study groups were comparable on these bases as well as with respect to age, 

percentage of males, body mass index, HDRS score, and both EPA and DHA levels in RBCs. 

Nemets et al. reported their sample’s mean current episode duration (EPA group: 44.6 days; 

placebo group: 43.1 days), time since diagnosis (EPA group: 7.6 years; placebo group: 8.0 

years), number of previous episodes (EPA group: 2.1; placebo group: 1.9), but not their age of 

onset.97 While statistical tests of significance were not employed, notable between-group 

differences at baseline were not observed for these variables. 

Only Nemets et al. controlled for two of these potential confounding influences by excluding 

participants if they had had substance abuse or unstable medical problems.97 Only Su et al. 

reported data reflecting the omega-3 fatty acid content of biomarkers at baseline, which by 

statistical analysis, were comparable between study groups. They did not, however, report the 

units of measurement for biomarker data (e.g., absolute level; percent of total fatty acids).96 

Intervention/exposure characteristics. Both Su et al.96 and Nemets et al.97 identified the 

source of their intervention as fish oil whereas Peet and Horrobin53 reported no details. Only Su 

et al. identified the exact type of source: menhaden fish.96 Nemets et al. compared 2 g/d E-EPA 

derived from 96% pure fish oil (stabilized with 0.2% vitamin E) and a matching, albeit undefined 

placebo.97 Peet and Horrobin employed 1 g/d, 2 g/d, 4 g/d or placebo (liquid paraffin) as their 

intervention.53 Su et al.’s participants received 6.6 g/d of omega-3 fatty acids (i.e., 4.4 g/d EPA 

and 2.2 g/d DHA) or placebo (i.e., olive oil ethyl ester).96 Only Su et al. used DHA in addition to 

EPA. Each RCT employed a placebo control and used the appropriate numbers of capsule and 

amounts of placebo content to equalize the total daily “intervention” across their study groups. 

Omega-3 fatty acid contents were delivered by capsule in each study. However, there are 

few clear data to suggest that all three studies were equally able to eliminate the possible 

confounding influence of having unequal amounts of calories, as energy, provided for their 

different study groups. Nemets et al.’s placebo was not defined, making it impossible to know 

whether participants in each study group received the same number of calories. Although it is 

possible, ultimately it is unclear whether a unit of Peet and Horrobin’s liquid paraffin, an inert 

lubricant laxative, provided the same caloric/energy content as that received from purified EPA. 

Given that the typical laxative dose is 15-30 g/d, and that Peet and Horrobin’s study, as well as 

others described in this review, have consistently used much smaller daily doses, it is unlikely 

that its laxative effect would be any worse than that produced by a similar food oil.87 Su et al., 

on the other hand, used olive oil ethyl ester to match their groups for energy/caloric intake. 

If, as it was decided in consultation with the TEP working with us on our review of the 

evidence regarding the effects of omega-3 fatty acids on asthma,72 and recognizing the FDA 

view that a 3 g/d dose of EPA and DHA is safe,160 then two of the standardized doses in the three 

studies met our criterion that 3 g/d is a high dose of omega-3 fatty acid supplementation: Su et 

al’s 6.6 g/d EPA plus DHA,96 and Peet and Horrobin’s 4 g/d E-EPA.53 
46 

None of the RCTs provided omega-6 fatty acids or any other supplement as cointervention, 

and none attempted to implement a specific on-study ratio of omega-6/omega-3 fatty acid intake 

through diet and/or supplementation. Nemets et al.97 and Peet and Horrobin53 did not report 

whether their study participants were told to maintain their background diet, to alter their 

background diet in some uniform fashion (e.g., modify omega-6 fatty acid intake and thereby 

change their omega-6/omega-3 fatty acid intake), or whether participants routinely complied 

with any such mandates. Only Su et al. established, for example, that study groups did not differ 

in terms of their on-study dietary frequency of fish intake as reported via 24-hour recall and 

three-day dietary records.96 Few compliance data, in general, were provided. Peet and Horrobin 

used capsule counts to report that at least 90% of the dose had been consumed in each of the four 

study groups.53 Even then, this method for determining compliance may not be overly accurate. 

Moreover, fatty acid content in biomarkers is likely not a perfect methodology either, given that 

EFA status can be influenced by various factors in addition to intake (e.g., oxidative 

degradation). Without hard data it is thus difficult to rule out the possibility in at least two 

studies that notable changes did not occur in the on-study background diet (i.e., Nemets et al., 

Peet et al.) or that protocol violations with respect to the number of capsules ingested did not 

occur, leaving unknown the extent of possible confounding with regards to clinical outcomes 

(i.e., from unplanned changes in the study groups’ equivalence of energy/caloric intake from the 

“exposure” or related to unplanned changes in the between-group difference in the amount of 

omega-3 fatty acid received from supplementation). 

Of the three trials, only Peet and Horrobin53 failed to report having stabilized their omega-3 

fatty acid doses with some form of anti-oxidant. Su et al. attempted to maintain blinding by 

having all capsules vacuumed to deodorize any odour, and having their contents blended with an 

orange flavor.96 Anti-oxidant tertiary butylhydroquinone (0.2 mg/g) and tocopherols (2 mg/g) 

were added to all capsules both to maintain blinding, by preventing oxidation and rancidity, and 

to avoid possible confounding that could occur if these were added only to active treatment 

capsules and actually produced psychotropic effects,. In spite of no effort to deodorize their 

intervention, Nemets et al.’s participants were unable to reliably guess which capsules they had 

taken.97 

For all three RCTs, the manufacturer of the omega-3 intervention was reported. Purity data 

were provided for two of the trials’ exposures.53,97 In the one study that evaluated the fatty acid 

content of biomarkers, no notable inappropriate methods to extract, prepare, store or analyze 

lipids were described.96 No study report included details as to whether, or how, the presence of 

methylmercury was tested or eliminated from the omega-3 fatty acid exposure. 

Cointervention characteristics. Given the focus of the present question is supplemental 

treatment, it could be argued that the omega-3 fatty acids are the cointervention. Nevertheless, to 

simplify matters, “cointervention” is defined as those other treatments or interventions that are 

provided concurrently, even if their initiation predated the omega-3 fatty acids intervention. 

Peet and Horrobin reported similar distributions of background treatment by type of 

antidepressant (i.e., tricyclics, serotonin selective reuptake inhibitors [SSRIs], and others) in each 

study group.53 They did not present data regarding whether or not this antidepressant use 

remained constant, by type or dose, over the study for any of their study groups. Nemets et al. 

described their participants as having received their antidepressants for at least three weeks at the 

current dose.97 However, antidepressant medication was not distributed equally by type or dose 

across study groups. There was similar fluoxetine and mirtazapine use and doses, but five 

placebo and one E-EPA participant received paroxetine, usually at 20 mg/d. As well, the E-EPA 
47 

study group included the only three users of fluvoxamine and the only recipient of citalopram. 

Moclobernide was given to a single participant in the placebo group. Participants on prestudy 

medication in Su et al.’s trial maintained their dosages on-study, with only oral 

sedatives/hypnotics (loazepam or zolpidem) permitted as additional therapy for possible anxiety 

or insomnia.96 They did report statistically-tested between-group baseline comparability for 

completers’ duration of antidepressant use prior to enrollment or their (fluoxetine equivalent) 

dose of antidepressants while being enrolled. 

Certain population characteristics have the potential to influence mental health outcomes if, 

in controlled investigations, study groups diverge significantly at baseline on these bases, or if 

unplanned on-study changes unrelated to the exposure occur in their status that vary notably 

across study groups (or within a single study group). Some cointerventional factors may exhibit 

a similar potential to confound clinical outcomes (e.g., psychological interventions, other licit 

drug use, use of complementary/alternative medicine/products, other supplement use with 

psychotropic potential). Not reported in the three included RCTs were data regarding the 

between-group comparability at baseline, or data regarding the on-study change in the status of 

these factors, making it difficult to rule out the possibility that these variables influenced clinical 

outcomes. 

Outcome characteristics. All three RCTs employed the validated HDRS as the primary 

outcome.53,96,97 While Peet used the validated MADRS and BDI as well, Su et al. assessed the 

omega-3 fatty acid content of biomarkers. 

Study quality and applicability. The three RCTs received a mean Jadad total quality score 

of 3.6, indicating sound internal validity (Summary Matrix 1). The trials conducted by Peet and 

Horrobin53 and Nemets et al.97 each received a score of 4, while Su et al.’s score was 3.96 The 

latter two studies96,97 each received an applicability rating of III, and a II was assigned to Peet 

and Horrobin’s UK trial.53 Overall, these studies’ individual or collective results were not 

readily generalizable to a North American population. 

Summary Matrix 1: Study quality and applicability of evidence regarding the supplemental treatment of 

depression 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I 

Author Year n Author Year n Author Year n

II PeetA 2002 70 

Author Year n Author Year n Author Year n

Applicability 

III NemetsU 2002 20 SuU 2003 28 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment 

Qualitative Synthesis of Individual Study Results 

Peet and Horrobin’s trial conducted both ITT (last observation carried forward) and perprotocol (PP) analyses, the latter assessing study completer data.53 Analyses of variance 
48 

(ANOVA) compared data reflecting change from baseline to study endpoint for each active 

treatment group with comparable data from participants receiving placebo. All of the ITT and 

PP analyses involving each of the 3 scales showed that participants in the 1 g/d group improved 

significantly more than did those in the placebo group. For the 2 g/d and 4 g/d groups no 

comparison reached a level of statistical significance, with only the 4 g/d results for the PP 

population approaching statistical significance. For the 1 g/d versus placebo contrast, the HDRS 

and MADRS differences were already statistically significant at 4 weeks; only the BDI scores 

failed to show statistically significant changes at 4 weeks. Eight-week data regarding 1g/d 

supplementation was only provided for the BDI, and changes in these scores at 8 weeks only 

approached statistical significance. Analyses of specific items from the rating scales (i.e., the 

three main components of the HDRS [items 1-3: depression; 4-6: sleep; 9-11: anxiety] and the 

ten MADRS items) demonstrated that, for the comparison involving the PP population, there 

were no significantly greater improvements in the 1 g/d group compared with the placebo group. 

Statistically significant differences in favor of the 1 g/d dose were observed on the BDI-defined 

items pertaining to sadness, pessimism, inability to work, sleep disturbance and libido. These 

results suggest improvements defined by both patient and clinician assessments. While results of 

tests of statistical significance were not reported, the number of participants exhibiting a 50% 

improvement was always higher, when compared with placebo rates, in the 1 g/d and 4 g/d 

groups for all three scale scores assessed in both the ITT and PP populations. Yet, response rates 

for placebo participants consistently exceeded those from participants receiving the 2 g/d dose. 

Analyses of covariance (ANCOVA) of Peet and Horrobin’s data for each of the rating scales 

at each of the followups assessed overall differences between study groups.53 They revealed that 

center (exact number unreported) and background medication, by class (i.e., tricyclic, selective 

serotonin reuptake inhibitor [SSRI], or either norepinephrine or mixed reuptake inhibitors), had 

no significant effects on any rating scale scores in the ITT and PP populations. Baseline HDRS 

score had no effect on the HDRS and MADRS outcomes in either of the ITT or PP populations 

yet had a significant effect on BDI outcome only in the ITT population. Treatment had a 

significant overall effect on all three rating scale scores for both the ITT and PP populations yet 

the p-value for the HDRS comparison in the ITT population barely missed indicating statistical 

significance. 

Nemets et al.’s multivariate analysis of covariance (MANCOVA), with baseline HDRS score 

as covariate, described a statistically significant treatment-by-time interaction in the ITT 

population (i.e., last value at week three carried forward, n=1).97 This observation was 

maintained after the week three HDRS score from the sole placebo dropout was excluded. 

Compared to placebo, E-EPA yielded significantly improved HDRS scores at each of weeks 2, 3 

and 4. The mean reduction in HDRS score in the E-EPA group (12.4 points) was greater than 

that in the placebo group (1.6), and was considered clinically meaningful. Only one of ten 

patients in the placebo group and six of 10 in the E-EPA group achieved a 50% reduction in 

HDRS score. Item analysis showed that E-EPA influenced core symptoms such as depressed 

mood, feelings of guilt, feelings of worthlessness and insomnia. The investigators did not 

remove from any analyses the one study patient who was receiving E-EPA as monotherapy. 

Su et al. observed, by week 4, and likewise for weeks 6 and 8, a statistically greater HDRSdefined improvement in the active treatment group.96 By repeated measures ANOVA it was 

found that the rate of reduction in HDRS scores was also significantly greater in the omega-3 

fatty acids group. Pre- and post-intervention RBC fatty acid status data were limited, with a 

significantly increased level of DHA seen at post-treatment for the EPA group (n=7) but not the 
49 

placebo group (n=6). No statistically significant increases in EPA levels were observed for 

either study group. 

Nemets et al. reported a single study dropout, from the placebo group, by week 3 because of 

worsening depressive symptoms.97 Six of 28 participants dropped out prior to week 8 in Su et 

al.’s trial; two had been receiving active treatment (one lost to followup, and one lost due to 

noncompliance), and four were in the placebo group (three lost to followup, one lost due to 

noncompliance).96 Ten participants left Peet and Horrobin’s trial,53 with four from the placebo 

group (one lost to followup, one withdrew consent during study, one violated protocol, one had 

an adverse event presumed to be unrelated to treatment) and two from each of the E-EPA groups 

(no data by group: three withdrew consent, one left due to lack of efficacy, one violated protocol, 

one had gastrointestinal adverse event). 

Quantitative Synthesis 

We decided it was reasonable to explore the possibility of conducting meta-analysis for this 

question. HDRS was chosen as the primary outcome measure. We aimed to extract the mean 

change from baseline in HDRS, together with the standard deviation of this change, for each 

study group. The goal was to focus on the ITT population. We requested data to afford this 

analysis from the lead investigators of the Peet and Horrobin53 and the Su et al. trials.96 Only the 

former replied, passing on our request to the company now holding their data. A representative 

of the company stated they would consider the request yet no further reply was received. 

In order to help decide on the possibility and appropriateness of meta-analysis, we created a 

forest plot of all possible combinable results. Length of follow-up varied notably between 

studies, so from each study we considered the longest followup data reported in addition to 4 

week and 8 week results where they were provided. Su et al.’s study96 used capsules containing 

EPA together with DHA to yield a very high total dose (6.6 g/d). The other two studies53,97

employed capsules exclusively containing E-EPA. The study by Peet et al.53 reported change in 

HDRS after 12 weeks of treatment for four different study groups (placebo, 1 g/d, 2 g/d, and 4 

g/d). Although the standard deviation of change from baseline was not reported, p-values for 

change from baseline relative to placebo were reported for each dose so that the standard error 

for each contrast could be inferred. Su et al.96 reported mean HDRS scores at baseline and posttreatment, but not the standard deviation in the change from baseline. We were nevertheless able 

to extract estimates from one of their graphs. 
50 

Figure 3. Estimates of the change in HDRS score between omega-3 fatty acid and placebo groups from 

studies evaluating the supplemental treatment of depression 

Difference in mean Hamilton Depression Rating Scale

-15 -10 -5 0 5

Peet

Peet

Peet

Su

Su

Nemets

2002

2002

2002

2003

2003

2002

1

2

4

6.6

6.6

2

Dose

(g/d)

12

12

12

4

8

4

Followup

(wks)

35

36

35

22

22

20

n

← → Favors Omega-3 Favors placebo

The Peet et al.53 and Nemets et al.97 studies reported ITT analyses (using a last observation 

carried forward strategy). Yet, it was unclear whether Su et al.96had also employed an ITT 

approach. In addition, their data concerning loss to followup at 4 weeks and 8 weeks were 

unclear. 

After a careful appraisal of the estimates and key study parameters, however, it was decided 

not to conduct meta-analysis. No pooled estimate was derived because of the variations in dose 

both within and among studies, and in view of variations in the length of followup. It should 

also be noted that, in the Peet and Horrobin study53 the estimates for the different doses 

involving placebo shared the same placebo group. As well, Su et al.’s intervention was the only 

one including DHA in addition to EPA,96 as the other trials employed purified forms of EEPA.53,97 All three RCTs employed different types of placebo. Finally, unlike the other two 

studies wherein patients had been formally (DSM-IV) diagnosed with major depression, Peet and 

Horrobin’s use of a HDRS cut-off score to identify study participants yielded, at worst, a 

population with persistent depressive symptomatology.53
51 

Impact of Covariates and Confounders 

Overall, the Su et al. study was the one exhibiting the best control of extra-interventional 

factors with the potential to influence, and thus confound, study results.96 Without repeating all 

of the details presented in the qualitative synthesis, these investigators indicated that study 

groups were balanced for key population (e.g., severity of depression, age of onset, absence of 

other Axis I or Axis II disorders) and cointervention parameters (e.g., patients asked to maintain 

constant on-study medication, although they did not demonstrate between-group baseline 

comparability for types and doses; established a maximum weekly frequency of background fish 

intake). Although Peet et al. provided few population data, their undiagnosed sample did not 

exhibit comorbid conditions and their study groups’ patterns of medication use were similar.53 

Nemets et al., on the other hand, did not evaluate whether study groups of depressed patients 

were similar at baseline in terms of the severity of their depressive symptomatology. They also 

reported that study groups varied in terms of their antidepressants. Still, their groups did not 

contain any individuals with unstable medical disease or substance abuse, and few comorbid 

conditions were observed. None of the studies reported data concerning prestudy/baseline 

omega-3 or omega-6/omega-3 fatty acid intake via diet or supplementation. Only Su et al. 

reported data regarding study groups’ baseline comparability in their baseline omega-3 fatty acid 

content of biomarkers.96 They did not, however, report the units of measurement for these data 

(e.g., absolute level; percent of total fatty acids). 

Dose, omega-3 fatty acid type, and whether the exposure was purified all failed to reliably 

predict clinical effects. For example, significant effects were associated with the largest (6.6 g/d 

EPA+DHA)96 and smallest doses (1 g/d E-EPA),53 various types of omega-3 fatty acid 

(EPA+DHA96 vs E-EPA53,97) and both EPA+DHA96 and E-EPA.53,97 Employed as a possible 

surrogate measure of background diet, or possibly even the background diet’s omega-6/omega-3 

intake ratio, the country in which a study was conducted did not predict study results. The 

lowest dose (1 g/d E-EPA), given to a UK population,53 and the highest dose (6.6 g/d 

EPA+DHA), given to a Chinese population,96 each yielded a significant clinical effect. The 

majority of study participants were female. Overall, though, there were too few studies with 

which to properly evaluate the impact of extra-interventional variables with the potential to 

influence study results. 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Depression? 

As observed in Summary Tables 3 through 6 (below), derived from Evidence Tables 1 

through 3 (Appendix E*

), three types of evidence met eligibility criteria addressing this question. 

The qualitative synthesis distinguishes evidence from these types of study published between 

1998 and 2004. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
52 

Overview of Relevant Studies 

Three RCTs,98-100 six observational studies48,80,81,107,110,111 and three cross-national ecological 

analyses47,108,109 were found to address this question. 

Plasma DHA gradually decreases during the last trimester of pregnancy and remains low for 

some time during the postpartum period, and particularly in lactating women.161 It has been 

postulated that brain DHA levels may be low during late pregnancy and the early postpartum 

period, and that these levels may contribute to the development of postpartum depression.162 

Postpartum depression is defined in DSM-IV as a major depressive, manic, or mixed episode in 

major depressive disorder, bipolar I or bipolar II disorder, or brief psychotic disorder. Llorente 

et al. thus attempted to determine the effect of DHA supplementation on the onset of postpartum 

depression as well as on plasma phospholipid DHA content in breastfeeding women (Summary 

Table 3).98 Mothers who planned to breastfeed their children (n=138; 18-42 years) were 

randomly assigned, in double-blind fashion, to receive either ~200 mg/d DHA or placebo 

(undefined) for the first four months after delivery. Clinical outcome was determined via the 

BDI, and was collected at baseline, 3 weeks, 2 months, and 4 months post-delivery. Depressionrelated data were obtained through the Structured Clinical Interview, DSM-IV, Axis I Disorders, 

Clinical Version (SCID-CV). As well, scores on the Edinburgh Postnatal Depression Scale 

(EPDS) of postpartum depression symptoms were obtained from subgroups of the sample. 

Plasma phospholipid data were collected just before delivery and at 4 months. 
53 

Summary Table 3: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

depression (RCTs) 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Notable clinical 

effects

Notable 

biomarker 

effects2,3

Internal 

validity Applicability 

Llorente, 

2003, US: 

4 mo 

parallel 

RCT98

~200mg/d 

DHA 

(n=44 

completers) 

pb 

(undefined) 

(n=45 

completers) 

NS bet-group BDI 

difference at any 

time; NS bet-grp 

differences in EPDS 

& SCID-CV scores 

8%Ï in 

plasma PL 

DHA in DHA 

grp vs 31%Ð

in pb grp;+

DHA content 

of DHA grp 

50% higher 

than pb grp+++ 

Jadad 

total: 5 

[Grade: 

A]; 

Schulz: 

Adequate 

II 

Wardle, 

2000, 

England: 

12 wk 

parallel 

RCT99

Mediterranean 

diet (with oily 

fish) 

(n=61) 

low fat diet 

(n=59)/ 

waiting list 

control 

(n=56) 

Ð BDI & anger 

reactions in both 

diets;+ Ð stress & 

anxiety only in 

Mediterranean diet;+ 

NS bet-grp 

differences in 

outcomes 

n/a Jadad 

total: 2 

[Grade: 

C]; 

Schulz: 

Adequate 

II 

Ness, 

2003, 

Wales: 

6 mo 

parallel 

RCT (one 

factor in 

factorial 

RCT)100

advice to eat 

fish 

(n=229) 

no advice 

to eat fish 

(n=223) 

NS ∆ in depression 

& anxiety for fish 

advice grp; NS betgrp differences for 

depression & 

anxiety 

n/a Jadad 

total: 2 

[Grade 

C]; 

Schulz: 

Unclear 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; BDI = Beck Depression Inventory; EPDS = 

Edinburgh Postnatal Depression Scale; SCID-CV = Structured Clinical Interview, DSM-IV, Axis I Disorders, Clinical 

Version; RBC = red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine 

phosphoglycerides; Jadad total = Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); 

Schulz = reporting of adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% 

confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Wardle et al.’s RCT investigated whether cholesterol-lowering diets influence mood, 

including depression, anxiety, anger/hostility, stress, and general psychological well-being.99 

Adult volunteers (n=176) with elevated serum cholesterol levels (>5.2 mM [198 mg/dL]) were 

allocated to a low-fat diet (n=59), a Mediterranean diet (n=61) or a waiting-list control (n=56). 

Dietary treatments were given in eight sessions over the 12-week period. Waiting-list controls 

were offered treatment at the end of their waiting period. Participants were exhibiting at least 

mild hypercholesterolemia by UK standards. Participants completed a 7-day dietary intake diary 

before the first assessment. Outcomes were assessed at baseline, 6 weeks and 12 weeks. These 

included the BDI, personal history of depression established through interview, and the 

following validated instruments: State-Trait Anger Inventory (STAI), the anxiety and anger 

subscales of the Profile of Mood States (POMS), the General Health Questionnaire (GHQ) to 
54 

assess general psychological well-being, and the Perceived Stress Scale (PSS). Dietary diaries 

were filled out at baseline and 12 weeks. 

Reflecting one factor of a factorial RCT investigating interventions to reduce mortality in 

angina (including: advice [not] to eat fruits and vegetables; [no] stress management), 452 males 

were allocated to receive advice to eat more fatty fish (i.e., mackerel, herring, kipper, pilchard, 

sardine, salmon, trout) or to receive no such advice. Study participants were supplied with 

MaxEPA® fish oil capsules if they did not like the taste of fish.100 Fish intake and mood 

(depression, anxiety) were assessed at baseline and at 6 months, the latter using the validated 

Derogatis Stress Profile (DSP). 

In a recently published observational study, Hakkarainen et al. investigated the relationship 

between the dietary intake of omega-3 fatty acids and low mood, major depression, and suicide

in males 50 to 69 years of age living in southwestern Finland in 1985 (Summary Table 4).111 

The study identified a cohort (n=29,133) from a primary prevention RCT (ATBC Cancer 

Prevention Study). Followup lasted 9 years. The intake of fatty acids and fish consumption 

were derived from a validated food use questionnaire focused on the “last 12 months.” Selfreported depressed mood, suicides and hospital-based treatments for major depressive disorder 

were evaluated. 
55 

Summary Table 4: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

depression (observational studies) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Hakkarainen, 

2004, Finland: 

9 y single 

prospective 

cohort from 

RCT111

males 50-69 y 

(n=29,133) from RCT’s 

intervention & placebo 

grps 

NS (adjusted) 

association of fish or n-3 intake 

(from fish, vegetables, or total) 

&: self-reported depressed 

mood or hospital treatment 

required due to major 

depressive disorder 

Total 

quality: 5 

[Grade: B] 

III 

Tanskanen, 

2001, Finland: 

single 

population 

cross-sectional 

survey81

 adult males & females 

(n=3,204) 

Mild-severe symptoms more 

prevalent in infrequent female 

consumers than frequent fish 

eaters;++ NS similar trend for 

males; infrequent consumption 

independently associated with 

symptoms (multiple 

regression);++ likelihood of mildsevere symptoms 31% higher in 

infrequent consumers than 

frequent ones;++ symptoms 

significantly associated with 

infrequent consumption for 

females only++

Total 

quality: 3 

[Grade: C] 

III 

Tanskanen, 

2001, Finland: 

single 

population 

cross-sectional 

survey 80

adult males & females 

(n=1,767) 

Adjusted depression & suicidal 

ideation risks Ð in frequent fish 

consumers+ 

Total 

quality: 4 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 

95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Tanskanen and colleagues undertook two non-overlapping cross-sectional surveys in 

Finland.80,81 Both were published in 2001. In a random sample of 3,204 Finnish adults (25-64 

years), depressive symptomatology was measured using the BDI.81 A single food-frequency 

question assessed fish consumption (fish type unspecified) regarding the previous 6 months. For 

this study, the sample was drawn from two coastal and two lakeside areas in 1992 (n=8,000). 

After health questionnaires were returned, and medical examinations completed, a random 

sample of participants was selected based on birthdays between the twelfth and the last day of 

each month (n=5,105). Following other clinical measurements, this group was given a 

questionnaire, which included psychosocial variables. The response rate was 67% (n=3,403), 

while another 199 individuals did not provide complete data sets. In all, 3,204 subjects became 

the study sample. 

In Tanskanen et al.’s other study a sample was selected, in 1999, based on a random 

population sample (National Population Register) of both sexes (n=3,004; 25-64 years).80 The 

number of respondents was 1,767 (59%), and they resided in Kuopio in the central-eastern part 
56 

of Finland (lakeside area). Data were gathered on fish consumption, depression (BDI) and 

suicidality. The latter was measured using a single BDI item. 

Three additional studies involved more specific definitions of population in evaluating the 

possible relationship between omega-3 fatty acid intake and the risk of geriatric depression 

(Summary Table 5). In 1991-1992, Woo et al. conducted a single cohort, 3-year prospective 

study examining the possible relationship of physical activity, dietary habits (e.g., fish 

consumption), smoking and alcohol consumption with three-year mortality as well as other 

health outcomes.110 Participants included 2,032 elderly Chinese subjects (mean age: 80 years) 

recruited by stratified (by age: e.g., 80-84 vs 85-89 vs >90 years) proportional random sampling. 

Summary Table 5: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

depression (observational studies) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Woo, 2002, 

China: 

36 mo single 

prospective 

cohort study110

elderly adults (n=2,032) NS association bet depressive 

symptoms & fish consumption 

Total quality: 

4 [Grade: B] 

III 

Suzuki, 2004, 

Japan: 

single 

population 

cross-sectional 

survey107

newly diagnosed primary 

lung cancer patients 

(n=902) 

Adjusted difference for 

depression bet upper & lower 

quartiles of ALA & total n-3 

intake, indicating inverse 

associations;+ NS adjusted 

difference for depression bet 

upper & lower quartiles of EPA, 

DHA & EPA+DHA intake; NS 

adjusted association bet 

depression & fish/seafood intake 

Total quality: 

7 [Grade: A] 

III 

Edwards, 1998, 

England: 

multiple-group 

cross-sectional 

study48

depressed 

patients 

(n=10) 

matched 

healthy 

controls 

(n=14) 

NS between-grp differences for 

n-3 or total energy intake; for 

depressed pts, negative 

correlations bet depressive 

symptoms & dietary intake of 

total n-3+++ and ALA;++ &, data 

from all pts revealed no dietary 

n-3 or n-6 variables predicted 

severity of depressive 

symptoms 

Total quality: 

6 [Grade: B] 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between;

grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

In a cross-sectional study examining the possible association of omega-3 fatty acid intake 

and the prevalence of depression in 902 Japanese individuals newly diagnosed with primary lung 

cancer, Suzuki et al. employed a food frequency questionnaire and the depression subscale from 

the validated Hospital Anxiety and Depression Scale (HADS).107 Data from 771 patients were 
57 

analyzed after excluding those failing to complete the HADS (n=73) or the food frequency 

questionnaire (n=62), or those having incorrectly completed the latter (n=24). 

Edwards et al. measured the dietary PUFA intake as well as the fatty acid content of RBCs in 

a cross-sectional study of ten depressed patients and fourteen matched healthy control subjects.48 

Biomarker results are described in a later section although the key study parameters are 

presented in relation to the current research question concerning the possible association of 

omega-3 fatty acid intake and depression. Analyses controlled for stress and smoking status. 

Cross-national, ecological analyses can highlight evidence concerning the possible 

relationship between intake of omega-3 fatty acids and risk of depression in spite of certain 

inherent limitations of these data (see Discussion). Hibbeln 47 utilized cross-national 

epidemiology data from eight (of the ten) countries in Weissman et al.’s study regarding major 

depression (and bipolar disorder),46 to which they added prevalence data from Japan (Summary 

Table 6).47 Weissman et al.’s study had evaluated 35,000 participants using a random 

prospective design, repeat sampling techniques, multiple community sampling, and a structured 

interview process with accepted diagnostic criteria.46 Apparent fish consumption was estimated; 

it is an economic measure of disappearance of seafood from the economy.108

Summary Table 6: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

depression (cross-national ecological analyses) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations 

Internal 

validity Applicability 

Hibbeln, 1998, 

9 countries: 

cross-national 

ecological 

analysis47

n=9 countries Negative correlation of apparent fish 

consumption & annual prevalence of 

major depression both with++ & without 

data from Japan+ 

Total 

quality: 

2 

[Grade: 

C] 

III 

Hibbeln, 2002, 

23 countries: 

cross-national 

ecological 

analysis108

 DHA, EPA, AA content 

(n=16 countries; 

n=14,532 pts); 

Seafood consumption 

(n=22 countries) 

Via simple regression & logarithmic 

model, Ï national seafood 

consumption predicted Ð prevalence 

rates of postpartum depression;++++ Ï

DHA in mother’s milk predicted Ð

prevalence rates++++ 

Total 

quality: 

7 

[Grade: 

A] 

III 

Peet, 2004, 

8 countries: 

cross-national 

ecological 

analysis109

n=8 countries Association bet high consumption of 

fish/seafood & a reduced prevalence 

of depression++ 

Total 

quality: 

3 

[Grade: 

C] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = omega-6 

FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study participants; 

NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group; 

wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

In a second ecological analysis, Hibbeln assessed the interrelationships among seafood 

consumption, the DHA content of mothers’ milk, and prevalence rates of postpartum depression 

(n=14,532 subjects in 41 studies).108 To maximize comparability the investigator identified only 

published prevalence data for postpartum depression that had used the EPDS, and correlated 
58 

these data with those indicating the EPA, DHA and AA content in mother’s milk as well as 

published seafood consumption rates from 23 countries. 

Peet’s cross-national ecological analysis focused on international variations in the prevalence 

of depression and the outcome of schizophrenia, and their possible prediction by patterns of 

omega-3 fatty acid intake.109 Data on food use were taken from the FAOSTAT database, and 

reflected apparent national food consumption.163 Data on depression prevalence were again 

borrowed from Weissman et al.46 and the same Japanese source used by Hibbeln.47 Two-year 

outcome data relating to schizophrenia were drawn from the WHO’s International Pilot Study of 

Schizophrenia (IPSS).164 A second source of schizophrenia outcome data was the Determinants 

of Outcome of Severe Mental Disorders (DOSMED) study.165 Schizophrenia results are 

presented later in this report. 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. One RCT employed a parallel design with two study arms,98 a 

second included three study groups,99 and the data from the third study came from one factor of a 

factorial RCT design (Summary Table 3; Evidence Table 1: Appendix E*).100 In one study, the 

focus was on the possible utility of omega-3 fatty acids to affect the likelihood or intensity of 

mood changes in a population at risk for postpartum depression.98 In the other two studies, the 

intervention given for a medical disorder conveniently allowed the investigators to examine the 

possible relationship between omega-3 fatty acid intake and mood.99,100 These two studies’ 

inclusion and exclusion criteria therefore pertained to the primary reasons these narrowly defined 

populations were studied in the first place: adults with elevated serum cholesterol levels, and for 

whom one of their cholesterol-lowering treatments was thought to have the potential to influence 

mood;99 and, males with angina, whose “fish advice” intervention was also thought to have the 

potential to affect mood.100 

The populations from the latter two studies did not include individuals with formal diagnoses 

of depression.99,100 Given the heterogeneous nature of the populations, it made little sense to 

synthesize many of the study characteristics (e.g., mean sample size). The interventions lasted 

an average of 18.4 (range: 12-26) weeks. Two of the studies were conducted in the UK99,100 and 

a third in the US.98 Llorente et al.’s study was supported by industry (Martek Biosciences 

Corporation),98 Ness et al.’s by the UK Medical Research Council,100 and Wardle et al.’s by 

government as well (Biotechnology and Biosciences Research Council).99

Three of the included observational studies were conducted in Finland.80,81,111 

Inclusion/exclusion criteria were published elsewhere for Hakkarainen et al.’s study,111 while 

eligibility criteria were delineated in each of Tanskanen et al.’s reports.80,81 None of the study 

reports made reference to a funding source. 

Woo et al.’s single prospective cohort was well-defined.110 Clearly delineated eligibility 

criteria regarding the cancer diagnosis were included in Suzuki et al.’s report.107 Their survey 

was filled out both prior to and during hospital admission. Edwards et al. reported well-defined 

exclusion criteria.48 Neither Woo et al.110 nor Edwards et al.48 identified their funding source(s). 

Funding for Suzuki et al.’s study was received as a Grant-in-Aid for Cancer Research and 

Second-Term Comprehensive Ten-Year Strategy for Cancer Control and Research of the 

Japanese Ministry of Health, Labour, and Welfare.107

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
59 

Eligibility criteria were sparse in Hibbeln’s first report of a cross-national ecological 

analysis47 and were explicitly stated in their second one.108 Peet’s descriptions of eligibility 

criteria were clear.109 Neither Hibbeln47 nor Peet109 reported their funding source. Hibbeln’s 

second study was funded in part by a Young Investigators Grant from the National Association 

for Research on Schizophrenia and Depression (NARSAD).108

Population characteristics. Given the heterogeneous nature of the included studies’ 

populations, again it made little sense to synthesize some of the population characteristics from 

the three RCTs (e.g., mean age, mean percent males). Racial/ethnic backgrounds included a 

potentially diverse UK sample,99 a predominantly Caucasian (82%) US population,98 and a likely 

Caucasian/European one.100 

In Llorente et al.’s trial, women intending to breast-feed were excluded if they exhibited a 

chronic medical condition, were current smokers, or had been pregnant more than five times.98 

No significant differences were observed for baseline BDI scores for depression. As well, there 

were no mean differences between study groups for mother’s age, education, racial/ethnic 

distibution, and several pregnancy/delivery/infant-related factors (i.e., parity, gravidity, delivery 

weight, prepregnancy weight, gestational ages of infants, infants’ birth weight, sex distibutuion 

of births, Apgar scores at 1 or 5 minutes). 

In Wardle et al.’s study, adults with elevated serum cholesterol levels (>5.2 mM [198 

mg/dL]) were excluded from the RCT if they were pregnant, lactating or planning pregnancy.99 

There were no significant differences among the study groups for any of the baseline mental 

health (i.e., BDI; depression, anxiety or anger scores on POMS; general psychological wellbeing; stress; state anger and anger reactions scores on STAI), background diet (i.e., g/d or 

percent of energy saturated fat; g/d fiber), or other characteristics (i.e., age, marital status, sex, 

BMI, total, HDL, LDL cholesterol and triglyceride parameters). Seven-day diary data showed 

that reported energy intakes were reasonable for adults this age. 

No statistical differences were observed with respect to the following baseline characteristics 

in Ness et al.’s RCT of adult males with angina: depression score, anxiety score, 

eicosapentaenoic acid (mg/d: measurment undefined), social class, past history of cardiovascular 

disease, smoking, fish intake, and fruit and vegetable intake.100 Data regarding the baseline 

between-group comparability, or on-study change, with respect to other factors with the potential 

to influence mental health were not reported for the three studies (e.g., stressors, social 

support).98-100 Likewise, data regarding the baseline comparability, or on-study change, with 

respect to key dietary characteristics (e.g., omega-3 or omega-6/omega-3 fatty acid content of the 

baseline or on-study diets) were not provided by study authors. For example, whether study 

groups’ caloric/energy intake was equivalent in any of the studies could not be determined from 

reports. 

The focus in Hakkarainen et al.’s observational study was on the mood experienced in the 4 

months prior to their previous study visit.111 Mood difficulties ranged from 5 to 8 years in 

duration (median=6). Alcohol consumption was also assessed via validated food-use 

questionnaire. Various covariates were entered into data analysis (see below). In each of 

Tanskanen et al.’s observational studies, the nature of the sampling meant that individuals varied 

in terms of their levels of depressive symptom, or even their thoughts of harming themselves.80,81 

Woo et al.’s population were elderly Chinese potentially experiencing depressive 

symptomatology110 while Suzuki et al.’s population of newly diagnosed primary lung cancer 

patients included 436 (of 771: 56.5%) with analyzable data, and who were exhibiting depressive 

symptomatology.107 Edwards et al. identified ten individuals with a major depressive episode 
60 

using DSM-IV criteria. Each was receiving antidepressant medication. Exclusion citeria 

included physical illness of a severity or nature suggestive of low omega-3 fatty acid levels. The 

14 healthy controls showed no history of psychiatric disorder although how this was determined 

was not reported. Matching was based on age, sex, social class, BMI, number of children, recent 

life events, smoking habits, and alcohol consumption. An assessment of these data revealed the 

soundness of the matching strategy. All study participants were evaluated using the BDI. 

Hibbeln’s cross-national ecological analysis47 identified its populations by using Weissman 

et al.’s cross-national prevalence study, which included a structured clinical interview 

employing accepted diagnostic criteria (DSM-III).46 The core symptoms of major depression, 

and not merely symptom severity as reflected in rating scale scores, were identified. Hibbeln 

drew data on the annual prevalence of major depression in Japan from the Ministry of Welfare 

(n=130,000). However, one limitation of these Japanese data is that they were not produced 

using a structured diagnostic instrument or random population sampling techniques. 

In his second analysis Hibbeln’s populations were drawn from countries varying in terms of 

their background diet.108 A high score indicated severe depressive symptomatology rather than a 

major depression. Prevalence data were derived from well-defined populations. Peet’s crossnational ecological analysis109 included data on depression prevalence once again borrowed from 

Weissman et al.46 and the same Japanese source used in Hibbeln’s first analysis.47 Two-year 

data concerning the outcome of schizophrenia were drawn from the WHO’s International Pilot 

Study of Schizophrenia (IPSS). A second source was the Determinants of Outcome of Severe 

Mental Disorders (DOSMED) study. 

Intervention/exposure characteristics. Given the great divergence of interventions or 

exposures, it likely makes little sense to synthesize many of the intervention/exposure 

characteristics (e.g., mean dose or serving size; number of studies utilizing a “high” dose or 

serving size). Two of the RCTs encouraged specific dietary patterns99,100 while the third 

provided supplementation capsules.98 Regarding the latter investigation, Llorente et al. provided 

~200mg/d DHA from algae-derived triglyceride capsules yet did not describe the number of 

capsules constituting a “dose” or what the placebo capsules contained.98 Wardle et al.’s RCT 

allocated adults with elevated serum cholesterol levels either to a low-fat diet (i.e., reduce energy 

from [saturated] fats to <20%, and ingest mostly polyunsaturates), a Mediterranean diet (i.e., 

increase intake of fruits and vegetables, oily fish; reduce fat to 30% of calories; use 

monounsaturated fats instead of saturated fats) or a waiting-list control (i.e., no advice given yet 

not discouraged from making dietary changes). This entailed educating participants about 

recommended dietary changes and included a cognitive-behavioral intervention focused on 

implementing changes in eating behavior. Participants were also given spreadable fat and oils 

consistent with their assigned diet. Finally, Ness et al. observed that, at 6 months, of the men 

allocated to fish advice, 78% were consuming fish weekly or taking fish oil capsules (21%), as 

compared to 14% of those who did not receive fish advice. These details, in addition to the 

observation that compliance data were not always available, raise some doubt that participants in 

the different study groups in each RCT actually received a constant difference in their amount of 

omega-3 fatty acid intake, or an equivalent intake of calories/energy over the intervention period, 

sufficient to control for possible confounding stemming from such protocol violations. 

None of the studies specifically identified the omega-6/omega-3 fatty acid content of their 

planned on-study99,100 or background diets.98 Llorente et al. did not report an attempt to maintain 

blinding via deodorizing their omega-3 fatty acid materials and/or by preventing oxidation and 

inevitable rancidity. Neither general purity data, nor data concerning possible methylmercury 
61 

contamination, were provided regarding their DHA supplementation.98 On the other hand, 

Llorente et al. appeared to use appropriate methods to handle blood lipid materials. 

Hakkarainen et al.’s observational study assessed habitual dietary intake over the previous 

year (measure undefined).111 This included fish consumption as well as the intake of omega-3 

fatty acid content from fish and vegetables, and total omega-3 fatty acid intake. Total omega-3 

fatty acid intake was calculated as 2.2 g/d or 0.47 g/d from fish, a value that they asserted is 

considerably higher than what is observed in North American populations.111

Tanskanen et al’s single food-frequency question assessed fish consumption over the past six 

months (“How often do you usually eat fish or fish meals? 1, < once a month or never; 2, once or 

twice a month; 3, once a week; 4, twice a week; 5, almost daily; 6, once a day or more often).81 

Responses of 2 or less constituted infrequent consumption. In their second observational study 

Tanskanen et al.80 estimated fish consumption via a food-frequency questionnaire (undefined) 

purported to produce comparable results to a 7-day food record.166 A frequent fish consumer 

was defined as someone eating fish at least twice a week. 

Fish intake in Woo et al.’s study was measured via a food frequency questionnaire 

administered at the participants’ residence.110 Suzuki et al. utilized a validated semiquantitative 

food frequency questionnaire regarding 138 foods, including 18 fish and seafood items. It had in 

the past exhibited a significant association with dietary record data.107 Participants were asked to 

report the average frequency, and usual serving size, of consumption during the year 

immediately preceding the onset of cancer symptoms. From this, Suzuki et al. calculated an 

average daily intake of food and nutrients. They then calculated the daily intake of omega-3 

fatty acid content using the Fatty Acid Composition Table of Japanese Foods.167 For the 771 

participants whose data were analyzed, total omega-3 fatty acid intake was primarily ingested 

from vegetable oils and fats (37% of total intake), followed by 17 types of fish (35%), soybean 

products (11%), seasonings (5%), and cereals (4%). The daily intake consisted of 62% ALA, 

20% DHA, and 11% EPA.107 Edwards et al. completed a full analysis of the current diet using a 

7-day weighted intake method.48 Although data are reported later in this report, it should be 

stated here that no notable inappropriate methods to extract, prepare, store or analyze lipids were 

described.48 

Hibbeln’s first ecological analysis estimated apparent fish consumption as: fish catch plus 

imports, minus exports.47 This method is not as reliable as direct dietary surveys but at least this 

analysis included comparable data across countries. In his second analysis apparent fish 

consumption data were drawn by Hibbeln from the National Marine Fisheries Service and the 

Food and Agriculture Organization of the United Nations.108 Data on food use were taken from 

the FAOSTAT database,163 and captured apparent national food consumption in Peet’s 

analysis.109 Food use was estimated from the total domestic production of food plus imports, 

minus exports, while taking into account changes in stocks (e.g., stored grain), and subtracted 

food lost to waste during processing. Fish and seafood data were included, and were expressed 

as supply in kilograms per capita per year. Annual food consumption was approximated closest 

to the years in which the clinical studies were conducted (i.e., IPSS=1970; DOSMED=1980; 

depression=1990).109 

The manufacturer of Llorente et al.’s intervention was Martek Biosciences Corporation.98 

Purity data concerning its contents were not provided. No study report included details as to 

whether, or how, the presence of methylmercury was tested or eliminated from their omega-3 

fatty acid exposure. 
62 

Cointervention characteristics. In Llorente et al.’s study, breast-feeding women were 

excluded if they used dietary supplements other than vitamins.98 Wardle et al. excluded 

participants if they were currently using, or had used within the last 3 months, lipid-lowering 

medication.99 In Ness et al.’s study, male adults were receiving anti-anginal medication, details 

of which were not provided in their report.100 The possible use of other products with 

psychotropic properties was not reported for these studies. 

Of the six observational studies,48,80,81,107,110,111 only the study by Edwards et al. reported on 

the status of possible cointerventions. Each individual diagnosed as depressed was receiving 

antidepressant medication.48 Similar data were not reported in any of the cross-national 

ecological analyses.47,108,109

Outcome characteristics. Llorente et al. employed the BDI, EPDS and the SCID-CV, with 

the latter supporting DSM-IV diagnostic criteria.98 Wardle et al. used the BDI, along with the 

STAI, anxiety and anger subscales of the POMS, GHQ to assess general psychological wellbeing, and the PSS. Dietary diaries were filled out at baseline and 12 weeks. Ness et al. used the 

DSP to measure depression and anxiety. 

Hakkarainen et al.’s study evaluated depressed mood via self-report (no measure 

identified).111 Assessments were recorded three times annually. Data on hospital-based 

treatments for major depressive disorder were drawn from the National Hospital Discharge 

Register, and suicides were identified from death certificates. Cox’s proportional hazards 

regression models estimated the relationships between baseline dietary intake of omega-3 fatty 

acids (from fish, vegetables, and total intake), calculated from the food-use questionnaire and 

categorized in tertiles (with the lowest tertile as reference category), and measures of mood level 

and hospital-based treatments for major depressive disorder. The following potential risk factors 

for major depressive disorder and suicide were entered, as covariates, into the regression models: 

age, BMI, energy intake, serum total cholesterol, HDL cholesterol level, alcohol consumption, 

education, marriage, self-reported depression, self-reported anxiety, and smoking. Dietary 

factors were adjusted for energy intake. 

The following BDI-defined distinctions were made in Tanskanen et al.’s first study: scores 

below 10 indicated no or minimal depressive symptoms; scores from 10-18 indicated mild 

symptoms; 19-29, moderate symptoms; and 30-63, severe symptoms.81 For bivariate analyses, 

the categories were normal mood, 0-9, and mild to severe symptoms, 10-63.81 Multiple logistic 

regression analysis assessed the relationship between BDI-indexed depressive symptomatology 

and fish consumption. Adjustments were made for these potential confounders: age, marital 

status, unemployment, current smoker status, irregular physical activity, female, BMI, more than 

120g per week of pure alcohol, at least seven cups per day of coffee, low education level, and 

serum cholesterol level. The other Tanskanen et al. study also employed the BDI, while 

analyzing separately data for the single item pertaining to suicide ideation.80 Analyses adjusted 

for the following potential confounders: sex, age, marital status, education, employment status, 

work ability, area of residence, financial status, general health smoker status, alcohol intake, 

coffee intake, and physical activity. 

Woo et al. utilized the GDS while adusting for age and baseline health status at the start of 

their 3-year study.110 From previous validational work it was reported that a score of at least 8 

on the 15-point GDS provides a sensitivity and a specificity of 96.3% and 87.5%, respectively, 

for a psychiatric diagnosis of depression in the local Chinese population. The HADS depression 

subscale was employed by Suzuki et al.107 A cutpoint of 4 out of 5 has previously been observed 

to reflect good sensitivity and specificity (91.5% and 58%, respectively) for screening depression 
63 

(e.g., major depression). Analyses adjusted for age, sex, performance status, clinical stage, 

histology, pain, breathlessness, employment status, smoker status, alcohol consumption, and 

BMI. Edwards et al.’s analyses controlled for stress and smoking status.48

Given the limitation of the Japanese data, in that they were not produced using a structured 

diagnostic instrument or via random population sampling techniques, data analysis in Hibbeln’s 

first cross-national assessment was completed both including and excluding data from Japan.47 

Since adverse personal, social and economic conditions can increase the risk of depressive 

symptomatology in the postpartum period, the following variables were controlled for in 

Hibbeln’s second cross-national ecological analysis: study time postpartum, low socioeconomic 

status, percentage of young mothers, percentage of mothers without partners, percentage of 

mothers with secondary education, and the influence of Asian cultures.108 Data on depression 

prevalence in Peet’s cross-national ecological analysis109 were captured from Weissman et al.46

and the same Japanese source used by Hibbeln.47 From the IPSS study, data on mean days out of 

hospital and percentage of patients with schizophrenia and severe social impairment were used 

as outcomes.109 In addition, a total outcome score was derived.145 It is a composite score taking 

into account all IPSS outcomes. From the DOSMED study, outcomes selected were percentage 

of patients never hospitalized and the percentage of patients with little social impairment. Urban 

data were used exclusively, where available. A “total best outcome” score was derived by 

adding data from various “best possible” DOSMED outcomes (e.g., remitting course with full 

remissions; on no antipsychotic medication during followup). 

Study quality and applicability. The mean total Jadad quality score was 3,98-100 with two of 

the three RCTs adequately concealing their allocation of participants to study groups.98,99 The 

third RCT received an Unclear allocation concealment rating.100 The mean quality score for the 

two single prospective cohort studies was 4.5, with both studies attaining a III applicability 

rating.110,111 All three cross-sectional surveys received an applicability rating of III, and together 

they achieved a mean quality score of 4.7.80,81,107 The single cross-sectional study received a 

quality score of 6 and an applicability rating of II.48 The three cross-national ecological analyses 

received a mean quality score of 4, with all achieving an applicability rating of III.47,108,109 Of all 

the studies, only the Edwards et al. one received an applicability rating other than III (i.e., II),48

and only three investigations achieved a study quality grade of A.98,107,108

Summary Matrix 2: Study quality and applicability of evidence regarding the association between omega-3 

fatty acid intake and onset, continuation or recurrence of depression (all designs) 

Study Quality

A B C 

Author Year n Author Year n Author Year n I 

Author Year n Author Year n Author Year n

II LlorenteA 2003 >89 Edwards 1998 24 NessU 

WardleA 2003 

2000 

452 

176 

Author Year n Author Year n Author Year n

Applicability 

III Suzuki 

Hibbeln 

2004 

2002 

902 

16C 

Hakkarainen 

Tanskanen 

Woo 

2004 

2001 

2002 

>29k 

>1k 

>2k 

Tanskanen 

Hibbeln 

Peet 

2001 

1998 

2004 

>3k 

9C 

8C 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment; C =Countries; k = 1,000’s 
64 

Qualitative Synthesis of Individual Study Results 

Llorente et al. reported data only for completers for whom they had baseline and 4-month 

data.98 After 4 months of supplementation, plasma phospholipid DHA content in the DHA group 

had increased by 8% while the DHA content in the placebo group had decreased by 31%, the 

former observation indicating a reversal in the typical decline in DHA levels. The DHA content 

of the DHA group was 50% higher than that of the placebo group 4 months post-delivery. 

However, there were nonsignificant statistical differences between study groups after 4 months 

for the BDI, EPDS and the SCID-CV (diagnostic counts). Yet, according to BDI scores, only 

nine women in the placebo group and 11 women in the DHA group achieved a score of at least 

10 at one of their followups, indicating minimal symptoms of depression (>9 may indicate mild 

symptoms). Two and four women in the placebo and DHA groups, respectively, had a BDI 

score of at least 20, indicating moderate symptoms. SCID-CV observations confirmed these 

results. Only seven women (DHA group=4; placebo group=3) met DSM-IV diagnostic criteria 

for a “current depressive episode” during the 4-month postpartum period. 

All three of Wardle et al.’s study groups showed significant within-group improvement on 

many of the mental health outcomes after 12 weeks (i.e., BDI score and anger reactions in both 

diet groups; stress and anxiety only in Mediterranean diet group).99 Yet, there were no 

significant between-group differences observed for any of the following clinical outcomes: 

depression, anxiety, anger/hostility, stress, and general psychological well-being. Thus, no 

reliable associations between intake of omega-3 fatty acids and any of the examined indices of 

mental health were observed. 

Ness et al. observed that self-reported fish intake was higher in the fish advice group at 

study’s end.100 No statistical difference was observed in the fish advice group either for 

depression or anxiety; and, controlling for baseline mood, the between-group difference for each 

outcome was not statistically different. This last observation did not change following an 

additional adjustment made for one’s status as having been randomized to the stress management 

arm, nor was there any statistical evidence of interaction between these factors in their effects on 

mood. Looking exclusively at the upper quartile of baseline depression or anxiety score did not 

contradict these observations. 

In Llorente et al.’s study no subject withdrew due to adverse effects related to the 

supplement.98 However, 37 of 138 women either withdrew or were dropped. Thirteen withdrew 

because of maternal illness, 14 were dropped due to lactation failure or excessive formula intake 

by the child (>20% of total intake), one mother moved away, five were dropped due to infant 

illness, and four discontinued participation. Wardle et al. reported that similar numbers of 

patient withdrew before 12 weeks in each study group (low-fat=7; Mediterranean=8; control=6), 

and typically due to attendance problems.99 Seven men died within 7 months of randomization 

into Ness et al.’s trial (fish advice group=3), and for reasons other than the intervention.100

Hakkarainen et al.’s attempt, in their observational study, to assess the possible relationship 

between low dietary intake of omega-3 fatty acids and depression revealed that, accounting for 

the above-noted covariates, there was no significant association of fish consumption or 

calculated intake of omega-3 fatty acids and self-reported depressed mood, hospital treatment 

required due to major depressive disorder, or suicide (data not reported).111 

Tanskanen et al. showed that, using BDI scores, 20% of their sample experienced mild 

depressive symptoms (n=647), 6.3% had moderate symptoms (n=201), and 1.5% reported severe 

symptoms (n=48).81 Sixty-four percent reported eating fish or fish meals once or twice a week 
65 

(n=2,053), 6.3% ate fish daily (n=201), and 30% ate fish once or twice a month, or less often 

(n=950). From bivariate analysis, mild to severe depressive symptoms were more prevalent 

among women who infrequently consumed fish (less than once a week) than those who were 

frequent fish eaters (more than once per week). A similar trend was observed among men, yet 

the results were not statistically significant. Compared with frequent fish consumers (bivariate 

analysis), infrequent consumers were younger, less physically active, less obese, less likely to 

have a lower serum cholesterol level, unmarried, smoked, and drank a lot of coffee. Yet, higher 

age, being unmarried, unemployment, smoking, lower levels of physical activity, greater degree 

of obesity, low level of education, and higher serum cholesterol level were associated with 

depressive symptoms. Multiple logistic regression analysis, including confounders, revealed that 

infrequent fish consumption was independently associated with depressive symptoms. The 

likelihood of exhibiting mild to severe depressive symptoms was 31% higher among infrequent 

fish consumers than frequent consumers. Depressive symptoms were significantly associated 

with infrequent fish consumption for females only. 

In their second cross-sectional study Tanskanen et al. observed that the risk of being 

depressed and the risk of suicidal ideation were significantly lower among those who frequently 

ate lake fish, compared with infrequent fish consumers.80 These relationships held after 

adjusting for the above-noted factors. 

Woo et al. found nonsignificant adjusted and unadjusted estimates of association involving 

fish intake and depressive symptoms in a Chinese elderly population although data were not 

reported per se.110 They also observed that increasing levels of physical activity and occasional 

intake of alcohol were associated with a reduced risk of depressive symptoms. After 36 months, 

341 participants (17%) had been lost to followup and 519 had died. 

For newly diagnosed lung cancer patients Suzuki et al. reported a statistically significant 

adjusted odds ratio for depression between upper and lower quartiles of ALA and total omega-3 

fatty acid intake, indicating a significant inverse association.107 They also found a statistically 

nonsignificant adjusted difference for depression between upper and lower quartiles of intake of 

EPA, DHA and EPA+DHA.107 Results of tests for trend paralleled these findings. But, no 

association was observed for depression and intake of fish or seafood, also following adjustments 

for potential confounders. 

There were no significant between-group differences for current intake of omega-3 fatty 

acids or total energy intake assessed by 7-day dietary intake in Edwards et al.’s study.48 Within 

the depressed patient group there was a significant negative correlation between the BDI-defined 

severity of depressive symptomatology and dietary intake of total omega-3 fatty acids as well as 

ALA. When data were pooled from patients and controls and entered into multiple regression, 

none of the dietary omega-3 or omega-6 fatty acid variables were significant predictors of 

depression. Data pertaining to smoker status and stress were entered only into analyses 

involving biomarker data. 

In their first cross-national ecological analysis Hibbeln found a significant, inverse 

correlation between apparent fish consumption (fish pounds per person; 1 pound = 0.4536 kg) 

and major depression.47 When data were excluded from Japan for the above-noted reason, a 

significant correlation was maintained. Data regarding potential confounders were not 

consistently available for each of the countries in Hibbeln’s second cross-national ecological 

analysis.108. Nevertheless, simple regression and a logarithmic equation revealed that higher 

national seafood consumption predicted lower prevalence rates of postpartum depression, that 

higher DHA content in mother’s milk predicted lower prevalence rates, and that the AA and EPA 
66 

content of mother’s milk were unrelated to prevalence rates of postpartum depression. Only low 

socioeconomic status, young maternal age, the percentage of women without partners, and 

percentage of mothers with a secondary education predicted prevalence rates. These 

relationships appeared to be influenced by data from Brazil and South Africa, suggesting that 

these results may have confounded the findings in the primary analyses. However, first 

excluding Asian countries’ data because of their stronger intake of omega-3 fatty acids in the 

background diet, and then data from Brazil or South Africa, yielded findings paralleling those 

from the primary analyses. This indicated the robustness of the main findings. 

Peet’s schizophrenia results are presented below.109 He observed a significant association 

between high consumption of fish and seafood and a reduced prevalence of depression.109 

Quantitative Synthesis 

Very few of the studies that met the eligibility criteria for this question actually demonstrated 

the inherent capacity to afford the drawing of causal inferences regarding the possible 

relationship between the intake of omega-3 fatty acids and the onset of depression as disorder or 

symptom. Only three of 12 studies were eligible for quantitative synthesis in that they were both 

controlled and prospective by design.98-100 The observation that these three RCTs employed 

highly different target populations, interventions, controls and outcomes made it inappropriate to 

consider conducting meta-analysis. Moreover, only one trial investigated the potential of 

specific amounts of omega-3 fatty acid content, via DHA supplementation, to protect its 

population (i.e., breastfeeding women) from developing (postpartum) depression.98 

Impact of Covariates and Confounders 

With such diverse designs, populations, exposures, controls and outcomes it is difficult to 

cull patterns of notable finding regarding the influence of extra-exposure variables on outcomes 

pertinent to this review. The designs with the greatest inherent potential to control for 

confounding influences (i.e., RCTs)98-100 did not yield a single significant result, although the 

primary goal in two of them did not entail demonstrating the potential of omega-3 fatty acids as 

protection against depression.99,100 At the same time, the three RCTs likely confirmed, in part, 

the success of their randomizations by showing that study groups were equivalent at baseline on 

certain important bases (e.g., mental health variables). 

Likewise, the multiple-group cross-sectional study did not reveal a significant association 

between omega-3 fatty acid intake and depression while also reporting that study groups were 

equivalent in their intake of omega-3 fatty acids, for example.48 And, while most of the 

uncontrolled observational studies did a reasonable job of adjusting for confounders in their 

analyses (e.g., age, smoker status, alcohol consumption),80,81,107,111 their results did not 

consistently show a significant association between the intake of omega-3 fatty acids and the risk 

of depression. Even the two surveys conducted in Finland, where fish intake is considerably 

higher than in North America, for example, failed to produce a consistent result for both 

sexes.80,81 

The ability to control for confounders in the three cross-national ecological analyses 

depended on the initial data collection strategies, which produced the databases from which the 

three studies’ data were obtained. Without all of the details, many of which were not published 
67 

in the included reports, it is difficult to draw conclusions about these three analyses’ successes or 

failures in controlling for key influences on outcomes. 

Is the Onset, Continuation or Recurrence of Depression 

Associated With Omega-3 or Omega-6/Omega-3 Fatty Acid 

Content of Biomarkers? 

As observed in Summary Tables 7 through 11 (below), derived from Evidence Tables 1 and 

2 (Appendix E*

), one RCT and various observational studies met eligibility criteria for this 

question. Studies were published between 1977 and 2003. 

Overview of Relevant Studies 

Seven multiple-group cross-sectional studies48,101-106 and one RCT98 provided data pertaining 

to this question. Two studies have already had their key study parameters introduced with 

respect to the question of the possible association of omega-3 fatty acid intake and the onset, 

continuation or recurrence of depression. Yet, the Llorente et al. RCT98 and Edwards et al.’s 

multiple-group cross-sectional study48 data were nevertheless placed in summary tables. 

Ellis and Sanders assessed the fatty acid content of plasma choline phosphoglycerides (CPG) 

and RBC ethanolamine phosphoglycerides (EPG) in patients diagnosed with endogenous 

depression (n=6), patients on the same ward yet with non-depressive psychiatric disorders (n=4; 

types undefined), and age- and sex-matched controls drawn from hospital staff (n=6) (Summary 

Table 7).105 Fehily et al. compared the fatty acid content of plasma CPG and RBC phospholipids 

in patients with: endogenous depression (n=26; mean age: 52 [21-74] years; 7 bipolar and 16 

unipolar diagnoses; 54% drug-free for at least 2 weeks before study), those with reactive 

depression (n=23; mean age: 38 [22-65] years; 65% drug-free for at least 2 weeks), other 

psychiatric disorders (n=11; mean age=35 [19-59] years; 6 schizophrenia and 5 personality 

disorder diagnoses; 46% drug-free for at least 2 weeks) and age- and sex-matched healthy 

controls (n=undefined; age undefined).106

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
68 

Summary Table 7: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of depression 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Ellis, 1977, 

England: 

multiple-group 

cross-sectional 

study105

endogenous 

depression 

(n=6) 

nondepressive 

psychiatric 

disorders 

(n=4)/ 

age- & sexmatched 

healthy 

controls 

(n=6) 

Proportions of plasma CPG 

EPA++ & DHA++ Ï in 

endogenous depression grp vs 

matched controls; NS bet-grp 

difference for AA; results less 

pronounced for RBC EPG data; 

NS bet non-depressed pts & 

healthy controls 

Total 

quality: 2 

[Grade: C] 

II 

Fehily, 1981, 

England: 

multiple-group 

cross-sectional 

study106

endogenous 

depression 

(n=26)/ 

age- & sexmatched 

controls 

(n=NR ) 

reactive 

depression 

(n=23)/ 

other 

psychiatric 

disorders 

(n=11) 

Concentrations of DHA+++ & 

EPA+

 in plasma CPG Ï, but LA 

Ð,

+++ in endogenous 

depression grp than controls; 

NS bet-grp difference for AA; 

NS plasma CPG in reactive 

depression or other disorders 

vs controls; DHA 

concentrations correlated with 

BDI severity in endogenously 

depressed,++ but not with 

reactive depression; smaller 

bet-grp differences for RBCs in 

endogenous depression vs 

controls (i.e., Ï DHA in EPGs;+ 

Ï EPA in serine 

phosphoglycerides+

)

Total 

quality: 3 

[Grade: C] 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; BDI = Beck Depression 

Inventory; RBC = red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine 

phosphoglycerides; Jadad total = Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts 

(/5); Schulz = reporting of adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 

95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Maes et al. examined the fatty acid composition of serum cholesterol esters and 

phospholipids in 36 patients with major depressive disorder (with [n=11] or without melancholia 

[n=25]), 14 with minor depression (i.e., adjustment disorder with depressed mood and 

dysthymia) and 24 healthy volunteer subjects (staff or their family members) (Summary Table 

8).103 
69 

Summary Table 8: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of depression 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Maes, 1996, 

Belgium: 

multiple-group 

cross-sectional 

study103

inpatients 

with major 

depression 

(with [n=11] 

or without 

melancholia 

[n=25]) 

(n=36) 

minor 

depression 

(i.e., 

adjustment 

disorder 

with 

depressed 

mood & 

dysthymia) 

(n=14)/ 

healthy 

volunteers 

(staff or 

their family 

members) 

(n=24) 

Age & sex as covariates, major 

depressed pts Ï AA/EPA in 

serum cholesteryl esters+

 & 

PLs++ & Ï total n-6/n-3 in 

cholesteryl ester fractions;++

NS in total n-3, total n-6, or n6/n-3, in PLs; correlations of 

HDRS & AA/EPA+

 or total n6/n-3+

 in PLs; major 

depressed pts Ð ALA in 

cholesteryl esters++ than 

controls; major depressed pts 

had Ð total n-3 in cholesteryl 

esters++ & Ð EPA in serum 

cholesteryl esters++++ & PLs; 

ALA, EPA & DHA cholesteryl 

ester fractions discriminated 3 

grps.++++ ALA, EPA & DHA 

cholesteryl ester fractions as 

dependent variables showed 

differences for 3 grps;++++ 

negative relationship bet EPA 

in cholesteryl esters & HDRS+

Total 

quality: 6 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; HDRS = Hamilton Depression 

Rating Scale; RBC = red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine 

phosphoglycerides; Jadad total = Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts 

(/5); Schulz = reporting of adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 

95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Peet et al. investigated fatty acid composition in the RBC membranes of 15 drug-free patients 

with major depressive disorder, unipolar variety, and 15 age- and sex-matched healthy controls 

(Summary Table 9).102 All medication was stopped for 8 to 91 days prior to blood sampling. 
70 

Summary Table 9: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of depression 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Peet, 1998, 

England: 

multiple-group 

cross-sectional 

study102

major 

depressive 

disorder 

(n=15) 

healthy 

controls 

(n=15) 

Ð RBC total n-3+

 & DHA+++ in 

depressive pts; Ð LA,+++

DGLA+ & total n-6;+

 NS for 

AA/EPA, AA/DHA or total n6/n-3 

Total 

quality: 4 

[Grade: B] 

II 

Edwards, 1998, 

England: 

multiple-group 

cross-sectional 

study48

depressed 

patients 

(n=10) 

matched 

healthy 

controls 

(n=14) 

RBC EPA,+

 DHA+ & total n-3+ 

Ð in depressed pts; NS for n-6; 

negative correlations for n-3 & 

BDI severity for ALA,+++ DHA++ 

& total n-3;+ only RBC ALA 

predicted BDI severity;++ when 

dietary & RBC data entered, 

only DHA++++ & LA+ predicted 

BDI severity

Total 

quality: 6 

[Grade: B] 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; HDRS = Hamilton Depression 

Rating Scale; BDI = Beck Depression Inventory; RBC = red blood cells; PL = phospholipid; Jadad total = Jadad total 

quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Edwards et al. measured the dietary PUFA intake as well as the fatty acid content of RBCs in 

a cross-sectional study of ten depressed patients diagnosed with major depression using DSM-IV 

criteria, and 14 matched healthy control subjects.48 Each depressed patient was receiving 

antidepressant medication. Analyses controlled for stress and smoking status. Additional details 

regarding exclusion criteria or matching requirements were presented in relation to the question 

concerning the possible association between omega-3 fatty acid intake and the onset, 

continuation or recurrence of depression. 

Maes et al.’s second study investigated 34 major depressed inpatients and 14 healthy 

volunteers in an attempt to establish whether major depression was associated with a decrease in 

omega-3 fatty acids or an increase in omega-6 fatty acids in serum phospholipids and cholesteryl 

esters (Summary Table 10).101 They also assessed the relationship between these PUFAs and 

levels of serum zinc (with a low level being a marker of the inflammatory response system’s 

activation), as well as the effects of 5 weeks of subchronic treatment with antidepressants (i.e., 

fluoxetine 20 mg/d alone or with trazodone 100 mg/d or pindolol 7.5 mg/d) on fatty acid levels 

in 20 patients. Patients underwent a 10-day drug-free period upon hospital admission. 
71 

Summary Table 10: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of depression 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Maes, 1999, 

Belgium: 

multiple-group 

cross-sectional 

study101

major 

depressed 

inpatients 

(n=34) 

healthy 

volunteers 

(n=14) 

Serum PLs= major depression 

had Ð EPA,+ Ï AA/EPA ratio 

fractions; Ð LA,++ Ð AA,+++ Ð

total n-6,+++ Ð ALA,+ Ð EPA,+

Ð DHA,+ & Ð total n-3++

concentrations; Serum 

cholesteryl esters= major 

depression Ð ALA,+++ EPA,++ 

total n-3,++ Ï total n-6/n-3,++ & 

Ï AA/EPA++ fractions; Ð LA,++

Ð total n-6,++ Ð ALA,+++ Ð

EPA,++ & Ð total n-3++

concentrations; NS 

correlations bet HDRS & FAs 

Total 

quality: 6 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; RBC = red blood cells; PL = 

phospholipid; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower 

Tiemeier and colleagues investigated whether community-dwelling elderly with depression 

have a fatty acid composition different from those who are not depressed (Summary Table 

11).104 As part of the Rotterdam population-based cohort study (n=7,983), 3,884 adults of at 

least 60 years of age were screened for depressive symptoms. Those that screened positive had a 

psychiatric interview to diagnose depressive disorders. After excluding individuals with other 

disorders (n=29), and following the loss of 14 subjects, study groups became: those with 

depressive disorder (n=106; 61-97 years), those with subclinical depressive symptoms (n=115; 

61-93 years) and randomly selected controls who had screened negative for depression in the 

Rotterdam study (n=461; 61-101 years). The analysis included an assessment of the possible 

roles played by atherosclerosis and the inflammatory response, the latter measured by C-reactive 

protein. Given that certain factors such as chronic diseases, smoking and cholesterol 

concentrations have been related in community-dwelling populations to depression and fatty acid 

composition,168 they were investigated for their possible roles as confounders. Other 

confounders included: age, sex, level of education, history of stroke, cognitive function (Mini 

Mental State examination), functional status, and blood pressure. 
72 

Summary Table 11: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of depression 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Tiemeier, 2003, 

Holland: 

multiple-group 

cross-sectional 

study104

depressive 

disorders in 

elderly 

(n=106) 

subclinical 

depressive 

symptoms 

(n=115)/ 

screened 

negative for 

depression 

(n=461) 

AA+

 & DHA+ Ï & Ð in 

depressed pts; Ï in depressed 

vs controls: total n-6/n-3+

 & 

AA/DHA.+ difference in n-6/n-3 

for depressed vs controls Ï with 

Ð concentrations of C-reactive 

protein;+

 only for those below 

median, depressed pts had Ð

%’s of certain n-3’s than 

controls; depressives had Ð

EPA,+

 DHA+ & total n-3;++ 

depressives had Ï n-6/n-3,++

AA/EPA++ & AA/DHA.+

Total 

quality: 5 

[Grade: B] 

III 

Llorente, 2003, 

US: 

4 mo parallel 

RCT98

~200mg/d 

DHA 

(n=44 

completers) 

pb 

(undefined) 

(n= 45 

completers) 

NS correlations bet plasma PL 

DHA content, either at baseline 

or 4 mo, &: BDI, EPDS or SCIDCV

Jadad 

total: 5 

[Grade: A]; 

Schulz: 

Adequate 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; BDI = Beck Depression Inventory; EPDS = 

Edinburgh Postnatal Depression Scale; SCID-CV = Structured Clinical Interview, DSM-IV, Axis I Disorders, Clinical 

Version; RBC = red blood cells; PL = phospholipid; Jadad total = Jadad total quality score: reporting of randomization, 

blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation concealment (adequate, inadequate, 

unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = 

decrease(d)/reduction/lower 

Llorente et al. assessed the effect of DHA supplementation on the onset of postpartum 

depression as well as on plasma phospholipid DHA content in women who breast-feed.98 

Mothers who planned to breast-feed their children (n=138; 18-42 years) were randomly assigned, 

in double-blind fashion, to receive either ~200 mg/d DHA or placebo (undefined) for the first 4 

months after delivery. Plasma phospholipid data were collected just before delivery and at 4 

months. Additional data regarding study, population and intervention parameters are presented 

with reference to evidence concerning the possible association of omega-3 fatty acid intake and 

the onset, continuation or recurrence of depression. 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. With the exception of Llorente et al.’s RCT,98 studies were crosssectional studies involving at least two groups.48,101-106 Some study reports provided very 

detailed inclusion/exclusion criteria establishing strong experimental controls,101,103 whereas 

others provided very little information.105 Other reports provided sufficient detail to allow for an 

appreciation of the rigor associated with these studies.48,98,102,104,106 Study sizes varied between 

16105 and 682 participants.104 Countries where the studies were conducted included 

England,48,102,105,106 Belgium,101,103 Holland104 and the US.98 Fehily et al’s study was supported 
73 

by a grant from the South Thames Regional Health Authority.106 The first Maes et al. study was 

funded by numerous sources, including the National Funds for Scientific Research (Belgium), 

the IUAP program (Belgium), as well as grants from the US Preventive Health Services 

(USPHS) and the Elisabeth Severance Prentiss and John Pascal Sawyer Foundations.103 One 

author was the receipient of a USPHS Research Center Career Scientist Award. The second 

Maes and colleagues study was funded in part by the National Funds for Scientific Research 

(Belgium), the Clinical Research Center for Mental Health (Belgium), in addition to an Staglin 

Investigator Award given to the lead investigator.101 Tiemeier et al.’s work was supported by the 

Research Institute for Diseases in the Elderly, which is funded by the Ministry of Education and 

Science, and the Ministry of Health, Welfare, and Sports through the Netherlands Organization 

for Scientific Research, and a grant from Numico Research.104 Llorente et al.’s study was 

supported by industry (Martek Biosciences Corporation).98 Three groups did not report a 

funding source.48,102,105

Population characteristics. Complete population age data were not reported for both the 

full sample and/or the different study groups in some studies, this despite the avowal of the 

authors that study groups were matched by age and sex.48,102,105 In the study by Fehily et al., the 

group of subjects with endogenous depression was older than the control group.106 The pregnant 

women examined in Llorente et al.’s study were between 18 and 42 years of age; there was no 

significant difference in ages of the participants between study groups.98 In each of Maes et al.’s 

studies, neither the between-group age of participants nor the between-group female/male ratio 

were significantly different.101,103 Neither age nor sex significantly predicted any omega-3 fatty 

acid fractions or any omega-6/omega-3 ratios in these two studies.101,103 Yet, both variables were 

entered as covariates in subsequent analyses due to their possible relationship with fatty acid 

levels.101,103 Peet et al.’s study population was between 18 and 65 years of age, and the authors 

confirmed successful matching for this possible confounder.102 Tiemeier et al.’s study groups 

were age-matched, with ages ranging from 61 to 101 years of age; subjects with depressive 

disorder were more likely to be female.104 Six of the study populations were not described in 

terms of ethnic/racial background, while Maes et al.’s participants were explicitly identified as 

Caucasian of Flemish origin.101,103 

The studies conducted by Ellis and Sanders105 and Fehily et al.106 each included 

heterogeneous subtypes of endogenous depression, with subtypes undefined in the former105 and 

with neither report presenting outcome data broken down by any of these subtypes. The 

remaining studies identified reasonably well-defined groups for which to compare biomarkers 

data. The Maes et al. studies likely serve as the best examples of a well-conceived and 

operationalized separation of study groups.101,103 In this regard, their depressed patients were 

identified using DSM-III-R diagnostic criteria applied via the SCID, patient version.101,103 Peet 

et al. employed DSM-IV criteria to identify depressed patients.102 Neither Ellis and Sanders nor 

Fehily et al. described their diagnostic criteria.105,106 Depressive disorders were identified by 

Tiemeier et al. via a score of at least 16 (i.e., clinically significant depressive symptoms) on the 

validated Dutch version of the Center for Epidemiologic Studies Depression scale (CES-D) 

during a home interview, followed by a psychiatric workup using the Dutch version of the 

Present State Examination (i.e., a semistructured interview from the validated Schedules for 

Clinical Assessment in Neuropsychiatry). DSM-IV criteria were used to guide the diagnosis, 

with categories including major depression and dsythymia in addition to minor depression.104

Few studies adequately ruled out the presence of possible psychopathology, or risks thereto, 

in subjects typically identified as “healthy volunteers” or “healthy controls.”102,105 Maes et al.’s 
74 

investigations carefully provided the basis for separating their study groups to achieve control of 

this confounder. Healthy volunteers were excluded for present, past and family (first degree) 

history of Axis I or Axis II disorders using the SCID, Lifetime version.101,103 All participants had 

low scores on the Zung Depression and Anxiety Scales (<32) and the BDI (<9).103 Controls 

were medication-free for at least 1 month prior to blood sampling.101,103 None had ever taken 

psychotropic drugs103 or was a regular drinker.101,103 

A few studies established the baseline severity of symptomatology. For example, Fehily et 

al. used the BDI,106 Maes et al. employed the HDRS, and Peet et al. used the MADRS (no data 

reported).102,103 In their first study Maes et al. observed that those with major depression had 

significantly higher baseline HDRS severity scores than did those with minor depression.103 

Ellis and Sanders, for example, did not measure severity.105 Baseline data concerning the 

duration of the current episode, age of onset, number of previous episodes, and time since 

diagnosis were rare. 

In attempts to control for possible confounding from variability due to comorbid conditions, 

some studies applied strict exclusion criteria. For example, in both of the studies by Maes et al., 

patients were excluded if they had Axis I diagnoses other than unipolar depression, including 

psychotic disorders, organic mental disorders, impulse control disorders, substance use disorder 

or substance abuse (within the last 6 months), or borderline and antisocial personality (Axis II) 

disorders.101,103 Also excluded were individuals with abnormal X-rays of heart and lungs, 

electrocardiogram or electroencephalogram.101,103 All study participants had normal chemical 

and hematologic tests relating to, for example, liver function and renal function,101,103 as well as 

electrolyte, thyroid hormone and thyroid stimulating hormone levels.101 All were free of medical 

illness (e.g., immune and endocrine disorders such as diabetes, inflammatory bowel syndrome, 

autoimmune disorders, essential hypertension and arteriosclerosis).101,103 None exhibited 

evidence of allergic, inflammatory or immune responses for at least 2 weeks prior to blood 

sampling.101,103 BMI was within normal limits.101,103 Heavy smokers (>15 cigarettes per day) 

were excluded.101 

Peet et al. excluded those individuals with a physical illness of a severity or nature 

associating it with abnormal levels of omega-3 fatty acid levels.102 Controls were medicationfree, and without a history of psychiatric illness, personality disorder, substance abuse or medical 

illness (method undefined). Yet, Tiemeier et al. noted differences in their study groups, with 

elderly individuals with depressive disorders more likely to have had a stroke and to exhibit 

significantly lower activities of daily living scores and cognitive scores compared with those 

without depressive symptoms.104 Some studies did not identify possible psychiatric comorbidity 

or control for it via the application of clearly stated exclusion criteria.105,106 Yet, Peet et al. did 

note the absence of significant between-group differences regarding smoker status or in the 

relationship between smoker status and PUFA content.102

Six of eight studies did not involve an intervention or exposure. Only Llorente et al. 

employed supplementation,98 as possible prophylaxis, and Edwards et al. assessed dietary intake 

of omega-3 fatty acids.48 In both Maes et al. studies all participants were consuming a normal 

Belgian diet (PS ratio=0.54+0.43); and, those on a low fat diet were excluded.101,103 No other 

studies controlled statistically for background diet in their analyses. No study reported 

inappropriate methods by which lipids were extracted, prepared, stored or analyzed. 

Ellis and Sanders did not describe the medication status of their participants (i.e., medicationnaïve, medication-free or medicated, with type and dose).105 Fehily et al. reported that different 

percentages of individual within study groups were drug-free, indicating heterogeneity within 
75 

diagnostic groups.106 This situation could confound the results. Those receiving medication 

were receiving a hypnotic and/or a tranquillizer. Two schizophrenic patients that had been 

admitted to the study, yet whose data were not analyzed separately, were taking a neuroleptic. 

The investigators reported that the fatty acid content of those taking these drugs and those who 

were medication-free was not different (no data or p-value reported).106 Peet et al.’s patients 

were drug-free at first assessment.102 Seven patients then received dothiepin, three took 

paroxetine, and one each received trazodone and lofepramine.102 

Maes et al. excluded those individuals receiving treatment with MAOIs, antipsychotic doses 

of neuroleptic, anticonvulsants, lithium or ECT in the previous year.101,103 Maes et al. also 

specified fluoxetine and trazadone in their second study.101 No cholesterol-lowering drugs were 

permitted.101 Use of any medication known to influence fatty acid metabolism or endocrine and 

immune function was prohibited as well.101 No significant between-group differences were 

observed for the prestudy use of antidepressants, benzodiazepines or antipsychotics in Maes et 

al.’s first study.103 Prestudy use of the different drug classes did not significantly predict any of 

the omega-3 fatty acid fractions or any omega-6/omega-3 ratios.103 All antidepressant, 

benzodiazepine or low dose antipyschotics were discontinued the month prior to an 8-10 day 

washout period.103 The second Maes et al. study mandated the discontinuation of antidepressants 

upon hospital admission.101 Twenty-six depressed patients had been treated with antidepressants 

during the depressive episode.101

Twenty-seven patients with depression in Maes et al.’s first study,103 and 18 patients in their 

second study,101 used a low dose of benzodiazepines for severe agitation, anxiety sleep disorders 

or suicidal ideation during the study period. There was no significant between-group difference 

in the use of these on-study medications.101,103 As well, there were no significant differences in 

EFA status data for those depressed patients who did or did not use on-study benzodiazepines.101

Outcome characteristics. Outcomes included all types of fatty acid, from various sources, 

and were expressed either as percentages, or fractions (i.e., composition), or concentrations. 

Study quality and applicability. The seven cross-sectional studies received a mean quality 

score of 4.6, with four achieving an applicability rating of II,48,102,105,106 and three attaining an 

applicability rating of III.101,103,104 The single RCT was assigned an Jadad total quality score of 

5, an Adequate allocation concealment rating, and an applicability score of I.98

Summary Matrix 3: Study quality and applicability of evidence regarding the association between omega-3 or 

omega-6/omega-3 fatty acid content of biomarkers and onset, continuation or recurrence of depression (all 

designs) 

Study Quality

A B C 

Author Year n Author Year n Author Year n I 

Author Year n Author Year n Author Year n

II LlorenteA 2003 >89 Peet 

Edwards 

1998 

1998 

30 

24 

Ellis 

Fehily 

1977 

1981 

16 

>60 

Author Year n Author Year n Author Year n

Applicability 

III 

 Maes 

Maes 

Tiemeier 

1996 

1999 

2003 

74 

48 

682 

 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment 
76 

Qualitative Synthesis of Individual Study Results 

The proportions of plasma CPG EPA and DHA were each significantly greater in the 

endogenous depression group as compared to healthy controls in the Ellis and Sanders study.105 

On the other hand, AA did not differ between these two groups. These differences were less 

pronounced for RBC EPG data (no data or p-values reported). There were no significant 

differences in fatty acid status between non-depressed patients and healthy controls. 

Concentrations of DHA and EPA in plasma CPG were each significantly higher, but LA was 

significantly lower, in Fehily et al.’s endogenous depression group compared with matched 

controls.106 There was no significant difference between these two groups in terms of AA levels. 

The plasma CPG status of patients with reactive depression or other psychiatric disorders did not 

differ from the controls. Eighty percent of those with endogenous depression had DHA levels of 

more than 54 mg/g total fatty acid esters detected, as compared to 19% of matched controls. 

DHA concentrations were correlated with BDI severity score for those identified as 

endogenously depressed, but not for those with reactive depression. Similar, but smaller, 

between-group differences were observed for the fatty acid content of RBCs of patients with 

endogenous depression compared with matched controls (i.e., higher DHA in EPGs; higher EPA 

in serine phosphoglycerides). 

By ANCOVA, with age and sex as covariates, major depressed patients exhibited a 

significantly higher AA/EPA ratio in both serum cholesteryl esters and phospholipids in addition 

to a significantly increased total omega-6/omega-3 ratio in cholesteryl ester fractions than did 

healthy volunteers or minor depressed subjects in Maes et al.’s first study.103 Significant 

between-group differences were not observed for total omega-3 or total omega-6 fatty acid 

content, or their ratio, in phospholipids. The only significant correlations involved the HDRS 

score with the AA/EPA or total omega-6/omega-3 fatty acid ratios in phospholipids. Major 

depressed patients had significantly lower ALA in cholesteryl esters compared with healthy 

controls. Major depressed patients showed significantly lower total omega-3 fatty acids in 

cholesteryl esters and significantly lower EPA in serum cholesteryl esters and phospholipids 

compared with minor depressed subjects or healthy controls. ALA, EPA and DHA cholesteryl 

ester fractions successfully discriminated the three study groups. MANOVA using ALA, EPA 

and DHA cholesteryl ester fractions as dependent variables showed highly significant differences 

among the three study groups. There was a significant negative relationship between EPA in 

cholesteryl esters and HDRS scores. 

Peet et al. observed a significant reduction in RBC membrane total omega-3 fatty acids and 

DHA content in drug-free depressive patients.102 They also observed a significant reduction in 

LA, DGLA and total omega-6 fatty acids. No significant between-group differences were found 

for AA/EPA, AA/DHA or total omega-6/omega-3 fatty acid ratios. Subsequent intervention with 

anti-depressants failed to have a significant effect on the RBC omega-3 fatty acid status. Yet, 

this study failed to fully control for possible confounding influences such as stress, smoking or 

diet. 

Edwards et al. reported that RBC membrane EPA, DHA and total omega-3 fatty acid levels 

were significantly lower in the depressed patient group.48 There were no significant differences 

for any omega-6 fatty acid levels. There were no significant between-group differences for 

current dietary intake of omega-3 fatty acids or total energy intake (via 7-day weighted intake). 

The only significant, and negative, correlations involved omega-3 fatty acids and BDI-defined 

severity score: for ALA, DHA and total omega-3 fatty acid content. Multiple regression revealed 
77 

that only RBC membrane ALA significantly predicted BDI score. When dietary and RBC 

membrane data were entered in stepwise fashion, DHA and LA emerged as the only predictors of 

BDI severity score. Neither current smoker status nor recent stress had an effect on RBC 

membrane values. 

Maes et al. found in serum phospholipids that major depression was associated with (all 

significant): higher MUFA fractions, lower adrenic acid (omega-6) yet higher (omega-6-)DPA,

lower EPA, lower (omega-3-)DPA, higher AA/EPA ratio, higher (omega-6-)DPA/DHA fractions 

(i.e., composition: weight as percent of total).101 In addition, lower concentrations (mg/dL) of 

SFAs, MUFAs, LA, AA, adrenic acid (omega-6), total omega-6 fatty acids, ALA, EPA, (omega3-)DPA, DHA, and total omega-3 fatty acids (all significant) were found in the serum 

phospholipids of patients with major depression.101 For serum cholesteryl esters, major 

depression was associated with (all significant): lower ALA, EPA, and total omega-3 fatty acids;

and, higher total omega-6/omega-3 fatty acids and AA/EPA fractions. Additionally, major 

depression was associated with lower total saturated fatty acids, MUFAs, LA, DGLA, total 

omega-6 fatty acids, ALA, EPA, and total omega-3 fatty acid concentrations (all significant), in 

serum cholesteryl esters.101 All analyses included age and sex as covariates. There were no 

significant correlations between HDRS score for depressive patients and any of the fatty acid 

variables. 

In the phospholipids of major depressed patients, serum zinc was significantly and positively 

correlated with the percentages and concentrations of EPA, DHA and total omega-3 fatty 

acids.101 Significant negative correlations were observed for percentage of total omega-6 fatty 

acids, AA/EPA, (omega-6-)DPA/DHA, and total omega-6/omega-3 fatty acids. In their 

cholesteryl esters, only the total omega-3 fatty acid percentage, and EPA, were significantly and 

positively correlated with major depression. There was no significant effect of antidepressant 

treatment on fatty acid levels. With a decrease of at least 50% in HDRS score defining a good 

clinical response to antidepressants after 5 weeks, depressed patients were divided into 

responders and non-responders.101 There were no significant differences in fatty acid 

percentages between responders and non-responders. 

Tiemeier et al. found no significant differences in the percentages or ratios of plasma 

phospholipid fatty acids between controls and those exhibiting subclinical depressive 

symptoms.104 When the comparisons involved depressed subjects and controls, only a few, 

marginal differences were observed. By ANCOVA, with the above-noted covariates, 

percentages of AA and DHA were higher and lower, respectively, in the depressed subjects 

compared with controls. The ratios of total omega-6/omega-3 fatty acids and AA/DHA were 

higher in the depressed subject group when compared to reference subjects. Neither the 

inflammation marker C-reactive protein nor atherosclerosis affected these results. A test of 

interaction showed that the relation between the omega-6/omega-3 ratios and depressive 

disorders depended on the C-reactive concentration. That is, the difference in the omega6/omega-3 ratio between depressed and reference subjects increased with lower concentrations of 

C-reactive protein. Stratification of the analysis at the median of C-reactive protein 

concentrations (1.5 mg/L), and involving subjects above this cutpoint, revealed no significant 

difference in fatty acid composition between the depressed and reference groups. Yet, when data 

were analyzed from those falling below the cutpoint, it was observed that depressed persons had 

significantly lower percentages of certain omega-3 fatty acids than did reference subjects. By 

ANCOVA, subjects with depressive disorder showed lower levels of EPA, DHA and total 
78 

omega-3 fatty acids. As well, depressed subjects showed higher values for total omega-6/omega3 fatty acids, AA/EPA and AA/DHA. 

In their RCT, Llorente et al. observed no statistically significant correlations between plasma 

phospholipid DHA content, either at baseline or at 4 months, and self-rating (BDI, EPDS) or 

syndromal measures of depression (SCID-CV).98

Quantitative Synthesis 

Although all of the included studies were controlled, only one was prospective by design. 

Thus, meta-analysis was considered inappropriate. The exact nature of the inappropriateness of 

cross-sectional study data to address the question of onset is described in the Discussion. 

Impact of Covariates and Confounders 

Numerous factors have the capacity to influence EFA levels, including dietary intake, 

smoking and alcohol consumption.101-103 Most of the studies did not control for smoking, for 

example, which alone could produce a picture of omega-3 fatty acid deficiency.60 Only a 

minority of studies adequately controlled for the possible influence of this or any other variable. 

The study by Peet et al.,102 and especially the two studies by Maes et al.,101,103 employed 

strict controls, and results suggested an omega-3 fatty acid deficiency in depressed patients. 

Edwards et al. controlled for stress and smoker status.48 However, less well-controlled studies—

for example, failing to formally rule out psychopathology in the controls—also produced a 

similar picture of an omega-3 fatty acid deficiency in depressed patients. It is possible that the 

between-group differences might have been more pronounced in the latter studies had the 

possible influence of this and other potential confounding factors been minimized. 

Failure to include even minimally homogeneous groups of depressed individual may have 

produced the only two study results suggesting that, compared with depressed patients, healthy 

controls exhibited an omega-3 fatty acid deficiency.105,106 As well, in studies where patients 

were either already receiving antidepressant medication,48 or received medication sometime after 

the initial blood sampling and were subsequently retested,101,102 analyses revealed that 

antidepressant medication did not substantially modify the between-group difference in omega-3 

fatty acid levels in biomarkers. The country in which the study was conducted could not readily 

be used as a surrogate for background diet in assessing the impact of the latter on study results 

since there was insufficient variability in study results. 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Suicidal Ideation or Behavior? 

As observed in Summary Table 12 (below), derived from Evidence Table 2 (Appendix E*

), 

two observational studies met eligibility criteria. The studies were published in 2001 and 2004. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
79 

Overview of Relevant Studies’ Characteristics and Results 

Each observational study has already had its key characteristics described with reference to 

the question of the possible association of omega-3 fatty acid intake and the onset, continuation 

or recurrence of depression. Hakkarainen et al. investigated the relationship between dietary 

intake of omega-3 fatty acids and low mood, major depression, and suicide in males 50 to 69 

years of age living in southwestern Finland in 1985.111 The study utilized a cohort (n=29,133) 

from a primary prevention RCT (ATBC Cancer Prevention Study). Followup lasted nine years. 

The intake of fatty acids and fish consumption were derived from a validated food use 

questionnaire focused on the “last 12 months.” Suicides were determined from Central 

Population Register data. 

Summary Table 12: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

suicidal ideation or behavior 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Hakkarainen, 

2004, Finland: 

9 y single 

prospective 

cohort from 

RCT111

males 50-69 y 

from RCT’s intervention 

& placebo grps 

(n=29,133) 

NS association 

(no data reported) 

Total 

quality: 5 

[Grade: B] 

III 

Tanskanen, 

2001, Finland: 

single 

population 

cross-sectional 

survey80

adult males & females 

(n=1,767) 

Adjusted depression & suicidal 

ideation risks Ð in frequent fish 

consumers+ 

Total 

quality: 4 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 95% 

confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Tanskanen et al.’s sample was selected based on a random population sample (National 

Population Register) of both sexes (n=3,004; 25-64 years).80 Data were gathered on fish 

consumption, depression (BDI) and suicidality. Suicidality was measured using a single BDI 

item. Given that the studies varied on the basis of their focus, that is, one on “successful” 

suicidal behavior and the other on suicidal ideation, and that the key study and population 

parameters have already been contrasted in an earlier part of the report, only the results are now 

presented. Quantitative analysis was considered inappropriate. 

Adjusting for numerous factors (i.e., age, sex, marital status, education, employement status, 

work ability, area of residence, financial status, general health, smoking, alcohol intake, coffee 

drinking, and physical activity), Tanskanen et al. found that the risk of suicidal ideation was 

significantly lower among frequent consumers of lakefish.80 Adjusting for many factors as well 
80 

(i.e., age, BMI, energy intake, serum cholesterol level, HDL level, alcohol use, education, 

marriage, self-reported depression and anxiety, and smoking), Hakkarainen et al. observed no 

significant association between fish consumption or intake of omega-3 fatty acids and suicide.111 

Both Hakkarainen et al. and Tanskanen et al.’s results, while indicating good statistical control 

for important key confounders, are insufficient to allow us to infer the role of any covariates or 

confounders. Meta-analysis was not considered since outcomes were not comparable. 

Study quality and applicability. Although they employed different research designs, both 

studies were assigned a level III for applicability, and together they received a mean quality 

score of 4.5.80,111

Summary Matrix 4: Study quality and applicability of evidence regarding the association between omega-3 

fatty acid intake and onset, continuation or recurrence of suicidal ideation or behavior (all designs) 

Study Quality

A B C 

Author Year n Author Year n Author Year n I 

Author Year n Author Year n Author Year n II 

Author Year n Author Year n Author Year n

Applicability 

III Hakkarainen 

Tanskanen 

2004 

2001 

>29k 

>1k 

 

n = number of allocated/selected participants; k = 1,000’s 

Are Omega-3 Fatty Acids Efficacious as Supplemental 

Treatment for Bipolar Disorder? 

As observed in Summary Table 13 (below), derived from Evidence Table 1 (Appendix E*), 

two controlled studies met eligibility criteria. While both were published, only Stoll et al. (1999) 

provided sufficient study-related data to permit its full review.112 Akkerhuis and Nolen (2003) 

reported some peripherally-related data in a letter to the editor in which they referred to the 

placebo-controlled study from which their anecdotal data were derived.93 A search via Pubmed 

did not locate a report of the full study. Thus, a comprehensive qualitative synthesis (or metaanalysis) could not be achieved (e.g., impact of covariates and confounders). A summary matrix 

could not be derived. 

Overview of Relevant Studies’ Characteristics and Results 

Stoll et al. randomized 44 patients with bipolar disorder (18-65 years) to receive either 9.6 

g/d of omega-3 fatty acids (6.2 g/d EPA, 3.4 g/d DHA) from menhaden fish body oil, via seven 

capsules twice daily, or identical gelatin placebo capsules containing olive oil ethyl ester 

(Summary Table 13).112 Capsules were vacuum deodorized, and both tertiary butylhydroquinone 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
81 

(0.2 mg/g) and tocopherols (2 mg/g) were added as antioxidants. Randomization was stratified 

by sex (n=9/14 completers in omega-3 fatty acid group; n=11/16 completers in placebo group), 

concurrent lithium use (n=6/14 completers in omega-3 fatty acid group; n=6/16 completers in 

placebo group), and rapid cycling status (n=7/14 completers in omega-3 fatty acid group; n=5/16 

completers in placebo group). Diagnosis was established using the SCID and DSM-IV criteria 

for Types I or II bipolar disorder (n=2/14 completers with Type II in omega-3 fatty acid group; 

n=3/16 completers with Type II in placebo group). Eight patients entered the study without 

receiving psychotropic medication, and a post hoc analysis of their data constituted an evaluation 

of omega-3 fatty acids as primary treatment (n=4 per study group). Mood states varied at study 

entry both across study groups and within each study group. 

Summary Table 13: Omega-3 fatty acids as supplemental treatment for bipolar disorder 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects 

Internal 

validity Applicability 

Stoll, 1999, 

US: 

4 mo 

parallel 

RCT112

9.6g/d 

EPA+DHA 

(6.2g/d 

EPA, 

3.4g/d 

DHA) 

(n=~22) 

olive oil 

ethyl ester 

pb 

(n=~22) 

n-3 grp had longer remission;++ same 

result for pts without medication;+ bet-grp 

differences on CGI,++ GAS,+

 & HDRS;++ 

sex, rapid cycling status or disorder type 

did not predict response 

Jadad 

total: 4 

[Grade: 

A]; 

Schulz: 

Adequate 

I 

Akkerhuis, 

2003, NR: 

4 wk 

“controlled 

study”93

maximum 

6g/d 

EPA ethyl 

ester 

(n=NR) 

pb 

(source 

undefined) 

(n=NR) 

NR Could not 

evaluate 

X 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; 

grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; HDRS = Hamilton Depression Rating Scale; CGI = 

Clinical Global Impression scale; GAS = Global Assessment Scale; YMRS = Young Mania Rating Scale; RBC = red blood 

cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine phosphoglycerides; Jadad total = Jadad 

total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Patients were free of notable medical and psychiatric comorbidity. They were required to 

have experienced at least one manic or hypomanic episode within the past year.112 The 

investigators argued that this inclusion criterion would enhance the study’s power to detect a 

difference since such episodes were likely to recur. Forty percent of participants had exhibited 

rapid-cycling symptoms (i.e., at least four mood episodes in the past year). While participants 

were permitted to continue with existing psychotherapies (data unreported), no new regimens 

were permitted. Those receiving psychotropic medication continued to do so on-study, at 

constant dosages, and irrespective of whether they were in the therapeutic range (n=4/14 and 

n=3/16 patients in the active and placebo arms, respectively, received no medication). However, 

there was considerable heterogeneity both between- and within-study groups in terms of which 

types of on-study medication (doses unreported) were taken. Clinical assessments took place 
82 

every second week for four months. The investigators defined the followup required to observe 

an effect as 30 days, thereby establishing the criterion for data that could be entered into analysis. 

While planned as a 9-month trial with 60 patients required based on a sample size 

calculation, a stoppage in the production of the fish oil material and a significant between-group 

difference observed via a preplanned interim analysis, conducted when 20 patients had either 

failed treatment or completed 4 months, together led to ending accrual and reanalyzing data from 

30 patients. P-values were adjusted accordingly. While it was reported that the exposure was 

produced by the National Marine Fisheries Fish Oil Program (US), no data were provided 

regarding its purity or whether the presence of methylmercury was tested or eliminated. 

There were no significant differences in the baseline characteristics of the study groups (i.e., 

age, sex, rapid cycling in past year, Clinical Global Impression [CGI] scale, Global Assessment 

Scale [GAS], Young Mania Rating Scale [YMRS], HDRS).112 Results of analyses involving 30 

evaluable patients were reported (n=14 in active treatment group).112 Kaplan-Meier survival 

analysis revealed that the active treatment group exhibited a significantly longer period of 

remission (i.e., duration of time remaining in the study) than did the placebo group. When data 

were analyzed exclusively from those subjects who entered the study without receiving 

psychotropic medication, the same difference was observed. For the full sample, the time to a 

50% rate of ending the trial prematurely (“nonresponse”) was 65 days for the placebo group. 

The investigators interpreted this result as being consistent with the study population. 

Significant differences in improvement on the CGI, GAS, and the HDRS were observed in favor 

of the active treatment group. The latter result suggests that depression was also positively 

affected by supplementation. Post hoc analyses showed that sex, rapid cycling status and bipolar 

disorder type did not predict response (no data reported). 

There was some evidence that the blind had been broken. A “fishy” aftertaste was more 

often reported in the active treatment group, such that 86% of participants guessed that they had 

received fish oil capsules. Only 63% in the placebo group guessed correctly. However, 

debriefing revealed that clinical response, or lack thereof, also played a role in tipping-off 

subjects to which study group they had been allocated. 

Akkerhuis and Nolen reported the spontaneous reduction of psoriasis in a double blind trial 

wherein patients with bipolar disorder were allocated either to a maximum of 6g/d EPA ethyl 

ester or placebo (undefined).93 Neither results relating to clinical outcomes nor other study 

details were provided. 

Study quality and applicability. The Stoll et al. trial received an internal validity grade of 

A (Jadad total score=4), exhibited Adequate concealment of allocation to study groups, and was 

rated as being applicable to a North American population.112 The Akkerhuis and Nolen report 

did not provide sufficient data to permit an evaluation of its study’s internal validity or 

applicability.93
83 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Bipolar Disorder? 

As observed in Summary Table 14 (below), derived from Evidence Table 3 (Appendix E*

), 

one study published in 2003 met eligibility criteria. A comprehensive qualitative synthesis (e.g., 

impact of covariates and confounders), summary matrix and meta-analysis were not possible. 

Overview of Relevant Study’s Characteristics and Results 

Noaghiul and Hibbeln conducted a cross-national ecological analysis assessing the possible 

association of seafood consumption and published lifetime prevalence rates (ages 18-64 years) of 

bipolar disorder and schizophrenia.90 Bipolar I disorder prevalence data from six countries (US, 

Canada, Puerto Rico, Taiwan, Korea and New Zealand) were obtained from the Cross-National 

Collaborative Group epidemiological study of 10 countries. To these were added data from 

Germany, Italy, Israel, Iceland and Switzerland. All studies used structured diagnostic 

instruments and appropriate sampling methods to obtain clearly defined community samples. 

For example, with the exception of Switzerland and Israel, all studies used the NIMH Diagnostic 

Interview Schedule (DIS). The former used the SPIKE and Schedule for Affective Disorders 

and Schizophrenia, respectively. A Hungarian study of bipolar II disorder met eligibility criteria, 

as did a study from Norway. The latter used the DIS yet did not provide data subdivided by 

diagnostic subcategory. Data from Norway were compared with those from other countries after 

data from different diagnostic subcategories were first combined. All rates were reported as 

cases per 100,000 persons. Prevalence rates drawn from the Cross-National Collaborative Group 

epidemiological study were standardized at each site, with a weight calculated per subject, and 

stratified for age and sex. Data from other sources could not be weighted in this manner since 

primary data were unavailable. Socioeconomic status and educational level were not taken into 

consideration. The female-to-male ratio was roughly equal at all sites, with slightly higher rates 

seen for Canada, Puerto Rico, Korea and New Zealand. Sources of lifetime prevalence data for 

schizophrenia are described later in our report. 

National seafood consumption data were obtained from the National Marine Fisheries 

Service and the Food and Agriculture Organization of the WHO. The rates of consumption 

appeared to be stable across the period in which the data were collected. As a measure of the 

disappearance of seafood from the economy per year, apparent seafood consumption 

(lb/person/year) was calculated as total catch plus imports minus exports. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
84 

Summary Table 14: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

bipolar disorder 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Noaghiul, 2003, 

11 countries: 

cross-national 

ecological 

analysis90

11 countries Logarithmic regression = greater 

seafood consumption predicted 

lower prevalence rates of bipolar I 

disorder,+

 bipolar II disorder+++ & 

bipolar spectrum disorder;+++ when 

subcategories combined, linear 

regression+++ & exponential decay 

regression+++ 

Total 

quality: 4 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 95% confidence 

interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Results indicated variability in the rates of bipolar disorder across the countries.90 By simple 

linear regression, greater national seafood consumption predicted lower prevalence rates of 

bipolar spectrum disorder and bipolar II disorder, but not bipolar I disorder, for which a 

nonsignificant association was observed. An investigation of the residual plots of these findings 

suggested that nonlinear models would better express the association. By logarithmic regression, 

greater seafood consumption predicted lower prevalence rates of bipolar I disorder, bipolar II 

disorder and bipolar spectrum disorder. The best curve fitting entailed a simple exponential 

decay regression whereby greater seafood consumption again predicted lower rates of bipolar I 

disorder, bipolar II disorder and bipolar spectrum disorder. When all subcategories were 

combined, both linear regression and exponential decay regression remained significant. When 

outlier data from Iceland (by far the highest seafood consumption, very low rates of bipolar I and 

bipolar spectrum disorder) were excluded, the association strengthened involving bipolar II 

disorder but did not change the results for bipolar I or bipolar spectrum disorder.

Study quality and applicability. Given its multiple national entries of data, Noaghiul and 

Hibbeln’s study received an applicability rating of III.90 Its total quality score was 4. 

Is the Onset, Continuation or Recurrence of Bipolar Disorder 

Associated With Omega-3 or Omega-6/Omega-3 Fatty Acid 

Content of Biomarkers? 

As observed in Summary Table 15 (below), derived from Evidence Table 2 (Appendix E*

), 

two studies met eligibility criteria. One was published in 1996 and the other in 2003. Since 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
85 

Mahadik et al.’s investigation was focused primarily on schizophrenia, with bipolar patients used 

as a comparator group along with normal controls, most of the details regarding this study are 

described with respect to the topic of schizophrenia.114 As a result, a full qualitative synthesis is 

not produced here. Nevertheless, it is clear from both study reports that the study of Chiu et al. 

more extensively controlled for possible confounding factors.113

Overview of Relevant Studies’ Characteristics and Results 

Both studies employed a cross-sectional design.113,114 Only Chiu et al. reported their funding 

source: three National Science Council grants, and the China Chemical and Pharmaceutical 

Company. 

Mahadik et al. investigated AA and DHA compositions of cultured skin fibroblasts of 

schizophrenic patients (n=12; eight drug-naïve and in a first episode of nonaffective psychosis, 

four drug-free although presently admitted for recurrence), bipolar patients (n=6; two in first 

manic episode) and normal controls (n=8).114 Bipolar patients were selected because they do not 

tend to manifest prominent negative symptoms. Mahadik et al. reported no significant 

differences between bipolar patients and normal controls for AA or DHA although schizophrenic 

patients exhibited significantly lower DHA compositions compared with either bipolar patients 

or normal controls.114 

Summary Table 15: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of bipolar disorder 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Mahadik, 1996, 

US: 

multiple-group 

cross-sectional 

study114

bipolar 

pts 

(n=6) 

drug-free 

schizophrenic 

pts (n=12)/ 

normal 

controls 

(n=8) 

NS differences for AA & DHA bet 

bipolar pts & normal controls 

Total 

quality: 5 

[Grade: B] 

I 

Chiu 2003, 

Taiwan: 

multiple-group 

cross-sectional 

study113

bipolar 

patients, 

acute 

manic 

episode 

(n=20) 

healthy 

volunteers 

(n=20) 

Ð AA+

 & DHA+ RBC in bipolar 

manic pts vs controls; NS total n3 or total n-6; NS AA/EPA or total 

n-6/n-3; NS impacts of 

medication, age, age of onset, 

smoker status, number of 

episodes or illness duration on 

FAs 

Total 

quality: 5 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; RBC = red blood cells; +

p<.05 or significant 

with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Chiu et al. examined whether there was a depletion of PUFAs in RBC membranes of patients 

admitted to hospital with DSM-IV diagnosed bipolar I disorder and whose most recent episode 

manic (n=20; 18-65 years), compared with healthy volunteer controls (n=20; 18-65 years).113 
86 

Excluded were bipolar patients with mixed symptom episodes or comorbid Axis I psychiatric 

disorders (i.e., due to a medical condition or induced by substance use). The mean age of onset 

of the bipolar patients was 26.5 (SD=9.9) years with an average duration of 11.1 (SD=9.6) years. 

The mean number of mood (i.e., manic or depressive) episodes was 5.2 (SD=4.5) and the mean 

number of hospitalizations was 3.8 (SD-3.2). The mean YMRS score was 32.1 (range: 14-42). 

During index hospitalization, all bipolar patients continued to receive their mood stabilizers, 

benzodiazepine or antipsychotic drugs. Fifteen patients were receiving mood stabilizers, 

including lithium (n=9), valproate (n=5), and valproate with carbamazepine (n=1). Of these, ten 

were taking antipsychotics. At the time of blood sampling, five patients had been free of 

psychotropic medication for at least one week. Healthy controls did not have a positive family 

history of psychiatric disorder or take psychotropic medication although no method to rule out 

psychiatric disturbance was described.113 All study participants were of Han background, were 

free of medical illness (e.g., immune or endocrine disorders) and were exluded if they were on a 

low fat or vegetarian diet. There were no significant between-group baseline differences for age, 

sex or BMI. 

Chiu et al. found significantly reduced AA and DHA compositions in RBC membranes in 

bipolar manic patients relative to healthy volunteers.113 There were no significant differences in 

either total omega-3 or total omega-6 fatty acid compositions. No significant differences were 

observed for either the AA/EPA or total omega-6/omega-3 fatty acid ratio. An assessment of the 

impact of medication on PUFAs in bipolar patients revealed no significant differences for AA 

and DHA levels. AA and DHA levels were not significantly correlated with age, age of onset, 

number of episodes or length of illness. There were no significant differences in AA or DHA 

levels for bipolar patients varying on the basis of their smoker status. No inappropriate methods 

to extract, prepare, store or analyze lipids were described in either report.113,114 

Although both included studies were controlled, neither was prospective by design. Thus, 

meta-analysis was not considered. That said, the studies collected fatty acid status data using 

two very different methodologies, and from different sources. The small numbers of study 

precluded any meaningful evaluation of the possible impact of covariates or confounders. 

Study quality and applicability. Mahadik et al. and Chiu et al.’s studies received 

applicability ratings of I and III, respectively. Each study received a quality score of 5. 

Summary Matrix 5: Study quality and applicability of evidence regarding the association between omega-3 or 

omega-6/omega-3 fatty acid content of biomarkers and onset, continuation or recurrence of bipolar disorder 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I Mahadik 1996 26 

Author Year n Author Year n Author Year n II 

Author Year n Author Year n Author Year n

Applicability 

III Chiu 2003 40 

n = number of allocated/selected participants 
87 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Anxiety? 

As observed in Summary Table 16 (below), derived from Evidence Table 1 (Appendix E*

), 

two studies met eligibility criteria. One was published in 2000 and the other in 2003. The key 

parameters describing these studies have already been presented with regards to the evidence for 

the possible association of intake of omega-3 fatty acids and the onset, continuation or 

recurrence of depression. Neither study included patients with diagnoses of anxiety disorder. 

Overview of Relevant Studies’ Characteristics and Results 

Wardle et al.’s RCT investigated whether cholesterol-lowering diets influence mood, 

including depression, anxiety, anger/hostility, stress, and general psychological well-being.99 

Adult volunteers (n=176) with elevated serum cholesterol levels (>5.2 mM [198 mg/dL]) were 

allocated to a low-fat diet (n=59), a Mediterranean diet (n=61), or a waiting-list control (n=56). 

Dietary treatments were given in eight sessions over the 12-week period. Participants completed 

a seven-day dietary intake diary before the first assessment. The outcome measure was the 

anxiety subscale of the POMS. Dietary diaries were filled out at baseline and 12 weeks. There 

were no significant between-group differences observed for anxiety. There was no reliable 

association between intake of omega-3 fatty acids and anxiety. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
88 

Summary Table 16: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

anxiety 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects 

Internal 

validity Applicability 

Wardle, 

2000, 

England: 

12 wk 

parallel 

RCT99

Mediterranean 

diet (with oily 

fish) 

(n=61) 

low fat diet 

(n=59)/ 

waiting list 

control 

(n=56) 

Ð anxiety only in Mediterranean diet;+ 

NS bet-grp difference in anxiety 

Jadad 

total: 2 

[Grade: 

C]; 

Schulz: 

Adequate 

II 

Ness, 

2003, 

Wales: 

6 mo RCT 

(one factor 

in factorial 

RCT)100

advice to eat 

fish 

(n=229) 

no advice 

to eat fish 

(n=223) 

NS ∆ in anxiety for fish advice group; 

NS bet-grp differences for anxiety 

Jadad 

total: 2 

(Grade: 

C]; 

Schulz: 

Unclear 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; BDI = Beck Depression Inventory; Jadad total 

= Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy 

of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Reflecting one factor within a factorial RCT investigating interventions to reduce mortality in 

angina (including: advice [not] to eat fruits and vegetables; [no] stress management), 452 males 

were allocated to receive advice to eat more fatty fish (i.e., mackerel, herring, kipper, pilchard, 

sardine, salmon, trout) or to receive no such advice. Ness et al. supplied MaxEPA® fish oil 

capsules to study participants if they did not like the taste of fish.100 Fish intake and mood 

(depression, anxiety) were assessed at baseline and at six months, the latter using the validated 

Derogatis Stress Profile (DSP). Ness et al. observed that self-reported fish intake was higher in 

the fish advice group at study’s end.100 No statistical difference was observed in the fish advice 

group for anxiety; controlling for baseline mood, the between-group difference was not 

statistically different. This last observation did not change following an additional adjustment 

made for randomization to the stress management arm, nor was there any statistical evidence of 

interaction between these factors in their effects on mood. These observations were not 

contradicted when they looked exclusively at the upper quartile of baseline anxiety scores. 

The very different interventions and outcomes precluded quantitative synthesis. The dearth 

of data concerning covariates and confounders did not permit a meaningful assessment of their 

possible influence. That said, neither study demonstrated a significant clinical effect. 

Study quality and applicability. Both RCTs received a Jadad total quality score of 2, 

indicating low quality, and level II applicability ratings.99,100 Wardle et al.’s trial99 described 

adequate allocation concealment while Ness et al.’s report was unclear.100
89 

Summary Matrix 6: Study quality and applicability of evidence regarding the association between omega-3 

fatty acid intake and onset, continuation or recurrence of anxiety 

Study Quality

A B C 

Author Year n Author Year n Author Year n I 

Author Year n Author Year n Author Year n

II 

NessU 

WardleA 2003 

2000 

452 

176 

Author Year n Author Year n Author Year n

Applicability 

III 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment 

Are Omega-3 Fatty Acids Efficacious as Supplemental 

Treatment for Obsessive-Compulsive Disorder? 

As observed in Summary Table 17 (below), derived from Evidence Table 1 (Appendix E*), 

one placebo-controlled crossover RCT published in 2004 met eligibility criteria. 

Overview of Relevant Study’s Characteristics and Results 

At one Israeli site, Fux et al. selected eleven patients from an anxiety disorders clinic (18-75 

years; racial/ethnic background unreported) meeting DSM-IV criteria for obsessive-compulsive 

disorder (duration: 14.1+8 years).115 Participants began either with 2 g/d E-EPA (96% pure 

semi-synthetic E-EPA; plus stabilized with 0.2% vitamin E) or matched 2 g/d placebo (liquid 

paraffin) gelatin capsules in a six-week, two-phase crossover RCT. Selection criteria included 

having been on a stable dose of SSRIs (paroxetine: n=8; fluvoxamine: n=1; fluoxetine: n=1) for 

at least 2 months, and having demonstrated some response to treatment yet without further 

improvement over the last 2 months. Exclusion criteria included no unstable medical disease, 

alcohol or drug abuse, or comorbid Axis II psychiatric diagnosis. Patients maintained their SSRI 

dose over the study. None received psychotherapy aside from basic clinical management or 

support. The primary outcome measures were scores on the Yale-Brown Obsessive-Compulsive 

Scale (YBOCS), HDRS, and the Hamilton Anxiety Rating Scale (HAM-A). The intervention 

was prepared by Laxdale, Ltd. No data described its purity or whether methylmercury was 

tested for and eliminated. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
90 

Summary Table 17: Omega-3 fatty acids as supplemental treatment for obsessive-compulsive disorder 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects 

Internal 

validity Applicability 

Fux, 2004, 

Israel: 

6 wk 

crossover 

RCT115

2g/d EEPA 

phase 

(n=11) 

 2g/d liquid 

paraffin pb 

phase 

(n=11) 

NS effects of treatment order on HDRS or 

HAM-A; main effect for time on YBOCS, 

with significant Ð by wk 6 for pb & EEPA;++ NS treatment effect for clinical 

outcomes; NS drug-by-time interaction 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; 

grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; HDRS = Hamilton Depression Rating Scale; HAM-A: 

Hamilton Anxiety Rating Scake; YBOCS = Yale-Brown Obsessive-Compulsive Scale; HAM-A = Hamilton Anxiety Rating 

Scale; Jadad total = Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = 

reporting of adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence 

interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Overall, 91% of the sample completed the full 12 weeks (n=10/11); however, data were 

analyzed based on an ITT basis, with the last value carried forward for the participant who 

dropped out at week 10 of the study (i.e., moved out of city). Results indicated that there were 

no effects of order of treatment on HDRS or HAM-A. Time had a main effect on YBOCS 

scores, with significant decreases by week 6 for both placebo and E-EPA phases. There was 

neither a treatment effect for any clinical outcome, or a significant drug-by-time interaction. No 

assessment of the impact of covariates or confounders was possible. This RCT received a Jadad 

total quality score of 3 and an applicability rating of III. 

Is the Onset, Continuation or Recurrence of Anorexia 

Nervosa Associated With Omega-3 or Omega-6/Omega-3 

Fatty Acid Content of Biomarkers? 

As observed in Summary Table 18 (below), derived from Evidence Table 3 (Appendix E*

), 

two cross-sectional studies published in 1985 and 1995 met eligibility criteria. 

Overview of Relevant Studies’ Characteristics and Results 

Both studies had a cross-sectional design and were conducted in the US.116,117 Langan and 

Farrell’s study was funded by the NIH117 while Holman et al.’s work was supported by the Carle 

Foundation, NIH, Harmel Foundation and by Scotia Pharmaceuticals.116

Langan and Farrell investigated the plasma fatty acid composition in a group of females with 

anorexia nervosa admitted to a hospital (n=17; mean age: 16.8 years; duration of anorexia: 17.2 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
91 

months) compared to healthy females serving as controls (n=11; mean age: 20.7 years).117 The 

anorexic patients were admitted because of an electrolyte imbalance, a greater than 25 percent 

loss of ideal body weight (mean: 28.5 pounds) and severe psychosocial problems. Patients varied 

in their degree of malnutrition. The control group was slightly older than the patient group. 

Compared with the control group, the weight-to-height ratio (lb/in) was significantly reduced in 

the patient group. 

Summary Table 18: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of anorexia nervosa 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Langan, 1985, 

US: 

multiple-group 

cross-sectional 

study117

anorexic 

females 

(n=17) 

healthy 

female 

controls 

(n=11) 

NS bet-grp difference in FA in total 

plasma lipids; Ð plasma PL LA++ & 

ALA+

 in anorexics; Ï plasma PL 

DHA in anorexics;+ Ð total n-6 in 

anorexics;+ Ï AA/LA in anorexics++ 

Total 

quality: 2 

[Grade: C] 

I 

Holman, 1995, 

US: 

multiple-group 

cross-sectional 

study116

young 

anorexic 

females 

(n=8) 

young 

healthy 

controls 

(n=19) 

Ð PL total n-6, EPA, DHA, ALA & 

total n-3 in anorexics;+++ NS bet-grp 

difference in plasma cholesterol 

esters n-3; Ð DGLA in anorexics; +

Ð total n-3 in plasma triglycerides 

in anorexics;+ Ð (n-6-)DPA & GLA 

in plasma triglycerides in anorexics+

Total 

quality: 1 

[Grade: C] 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 fatty acids; n-6 = omega-6 fatty 

acids; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; EEPA = ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant statistical 

difference; N/A = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; ∆ = change; RBC = 

red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine phosphoglycerides; Jadad total = 

Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Holman et al. compared the plama phospholipid fatty acid composition in young females 

with anorexia nervosa (n=8; mean age: 18.4 [15-24] years) admitted to a treatment program in an 

urban clinic, with that of healthy female adults (n=19; mean age: 23.5 years).116 All patients had 

lost at least 15% of their usual body weight. No inappropriate methods to handle lipids were 

described in either study. 

Langan and Farrell showed that there were no significant between-group differences in the 

fatty acid composition of total plasma lipids.117 Only plasma phospholipid LA and ALA were 

significantly reduced in the group with anorexia compared with controls, while DHA was 

significantly higher in the females with anorexia. The total amount of omega-6 fatty acids was 

significantly lower in those with anorexia compared with normal controls, yet the AA/LA ratio 

was significantly higher among patients with anorexia compared with controls. 

Holman et al. observed that the phospholipid content of total omega-6 fatty acids was 

significantly reduced in the patients with anorexia compared with controls.116 The same 

observation was made with respect to EPA, DHA, ALA and total omega-3 fatty acids. When the 

analysis was performed on plasma cholesteryl esters, there were no significant between-group 

differences for the omega-3 fatty acids, while DGLA was significantly lower in patients than in 

controls. For the plasma triglycerides fraction, total omega-3 fatty acid content was significantly 
92 

reduced in patients compared to healthy subjects. The only two omega-6 fatty acids exhibiting a 

significant reduction in the patient group were DPA and GLA. 

Study quality and applicability. Both studies received an applicability rating of I. Their 

mean quality score was 1.5. 

Summary Matrix 7: Study quality and applicability of evidence regarding the association between omega-3 or 

omega-6/omega-3 fatty acid content of biomarkers and onset, continuation or recurrence of anorexia nervosa 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I 

Holman 

Langan 

1995 

1985 

27 

28 

Author Year n Author Year n Author Year n II 

Applicability 

Author Year n Author Year n Author Year n

III 

n = number of allocated/selected participants 

Although all of the included studies were controlled, none were prospective by design. Thus, 

meta-analysis was not considered. Insufficient data precluded an assessment of the possible 

impact of covariates and confounders. 

Are Omega-3 Fatty Acids Efficacious as Primary Treatment 

for Attention Deficit/Hyperactivity Disorder? 

As observed in Summary Table 19 (see below), derived from Evidence Table 1 (Appendix 

E*

), three RCTs and one comparative before-after study met eligibility criteria. Studies were 

published between 2001 and 2004. 

One RCT conducted by Brue et al. included children allocated, in part, on the basis of 

whether or not they were receiving methylphenidate (Ritalin®).118 As a result, data for those not 

receiving this medication reflect the primary treatment of AD/HD and are reviewed here. Other 

data from this RCT are presented below as evidence concerning the supplemental treatment of 

AD/HD. To minimize the presentation of redundant information, Brue et al.’s study is described 

once in detail. 

Overview of Relevant Studies 

Richardson and Puri’s RCT evaluated the effects of supplementation with highly unsaturated 

(HUFA) fatty acids in children (n=41; 8-12 years) with both AD/HD-related symptoms and 

specific learning difficulties (mainly dyslexia).119 Children were not formally assigned a 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
93 

diagnosis of AD/HD. Teacher-identified children were allocated to receive for 12 weeks either 

olive oil placebo or a “cocktail” including 186mg/d EPA, 480mg/d DHA, 96mg/d GLA, 60 IU/d 

vitamin E (as antioxidant), 864mg/d cis-linolenic acid, 42mg/d AA and 8mg/d thyme. 

Behavioral and learning problems associated with AD/HD were assessed using Conners Parent 

Rating Scale (CPRS). Analyses of teacher ratings were not conducted given that the children 

were new to their school. 

Summary Table 19: Omega-3 fatty acids as primary treatment forattention deficit/hyperactivity disorder 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects

Internal 

validity Applicability 

Richardson, 

2002, UK: 

12 wk parallel 

RCT119

186mg/d EPA, 

480mg/d DHA, 

96mg/d GLA, 

864mg/d cislinolenic acid, 

42mg/d AA & 8mg/d 

thyme (n=22) 

olive oil pb 

(n=19) 

All PP analyses: Ð DSM 

Inattention,+

 Conners 

ADHD Index+

 & 

psychosomatic symptoms+

in treatment grp 

Jadad 

total: 5 

[Grade: 

A]; 

Schulz: 

Adequate 

II 

Hirayama, 

2004, Japan: 

2 mo parallel 

RCT120

3.6g/wk DHA & 

700mg/wk EPA 

(n=20) 

 

olive oil pb 

(n=20) 

No improvement of AD/HD 

symptoms; Ð errors of 

commission++ & Ï

shortterm memory in 

controls+

 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

III 

Brue, 2001, 

US: 

12 wk 

parallel 

RCT118

No Ritalin: 2g/d 

flaxseed + dietary 

supplements 

(n=15)/ 

No Ritalin: dietary 

supplements + 

slippery elm pb 

(n=15) 

Ritalin: 2g/d 

flaxseed + 

dietary 

supplements 

(n =15)/ 

Ritalin: dietary 

supplements + 

slippery elm 

pb 

(n = 15) 

No Ritalin pts: NS effect for 

parent & teacher rated 

inattentiveness; Ð

teacher-rated 

hyperactivity/impulsivity+ in 

flaxseed+supplement grp 

whereas opposite 

observed for parent 

ratings+ 

Jadad 

total: 2 

[Grade: 

C]; 

Schulz: 

Unclear 

I 

Harding, 

2003, US: 

 4 wk 

comparative 

before-after 

study121

 180 mg/d EPA + 

120 mg/d DHA 

(n=10) 

Ritalin 

(n=10) 

for both grps: Ï FSRCQ++

& Ï FSACQ;+++ NS betgrp differences on FSRCQ 

& FSACQ; NS bet-grp 

differences yet both 

groups’ Ï for ARCQ,++ 

VRCQ,+

 AAQ++ & VAQ++ 

Total 

quality: 4 

[Grade: 

C] 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 fatty acids; n-6 = omega-6 fatty 

acids; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; EEPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between;

grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; FSRCQ = Full Scale Response Control Quotient; FSACQ 

= Full Scale Attention Control Quotient; ARCQ = Auditory Response Control Quotient; VRCQ = Visual Response Control 

Quotient; AAQ = Auditory Attention Quotient; VAQ = Visual Attention Quotient; Jadad total = Jadad total quality score: 

reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation concealment 

(adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower 

Hirayama et al. investigated primarily the effects of DHA on symptoms of AD/HD.120 They 

conducted an RCT of children (6-12 years) recruited by psychiatrists. Children were assigned to 
94 

receive, for 2 months, either 3.6 g/wk DHA plus 700mg/wk EPA from fish oil contained in 

active foods (fermented soybean milk, bread rolls and steamed bread) or these same foods 

without fish oil. Most of the children were not receiving medication (n=34/40). AD/HD related 

symptoms, aggression, visual perception, visual and auditory short-term memory, development 

of visual-motor integration, continuous performance and impatience were assessed in this study. 

 Brue et al. conducted two 12-week trials to evaluate the efficacy of a dietary supplement 

combination and flaxseed for the treatment of inattentiveness and hyperactivity in children with 

AD/HD (mean age: 8.4 years; 4-12 years).118 Each child was supposed to participate in both 

studies. However, 51 of 60 children enrolled in the first study completed the second RCT as 

well. To initiate the first RCT, 30 children were chosen randomly from a group not taking any 

stimulant medication and 30 were randomly chosen from those taking methylphenidate. Each 

RCT included two experimental and two control groups. Here, we are interested only in the 

second trial because the first one did not include an omega-3 fatty acid exposure. 

The second trial consisted of unmedicated patients randomly allocated to receive either 2 g/d 

flaxseed plus a dietary supplement combination (40 mg/d Ginkgo biloba [proposed effect: mental 

clarity/alertness], 800 mg Melissa officinalis [proposed effect: relaxing effect], 120 mg Grapine 

[proposed effect: attention, memory], 140 mg dimethyaminoethanol [proposed effect: memory, 

learning], 400 mg L-glutamine [proposed effect: mental clarity/alertness]) or the dietary 

supplement combination paired with a slippery elm supplement as placebo (amount not 

reported).118 As will be described below, children taking methylphenidate were likewise 

randomized to these study groups. Participants were instructed to take their intervention twice 

daily, once with breakfast and then with an afternoon snack or dinner. Only the results with 

respect to unmedicated children are presented here. Data from children receiving the 

intervention supplemental to methylphenidate are described below. The CPRS and CTRS were 

used to measure study outcomes. 

Harding et al. conducted a study in children (7-12 years) with AD/HD. They were recruited 

by a clinical child psychologist. They were then divided, by parental choice, into two groups. 

They received, for 4 weeks, either Ritalin at a dose of 5-15 mg two to three times daily (n=10), 

or dietary supplementation containing a mix of essential fatty acids (e.g., 180 mg/d EPA and 120 

mg/d DHA from 1g salmon oil), a multiple vitamin (e.g., thiamine, niacin), multiple minerals 

(e.g., magnesium, calcium), phytonutrients, phospholipids (soy lecithin), probiotics (n=10) and 

amino acids (e.g., glutamine). 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. Three parallel RCTs118-120 and one comparative before-after study,121

each involving children, were conducted to evaluate the efficacy of omega-3 fatty acids as a 

primary treatment for AD/HD. Inclusion and exclusion conditions were well-defined in three 

studies.118,119,121 Hirayama et al. did not specify any exclusion criteria.120 Only Brue et al.118

employed a design having more than two groups (i.e., 4). However, only one of their study arms 

addressed the present question. A total of 161 children were randomized. The mean sample size 

for the four studies was 40.25 (range: 20-60) participants, with the Brue et al. trial being the 

largest (n=60) and the Harding et al. study being the smallest (n=20). Study participants 

received the intervention for an average of 9 weeks, with the Harding et al. intervention being the 

shortest (i.e., 4 weeks).121 The RCTs were conducted in the US,118 the UK 119 and Japan.120 The 

UK RCT was funded by the Dyslexia Research Trust Funding,119 and the study from Japan by 
95 

Japan Fisheries Association and the Foundation for Total Health Promotion.120 The funding 

sources for the two US trials were not reported.118,121

Population characteristics. The mean age of study participants across the four trials was 

impossible to determine given that full sample means were not provided in two trials.120,121 The 

age of the participants ranged from 4 to 12 years when all studies were combined. The sex ratio 

was provided in three studies.118-120 Males were consistently more strongly represented in these 

studies (80%-86%). With respect to racial/ethnic backgrounds, Hirayama et al.’s study likely 

included an Asian population120 while similar data were not reported for the UK, or for the US, 

sample populations.118,121,121

All studies used DSM-IV criteria to identify AD/HD.118-121 Hirayama et al. reported that 

eight of 40 children might not have been identifiable as AD/HD according to DSM-IV criteria 

but this diagnosis was nevertheless “strongly suspected” by two psychiatrists.120 Even though 

there were no significant differences between the two study groups on a number of bases, it 

should be noted that, in the control group there were more patients taking 

medication/polymedication (4 vs 2) than in the DHA group. As well, there were more patients in 

the control group with a comorbid condition (15 vs 12), including Asperger’s syndrome (7 vs 2), 

conduct disorder (3 vs 0) or mood disorder (5 vs 1). Conversely there were more patients with 

learning disorders in the DHA group than in the controls (10 vs 5).120 Overall, almost threequarters (n=27/40) of the children exhibited comorbidity. At baseline, no significant betweengroup differences were observed on outcome measures. 

In the study conducted by Richardson et al. the participants had, in addition to AD/HDrelated symptoms, specific learning difficulties assessed by the Similarities and Matrices subtests 

from the British Ability Scales (BAS).119 Patients with a history of any other neurological or 

major psychiatric disorder or significant medical problems were excluded. No patients were 

receiving any medication. At baseline, the two groups did not differ significantly for age, sex, 

ethnicity or on any of the Conners scales. 

The Brue et al. report indicated that participants taking a stimulant medication other than 

methylphenidate were excluded, as were those with serious and preexisting medical or 

psychological conditions such as asthma or depression.118 These authors did not report any 

baseline data. Harding et al. excluded patients with co-existing conduct disorder or oppositional 

defiant disorder, medication use, street drugs, or use of other nutritional or botanical 

supplements.121 

Intervention/exposure characteristics. In the study conducted by Richardson and Puri, 

children in the treatment group received a supplement containing both omega-3 and omega-6 

fatty acids. The sources of these agents were not identified. Vitamin E was added as an 

antioxidant. The placebo group received an unspecified dose of olive oil in identical capsules.119 

In the study by Hirayama et al., the treatment group received active foods containing fish oil 

(fermented soybean milk; bread rolls and steamed bread) that provided 3.6 g/wk DHA and 700 

mg/wk EPA.120 Fermented soybean milk was given three times per week and provided 600 mg 

DHA per 125 mL. Bread rolls and steamed milk were given twice a week, providing 300 mg 

DHA per 45g and 600 mg DHA per 60g, respectively. The placebo group received the same 

foods but containing olive oil.120 The authors masked the fishy taste in the milk product using 

special flavors (no method reported). For the other active foods, the fish oil was emulsified with 

fruit juices. No mention was made as to whether these same procedures were applied to placebocontaining foods. Parents were asked to maintain their child’s habitual diet other than reducing 

bread consumption to accommodate the inclusion of breads containing the exposure.120 Brue et 
96 

al.’s dietary supplement “cocktail” is well described above. Harding et al.’s active ingredients 

are too numerous to mention them all here.121

Not one of the trial reports described the manufacturers of the sources of their interventions, 

the purity of their exposures, or whether, or how, the presence of methylmercury was tested for, 

or eliminated from, the sources.118-121 

Cointervention characteristics. Omega-3 fatty acids were often given concurrently with 

other agents, including omega-6 fatty acids, vitamins, minerals, polynutrients, probiotics and 

amino acids.119,121 Hirayama et al. stated that DHA, from fish oil, was added to foods (fermented 

soybean milk, bread rolls and steamed bread).120 However, the nutritional content of these foods 

was not reported. In these investigators’ control group, four patients were receiving medication, 

including methylphenidate (n=1), methylphenidate plus risperidone (n=1), carbamazepine plus 

fluvoxamine (n=1) or carbamazepine plus sulpiride (n=1).120 Two patients in the DHA group 

were exclusively taking methylphenidate. 

Outcome characteristics. Richardson and Puri defined changes in CPRS scores (AD/HD 

subscales, AD/HD global scales) as the primary outcome.119 Hirayama et al. powered their study 

to assess changes in aggression using a questionnaire developed by the authors.120 Other 

assessments included AD/HD-related symptom criteria based on DSM-IV, visual perception, 

visual and auditory shortterm memory, visual-motor integration, a continuous performance test 

and an impatience test. Brue et al. employed the DSM-IV Inattentive and Hyperactive-Impulsive 

subscales.118 The primary outcome in the Harding et al. study was the Intermediate Visual and 

Auditory/Continuous Performance Test (IVA/CPT) although CPRS data were obtained as 

well.121 Two major quotients are derived from the six primary IVA/CPT scales: the Full Scale 

Response Control Quotient (FSRCQ: prudence, consistency, stamina) and the Full Scale 

Attention Control Quotient (FASCQ: vigilance, focus, speed). 

Study quality and applicability. The three RCTs received a mean Jadad total quality score 

of 3.3, indicating sound internal validity.118-120 Their three applicability ratings ranged from I to 

III. The applicability rating for the comparative before-after study was I, and it received a total 

quality score of 4. 

Summary Matrix 8: Study quality and applicability of evidence regarding the primary treatment of attention 

deficit/hyperactivity disorder (all designs) 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I 

BrueU 

Harding 

2001 

2003 

60 

20 

Author Year n Author Year n Author Year n

II RichardsonA 2001 41 

Applicability 

Author Year n Author Year n Author Year n

III HirayamaU 2003 40 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment 
97 

Qualitative Synthesis of Individual Study Results 

Richardson and Puri compared the changes in CPRS subscale scores after 12 weeks.119 From 

the 41 patients enrolled, 15 in the active group and 14 in the placebo group completed the study. 

Analyses at endpoint revealed that the active treatment group had significantly lower scores on 

DSM Inattention, Conners ADHD Index and psychosomatic symptoms. 

Hirayama et al. reported that all subjects completed the study. Data analyses did not show 

any improvement in AD/HD symptoms (e.g., problems of inattention, hyperactivity/impulsivity) 

in the DHA group compared to the placebo group. The number of errors of commission on the 

continuous performance test decreased significantly in the control group. Visual short-term 

memory was significantly improved in the control group. Excluding data from those receiving 

medication (i.e., supplemental treatment patients) or from those only suspected of being AD/HD 

did not change these results (no data reported). Food consumption was estimated to be close to 

100% (no data reported). 

Brue et al.’s results indicated no significant between-group differences on parent and teacher 

ratings of inattentiveness. Teacher-reported hyperactivity/impulsivity was significantly lower in 

the flaxseed plus supplement combination group, compared with the supplement combination 

plus placebo group. However, the opposite was observed for parent ratings. 

Significant improvements were observed on both the FSRCQ and FSACQ in each of the 

study groups of Harding et al.121 There were no significant between-group differences on either 

the FSRCQ or the FSACQ. No significant between-group differences were observed for the 

following four subquotients although both study groups’ improvements were statistically 

significant: Auditory Response Control Quotient, Visual Response Control Quotient, Auditory 

Attention Quotient and the Visual Attention Quotient. 

Quantitative Synthesis 

Meta-analysis was not attempted for several reasons. The two studies employing DHA and 

EPA as active treatment employed different research designs (i.e., Harding et al.’s 

noncomparative before-after study121 vs Hirayama et al.’s RCT120). More importantly, though, in 

the only two studies using a common comparator (i.e., olive oil pacebo), their active treatments 

were completely different (i.e., Richardson and Puri’s “cocktail”119 vs Hirayama et al.’s 

DHA+EPA exposure120). 

Impact of Covariates and Confounders 

A few studies attempted to control for possible confounding, including the study of Harding 

et al.,121 which excluded children with externalizing disorders commonly associated with 

AD/HD (i.e., conduct disorder, oppositional defiant disorder), as well as the study of Hirayama 

et al., where the children maintained their background diets.120 On the other hand, the latter 

study also included subjects with a wide range of comorbid conditions;120 and, Richardson and 

Puri included children with a variety of learning difficulties.119 Yet, the inconsistent findings, 

including a small number of significant clinical effects, and the variability in both the types of 

intervention and comparator made it impossible to begin to reliably identify key covariables 

affecting clinical outcomes. 
98 

Are Omega-3 Fatty Acids Efficacious as Supplemental 

Treatment for Attention Deficit/Hyperactivity Disorder? 

As observed in Summary Table 20 (see below), derived from Evidence Table 1 (Appendix 

E*

), three RCTs met eligibility criteria. Studies were published in 2001 or 2003. Results for 

children on methylphenidate from the Brue et al. trial are described here. 

Overview of Relevant Studies 

Voigt et al. conducted an RCT investigating DHA supplementation in children (n=63; 6-12 

years) diagnosed with AD/HD.122 Children being treated successfully with stimulant medication 

were recruited by a pediatrician. They were randomly assigned to receive either 345mg/d DHA 

or placebo (undefined) for 4 months. Children with comorbid conduct disorder or oppositional 

defiant disorder were eligible. Measures of attention and impulsivity were assessed by changes 

in scores on the Test of Variables of Attention (TOVA) and the Children’s Color Trails Test. 

Other outcomes included scores on the Child Behavior Checklist (CBCL), and the Conners 

Rating Scale, in addition to plasma phospholipid fatty acid concentrations. 

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
99 

Summary Table 20: Omega-3 fatty acids as supplemental treatment for attention deficit/hyperactivity disorder 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Notable 

clinical 

effects

Notable 

biomarker 

effects2,3

Notable 

clinicalbiomarker 

correlations 

Internal 

validity Applicability 

Brue, 

2001, US: 

12 wk 

parallel 

RCT118

No Ritalin: 

2g/d 

flaxseed + 

dietary 

supplements 

(n=15)/ 

No Ritalin: 

dietary 

supplements 

+ slippery 

elm pb 

(n=15) 

Ritalin: 2g/d 

flaxseed + 

dietary 

supplements 

(n =15)/ 

Ritalin: 

dietary 

supplements 

+ slippery 

elm pb 

(n = 15) 

Flaxseed + 

supplement: 

fewer 

attention 

problems 

(teacher 

only);+

 NS 

difference: 

hyperactivity/ 

impulsivity 

n/a n/a Jadad 

total: 2 

[Grade: 

C]; 

Schulz: 

Unclear 

I 

Voigt, 

2001, US: 

4 mo 

parallel 

RCT122

345mg/d 

DHA 

(n=32) 

pb 

(undefined) 

(n=31) 

NS bet-grp 

differences 

on TOVA, 

Color Trails 

tests, CBCL 

or Conners 

NS ∆ DHA 

in pb; Ï

DHA++ & 

Ð (n-3-) 

DPA++ in 

DHA grp 

NS 

correlations 

for plasma 

PL DHA & 

TOVA or 

Color Trails 

Jadad 

total: 4 

[Grade: 

A]; 

Schulz: 

Adequate 

I 

Stevens, 

2003, US: 

4 mo 

parallel 

RCT123

480mg/d 

DHA, 

80mg/d 

EPA, 

40mg/d AA, 

96mg/d GLA 

& 24mg/d 

vitamin E 

(n=25) 

6.4g/d olive 

oil pb 

 (n= 25) 

2/16 

improved 

outcomes: 

conduct 

problems+

 & 

attention 

symptom;+

more 

oppositional/

defiant 

disorders 

improved in 

PUFA grp+ 

NS bet-grp 

differences 

for ∆ in 

plasma 

FAs; size 

of Ð RBC 

AA greater 

in PUFA 

group+ 

% ∆ in 

parent ASQ 

negatively 

correlated 

with % ∆ in 

RBC EPA+

 & 

positively 

with RBC 

AA;+

 % ∆ in 

teacher 

attention 

negatively 

correlated 

with RBC 

DHA+

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Adequate 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 fatty acids; n-6 = omega-6 fatty acids; ALA 

= alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA = ethyl 

eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study participants; NR = not 

reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); 

mo = month; wt = weight; ∆ = change; ASQ = Abbreviated Symptom Questionnaire; CBCL = Child Behavior Checklist; DBD = 

Disruptive Behavior Disorders; RBC = red blood cells; PL = phospholipid; Jadad total = Jadad total quality score: reporting of 

randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation concealment (adequate, 

inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower 

Stevens et al. conducted an RCT to evaluate the effects of supplementation with PUFA on 

the behavior and blood fatty acid composition of children (n= 50; 6-13 years) with AD/HD-like 

symptoms, who were also reporting thirst and skin problems potentially indicative of omega-3 

fatty acid deficiency.123 Fifty children were randomized to receive daily either the PUFA 

supplement Efalex® (480 mg/d DHA, 80 mg/d EPA, 40 mg/d AA, 96 mg/d GLA and 24 mg/d 

vitamin E as anti-oxidant preservative) or 6.4 g/d olive oil as placebo for 4 months. Only five 

participants in each group were not receiving medication. The primary outcome measures were 

the parent- and teacher-endorsed Conners Abbreviated Symptom Questionnaires (ASQ) and the 
100 

Disruptive Behavior Disorders (DBD) Rating Scale. Other outcomes measures were the Conners 

CPT and the Woodcock-Johnson Psycho-Educational Battery-Revised (WJ-R). Brue et al. 

conducted the third RCT, described with respect to the primary treatment of AD/HD.118

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. Three RCTs examined the use of omega-3 fatty acids as 

supplemental treatment for AD/HD.118,122,123 A total of 131 children were randomized. The 

mean sample size for the three studies was 43.3 (range: 30-51) children. Participants received 

the intervention for an average of 14.6 weeks (range: 12-16 weeks). All three studies were 

conducted in the US. The study conducted by Voigt was funded in part by the US Department of 

Agriculture.122 The Stevens et al. study was funded by grants from the NIMH, National 

Fisheries Institute and Scotia Pharmaceuticals, Ltd.123 Brue et al.’s funding source was not 

reported.118 

Population characteristics. The mean age of children enrolled in these 3 trials was 

approximately 9.16 years (range: 4-13 years).118,122,123 Those in the Brue et al. study tended be 

younger (mean: 8.4 years). Males were consistently better represented in the three studies 

(~80%). The percentage of white participants in Voigt et al.’s study was 100% in the DHA 

group and 85% in the placebo group.122 These data were not provided for the other two 

RCTs.118,123

Two studies employed DSM-IV diagnostic criteria118,122 while a third one did not report how 

AD/HD was identified.123 Brue et al. excluded children with serious and preexisting medical or 

psychological conditions such asthma or depression.118 Voigt et al. excluded patients who had 

experienced ineffective treatment with stimulant medication, treatment with other psychotropic 

medications, previous diagnoses of other childhood psychiatric disorders, use of dietary 

supplements other than vitamins, occurrence of a significant life event in the past six months, a 

history of head injury, receipt of special education services for mental retardation or a pervasive 

developmental disorder, premature birth, exposure to tobacco, drugs or alchol, or the diagnosis 

of a disorder of lipid metabolism or any other chronic medical condition.122 There were no 

significant between-group baseline differences for sex, methyphenidate dose, TOVA scores or 

Color Trails scores. All participants in the DHA group were white compared to 85% in the 

placebo group. While 22 of those allocated to the DHA group received a DSM-IV subtype 

diagnosis of combined (inattentive plus hyperactive) AD/HD and five were identified as 

predominantly inattentive, all children in the placebo group met criteria for combined subtype. 

Thirteen children in the DHA group and 15 children in the placebo group met DSM-IV criteria 

for oppositional defiant disorder. Six children in the DHA group and two children in the placebo 

group met criteria for conduct disorder. Minor between-group differences for age (i.e., slightly 

older in placebo group) and AD/HD subtype were controlled for in analyses. 

Stevens et al. included children under the care of a clinician for AD/HD who were receiving 

standard therapy and were required to have a high frequency of skin/thirst symptoms evaluated 

by a questionnaire administered to parents.123 They excluded children with chronic health 

problems such as diabetes and kidney disease. Study groups were balanced for sex and 

medication status. No significant between-group differences were observed for age, height, sex, 

medication status, frequency of thirst/skin symptoms or nutrient intake. At baseline, few 

between-group differences in clinical outcomes were noted. The inattention score on the 

Disruptive Behavior Disorders (DBD) Rating Scale scores was higher in the placebo group. 
101 

Parent-rated, Conners-related Abbreviated Symptom Questionnaire (ASQ) scores were also 

higher in the placebo group. Inconsistent between-group differences were seen for measures of 

reaction time. No significant between-group differences were seen for either plasma or RBC 

fatty acid levels. 

Intervention/exposure characteristics. Voigt et al. identified the source of their 

intervention as an algae-derived triglyceride capsule providing 345mg of DHA per day. 

Although, it was stated that the placebo was identical in appearance and was supplied by the 

same company, the content was not defined.122 Patients in the Steven et al. study received either 

eight capsules a day of Efalex® or placebo.123 The intervention characteristics of the study 

conducted by Brue et al. have been described previously (see above).118 Voight et al. reported 

their exposure’s manufacturer (Martek Biosciences Corporation, Columbia, MD)122 as did 

Stevens et al. (Efamol Ltd).123 None of the reports provided either purity data regarding their 

treatments or descriptions about whether, and how, the presence of methylmercury was tested or 

eliminated from the omega-3 fatty acid exposure. In the two studies that evaluated the fatty acid 

content of biomarkers, no notable inappropriate methods to extract, prepare, store or analyze 

lipids were described.122,123 

Cointervention characteristics. In each study, omega-3 fatty acids were supplied as 

supplemental treatment. The patients enrolled in Voigt et al.’s trial received either 

methyphenidate at a dose of 29.2+30.1 mg/d in the DHA group (n=25) or 29.3+17.6 mg/d in the 

placebo group (n=22), dextroamphetamine at a dose of 15.0 mg/d (n=1) in the DHA group or 

16.3+8.8 mg/d in the placebo group (n=2) or amphetamine/dextroamphetamine at a dose of 10 

mg/d (n=1) in the DHA group or 15.0+/-8.7 in the placebo group (n=3).122 The treatment 

duration was 26.3 months in the DHA group compared to 29.5 months in the placebo group. In 

the Stevens et al. trial, children received methylphenidate, methylphenidate plus an 

antidepressant, or other medication such as pemoline or dextroamphetamine salts. Both study 

groups in the Brue et al. RCT were receiving methylphenidate.118

Outcome characteristics. Voigt et al. employed as primary outcome the changes in scores 

on the TOVA.122 They also evaluated the impact of supplementation on the omega-3 fatty acid 

content of plasma phospholipid fractions. In Stevens et al.’s trial, the parent- and teacher-rated 

ASQ and the DBD were the primary outcomes.123 Brue et al. employed the DSM-IV’s 

Inattentive and Hyperactive-Impulsive subscales as outcomes.118 

Study quality and applicability. The mean Jadad total quality score was 3, with each RCT 

receiving an applicability rating of I.118,122,123

Summary Matrix 9: Study quality and applicability of evidence regarding the supplemental treatment of 

attention deficit/hyperactivity disorder 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I VoigtA 2001 63 StevensA 2003 50 BrueU 2001 60 

Author Year n Author Year n Author Year n

II 

Author Year n Author Year n Author Year n

Applicability 

III 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment 
102 

Qualitative Synthesis of Individual Study Results 

Voigt et al. only conducted statistical analyses on complete TOVA and Color Trails test data 

available at baseline and at the end of the 4-month study.122 This amounted to data from only 49 

(DHA=25, placebo=24) of the 63 randomized children. Capsule counts indicated high levels of 

compliance. After 4 months, there were no statistically significant between-group differences in 

scores on any component of the TOVA, for scores from either of the Color Trails tests, on the 

parent-endorsed CBCL or Conners Rating Scales. The plasma phospholipid DHA content in the 

placebo group remained unchanged, whereas that of the DHA group increased significantly. 

This increase was accompanied by a nonsignificant decline in AA, and a significant decrease in 

(omega-3-)DPA. No significant correlations were seen between initial plasma phospholipid 

DHA content and initial TOVA scores, final plasma phospholipid DHA content and final TOVA 

scores, or between changes in these two variables. The same patterns held for Color Trails data. 

In the Stevens et al. study, the analyses of primary endpoints ASQ and DBD were conducted 

on those subjects who completed the 4-month intervention and had a minimum compliance of 

75%.123 The total number of subjects evaluated for clinical outcomes at the end of the study 

were 18 in the PUFA group and 15 in the placebo group. Secondary analyses were performed on 

an ITT basis, with the last observation carried forward for all subjects who were randomized and 

who had received the first dose of the supplement. 

A clear benefit of PUFA supplementation on behavioral characteristics of AD/HD was not 

observed. A significant improvement in the PUFA compared to placebo was observed in only 

two of sixteen outcome measures: conduct problems rated by parents and attention symptoms 

rated by the teacher. Only one of eight DBD rating scales showed a treatment effect, with a 

significantly greater proportion of children’s oppositional defiant disorder improving clinically in 

the PUFA group. Supplementation did not produce a significant benefit in decreasing the 

frequency of thirst/skin symptoms. No significant between-group differences were found related 

to changes in plasma fatty acid levels. The magnitude of the decrease in RBC AA was 

significantly greater in the PUFA group. The percentage change in parent-rated ASQ scores was 

significantly and negatively correlated with the percentage change in RBC EPA and positively 

correlated with RBC AA. Percentage change in teacher-endorsed Attention scores on the DBD 

was significantly and negatively correlated with RBC DHA. 

Brue et al.’s teacher-endorsed data revealed that children taking the dietary supplement 

combination, with flaxseed in addition to methylphenidate, manifested significantly less 

inattentiveness. Parent data did not confirm this finding. No significant between-group 

differences for either parent or teacher ratings of hyperactivity/impulsivity were found. 

Quantitative Synthesis 

Given the lack of comparability in the interventions, comparators, and their combinations, in 

addition to the variability in the three studies’ populations especially related to the presence of 

varying types of comorbid condition, meta-analysis was not performed. Only one report 

explicitly identified the AD/HD subtypes included in their RCT.122 This is a key population 

source of clinical heterogeneity. 
103 

Impact of Covariates and Confounders 

Voigt et al.’s trial was the best controlled of the three studies.122 They identified the subtypes 

of DSM-IV AD/HD allocated to each study group although their baseline assessments revealed 

that the DHA group contained a less homogeneous distribution of subtypes than did their control 

group. They also controlled for other confounders (e.g., other psychiatric diagnoses, use of 

dietary supplements), while at the same time allowing entry into the study various types of 

comorbid condition with the potential to influence outcomes (e.g., oppositional defiant disorder, 

conduct disorder). Voigt et al. provided the simplest of the three active treatments, focusing 

exclusively on DHA supplementation. Yet, they found no benefits relating to their very small 

dose, which in and of itself may have contributed to the failure to find a significant clinical 

effect. 

The other two trials exercised considerably less experimental control, and when viewed 

together, the three studies provided at best an inconsistent picture of the benefits of providing 

omega-3 fatty acids. Thus, as with the topic pertaining to the primary treatment of AD/HD, the 

inconsistent findings, including a small number of significant clinical effects, and the variability 

in both the types of intervention and comparator made it impossible to begin to reliably identify 

key covariables affecting clinical outcomes. 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Attention Deficit/Hyperactivity Disorder? 

As observed in Summary Table 21 (below), derived from Evidence Table 3 (Appendix E*), 

one cross-sectional study published in 1999 met eligibility criteria. 

Overview of Relevant Study’s Characteristics and Results 

Yang et al. employed a cross-sectional design to investigate whether there were any 

differences in dietary intake between children diagnosed with AD/HD and normal healthy 

children.94 The AD/HD group (n=20; 4-8 years) consisted of outpatients (90% male) with a 

mean age of 5.7 (SD=0.9) years, who met DSM-IV criteria for AD/HD (duration not reported). 

Inclusion criteria for this group included a score of greater than 80% on the Standard Child 

Activity Level Form filled out by parents and teachers. The normal control group (n=32) 

consisted of children (91% male) with a mean age of 5.2 (SD=1.1) years recruited from junior 

and senior kindergarten, as well as grades one and two from schools in Taipei, Taiwan. 

Inclusion criteria for controls included being ages 4 to 8 years, and verification of good health. 

Excluded were children with AD/HD. The male–to-female ratio in the control group 

approximated that of the AD/HD group. 

Anthropometric measurements were taken and participants filled out a dietary survey 

containing four categories: dietary intake from the previous 24 hours, 3-day dietary records, 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
104 

frequency of food intake, and dietary history. During the initial visit participants completed all 

categories of the dietary survey except for the 3-day dietary record. The latter was filled out 

following the initial visit and returned by mail. Given the extremely shortterm followup, and the 

data collected regarding past and present dietary intake, the study was considered a crosssectional design. Funding was provided by the Chun Qing Infant and Child Nutritional 

Research Foundation. 

Summary Table 21: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

attention deficit/hyperactivity disorder 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Yang, 1999, 

Taiwan: 

multiple-group 

cross-sectional 

study94

AD/HD 

children 

(n=20) 

healthy 

controls 

(n=32) 

via 24-hour dietary recall, the 

hyperactive grp had lower intake of 

LA+

 & ALA;+ only ALA+ Ð in 

AD/HD via 3-day dietary record 

Total 

quality: 5 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 95% confidence 

interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Response rates for the 3-day dietary record for the AD/HD and control subjects were 60% 

(n=12) and 87.5% (n=28), respectively. The two groups did not differ significantly in age, 

height, body weight, weight-for-length index, chest circumference or tricep skin thickness. 

There were no significant between-group differences in intake of tryptophan, cholesterol or 

saturated fatty acids. According to the 24-hour dietary recall, the hyperactive group had 

significantly lower intake of LA and ALA. Only ALA was reduced in AD/HD children, relative 

to controls, measured by the 3-day dietary record. 

Meta-analysis was not considered, and the existence of a single study, reporting few details, 

made it impossible to assess the possible impact of covariates and confounders. Yang et al.’s 

study received an applicability rating of III and a total quality score of 5. 

Is the Onset, Continuation or Recurrence of Attention 

Deficit/Hyperactivity Disorder Associated With Omega-3 or 

Omega-6/Omega-3 Fatty Acid Content of Biomarkers? 

As observed in Summary Table 22, derived from Evidence Table 2 (Appendix E*

), three 

cross-sectional studies met eligibility criteria. Studies were published between 1983 and 1995. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
105 

Overview of Relevant Studies’ Characteristics and Results 

Mitchell et al.’s study was supported by Efamol Research Ltd. and the Medical Research 

Council of New Zealand,125 Stevens et al.’s funding source was the State of Indiana,124 and the 

second Mitchell et al. study did not report this information.126

Mitchell et al. investigated the RBC fatty acid content in hyperactive children compared to 

normal control children.126 Inclusion and exclusion criteria were not described, and a formal 

diagnosis was not assigned. Enrolled were children (n=23; 91% male; 7.5-13 years) identified 

with “maladjusted disorder” (nomenclature not reported) from a residential school for 

maladjusted children. The central clinical feature was hyperactivity. The controls were children 

(n=20; 50% male; 10-13 years) from a regular intermediate school. No inappropriate methods to 

extract, prepare, store or analyze lipids were described. 

Summary Table 22: Association between omega-3 or omega-6/omega-3 content of biomarkers and onset, 

continuation or recurrence of AD/HD 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Mitchell, 1983, 

New Zealand: 

multiple-group 

cross-sectional 

study126

maladjusted 

(hyperactive) 

children 

(n=23) 

normal 

children 

(n=20) 

NS bet-grp differences in RBC 

FA content 

Total 

quality: 1 

[Grade: C] 

III 

Mitchell, 1987, 

New Zealand: 

multiple-group 

cross-sectional 

study125

hyperactive 

children 

(n=48) 

age- & 

sexmatched 

normal 

children 

(n=49) 

Ð DHA,+

 DGLA++ & AA+ in 

hyperactive children 

Total 

quality: 4 

[Grade: B] 

III 

Stevens, 1995, 

US: 

multiple-group 

cross-sectional 

study124

hyperactive 

boys 

(n=53) 

normal 

boys 

(n=43) 

Ï PUFA intake in AD/HD;+ Ð

plasma AA,+

 EPA,+ DHA+ & 

total n-3+++ in AD/HD; Ï n-6/n3 in AD/HD;++ Ð RBC AA & 

DPA in AD/HD+

 

Total 

quality: 3 

[Grade: C] 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 fatty acids; n-6 = omega-6 

fatty acids; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant 

statistical difference; N/A = not applicable; pb = placebo; grp = group; wk = week(s); mo = month; RBC = red blood cells; 

PL = phospholipid; Jadad total = Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts 

(/5); Schulz = reporting of adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 

95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase; Ð = decrease/reduction 

Mitchell et al.’s 1987 study examined the clinical characteristics and serum phospholipid 

EFA levels in DSM-III diagnosed hyperactive children (n=48; mean age: 9.1 years) compared 

with age- and sex-matched controls (n=49; mean age: 8.7 years).125 Subjects were recruited from 

the general population of Auckland using the Revised Behaviour Problem Checklist (RBPC) and 

the Conners Teacher Rating Scale (CTRS). The control group was drawn from two primary 

schools. The study groups exhibited no statistically significant differences for age, sex, ethnicity 

(92% European) and socioeconomic status. Some children in the hyperactive group (n=12) were 

on special diets, with ten on the Feingold diet and seven on sugar reduction diets. Between-
106 

group baseline differences were statistically significant for the RBPC Inattention subscale and 

CTRS scores, with higher scores in the hyperactive children. There was no significant betweengroup difference in medication use (no data reported). 

Stevens et al. evaluated the RBC and plasma fatty acid content in boys with AD/HD and sexmatched children without this disorder.124 The sample was drawn from the general population. 

The diagnosis was made using the CPRS and CTRS. Questionnaires measured food intake and 

health information. The AD/HD children (n=53, mean age: 9.1 years) and normal controls 

(n=43, mean age: 9.1 years) were well matched for age, height, weight BMI and socioeconomic 

status. AD/HD children were less likely to have been breastfed but more likely to have temper 

tantrums, problems getting to sleep and waking up, to be taking medications (e.g., Ritalin), to 

have stomachaches, ear infections and asthma. Baseline Conners scores were significantly 

higher in the AD/HD group. 

By univariate analysis, Mitchell et al. showed that there were no significant between-group 

differences for any RBC fatty acid content.126 Multivariate analysis revealed that a model 

involving ALA and AA, among other fatty acids, distinguished maladjusted and control children. 

There was no significant difference for RBC PUFA content between the sexes. 

In Mitchell et al.’s second study the absolute levels of DHA, DGLA and AA in serum 

phospholipids were significantly lower in hyperactive children compared to controls.125 No 

other omega-3 or omega-6 fatty acid compositions distinguished the two study groups. When 

hyperactive children were subdivided on the basis of their concentrations of DHA, DGLA and 

AA, high and low DHA subgroups did not differ significantly on any clinical outcomes. Higher 

probabilities of speech difficulties, slower development and learning difficulties were each 

associated with low AA levels. 

Stevens et al. demonstrated that the hyperactive group had a significantly higher PUFA 

intake in their diet compared to controls.124 The plasma levels of AA, EPA, DHA and total 

omega-3 fatty acids were significantly lower in hyperactive children. The plasma omega6/omega-3 fatty acid ratio was significantly higher in the hyperactive group. Patients with 

hyperactivity had significantly lower RBC AA and (omega-6-)DPA levels. There was a 

significant and negative correlation between DHA concentration and CPRS scores. 

Each of the Mitchell et al. studies received an applicability rating of III while the Stevens et 

al. study was assigned a I. Mean study quality for these studies was 2.7. 

Summary Matrix 10: Study quality and applicability of evidence regarding the association between omega-3 

or omega-6/omega-3 fatty acid content of biomarkers and onset, continuation or recurrence of attention 

deficit/hyperactivity disorder 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I Stevens 1995 96 

Author Year n Author Year n Author Year n II 

Author Year n Author Year n Author Year n

Applicability 

III Mitchell 1987 97 Mitchell 1983 43 

n = number of allocated/selected participants 
107 

Although all of the included studies were controlled, none were prospective by design. Thus, 

meta-analysis was not considered. As well, the three studies did not investigate the same 

biomarker sources. Given the small number of studies, and the variability in the definition of the 

study populations and their controls, it was impossible to meaningfully explore the possible 

impact of predefined covariates or confounders. 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Mental Health Status Difficulties? 

As observed in Summary Table 23 (below), derived from Evidence Table 2 (Appendix E*

), 

one cross-sectional study published in 2002 met eligibility criteria. 

Overview of Relevant Study’s Characteristics and Results 

Silvers and Scott conducted a cross-sectional survey investigating the possible association 

between dietary intake of fish and self-reported mental health status in adults (15-65+ years) 

living in New Zealand.127 The data collected were from a combined 1996/1997 health survey 

and a 1997 nutrition survey. Participants were sampled using a stratified design based on 

contingent geographic areas. The sample consisted of 11,921 households. The final response 

rate was 73.8% (n=7,862) for the health survey and 50% (n=4,644) for the nutrition survey. 

Analysis was conducted on data from 4,644 participants. Participants completed the SF-36 

questionnaire regarding their self-reported mental health status. Adjustments were made for the 

following potential confounders: age (four groups: 15-24 years; 25-44 years; 45-64 years; 65+ 

years), annual household income (four groups: < $20,000; $20,001-30,000; $30,001-50,000; 

$50,000+), smoking status (smokers, ex-smokers and non-smokers), alcohol use (non-drinkers, 

moderate drinkers scoring 1-7 on Alcohol Use Disorders Identification Test [AUDIT], problem 

drinkers scoring 8+ on AUDIT), and eating patterns (meat eaters, vegetarians, vegans). Funding 

was provided by the New Zealand Ministry of Health. 

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
108 

Summary Table 23: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

mental health difficulties 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Silvers, 2002, 

New Zealand: 

single 

population 

cross-sectional 

survey127

householders 

(n=4,644) 

Univariate analysis: NS correlation 

between fish consumption & 

mental health status; hierarchical 

regression, with age & income 

adjustments, association 

observed;+++ adjusting for age & 

household income, mental health 

status Ð in fish consumers;+++ 

adjusting for age, household 

income, smoking, alcohol 

consumption, & eating patterns an 

association++ 

Total 

quality: 5 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 95% confidence 

interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Respondents were divided on the basis of those who did (<once a month, to at least twice a 

day), or did not, consume fish.127 Univariate analysis revealed no significant correlation between 

fish consumption and mental health scores. By hierarchical regression, with age and income 

adjusted for, there was a significant association between fish consumption and mental health 

status. The mental health score was significantly lower in the group which consumed no fish, 

compared with the fish eaters. After adjusting for age, household income, smoking, alcohol 

consumption, and eating patterns this difference remained significant. This study received an 

applicability rating of III and a total quality score of 5. 

Given that only one study was identified, meta-analysis and a formal assessment of the 

potential influence of covariates and confounders were not undertaken. Although this study 

conducted their analysis by controlling for several confounders, results need to be replicated 

before any meaningful conclusions can be drawn. 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Tendencies or Behaviors With the Potential 

to Harm Others? 

As observed in Summary Tables 24 through 28 (below), derived from Evidence Tables 1 

through 3 (Appendix E*

), seven studies met eligibility criteria. These studies were published 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
109 

between 1996 and 2004. Five studies employed an RCT design while one cross-sectional study 

and a cross-national ecological analysis were also included. Although each question addressed 

the possible association of omega-3 fatty acid intake with the onset of tendencies or behaviors 

with the potential to harm others, the types of population fit into three categories. This is the 

order in which the studies are presented. 

The first three RCTs investigated the possible protective effects of omega-3 fatty acids 

against aggression in healthy volunteers.128-130 One RCT and a cross-sectional survey examined 

the possible protective potential of the exposure against anger and/or hostility in populations 

identified at risk for heart disease132 or identified as having cholesterol problems.99 The latter 

study, by Wardle et al., has been reviewed elsewhere with respect to depression and anxiety.99 

One RCT assessed the possible protective effect on the antisocial behavior in young adult 

prisoners, making this the only study designed specifically to investigate the exposure’s possible 

influence on the continuation of this behavior (i.e., secondary prevention).131 The final study 

assessed the possible association of seafood consumption and homicide mortality.133

Overview of Relevant Studies 

Hamazaki and colleagues conducted all three of the RCTs investigating the effect of omega-3 

fatty acid supplementation on aggression.128-130 The first two studies assessed the possible 

benefits of the exposure on healthy college volunteers129,130 while the final RCT enrolled elderly 

volunteers.128 

Hamazaki et al.’s first trial randomly assigned nonsmoking university students to receive 3 

months of either 1.5-1.8 g/d DHA (from fish oil; n=26) or control oil capsules (n=27) containing 

some omega-3 fatty acid content (97% soybean oil plus 3% fish oil; exact omega-3 fatty acid 

content not reported). The active intervention also contained some EPA and some omega-6 fatty 

acid content (see intervention/exposure characteristics below). Doses varied because they were 

adusted according to participants’ weight. The study began at the end of the students’ summer 

vacation and was completed in the middle of final exams (i.e., the stressor). The rationale was to 

see if stress could be prevented from becoming frustration and aggression. 
110 

Summary Table 24: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

tendencies or behavior with the potential to harm others (RCTs) 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects

Notable 

biomarker 

effects2,3

Internal 

validity Applicability 

Hamazaki, 

1996, 

Japan: 

3 mo 

parallel 

RCT130

1.5-

1.8g/d 

DHA & 

some 

EPA 

(n=27) 

oil capsules 

(97% 

soybean oil 

+ 

3% fish oil) 

(n=26) 

extraggression Ï in 

controls;++ NS ∆ for DHA 

grp; bet-grp difference+ 

NS bet-grp 

differences 

in ∆ for AA, 

EPA or DHA 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

III 

Hamazaki, 

1998, 

Japan: 

3 mo 

parallel 

RCT129

1.5 g/d 

DHA 

capsules 

(n=29) 

control 

capsules 

with some 

ALA & DHA 

(n=30) 

extraggression Ð in 

controls;+

 NS ∆ for DHA 

grp; bet-grp difference;+

 

NS ∆ hostility in either 

study group 

Ï RBC 

DHA+++ & 

EPA+++ in 

DHA grp; Ï

LA++ in 

controls 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

III 

Hamazaki, 

2002, 

Thailand: 

2 mo 

parallel 

RCT128

1.5g/d 

DHA + 

0.2g/d 

EPA 

from 3g/d 

fish oil 

capsules 

(n=20) 

3g/d mixed 

plant oil 

control 

(n=21) 

NS ∆ for extraggression 

for university controls; 

Ðfor DHA grp;+

 bet-grp 

difference in 

extraggression;+ NS betgrp difference for villagers; 

university= NS ∆ for 

controls; Ð for DHA grp;+

 

villagers= NS bet-grp 

difference for 

extraggression 

NS changes 

in FA in 

controls; In 

DHA group 

EPA & DHA 

Ï;

+++ AA 

Ï++ 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; 

grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; RBC = red blood cells; PL = phospholipid;; Jadad total = 

Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ï = decrease(d)/reduction/lower 

Hamazaki et al.’s second trial examined possible protective effects against aggression in 

normal volunteers under nonstressful conditions.129 Fifty-nine nonsmoking university students, 

with 15 males per study group, were randomized to receive 3 months of either DHA-rich fish oil 

capsules containing 1.5 g/d DHA (n=29) or the same control oil capsules (97% soybean oil plus 

3% fish oil; n=30) used in their first study. None of the participants had been enrolled in the first 

RCT. The timing of the trials’ initiation and completion determined that volunteers would not 

likely be subjected to the same stressful conditions as arranged in the first study (i.e., final 

exams). 

The third study focused on elderly Thai subjects.128 Forty-one subjects (50-60 years) were 

randomly assigned to receive either 1.5 g/d DHA (n=20) via 3g/d fish oil capsules or 3g/d of 

mixed plant oil via capsules (n=21) for 2 months. Extraggression was assessed at the beginning 

and end of the study. Immediately prior to its assessment at study end subjects were shown a 20-

minute, stress-inducing videotape of real crimes and accidents as the study’s stressor. 

Participants were recruited from two sources: university employees and villagers. 

Wardle et al.’s RCT investigated whether cholesterol-lowering diets influence mood, 

including depression, anxiety, anger/hostility, stress, and general psychological well-being.99 
111 

Adult volunteers (n=176) with elevated serum cholesterol levels (>5.2mM [198mg/dL]) were 

allocated to a low-fat diet (n=59), a Mediterranean diet (n=61), or a waiting-list control (n=56). 

Dietary treatments were given in eight sessions over the 12-week period. Participants completed 

a seven-day dietary intake diary before the first assessment. Outcomes included the STAI, the 

anger subscale of the POMS, GHQ to assess general psychological well-being, and the PSS. 

Dietary diaries were filled out at baseline and 12 weeks. 

Summary Table 25: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

tendencies or behavior with the potential to harm others (RCT) 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Notable clinical 

effects

Notable 

biomarker 

effects2,3

Internal 

validity Applicability 

Wardle, 

2000, 

England: 

12 wk 

parallel 

RCT99

Mediterranean 

diet (with oily 

fish) 

(n=61) 

low fat diet 

(n=59)/ 

waiting list 

control 

(n=56) 

All grps had withingrp improvement for 

STAI’s anger 

reactions;+

 NS betgrp differences for 

anger/hostility, 

stress, or general 

psychological wellbeing 

n/a Jadad 

total: 2 

[Grade: 

C]; 

Schulz: 

Adequate 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = 

between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; STAI = State-Trait Anger Inventory; Jadad 

total = Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of 

adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Iribarren et al. assessed the possible association between dietary omega-3 fatty acids, omega6 fatty acids and fish intake with the level of hostility in a sample of 3,581 urban white and black 

young adults.132 Their cross-sectional survey was conducted as part of the ongoing CARDIA 

cohort study investigating heart disease risk factors and subclinical coronary disease. The 

dietary assessment took place in 1992-1993, while data pertaining to hostility and other 

covariates were collected in 1990-1991. At baseline (1985-1986; n=5,115) participants had been 

18 to 30 years of age. Sampling ensured a balanced racial distribution, and included randomdigit dialing (Birmingham, Alabama), door-to-door recruitment (Minneapolis, Minnesota) and 

random selections from files at a medical care program (Oakland, California). Reassessments 

took place 2, 5, 7, 10 and 15 years from baseline. Retention was high even after 15 years (73%). 
112 

Summary Table 26: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

tendencies or behavior with the potential to harm others (cross-sectional study) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Iribarren, 2004, 

US: 

single 

population 

cross-sectional 

survey132

urban white & black 

young adults (n=3,581): 

black females (n=967) 

& males (n=672), white 

females (n=1,017) & 

males (n=925) 

Adjusted multivariate odds ratios 

of scoring in the upper quartile of 

hostility scores associated with 

one standard deviation increase 

in DHA intake;+

 consumption of 

fish rich in omega-3 fatty acids, 

when compared to no 

consumption, was associated 

with lower odds of high hostility.+

 

Total 

quality: 5 

[Grade: B] 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 

95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Gesch et al. empirically tested whether a “cocktail” of vitamins, minerals and essential fatty 

acids (0.08 g/d EPA, 0.044 g/d DHA, 1.26 g/d LA and 0.16 g/d GLA) would produce a reduction 

of antisocial behavior in adult prisoners at least eighteen years of age when compared to 

placebo.131 It had been hypothesized that offenders suffer from a lack of essential nutrients. The 

main focus was on whether or not antisocial behavior leading to disciplinary incidents would 

decrease from baseline. Given the requirements of life in an institution (e.g., parole), the 

analysis allowed participation ranging from 2 weeks to 9 months. Although 231 volunteers were 

identified, the number randomized to each group was not reported. The average time spent on 

supplementation was 142.6 days for the active treatment group (n=57 completers) and 142 days 

for the placebo group (n=55 completers). Randomization was stratified based on the four wings 

of the institution in which participants resided. 
113 

Summary Table 27: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

tendencies or behavior with the potential to harm others (RCT) 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects 

Internal 

validity Applicability 

Gesch, 

2002, UK: 

~142-day 

(mean) 

RCT131

0.08g/d EPA, 

0.044g/d 

DHA, 1.26g/d 

LA & 0.16g/d 

GLA) 

capsules & 

vitamin/ 

mineral 

capsules 

(n=57 

completers) 

identical 

vegetable oil 

placebo 

capsules for 

fatty acids & 

identical 

vegetable oil 

placebo 

capsules for 

vitamins/ 

minerals 

(n=55 

completers) 

Bet-grp difference in favor of fewer 

offences for those receiving active 

treatment;+

 using data from those 

who received at least two weeks of 

supplementation, only for those 

receiving supplementation did the 

number of incidents Ð;

+

 greatest Ð

was observed for most serious 

incidents;++ minor reports exhibited 

the same bet-grp difference 

Jadad 

total: 5 

[Grade: 

A]; 

Schulz: 

Adequate 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study 

participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; 

grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; Jadad total = Jadad total quality score: reporting of 

randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation concealment (adequate, 

inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; ITT = intentionto-treat analysis; PP = per-protocol analysis (e.g., completers); Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Hibbeln undertook a cross-national ecological analysis investigating the possible association 

between seafood consumption and homicide mortality.133 They posited that, since rates of death 

due to homicide demonstrate a 20-fold variation across countries paralleling cross-national 

differences in mortality from cardiovascular disease, then similar dietary factors might underlie 

both patterns. They argued that this relationship might be important since factors like hostility, 

depression and anger can increase the risk of cardiovascular morbidity. They considered violent 

behavior to sit at the extreme of a continuum that includes hostility. Homicide rates were taken 

from the 1995 Annual Health Statistics report of the WHO. Data concerning apparent seafood 

consumption were taken from the FAOSTAT database as was achieved in numerous other crossnational ecological analyses. Planned analysis included data from 26 countries. 
114 

Summary Table 28: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

tendencies or behavior with the potential to harm others (cross-national ecological analysis) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Hibbeln, 2001, 

26 countries: 

cross-national 

ecological 

analysis 133

n=26 countries Simple++ & logarithmic 

regressions:+++ countries with Ð

apparent seafood consumption 

had Ï rates of homicide 

mortality; excluding Asian data 

maintained the association++

Total 

quality: 4 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; RBC = red blood cells; PL = 

phospholipid; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. Five RCTs,99,128-131 one cross-sectional survey132 and one crossnational ecological analysis133 were deemed relevant for the review. Two of the RCTs were 

conducted in Japan,129,130 two in the UK99,131 and one in Thailand.128 The cross-sectional survey 

was undertaken in the US132 while the cross-national ecological analysis obtained data from 

many countries.133 Except the cross-sectional ecological analysis, eligibility criteria for each of 

the studies were adequately described. Hamazaki et al.’s first trial was funded by the Nissin 

Seifun Foundation and a grant from the Japan-US Cooperative Medical Science Program.130 

Their second study was supported by the Shorai Foundation for Science and Technology and by 

the Special Coordination Funds for Promoting Science and Technology of the Science and 

Technology Agency of the Japanese government.129 Their study of elderly volunteers received 

funds from the Special Coordination Funds for Promoting Science and Technology of the 

Science and Technology Agency of the Japanese government in addition to the Goho Life 

Sciences International Fund and a grant from the Japan-US Cooperative Medical Science 

Program.128 Wardle et al.’s trial was supported by a grant from the Biotechnology and 

Biological Sciences Research Council.99 Iribarren and colleagues received two NIH grants from 

the National Heart, Lung and Blood Institute, with the lead author also awarded a Scientist 

Development Grant from the American Heart Association.132 Gesch et al.’s study was supported 

by a grant from the research charity Natural Justice and its various contributors.131 Funding 

support for Hibbeln’s ecological analysis was not reported.133

Population characteristics. The “healthy” status of student volunteers in the first two 

Hamazaki et al. RCTs was determined by physical examination and interview,129,130 although one 

also included blood tests completed three to four months prior to study entry.130 In their second 

and third studies, Hamazaki et al.’s volunteers had to be free of chronic illness, including 

alcoholism and any regular medication use.128-130 Additional reasons for exclusion in the trial 

with elderly subjects were health problems such as myocardial or cerebral infarction, cancer, 

severe hypertension and other serious diseases.128 Both samples of student were asked to keep 

their body weight and physical activity constant during the study129,130 In their study involving a 
115 

stressor component, Hamazaki et al. described their students as ranging in age from 19 to 30 

years, with more than half being female (n=34/53).130 In the RCT conducted without a stressor, 

subjects ranged from 20 to 30 years and slightly more than half were male (n=30/59).129 Elderly 

Thai subjects were between the ages of 50 and 60 years, with more male participants 

(n=22/41).128 

There were no significant differences among the study groups for any of the baseline mental 

health (i.e., anger scores on POMS; general psychological well-being; stress; state anger and 

anger reactions scores on STAI), background diet (i.e., g/d or percent of energy saturated fat; g/d 

fiber), or other characteristics (i.e., age, marital status, sex, BMI, total, HDL and LDL cholesterol 

and trigyceride parameters) in Wardle et al.’s trial.99 Iribarren et al.’s observational study 

evaluated young adult white and black males and females.132 Significant heterogeneity was 

observed when the different subgroups were compared. For example, the mean hostility score 

was highest in black males, followed by white males, black females and white females. White 

participants were older than black subjects. Total energy intake was highest in black males, 

followed by white males, black females and white females. Intake of LA and ALA were each 

highest in black females, lowest in white females, and intermediate in males. Intake of AA was 

highest in black males and lowest in white females. Intake of EPA and DHA were each higher 

in black than white subjects. Omega-6/omega-3 fatty acid intake was significantly lower in 

white females than any of the other subgroups. Black participants consumed more total omega-6 

fatty acid and total omega-3 fatty acid content than did white subjects. Alcohol intake was 

higher among males than females, and higher in white females than black females. While total 

fish intake did not vary by sex and/or race, black subjects consumed more fish rich in omega-3 

fatty acids than did white participants. In black subjects, the proportion of current smokers and 

the prevalence of unemployment were higher while the level of education and the likelihood of 

being married were lower. 

There were no statistically significant between-group differences at baseline on any of the 

measures of intelligence, verbal ability, anger, anxiety, malaise or depression in Gesch et al.’s 

trial.131 Countries included those from Asia (e.g., Japan, Hong Kong), continental Europe (e.g., 

Germany, Holland), the UK, Scandinavia (e.g., Norway, Sweden), South America (e.g., Chile), 

the Middle East (e.g., Israel), Australia, New Zealand, Canada and the United States in Hibbeln’s 

cross-national ecological analysis.133 This suggests considerable variability in the background 

diet in general and not merely related to fish consumption. 

Intervention/exposure characteristics. The exposure was weight-adjusted only in 

Hamazaki et al.’s first trial.130 In both studies involving students, each capsule contained 300mg 

of oil with the antioxidant α-tocopherol (0.3%) added to stabilize the exposure.129,130 The fish oil 

received by those in the DHA group contained 49.3% (wt/wt) DHA, 6.7% EPA, 9% palmitic 

acid, 7.3% oleic acid, 3.2% AA, 3.2% palmitoleic acid, 2.3% stearic acid and other contents (no 

data reported).129,130 The control oil was not inactive in that it contained 3% concentrated sardine 

oil that had been partially deodorized, and included 54.1% LA, 22.3% oleic acid, 10.8% palmitic 

acid, 6.8% ALA, 3.7% stearic acid, 0.5% DHA and other contents (no data reported).129,130 In 

the study of elderly Thai subjects, the DHA group took 1.5g/d DHA in addition to 0.2g/d 

EPA.128 Controls received 3g/d of mixed plant oil (47% olive oil, 25% rapeseed oil; 25% 

soybean oil, 3% fish oil), indicating that these subjects received some omega-3 fatty acid content 

as well.128 Capsules were typically taken around meal time.128-130 In none of the Hamazaki et al. 

trials were descriptions provided indicating the inappropriate handling of lipids.128-130
116 

On three occasions, participants in Hamazaki et al.’s first RCT were asked to complete a 

food frequency questionnaire, to provide data concerning their dietary intake of various lipids, 

and to maintain their background diet.130 Participants in Hamazaki et al.’s last two trials 

completed the food frequency questionnaire at study’s start and end.128,129 Compliance was 

monitored by capsule counts in their first RCT.130 Only 45% of subjects in each study group in 

the second trial reliably guessed which exposure they had been receiving.129 Likely due to 

having placed some fish oil in the control exposure, and perhaps also because of a briefing at 

study initiation which outlined this plan for study participants, elderly subjects could not reliably 

guess which exposure they had received (although villagers did significantly better).128 

Portion sizes were established in Iribarren et al.’s observational study using cups and spoons, 

and reference was made to intake during the month preceding each clinical visit.132 Daily 

nutrient intake was estimated using the validated CARDIA diet history questionnaire. The intake 

of omega-3 and omega-6 fatty acid content was expressed as nutrient density (kcal/1000kcal/d). 

Intake of total fish or fish rich in omega-3 fatty acids (i.e., salmon, mackerel, trout, herring, eel, 

cod) were expressed as occasions per week. 

The vitamin/mineral supplement combination (Vitamins A, D, B1, B2, B6, B12, C, E, K; 

biotin, nicotinamide, pantothenic acid, folic acid, calcium, iron, copper, magnesium, zinc, iodine, 

manganese, potassium, phosphorus, selenium, chromium, molybdenum) in Gesch et al.’s trial of 

young adult prisoners was matched with a vegetable oil placebo given in an identical, opaque 

bicolored gelatin shell.131 To this was added an Efamol Marine® product containing both 

omega-3 and omega-6 fatty acids. The daily dose was 80 mg EPA, 44 mg DHA, 1260 mg LA 

and 160 mg GLA. A vegetable oil placebo of identical color was delivered via a clear gelatin 

shell. Diet was assessed via a 7-day food diary. Meal portion weights were determined as well. 

Compliance was 89.3% and a significant between-group difference was not observed. 

Participants could not reliably guess which exposure they had been receiving.131 Hibbeln’s 

apparent seafood consumption was defined as catch plus imports minus exports. Wardle et al.’s 

dietary changes have been described twice already and these details are not repeated here.99

Only Gesch et al. identified the manufacturer of their omega-3 fatty acid exposure (Efamol 

Ltd.),131 with no reports of interventional studies describing purity data or details as to whether, 

and how, the presence of methylmercury was tested or eliminated from the omega-3 fatty acid 

exposure. 

Cointervention characteristics. No cointervention data were described in any of the study 

reports. 

Outcome characteristics. All three of Hamazaki et al.s’ trials used the Japanese version of 

Rosenzweig’s validated adult Picture-Frustration test at pre- and poststudy.128-130 First responses 

to cards depicting frustrating scenarios were categorized as aggression varying in terms of its 

direction (extraggression: toward others; intraggression: toward self; imaggression: against 

nobody). In the second study, the Cook and Medley hostility scale (0/low to 50/high)was also 

employed.129 Blinded ratings were highly reliable (no data reported).130 The fatty acid 

composition of serum phospholipids was assessd in their first study,130 with phospholipid 

fractions of RBCs measured in their other two trials.128,129

Hostility was measured using the Cook-Medley Scale in Iribarren et al.’s observational 

study.132 Two types of incident report were defined by Gesch et al.: serious (e.g., violence) and 

minor (i.e., failure to comply with requirements).131 Homicide mortality rates were collected by 

Hibbeln.133 Wardle et al.’s outcomes are described above.99
117 

Study quality and applicability. The five RCTs received a mean Jadad total quality score 

of 3.2, indicating sound internal validity.99,128-131 Two studies achieved a rating indicating 

Adequate allocation concealment,99,131 and three received an Unclear rating regarding allocation 

concealment.128-130 Three RCTs attained an applicability rating of III,128-130 whereas two trials 

achieved an applicability score of II.99,131 The cross-sectional survey was assigned a quality 

score of 5 and an applicability rating of II.132 The cross-sectional ecological analysis achieved a 

quality score of 4 and an applicability rating of III.133

Summary Matrix 11: Study quality and applicability of evidence regarding the association between omega-3 

fatty acid intake and onset, continuation or recurrence of tendencies of behavior with the potential to harm 

others 

Study Quality

A B C 

Author Year n Author Year n Author Year n I 

Author Year n Author Year n Author Year n

II GeschA 2002 112 Iribarren 2004 >3k WardleA 2000 176 

Author Year n Author Year n Author Year n

Applicability 

III 

 HamazakiU 

HamazakiU 

HamazakiU 

Hibbeln 

1996 

1998 

2002 

2001 

53 

59 

41 

26C 

 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment; C = Countries; k = 1,000’s 

Qualitative Synthesis of Individual Study Results 

In Hamazaki et al.’s first study, dropouts and withdrawals did not present a notable barrier to 

the integrity of their study or in turn the meaningful interpretation of their results. Aggression 

directed toward others (extraggression) at times of stress was significantly increased in the 

control group by study’s end, while no significant change was observed in the DHA group.130 

The between-group difference was significant. Yet, under nonstresssful conditions (second 

study) it was found that extraggression decreased significantly in the control group whereas no 

significant change was observed for the DHA group.129 The between-group difference was 

barely significant. Hostility scores did not change significantly within either study group.129 

There were no significant differences in changes in extraggression over Hamazaki et al.’s 

study of elderly Thai subjects for either males and females or for those varying in terms of their 

smoker status.128 Given that villagers in the control group had their extraggression scores 

decrease significantly more than did university employees, their data were analyzed separately. 

Extraggression did not change for those university employees receiving the control exposure 

while it did decrease significantly for those taking the DHA capsules. There was also a 

significant difference in extraggression between the two study groups. There was no significant 

between-group difference for the villager subjects. Results relating to the university employees 

showed that extraggression did not change over time for the control group yet decreased 

significantly for participants receiving DHA. For those subjects receiving the control exposure, 

the fact that they had been consuming approximately 150-160 mg/d of DHA from their regular 

food sources was insufficient to have a positive effect on responses to the test procedure.128
118 

No significant between-group differences in changes from baseline were observed for AA, 

EPA or DHA in Hamazaki et al.’s first study.130 But, in their second trial they found significant 

increases in RBC membrane DHA and EPA in the DHA group while LA increased in the control 

group.129 AA decreased significantly in the DHA group as well.129 The two studies evaluated 

different biomarker sources. Hamazaki et al.’s trial enrolling elderly Thai subjects found no 

significant differences in fatty acid compositions between those varying on the basis of their sex, 

smoker status or urban status.128 As a result, these data were combined in subsequent analyses. 

No significant changes in fatty acid composition were observed in the control group. In the 

DHA group both EPA and DHA levels increased significantly over the trial. At the same time 

AA decreased significantly. 

Each of Wardle et al.’s three study groups showed a significant within-group improvement 

only for the STAI’s anger reactions after 12 weeks.99 Yet, there were no significant betweengroup differences observed for any of the following clinical outcomes: anger/hostility, stress, or 

general psychological well-being. 

Iribarren et al. reported that total energy was positively correlated with hostility for the full 

sample and for all sex-by-race groups.132. ALA was exclusively and negatively associated with 

hostility for black males. EPA intake for all subjects was negatively correlated with hostility. 

Among black males, intakes of DHA, LA, total omega-6 fatty acid content, total omega-3 fatty 

acid content and of fish rich in omega-3 fatty acids were each correlated negatively with 

hostility. Omega-6/omega-3 fatty acid intake was uncorrelated with hostility for each of the sexby-race groups. Alcohol intake was positively associated with hostility only in black subjects. 

Total energy and alcohol consumption were significantly and positively correlated with high 

hostility (>75th percentile). Adjusting for age, sex, race, center, educational level, marital status, 

BMI, smoking, alcohol consumption and physical activity, the multivariate odds ratios of scoring 

in the upper quartile of hostility scores associated with one standard deviation increase in DHA 

intake was statistically significant. Consumption of fish rich in omega-3 fatty acids, when 

compared to no consumption, was significantly associated with lower odds of high hostility. 

When consumption of fish rich in omega-3 fatty acids was entered into a multivariate model 

along with intake of DHA, the association of the former variable with hostility was no longer 

significant. The investigators suggested that the original significant association was accounted 

for by DHA content. 

Gesch et al.’s ITT analysis (n=231) revealed a statistically significant between-group 

difference in favor of fewer offences for those receiving active treatment. Those receiving active 

capsules showed a reduction of 26% compared to those taking placebo. Using data exclusively 

from those who received at least two weeks of supplementation (n=172; study group sizes not 

reported), only for those receiving supplementation did the number of incidents decrease 

significantly. The greatest reduction was observed for the most serious incidents. Minor reports 

exhibited the same pattern of difference between active and placebo groups. 

US data were excluded from Hibbeln’s cross-national ecological analysis since their rate of 

mortality due to homicide was 20 per 100,000 persons, making it more than double the rate from 

any other country, or 10-fold greater than the mean.133 Simple regression and logarithmic 

regression respectively revealed that countries with lower apparent seafood consumption had 

higher rates of death due to homicide. Excluding data from logarithmic regression for Asian 

countries (n=21 countries), which exhibited both high rates of seafood consumption and low 

rates of homicide mortality, maintained the significant relationship. 
119 

Quantitative Synthesis 

Meta-analysis was not conducted because of noncomparable outcomes (i.e., aggression vs 

anger/hostility vs antisocial behavior vs homicide), populations (i.e., healthy vs at risk for heart 

disease vs cholesterol problems vs young adult prisoners vs multiple national populations) and 

designs (RCTs vs observational studies vs cross-national ecological analyses). As well, of the 

three studies investigating the possible protective influence of exposures containing omega-3 

fatty acids on aggression, one included a narrowly defined population (i.e., elderly volunteers).128 

The remaining two Hamazaki et al. studies129,130 varied in terms of whether they weight-adjusted 

their doses, and only one of them employed a stressor against whose effects the exposure was 

targeted. More importantly, since the latter two studies used “cocktails” from which the exact 

contributions of omega-3 fatty acids could not readily be teased out, any attempt to combine their 

results would fail to elucidate the possible protective influence of omega-3 fatty acids per se. 

Impact of Covariates and Confounders 

Given the noncomparability of the studies, it is difficult to identify threads of consistency 

across all of them. Even looking at the most homogeneous collection of studies, what cannot be 

ascertained are the individual or collective impacts on study outcomes of Hamazaki et al.’s 

attempts to control for body weight, physical activity and background diet in all three RCTs,128-

130 smoking in their two RCTs with university students,129,130 for alcohol consumption in their 

second and third studies,128,129 their stratification for age and sex in their second study129 or for 

sex and smoker status in their study of the elderly.128 In their first trial report, Hamazaki et al. 

noted that there were no significant differences in the intake of DHA, EPA, LA, total omega6/omega3 fatty acids or total lipid intake per day.130 This likely eliminated several possible 

sources of confounding. Other sources were seen to have been similarly controlled by virtue of 

specific observations. For example, the on-study intake of total energy did not change 

significantly for either study group in Hamazaki and colleagues’ second trial;129 and, in their 

third study, daily on-study intake of DHA from food sources was similar for both study groups 

although the result of a statistical test was not reported.128

In other studies, many variables with confounder potential were likewise controlled. Wardle 

et al. found no between-group differences for age, sex, marital status or baseline clinical outcome 

scores for any disorder/condition, and not just anger.99 Iribarren adjusted analyses for age, sex, 

race, center, educational level, marital status, BMI, smoking, alcohol consumption and physical 

activity.132 Gech et al. noted no clinically significant between-group differences with respect to 

dietary intake.131 On the other hand, Hibbeln failed to control for important confounding factors 

such as alcohol consumption and smoking.133 Yet, regardless of these observations it is not 

possible to abstract clear and consistent patterns of influence by covariates and confounders. 
120 

Is the Onset, Continuation or Recurrence of Tendencies or 

Behaviors With the Potential to Harm Others Associated With 

Omega-3 or Omega-6/Omega-3 Fatty Acid Content of 

Biomarkers? 

As observed in Summary Table 29 (below), derived from Evidence Table 2 (Appendix E*), 

three cross-sectional studies published between 1987 and 2003 met eligibility criteria. 

Overview of Relevant Studies’ Characteristics and Results 

Hibbeln et al.’s research was supported by the National Association for Research on 

Schizophrenia and Depression (NARSAD)134 while Buydens-Branchey et al.’s study was funded 

by the Veterans Administration, the National Institute of Drug Abuse (NIDA) and the National 

Institute of Alcohol Abuse and Alcoholism (NIAAA).136 Virkkunen et al. did not report their 

funding source.135

Virkkunen et al. evaluated EFA levels in plasma phospolipids in two groups of habitually 

violent and impulsive male offenders (n=34, mean age: 33.2 years) compared to a healthy 

control group (n=16; mean age: 33 years).135 Each participant in the former had commited at 

least one violent crime and had had at least two discrete episodes of loss of control of aggressive 

impulses. The first subgroup included males meeting DSM-III criteria for antisocial personality 

(n=15) and had exhibited evidence of conduct disorder since childhood. The second subgroup of 

patients were habitually violent and had had problems with impulsivity only in adulthood. Their 

behavior satisfied DSM-III criteria for intermittent explosive disorder. Exclusion criteria were 

patients with mental retardation, chromosome abnormalities, antisocial personality without any 

habitually violent tendencies or schizophrenia. All fulfilled DSM-III criteria for alcohol abuse, 

yet without liver disease. They had been in prison an average of 5 months, with no access to 

alcohol. Patients and controls were well matched by age and weight. Controls were healthy men 

drawn from the personnel of a Psychiatric Clinic. None exhibited problems with aggression or 

alcohol. The diet of controls and patients was maintained in the hospital for 3 days prior to 

blood sampling, and none took any medication over that period. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
121 

Summary Table 29: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of tendencies or behaviors with the potential to harm others 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Virkkunen, 

1987, Finland: 

multiple-group 

cross-sectional 

study135

violent 

antisocial 

personality 

(n=15) 

intermittent 

explosive 

disorder 

(n=19)/ 

healthy 

controls 

(n=16) 

Ð LA in intermittent explosive 

disorder vs controls;+++ Ï DGLA 

in both patient grps vs 

controls;++ Ð DHA in violent 

antisocial personality disorder vs 

controls++ 

Total 

quality: 4 

[Grade: B] 

III 

Hibbeln, 1998, 

US: 

multiple-group 

cross-sectional 

study134

violent 

group 

(n=27) 

nonviolent 

control 

group 

(n=31) 

NS bet grps for n-3 & n-6 FA; Ð

CSF 5-HIAA in violent pts+ Total 

quality: 2 

[Grade: C] 

I 

BuydensBranchey, 

2003, US: 

multiple-group 

cross-sectional 

study136

aggressive 

cocaine 

addict 

males 

(n=6) 

nonaggressive 

cocaine 

addict 

males 

(n=18) 

NS total FA, PUFA & total n-6 

FA bet grps; Ð DPA,+

 total n-3 

FA+

 & DHA++ in aggressive pts 

Total 

quality: 4 

[Grade: B] 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 fatty acids; n-6 = omega-6 

fatty acids; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant 

statistical difference; N/A = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; RBC = 

red blood cells; PL = phospholipid; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; 

++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower; 5-HIAA = 5-hydroxindolacetic acid; HVA = 

homovanillic acid 

Hibbeln et al. assessed plasma EFA contents and their correlation with serotonin and 

dopamine metabolites in cerebrospinal fluids in violent and nonviolent subjects (n=31; 71% 

male; mean age: 39.9 years).134 The group of violent subjects (n=27; 78% male; mean age: 38.5 

years) were included if they had a history, within the last 3 months, of more than five episodes of 

violent, physical aggression that could cause bodily harm. Violent and control subjects were 

excluded if they had a history of a major psychotic or major affective disorder, panic disorder, 

illicit drug dependence, seizure or other neurological disorders. The controls were also excluded 

if they had a history of one episode of violent physical aggression. Thirteen violent participants 

met DSM-III-R diagnostic criteria for current alcohol dependence. No participants were taking 

any medication. The diagnostic tests used to perform the multidimentional clinical assessment 

were the Brown-Goodwin Lifetime Aggression Rating scales and the Buss-Durkee Hostility 

Inventory scales. Baseline scores on both scales were significantly higher in the violent subject 

group. All subjects were maintained on a low-monoamine diet for at least 3 days prior to blood 

and cerebrospinal fluid sampling. Confounders controlled for were age, alcohol consumption 

and alcohol-related liver damage. 

Buydens-Branchey et al. examined the plasma levels of fatty acids in cocaine addicted males 

with or without aggressive behavior.136 The enrolled subjects were hospitalized for treatment of 

their DSM-IV diagnosed cocaine dependence. They were physically healthy and were not 

receiving any medication. The diagnostic test employed to assess aggression was the BrownGoodwin Assessment for Life History of Aggression, and subjects with a score of 8 or more 
122 

were considered to have a history of aggression (n=6; mean age: 38 years). The control group 

(n=18; mean age: 39.6 years) included non-aggressive cocaine addicts. No significant betweengroup baseline differences were observed for age, weight, number of years of cocaine use and 

amounts of cocaine used during the preceeding month. None of the three studies provided 

descriptions indicating inappropriate handling of lipids.

Virkkunen et al. found that the patients with intermittent explosive disorder had a 

significantly lower content of LA in plasma phospholipids compared to controls.135 DGLA was 

significantly higher in both violent groups compared with controls. The content of DHA was 

significantly reduced in the group of patients with violent antisocial personality disorder 

compared to controls. 

Hibbeln et al. observed no significant between-group differences for omega-3 or omega-6 

fatty acid content in plasma.134 The violent subjects group had a significantly lower 

concentration of cerebrospinal 5-hydroxindolacetic acid (CSF 5-HIAA) than did controls. Age, 

height, weight, plasma total cholesterol, frequency and quantity of alcohol consumed, lifetime 

alcohol consumption, Hollingshead socioeconomic scale, Michigan Alcohol Screening Test 

(MAST) and CAGE scores (derived from MAST) were not significantly associated with CSF 5-

HIAA, CSF homovanillic acid (HVA), cholesterol, or plasma fatty acid contents (e.g., DHA). 

Buydens-Branchey et al. did not find a significant full-sample correlation between EFA 

levels and patients’ age, weight, number of years of cocaine use or amount of cocaine used 

during the preceeding month.136 No significant between-group differences were observed for 

plasma total fatty acids, PUFA content or total omega-6 fatty acid composition. (Omega-6)DPA, 

total omega-3 fatty acids and DHA were significantly lower in the aggressive patients compared 

to nonaggressive addicts. The omega-6/omega-3 fatty acid ratio was higher in the aggressive 

patient group, and the difference was only marginally nonsignificant (p = 0.055). 

 Study quality and applicability. Two of the studies received an applicability rating of 

I

134,136 and a third was assigned a III.135 Mean study quality for the studies was 3.3. 

Summary Matrix 12: Study quality and applicability of evidence regarding the association between the 

omega-3 or omega-6/omega-3 fatty acid content of biomarkers and onset, continuation or recurrence of 

tendencies or behavior with the potential to harm others 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I 

BuydensBranchey 2003 24 Hibbeln 1998 58 

Author Year n Author Year n Author Year n II 

Applicability 

Author Year n Author Year n Author Year n

III Virkkunen 1987 50 

n = number of allocated/selected participants 

Quantitative Synthesis 

Although all of the included studies were controlled, none were prospective by design. Thus, 

meta-analysis was not considered. 
123 

Impact of Covariates and Confounders 

Too few studies, reporting too few details, and involving different combinations of target and 

control populations, precluded even an informal assessment of the possible influence of 

covariates and confounders. 

Is the Onset, Continuation or Recurrence of Alcoholism 

Associated With Omega-3 or Omega-6/Omega-3 Fatty Acid 

Content of Biomarkers? 

As observed in Summary Table 30 (below), derived from Evidence Table 2 (Appendix E*

), 

two cross-sectional studies published in 1984 and 1998 met eligibility criteria. 

Overview of Relevant Studies’ Characteristics and Results 

Alling et al.’s study was supported by the Swedish Medical Research Council and the 

pharmaceutical company Merck Darmastadt.138 Hibbeln et al.’s investigation was funded by the 

National Alliance for Research on Schizophrenia and Depression (NARSAD).137

Alling et al. measured the RBC and plasma fatty acid compositions in males with chronic 

alcoholism hospitalized for detoxication after a heavy drinking period (n=13; mean age: 54 [41-

68] years) compared to healthy male controls drawn from hospital ward staff (n=21; mean age: 

39 [22-58] years).138 Data included in this review focus exclusively on the baseline period, 

before detoxification began. No attempts to control for confounders were reported. 

Hibbeln et al. investigated the relationship between concentrations of plasma EFAs and CSF 

5-HIAA in abstinent alcoholics and healthy volunteers.137 Patients were admitted to the National 

Institute on Alcohol Abuse and Alcoholism (early-onset: n=88; late-onset: n=39). The diagnosis 

was made using different tools, including the Research Diagnostic Critera for alcoholism, the 

Schedule of Affective Disorders and Schizophrenia-Lifetime (SADS), MAST scores, 

Hollingshead ratings of socioeconomic class, the SCID (DSM-III-R) and the HDRS. The 

healthy volunteers (n=49, mean age: 37 years, 77.5% male) had to have a negative alcohol breath 

test and urine drug test in addition to a clinical history indicating no current or lifetime 

psychiatric or substance abuse disorders. Subjects with a history of major psychotic illness or 

bipolar affective disorder were excluded. All patients were medication-free. Both patients and 

controls were maintained on a low-monoamine diet for at least three days prior to blood 

sampling. Late-onset alcoholics were significantly older than early-onset ones, but there was no 

difference in age between either group and healthy controls. There were no significant 

differences between the three groups in terms of height, weight or BMI. The alcoholic patients 

did have a significantly higher number of cigarettes smoked per year as well as met more criteria 

indicating antisocial tendencies than did controls. Controls had a significantly higher 

Hollinghead score than did the early-onset alcoholics.

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
124 

Summary Table 30: Association between omega-3 and omega-6/omega-3 fatty acid content of biomarkers 

and onset, continuation or recurrence of alcoholism 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Alling, 1984, 

Sweden: 

multiple-group 

cross-sectional 

study138

chronic 

alcoholic 

males 

(n=13) 

healthy 

control 

males 

(n=21) 

Ð EPG RBC LA,+++ DGLA, AA 

& DHA++ in pts vs controls; Ð

LA++ & AA+++ in CPG RBCs & 

plasma in patients vs controls 

Total 

quality: 2 

[Grade: C] 

III 

Hibbeln, 1998, 

US: 

multiple-group 

cross-sectional 

study137

abstinent 

early-onset 

(<25 y age) 

alcoholics 

(n=88) 

abstinent 

late-onset 

alcoholics 

(n=39)/ 

healthy 

controls 

(n=49) 

Ï plasma DHA, LA, DGLA & 

AA in pts vs. controls;++++ NS 

bet early & late-onset alcoholics

Total 

quality: 3 

[Grade: C] 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 fatty acids; n-6 = omega-6 

fatty acids; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant 

statistical difference; N/A = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; RBC = 

red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine phosphoglycerides; Jadad 

total = Jadad total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of 

adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Alling et al. found significantly reduced phosphatidylcholine RBC membrane concentrations 

of LA, DGLA, AA and DHA in chronic alcoholic patients compared to healthy controls.138 

There was a significantly reduced LA and AA content in phosphatidylethanolamine RBC 

membrane concentrations and in plasma in patients compared with controls. 

Each of Hibbeln et al.’s alcoholic patient groups had significantly higher plasma cholesterol 

concentrations of total PUFAs, LA, AA, (omega-6-)DPA and DHA compared with healthy 

controls.137 No significant between-group differences characterized the remaining omega-3 and 

omega-6 fatty acid contents. Only the plasma concentration of DHA predicted CSF 

neurotransmitter metabolite concentrations in all three study groups.

Study quality and applicability. The mean study quality score was 2.5. Alling et al.’s 

study138 received an applicability rating of III whereas Hibbeln et al.’s rating was I.137

Summary Matrix 13: Study quality and applicability of evidence regarding the association between the 

omega-3 or omega-6/omega-3 fatty acid content of biomarkers and onset, continuation or recurrence of 

alcoholism 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I Hibbeln 1998 176 

Author Year n Author Year n Author Year n II 

Author Year n Author Year n Author Year n

Applicability 

III Alling 1984 34 

n = number of allocated/selected participants 
125 

Quantitative Synthesis 

Although all of the included studies were controlled, none were prospective by design. Thus, 

meta-analysis was not considered. 

Impact of Covariates and Confounders 

Too few studies, focusing on different biomarker sources, and involving different 

combinations of target and control populations, precluded even an informal assessment of the 

possible influence of covariates and confounders. 

Are Omega-3 Fatty Acids Efficacious as Primary Treatment 

for Borderline Personality Disorder? 

As observed in Summary Table 31 (below), derived from Evidence Table 1 (Appendix E*), 

one RCT published in 2003 met eligibility criteria. Meta-analysis was not considered. 

Overview of Relevant Study’s Characteristics and Results 

Zanarini et al. randomized 30 female outpatients (76.7% Caucasian; mean age: 26.3 

[SD=6.2] identified with borderline personality disorder (duration unreported).139 Participants 

received either 1 g/d (97% pure; Laxdale Ltd.) E-EPA (n=20) or placebo (mineral oil; n=10) in a 

parallel design for 8 weeks (followups at 2, 3, 4, 6, and 8 weeks). The 2:1 randomization ratio 

was selected to permit the investigators to gain experience working with E-EPA as an exposure. 

Participants had to meet both the Revised Diagnostic Interview for Borderlines (DIB-R) and 

DSM-IV criteria for borderline personality disorder. By these criteria, patients were considered 

moderately ill. Exclusion criteria were those patients who were currently on psychotropic 

medication, medically ill, taking E-EPA supplements, eating more than one to two servings of 

fatty fish per week, alcohol or drug abusers, acutely suicidal, meeting current or lifetime criteria 

for schizophrenia, schizoaffective disorder, bipolar I, bipolar II or in the midst of a major 

depressive episode. Scores over the course of the study on the Modified Overt Aggression Scale 

(MOAS) and MADRS served as the primary outcome measures. Funding was provided by 

NARSAD. 

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm. 
126 

Summary Table 31: Omega-3 fatty acids as primary treatment for borderline personality disorder 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects 

Internal 

validity Applicability 

Zanarini, 

2003, US: 

8 wk 

parallel 

RCT139

1g/d EEPA 

(n=20) 

mineral oil 

pb 

(n=10) 

E-EPA grp had Ð MADRS++++ & 

MOAS++++ at study end 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 

= omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; MADRS = MontgomeryAsberg Depression Rating Scale; MOAS = Modified Overt Aggression Scale; Jadad total = Jadad total quality score: 

reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation 

concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Ninety percent of both E-EPA (n=20 with at least two followups) and placebo participants 

(n=10 with at least three followups) completed the 8-week trial. The three participants who 

dropped out of the study did so because of life events unrelated to the study or intervention. 

Statistical analyses were conducted on those participants who completed the full 8-week 

intervention. At baseline, results showed that there were no significant between-group 

differences on demographic characteristics or history of treatment (i.e., n=7/30 [23.3%] had 

taken psychotropic medication; 25/30 [83.3%] had received psychotherapy; n=3/20 [10%] had 

been hospitalized for psychiatric reasons). There were also no significant differences between 

the groups at baseline on either the MADRS or MOAS. This study report did not provide details 

as to whether, or how, the presence of methylmercury was tested or eliminated from the omega-3 

fatty acid exposure. It received an applicability rating of I and an Jadad total quality score of 3, 

indicating good internal validity. There were significant clinical effects over the course of the 

study, as the E-EPA group had, at study end, significantly lower mean scores on both the 

MADRS and MOAS compared to the placebo group. 

Are Omega-3 Fatty Acids Efficacious as Primary Treatment 

for Schizophrenia? 

A publication by Peet et al. in 2001 reported one study examining the use of omega-3 fatty 

acids as a primary treatment for schizophrenia, as well as a second study describing its use as a 

supplemental treatment for schizophrenia.58 The former is described here (Summary Table 32; 

Evidence Table 1: Appendix E*). Meta-analysis was not considered, and a meaningful 

assessment of the impact of covariates and confounders was not possible. 

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
127 

Overview of Relevant Study’s Characteristics and Results 

Peet et al.’s pilot RCT allocated 30 DSM-IV diagnosed, drug-free schizophrenic patients to 

receive either 3 months of 2g/d EPA of enriched oil (Kirunal®; n=15) or corn oil placebo (n=15) 

via identical capsules (Summary Table 32).58 Patients were either newly diagnosed or had 

relapsed. For ethical reasons, medication was permitted, as required. Clinical judgement, and 

not predetermined criteria, guided these decisions. No significant between-group differences 

were observed for age, sex, duration of the illness, baseline total Positive and Negative 

Syndrome Scale (PANSS) or PANSS positive symptoms scores. Nine patients were drug-naïve 

and the others had had no medication for at least 2 weeks. Outcomes included the need for, and 

duration of, conventional medication in addition to the PANSS assessed at baseline and at 

study’s end. Some financial assistance for this project was provided by a colleague of the 

investigators and by Laxdale Limited, the manufacturer of the EPA product. Purity data were 

not reported. No attempts to test for and eliminate methylmercury from the exposure were 

described. 

Summary Table 32: Omega-3 fatty acids as primary treatment for schizophrenia 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects 

Internal 

validity Applicability 

Peet, 2001, 

India: 

3 mo 

parallel 

RCT58

2g/d EPA 

(n=15) 

corn oil 

placebo 

(n=15) 

12/12 pb & 6/14 EPA required 

antipsychotic medication by study’s 

end;+

 EPA pts spent fewer days on 

medication;+

 EPA pts had Ð total 

PANSS+

 & PANSS positive;+ 

responder analysis 2/12 placebo & 

8/14 EPA pts were responders+

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Adequate 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample 

size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = 

placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; PANSS = Positive and 

Negative Syndrome Scale; Jadad total = Jadad total quality score: reporting of randomization, blinding, 

withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = 

decrease(d)/reduction/lower 

Analyses were based on sixteen completers with final PANSS scores (n=12/15 in placebo 

group). Three patients were lost to followup, and one died of accidental burns unrelated to the 

illness or study protocol. All 12 patients in the placebo group and six of fourteen in the 

treatment group required antipsychotic medication by study’s end. Of the latter six patients, four 

required no medication over the 3 month period, one needed antipsychotic medication during the 

first week, and one received a dose of depot antipsychotic medication (25 mg flupenthixol 

deconoate) at study initiation. Patients receiving EPA spent significantly fewer days on 

medication. In spite of the positive effect on symptoms that may have accrued to placebo 

patients, those receiving EPA had significantly lower total PANSS and PANSS positive scores 

when compared with placebo patients. The small sample size did not permit a statistical 
128 

comparison of scores based on patients who were and were not drug-naïve. Responder analysis 

(50% improvement on PANSS positive) revealed that two of 12 placebo patients and eight of 14 

EPA patients achieved responder status. This trial received a Jadad total score of 3, indicating 

good quality, an allocation concealment rating of Adequate, and an applicability rating of III. 

Are Omega-3 Fatty Acids Efficacious as Supplemental 

Treatment for Schizophrenia? 

Four RCTs published either in 2001 or 2002 were identified as addressing this question 

(Summary Tables 33 through 36; Evidence Table 1: Appendix E*). The second study in Peet et 

al.’s report is reviewed here.58

Overview of Relevant Studies 

Peet et al. have pointed out that EPA and DHA exhibit different metabolic functions. DHA 

is primarily a membrane structural component and EPA is implicated in eicosanoid synthesis.58 

These metabolites have also been observed to have varying physiological effects.169 Together, 

these patterns suggest the need to differentiate between the possible effects of EPA and DHA in 

the treatment of schizophrenia. 

As a result, Peet et al. conducted an RCT (n=55 allocated) designed to examine the impact, 

over 3 months, of 2 g/d EPA enriched fish oil (Kirunal®; 15 completers), 2 g/d DHA enriched 

oil (source undefined; 16 completers) or a corn oil placebo (14 completers) on symptomatic 

(PANSS score of at least 40), DSM-IV diagnosed schizophrenic individuals (Summary Table 

33).58 Delivery of the exposure involved pourable bottles of oil. Participants were to continue 

on-study with stable doses of antipsychotic medication, and the study protocol anticipated that no 

changes in dose would be required. A psychiatrist monitored on-study medication. Outcomes 

included the PANSS score and RBC PUFA levels. 

 

∗ Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
129 

Summary Table 33: Omega-3 fatty acids as supplemental treatment for schizophrenia 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Notable 

clinical 

effects

Notable 

biomarker 

effects2,3

Notable 

clinicalbiomarker 

correlations 

Internal 

validity Applicability 

Peet, 

2001, 

England: 

3 mo 

parallel 

RCT58

2g/d EPA 

enriched 

fish oil 

(n=15 

completers) 

2g/d DHA 

enriched oil 

(source 

undefined) 

(n=16 

completers)/ 

corn oil pb 

(n=14 

completers) 

EPA’s total 

PANSS Ð

than pb;+

 

treatment 

effect for 

EPA over 

DHA ((+) 

PANSS+

 ); Ï

Ð in EPA 

than DHA;+ 

NS for (-) 

symptoms; 

EPA pts had 

Ï Ð for EPA 

than DHA+

 or 

pb+

 grps 

Largest Ï

in EPA & 

DHA in 

EPA+++ & 

DHA 

grps;+++

Smaller Ï

in EPA & 

DHA in 

DHA+

 & 

EPA grps;+

NS ∆ for 

AA 

EPA grp = 

greatest Ð

in total 

PANSS had 

highest 

baseline 

EPA+

 & AA;+ 

baseline 

EPA 

predicts 

clinical Ð;

+

 

NS 

correlations 

in all other 

grps 

Jadad 

total: 4 

[Grade: 

A]; 

Schulz: 

Adequate 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = omega-6 

FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study participants; 

NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group;

wk = week(s); mo = month; wt = weight; ∆ = change; PANSS = Positive and Negative Syndrome Scale; Jadad total = Jadad 

total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower; (+) = positive; (-) = negative 

Fenton et al. conducted an RCT evaluating the efficacy of 16 weeks of 3 g/d E-EPA (n=45) 

compared to placebo (n=45) in 90 outpatients diagnosed with DSM-IV schizophrenia (n=61/87) 

or schizoaffective disorder (n=26/87) and clinically significant residual symptoms (Summary 

Table 34).89 Residual symptoms were defined as one or more positive and/or negative symptom 

scores greater than 4, or total scores greater than 45 with a score of 3 or more on at least three 

positive or negative items on the PANSS. Blind assessments took place at baseline and then 

every second week. The EFA content of RBCs was assessed at baseline and at study’s end. 

Three patients withdrew consent in the first week of the trial (n=2 in placebo group). 
130 

Summary Table 34: Omega-3 fatty acids as supplemental treatment for schizophrenia 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Notable 

clinical 

effects

Notable 

biomarker 

effects2,3

Notable 

clinicalbiomarker 

correlations 

Internal 

validity Applicability 

Fenton, 

2001, US: 

16 wk 

parallel 

RCT89

3g/d EEPA 

(n=45) 

mineral oil 

pb 

(n=45) 

Time effect on 

total 

PANSS,+++

MADRS+++ & 

CGI;+++ NS 

time-by-grp 

interaction; 

NS effects for 

time or timeby-grp for 

cognitive 

impairment, 

EXP or TD; 

NS effects on 

(+) or (-) 

PANSS; 

improvement 

in pb in 1st 2 

wk 

EPA grp had 

higher % 

EPA+++ & Ð

% AA;+++

EPA Ïin pb 

grp;+ 

AA/EPA Ð

greater for 

EPA;+++

DHA % Ð in 

smokers++

vs 

nonsmokers, 

& males had 

Ð DHA+

 & 

EPA %’s+

 vs 

females 

∆ in AA/EPA 

not linked to 

efficacy; 

DHA ∆

negatively 

correlated 

with ∆ in (+) 

symptoms;++

sex & 

current 

smoking 

status 

related to FA 

compositions 

+ - ++

Jadad 

total: 4 

[Grade: 

A]; 

Schulz: 

Unclear 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = omega-6 

FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study participants; 

NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group; 

wk = week(s); mo = month; wt = weight; ∆ = change; MADRS = Montgomery-Asberg Depression Rating Scale; PANSS =

Positive and Negative Syndrome Scale; CGI = Clinical Global Improvement Scale; Jadad total = Jadad total quality score: 

reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of allocation concealment 

(adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower; TD = tardive dyskinesia; EXP = extrapyramidal symptoms; (+) = positive; 

(-) = negative 

Emsley et al. undertook a trial including 40 (18-55 years) DSM-IV diagnosed schizophrenic 

patients with persistent symptoms, randomized to receive, via 500 mg capsules twice daily, 

either 3 g/d E-EPA or placebo (liquid paraffin) as 12 weeks of supplemental treatment (Summary 

Table 35).140 All had received stable doses of antipsychotic for 6 months and had a total PANSS 

score of greater than 50. Patients were assessed at baseline and every 3 weeks thereafter using 

the PANSS and Extrapyramidal Symptom Rating Scale. 
131 

Summary Table 35: Omega-3 fatty acids as supplemental treatment for schizophrenia 

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable clinical effects 

Internal 

validity Applicability 

Emsley, 

2002, 

South 

Africa: 

12 wk 

parallel 

RCT140

3g/d EEPA 

(n=20) 

liquid 

paraffin pb 

(n=20) 

With+

 or without+ controls, total PANSS Ð’s 

greater in E-EPA grp; difference favored EEPA patients in % ∆ of general 

psychopathology (PANSS);+

 dyskinesia Ð

greater for E-EPA pts at 12 wk++ 

Jadad 

total: 3 

[Grade: 

B]; 

Schulz: 

Unclear 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = omega-6 

FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study participants; 

NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group;

wk = week(s); mo = month; wt = weight; ∆ = change; PANSS = Positive and Negative Syndrome Scale; Jadad total = Jadad 

total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Peet and colleagues conducted a dose-ranging study of the effects of E-EPA on outpatients 

(n=122; 18-70 years) with persistent schizophrenic symptoms despite treatment with adequate 

doses of antipsychotic drug (typical [n=36 in ITT population], new atypical [n=48 in ITT 

population] or clozapine [n=31 in ITT population]) (Summary Table 36).87 Participants across 

nine sites were diagnosed as schizophrenic via DSM-IV criteria and were randomized to receive 

twelve weeks of either 1 g/d, 2 g/d or 4 g/d E-EPA, or placebo (liquid paraffin in identical gelatin 

capsule). These investigators selected EPA since it can inhibit the enzyme phospholipase A2. 

This enzyme’s cycle entails the release of AA, and its overactivity and the concomitant loss of 

AA from cell membranes have been observed in association with schizophrenia.87 Change from 

baseline on the PANSS was the primary outcome. Assessments were conducted at baseline and 

then every 4 weeks. 
132 

Summary Table 36: Omega-3 fatty acids as supplemental treatment for schizophrenia 

Study groups1 

Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 

4 

(n)

Group

2 

(n)/ 

Group 

3 

(n)

Notable clinical 

effects

Notable 

biomarker 

effects2,3

Notable 

clinicalbiomarker 

correlations 

Internal 

validity Applicability 

Peet, 

2002, 

England: 

12 wk 

parallel 

RCT87

4g/d EEPA 

(n=27)/ 

liquid 

paraffin 

pb 

(n=31) 

2g/d EEPA 

(n=32)/ 

1g/d EEPA 

(n=32) 

typical 

neuroleptics: all 

doses improved 

total PANSS 

(size of ∆

covaries with 

dose);+ - ++ large 

pb effects;+ - ++ 

NS differences vs 

pb; atypical 

neuroleptics: 

improvement for 

1g/d+ - +++ & 2g/d+ 

- +++ (total & 

subscale); NS 

effect for 4g/d; 

pb effects;+++ NS 

differences vs pb; 

clozapine: all 

doses had 

effects;+ - +++ 2g/d 

had greatest % 

∆; 2g/d E-EPA 

effect on total 

PANSS+

 & 

general 

psychopathology+ 

∆ in pb grp: Ï

in AA in pts on 

atypical 

antipsychotics;+

 

clozapine: Ï in 

AA+

 in 2g/d 

grp; Ð for 

DHA+ & AA+ in 

4g/d grp on 

atypical 

antipsychotics 

∆ in AA 

positively 

related to ∆

in all clinical 

outcomes;+ - 

+++ ∆ in 

DHA or EPA 

unrelated to 

∆ in clinical 

outcomes 

Jadad 

total: 4 

[Grade: 

A]; 

Schulz: 

Adequate 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = omega-6 

FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; pts = study participants; 

NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group;

wk = week(s); mo = month; wt = weight; ∆ = change; PANSS = Positive and Negative Syndrome Scale; Jadad total = Jadad 

total quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. Two of the trials were conducted in England,58,87 one in the US,89

and one in South Africa.140 Peet et al.’s RCT provided, by far, the most comprehensive 

information concerning inclusion and exclusion criteria. All trials employed a parallel design, 

with the number of groups ranging from two to four. All included a placebo control. An average 

of 76.8 patients were randomized, with a range of 40 to 122 patients. Studies’participants 

received the intervention for an average of 13.3 (range: 12-16) weeks. Some financial assistance 

for Peet et al.’s first project was provided by the investigators’ colleague and by Laxdale 

Limited, the manufacturer of the EPA product.58 Fenton et al.’s RCT was supported by a grant 

from the Stanley Foundation/National Alliance for the Mentally Ill Research Institute.89 Emsley 

et al.’s study was supported by a grant from the Medical Research Council of South Africa, with 
133 

the study exposure supplied by Laxdale Limited (Stirling, Scotland).140 Peet and colleagues’ 

second trial received funding from Laxdale Limited, the manufacturer/supplier of their 

exposure.87 

Population characteristics. Mean age data across all four included studies could not be 

calculated given that not all studies reported full sample data while some only provided 

demographic data for study completers.58 Participants’ ages ranged from approximately 18 to 65 

years across the four RCTs. 

Age data only from completers were reported for Peet et al.’s study.58 For these outpatients, 

mean ages by study group were similar (42-44 years) although a formal statistical test was not 

performed. Patients’ average age in Fenton et al.’s study was 40 years (SD=10; range: 18-65 

years).89 Emsley’s et al.’s RCT involved patients between the ages of 18 and 55 years.140 

Baseline demographic were similar for their two study groups (no statistical tests reported). For 

example, mean ages for the E-EPA (46.2 years; SD=10.6) and placebo groups (43.6 years; 

SD=13.9) were comparable.140 Peet and colleagues’ patients ranged from 20 to 62 years of age, 

with study group means making their sample population the youngest of all four trials (34-39 

years).87 In this last RCT, study group mean ages were comparable although no test of statistical 

significance was reported. At baseline, patients in the 2g/d E-EPA group were slightly younger 

than those in the other three study groups. 

Peet et al. found that males exceeded females in the EPA (67% male) and DHA (75% male) 

groups, and to a lesser extent in the placebo group (57% male).58 In their second study, male 

composition of the study groups ranged from 63% to 71%.87 Fenton et al.’s study randomized 

mostly males (61%).89 Emsley et al. did not report any data regarding sex.140 Only one study 

report provided ethnicity/race data,89 with 84% being Caucasian. In Fenton et al.’s study, 80% 

were single and 70% were high school graduates. 

All studies employed DSM-IV criteria to identify outpatients with schizophrenia, while one 

study included diagnoses of schizophrenia and schizoaffective disorder.89 Only three study 

reports explicitly stated that patients were currently experiencing persistent, residual symptoms 

despite antipsychotic medication.87,89,140 Three RCTs used PANSS scores to demonstrate the 

presence and extent of persistent symptomatology87,89,140 while a fourth likely used these scores 

for this purpose.58 Peet et al. set a criterion PANSS total score of at least 40.58 No significant 

between-group baseline differences in PANSS total scores were noted in Peet et al.’s trial, 

although the mean score was the lowest in the EPA group.58 Residual symptoms were defined 

by Fenton et al. as one or more positive and/or negative symptom score(s) greater than 4, or total 

scores greater than 45 concomitant with a score of 3 or more on at least three PANSS positive or 

negative items.89 Emsley established a score of greater than 50 while Peet and colleagues 

required a total PANSS score of at least 50 in addition to a score of at least 15 on the positive 

PANSS.87 In the latter study little difference between study groups was seen for baseline total 

PANSS or MADRS scores. Baseline scores on the Liverpool University Neuroleptic Side 

Effects Rating Scale (LUNSERS), AIMS, Barnes Akithisia Scale (BAS) and the Simpson-Angus 

Scale for abnormal movements (SAS) were low and similar across study groups.87 

In Peet et al.’s study, patients with symptomatic schizophrenia were also selected on the 

basis of failing to exhibit evidence of significant physical illness or other psychiatric disorders 

(e.g., mood disorders, learning disability).58 Substance abuse and significant medical conditions 

were exclusion criteria in Emsley et al.’s trial.140 An additional inclusion criterion in the Fenton 

et al. trial was that there could not be any change in antipsychotic medication in the thirty days 

preceding the trial, and no on-study change was expected.89 Exclusion criteria included 
134 

diagnoses of substance dependence or mental retardation, bleeding disorders, taking fish oil 

supplements, anticoagulants, cholestramine or clofibrate antilipemic agents. However, Fenton et 

al. did not describe statistical tests designed to establish the baseline comparability of patients on 

key study outcomes.89 Their ITT group involved those patients with their last observation 

carried forward (n=87), and to achieve “completer” status patients had to experience no increase 

in neuroleptics over the study and at least 12 weeks of treatment (n=75; n=37 receiving EPA). 

As with trial completers and noncompleters, their two study groups did not differ significantly 

for any patient characteristics, including prestudy/baseline consumption of omega-3 fatty acids in 

the daily diet, or current smoker status.89 Prestudy/baseline between-group comparability in 

terms of dietary intake of omega-3 fatty acids or of omega-6/omega-3 content was not assessed 

in the remaining three RCTs.58,87,140 

Few data were reported for key characteristics such as age of onset or time since diagnosis. 

In Peet and colleagues’ RCT, patients were required to exhibit a time since first diagnosis of no 

more than 20 years and the absence of other important medical conditions.87 Mean illness 

durations were similar for Emsley et al.’s two study groups (no statistical tests reported) (E-EPA: 

23.1 years, SD=8.5; placebo: 22.1 years, SD=12.4).140 Patients in Fenton et al.’s study first 

became ill at a mean age of 20.8 years, were first hospitalized at (mean) age 21.8 years, and had 

had an average of 10.7 prior hospitalizations. 

Intervention/exposure characteristics. While each of the four studies employed an 

exposure from the same company (Laxdale Limited), only one explicitly stated its exact source 

(i.e., concentrated fish oil).58 The other studies referred to E-EPA, a purified form of EPA, yet 

did not identify its source or describe the process of purification.87,89,140 Dose contrasts included 

3 g/d E-EPA or placebo (liquid paraffin),140 3g/d E-EPA or placebo (mineral oil) in addition to 4 

mg of vitamin E to retard spoilage,89 three different doses of E-EPA (4 g/d, 2 g/d, 1g /d) or 

placebo (liquid paraffin),87 and 2 g/d EPA enriched oil as opposed to 2g/d DHA enriched oil or 

placebo (corn oil).58 However, there were few data allowing us to conclude definitively that 

these studies were equally able to eliminate the possible confounding influence of having 

unequal amounts of calories, as energy, provided for their different study groups. 

In three RCTS, the omega-3 fatty acid contents were delivered by capsule,87,89,140 and one 

study provided their exposure via identical bottles.58 Of those using capsules, all provided some 

information suggesting that the appropriate numbers of capsule and amount of placebo content 

were used to equalize the total daily “intervention” per study group.87,89,140 Two of these trial 

reports did not describe whether the capsules were identical89,140 whereas the third did.87 Fenton 

et al.’s tasteless and odourless contents likely contributed to their patients’ inability to reliably 

guess which exposure they were receiving.89 They also employed capsule counts to assure 

compliance. 

The pourable oils (from identical bottles) used in Peet et al.’s trial58 were described as being 

indistinguishable by colour, texture and taste; however, no details were provided as to how the 

fishy taste or odour were controlled so as to preclude breaching the blind. That the exposure was 

delivered through pourable bottles raises an issue that was not addressed in Peet et al.’s report;58

such a poorly controlled approach to delivery typically complicates the interpretation of results 

(see Discussion).72 

Three of the four trials employed a high dose, that is, one including at least 3 g/d of omega-3 

fatty acids.87,89,140 As with the three supplemental treatment trials in depression, none of the 

studies provided omega-6 fatty acids or any other supplement as cointervention, and none 

attempted to implement a specific on-study ratio of omega-6/omega-3 fatty acid intake through 
135 

diet or supplementation. Patients in the four trials were not instructed to maintain their 

background diet although Emsley et al. had a dietitian review the dietary intake of study 

participants at baseline and during the study.140 EPA intake was derived from standard food 

supplementation tables (South African Medical Research Council). During their study, no 

between-group differences were observed for the dietary intake of omega-3 fatty acids. A 

balanced diet (undefined) was attributed to study participants both at baseline and during the 

trial.89 Fenton et al. employed the Willett Dietary Survey to estimate baseline fatty acid 

consumption. Dietary EPA intake was low, ranging from 0.56 g/wk to 1.13 g/wk.89 For the 

other RCTs, possible between-or within-group group variability data regarding dietary intake 

were not provided. Thus, this potential confounder was not controlled for. 

Only Fenton et al. used an antioxidant to retard spoilage.89 None of the trials described 

efforts to deodorize their exposures to maintain blinding. In the three studies evaluating 

biomarker data, no notable inappropriate methods to extract, prepare, store or analyze lipids were 

described.58,87,89 Purity data regarding the exposure were not provided by any of the trialists. No 

study report included details as to whether, or how, the presence of methylmercury was tested or 

eliminated from the omega-3 fatty acid exposure. 

Cointervention characteristics. In Peet et al.’s study, patients with symptomatic 

schizophrenia were receiving various types of antipsychotic medication, including both oral and 

depot preparations (no data reported).58 Some required anticholinergic medication to address 

side effects from the primary medications (no data reported). Fenton et al. reported that all but 

one patient used a neuroleptic, with 19 taking two neuroleptics, 34 using risperidone, olanzapine 

or quetiapine, and 24 receiving clozapine.89 Eight participants required an increased neuroleptic 

dose (four per study group) and four were terminated by week 12 for nonadherence to study 

medication protocol (two per study group). Peet and colleagues asked that their participants be 

maintained on their regular antipsychotic medication and dose for at least one month: clozapine 

(n=31 in ITT population), novel atypical antipsychotic drugs (i.e., olanzapine, risperidone or 

quetiapine; n=48 in ITT population) or typical antipsychotic medication (n=36 in ITT 

population).87 The proportions of patient on the different antipsychotic medications were similar 

although fewer individuals were taking standard neuroleptics in the 2 g/d E-EPA group. 

Antipsychotic doses, expressed as chlorpromazine equivalents in the Emsley et al trial, were 

slightly different (E-EPA: 1011 mg/d, SD=532; placebo=931 mg/d, SD=652), although results of 

a statistical test were not reported.140 Nine patients in each group were receiving clozapine, with 

the rest taking conventional medication (undefined). The types and doses of antipsychotic 

medication did not change during the study. No additional medication had to be prescribed 

during the study except for occasional analgesics for headache or lorazepam for insomnia. 

Outcome characteristics. Peet et al. employed the PANSS and assessed RBC PUFA 

composition.58 In Fenton et al.’s study, outcomes included the PANSS, the Abnormal 

Involuntary Movement Scale (AIMS), Simpson-Angus Rating Scale, MADRS and the CGI.89 

The Repeatable Battery for the Assessment of Neuropsychological Status was used at baseline 

and 16 weeks. Adverse events were solicited at each study visit using open-ended queries. The 

fatty acid content of RBCs was also investigated. 

PANSS change scores and Extrapyramidal Symptom Rating Scale (total score and subscale 

scores for dyskinesia, dystonia, akathisia and parkinsonism) were evaluated by Emsley et al.140 

Peet et al. assessed change in scores on the PANSS and its subscales.58 Other outcomes included 

the MADRS, the LUNSERS, AIMS, BAS, and SAS.87 Peet et al.’s ITT population included 115 

patients (of 122 randomized) who had had at least one post-baseline assessment, which was then 
136 

carried forward.87 Given that E-EPA appears to act on membrane phospholipids, and different 

classes of neuroleptic have been seen to act on phospholipids differently, it was argued that 

patients receiving different antipsychotic medications would respond differently.87 Data from 

the three groups of patient receiving different types of antipsychotic were analyzed separately by 

Peet and colleagues87 Logistic regression took into consideration center, baseline scores, illness 

duration and type of antipsychotic medication. Peet and colleagues also assessed the impact on 

RBC PUFA. 

Two additional analyses were conducted with Fenton et al.’s data.89 The first assessed some 

of the details defining the strong placebo response observed in the study (see below).88 The 

second60 assessed the impact on RBC fatty acid compositions of current smoker status, as one 

pro-oxidant factor with known degrading effects on PUFAs.170 Schizophrenic patients have 

disproportionately high rates of smoking.171 Analyses also evaluated the possible impact of 

another factor with the potential to degrade PUFAs (alcohol172), which, for example, was not 

controlled for by Peet et al.58 Other variables whose possible impacts were assessed were 

antipsychotic medication, sex, dietary intake, age, psychopathology, diagnostic subclassification 

and illness duration. Results from this second additional analysis by Hibbeln et al.60 could not be 

used to address the present review’s question about the possible association of the fatty acid 

content of biomarkers and disease states since only schizophrenic patients were a priori selected 

as study participants. This review required controlled studies to address this question. 

Study quality and applicability. The four RCTs received a mean Jadad total quality score 

of 3.8, indicating sound internal validity. Two each received allocation concealment ratings of 

Adequate58,87 or Unclear.89,140 Two received applicability ratings of II,58,87 and two received 

ratings of III.89,140

Summary Matrix 14: Study quality and applicability of evidence regarding the supplemental treatment of 

schizophrenia 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I FentonU 2001 90 

Author Year n Author Year n Author Year n

II PeetA 

PeetA 2001 

2002 

55 

122 

Applicability 

Author Year n Author Year n Author Year n

III EmsleyU 2002 40 

n = number of allocated/selected participants; RCT = AAdequate vs UUnclear allocation concealment 

Qualitative Synthesis of Individual Study Results 

Ten of Peet et al.’s schizophrenic patients discontinued treatment (never started, n=3; lost to 

followup, n=2; felt better, n=1; adverse events described below), leaving data from 45 

participants to be entered into the analysis.58 At study’s end, the EPA group’s total PANSS score 

was significantly lower than that in the placebo group. Taking baseline scores into account, 

repeated measures ANOVA revealed a significant treatment effect in favor of EPA over DHA 

using positive PANSS scores. EPA produced significantly greater improvement than did DHA 
137 

yet the EPA versus placebo difference only approached statistical significance for positive 

PANSS scores. No significant differences were found for negative symptom scores. When 

patients were divided on the basis of their type of response (i.e., >25% improvement vs < 25% 

improvement or unchanged or worse), the groups were significantly different, with EPA patients 

more likely to show greater than or less than 25% improvement. Additional, pairwise 

comparisons revealed a significant difference between EPA and either DHA or placebo.

Including data from twelve patients in each of the three groups, analyses of RBC fatty acid 

levels from Peet et al.’s study showed the largest increases in EPA and DHA in the EPA and 

DHA groups, respectively.58 Smaller rises in EPA and DHA were observed in the DHA and 

EPA groups, respectively. No significant changes were observed for AA. For EPA group 

participants, patients showing the greatest improvement in total PANSS also had the highest 

baseline levels of EPA and AA; and, multiple regression identified baseline EPA as a significant 

predictor of clinical improvement. No similar significant results were found for the DHA group, 

the placebo group or the full sample. 

In Fenton et al.’s study, repeated measures ANOVA showed a small but significant time 

effect for patients on each of total PANSS, MADRS and CGI scores.89 Both EPA and placebo 

patients benefited from their exposures. No time-by-group interaction effect was observed. No 

significant effects for time or a time-by-group interaction were found for ratings of cognitive 

impairment, extrapyramidal symptoms or tardive dykinesia. No significant differences were 

observed for the positive or negative PANSS scores. Results from analyses of data from study 

completers (n=75) were similar. Dickerson et al.’s followup assessment of the placebo response 

in the 37 patients receiving placebo revealed that most of the improvement occurred during the 

first 2 weeks of the study, with no PANSS score (total, positive, negative, general 

psychopathology) exhibiting significant change from week 2 to week 16.88

Analyses of biomarker data were reported by Fenton et al.89 and Hibbeln et al.60 No evidence 

of baseline bimodal distributions of RBC EPA, DHA or AA compositions was found to 

characterize the schizophrenic patients. By study’s end, the EPA group exhibited higher percent 

compositions of EPA and (omega-3-)DPA, and lower percent compositions of DGLA, AA, and 

(omega-6-)DPA. A decrease in DHA in the EPA group was observed yet it did not reach 

statistical significance. EPA increased significantly in the placebo group. The decrease in the 

AA/EPA ratio over the study was significantly greater for patients receiving EPA.89 After 

adjusting for multiple testing, the change in AA/EPA ratio was not significantly associated with 

any clinical variables. Changes in DHA composition were negatively correlated with changes in 

positive symptoms and positively associated with changes in involuntary movement.

Of many investigations using various factors (e.g., diagnostic subclassification), only sex and 

current smoking status were significantly related to fatty acid compositions.89 The DHA percent 

was reduced in smokers compared to nonsmokers, and males had lower DHA and EPA percents 

compared to females. For patients exclusively receiving EPA, neither sex nor smoker status 

predicted changes in EPA, DHA or AA. Other findings are reported briefly in the Discussion. 

With or without controlling for dietary EPA intake, medication, illness duration and sex, total 

PANSS score decrements were significantly greater in the E-EPA group in Emsley et al.’s 

trial.140 This significant difference was observed by week 3. The reduction in E-EPA patients 

taking clozapine was greater yet it did not achieve statistical significance. The only subscale 

score that produced a significant difference favored E-EPA patients for percent change in the 

general psychopathology score (PANSS). The only between-group difference on the dyskinesia 

scores from the Extrapyramidal Symptom Rating Scale involved a significantly greater reduction 
138 

in scores for E-EPA participants at 12 weeks. Yet, ANCOVA with total PANSS change as the 

dependent variable and change in dyskinesia entered into the analysis revealed no significant 

between-group differences, suggesting that reduction in total PANSS scores is related to 

reduction in dyskinesia scores. One participant in the E-EPA group was withdrawn after an 

overdose of antipsychotic medication. 

Peet et al. reported that nine patients experienced an adverse event leading to withdrawal 

although none were associated with the intervention.87 Four of these participants had been in the 

1 g/d E-EPA group. This active treatment group had the highest number of “failures” other than 

a protocol violation (n=12/32) although these data included individuals providing more than one 

reason (data not reported). No demographic or clinical differences were observed for those who 

dropped out and those who completed the trial. Peet and colleagues observed no or minor 

reductions in LUNSERS, AIMS, BAS and SAS scores across the study, with no significant 

between-group differences.87 

Changes in the total PANSS, its subscales and the MADRS for patients on typical 

neuroleptic drugs indicated that all E-EPA dosing groups improved significantly from baseline 

on the total PANSS, with the magnitude of the change covarying with the dose size.87 Only the 2 

g/d and 4 g/d E-EPA groups improved significantly on positive PANSS scores, with the 

magnitude of the change covarying with the dose size. A similar pattern was found for negative 

PANSS scores although the magnitude did not covary with the dose size. For the general 

psychopathology subscale of the PANSS, equivalent improvements were seen in the 1 g/d and 4 

g/d E-EPA study groups. No significant changes were seen for MADRS scores. However, large 

placebo effects were found such that significant improvements from baseline were observed for 

each of these clinical outcomes, including the MADRS. However, when compared to placebo, 

no significant differences were observed for patients on typical neuroleptics. 

Results from patients receiving atypical neuroleptics indicated significant within-group 

improvement for typical neuroleptics for the 1 g/d and 2 g/d E-EPA doses with respect to the 

total and subscale scores on the PANSS as well as the MADRS, yet the 4 g/d E-EPA did not 

yield any significant improvement on any of the clinical outcomes.87 Significant improvements 

were seen for all clinical outcomes for placebo patients, contributing to the lack of significant 

between-group differences. 

Patients on clozapine exhibited a different pattern of results.87 Results indicated that patients 

receiving placebo showed no significant improvements from baseline for any clinical outcome. 

Yet, except for the MADRS and the general psychopathology score on the PANSS, which were 

characterized by an absence of significant change, all three E-EPA doses showed significant 

improvements from baseline. The 2 g/d dose exhibited the greatest magnitudes of percent 

change in scores. Unlike what was found when the other two types of medication were 

examined, patients on 2 g/d E-EPA added to clozapine improved significantly relative to placebo 

on the total PANSS scale and the PANSS general psychopathology subscale.

Fatty acid composition data were analyzed by antipsychotic medication.87 The only 

significant change in the placebo group was a significant mean increase from baseline in AA 

within the group of patients taking atypical antipsychotics. In all drug groups except for 1 g/d EEPA given in addition to clozapine, there were significant dose-related increases in EPA levels 

from baseline. In patients taking clozapine, a significant increase in AA was observed in the 2 

g/d E-EPA group. The increment in DHA in the 2 g/d E-EPA group did not achieve statistical 

significance. Significant decreases were observed for both DHA and AA levels in the 4 g/d E-
139 

EPA group of patients also taking atypical antipsychotics. No other significant differences were 

observed. 

Mean percentage change data for the total PANSS score as well as PANSS subscale scores 

and the MADRS from each of the twelve groups of patient (4 treatment levels by 3 types of 

neuroleptic) were assessed for their possible association with mean percentage change data for 

each of EPA, DHA and AA RBC levels.87 Peet et al. found that changes in AA were 

significantly and positively related to changes in all clinical outcomes. Changes in DHA or EPA 

were unrelated to changes in clinical outcomes. 

A known side effect of clozapine, elevated levels of triglycerides were either prevented (in 

placebo and 1g/d E-EPA groups) or baseline levels were reduced significantly (2 g/d E-EPA and 

4 g/d E-EPA).87 

Quantitative Synthesis 

Given the available data, total PANSS score was chosen as the primary outcome measure. 

Since each of the RCTs measured PANSS at baseline and 12 weeks post-treatment, we aimed to 

extract the mean change from baseline in PANSS, together with the standard deviation of this 

change, for each treatment group. Where possible, data for ITT populations were used. Since 

only one study included more than one dose level of EPA, only placebo-controlled data were 

analyzed.87 A single study included one DHA dose,58 which yielded no benefit when compared 

to placebo. 

In two reports,58,140 summaries and statistical analyses were reported in terms of percent 

change. However, percent change has undesirable statistical properties.173 Thus, the authors of 

both reports were contacted and change from baseline data were requested. 

Only one author provided the requested data.140 In the Peet et al. report,58 post-treatment 

means and standard deviations were used instead of those for change from baseline.174 In Fenton 

et al.’s publication,89 the mean and standard deviation of PANSS were reported at baseline and at 

followup, but the standard deviation of change from baseline was not provided. The author was 

contacted but no reply was received, and post-treatment means and standard deviations were 

used instead of those for change from baseline. In Peet and colleagues’ report,87 results were 

reported separately by background treatment (typical neuroleptics, atypical neuroleptics, and 

clozapine), and for four different treatment groups (placebo and three different E-EPA doses). 

Although the standard deviation of change from baseline was not reported, p-values for change 

from baseline were provided, enabling us to infer the standard deviation. For each treatment 

group, the mean change was pooled across primary treatments using a weighted mean, and the 

standard deviation of the change was pooled across these treatments using a pooled standard 

deviation. 

Pooling was conducted using the weighted mean difference approach and the random effects 

method of DerSimonian and Laird.175 Statistical heterogeneity was assessed using the chi-square 

test with a significance level of 0.10. In all but one study,58 results from ITT analyses were 

available (using a last-observation-carried-forward strategy). 
140 

Figure 4. Estimates of the difference in mean total PANSS score between EPA and placebo groups, by study 

evaluating the supplemental treatment of schizophrenia 

Difference in mean total PANSS score

-20 -15 -10 -5 0 5 10

Emsley

Peet

Peet

Peet

Fenton

Peet

2002

2002

2002

2002

2001

2001

3

1

2

4

3

2

Dose

(g/d)

12

12

12

12

12

13

Followup

(wks)

40

60

59

58

87

29

n

← → Favors EPA Favors placebo

No pooled estimate is shown in Figure 4 because of the variation in dose within and among 

studies. Additionally, it should be noted that in the Peet and colleagues study87 the estimates for 

different doses versus placebo share the same placebo group. It was thus decided to investigate 

separately the placebo-controlled impacts of high- and low-dose EPA supplementation (i.e. <3 

g/d vs >3 g/d). 
141 

Figure 5. Estimates of the difference in mean total PANSS score between low dose (<3 g/day) EPA and 

placebo groups. Percentage weights contributed by each study to the pooled estimate are shown on the 

right-hand side. 

Difference in mean total PANSS score

-20 -15 -10 -5 0 5 10

Peet

Peet

Peet

2002

2002

2001

1

2

2

Dose

(g/d)

12

12

13

Followup

(wks)

60

59

29

n

50%

50%

Random effects

pooled estimate

← → Favors EPA Favors placebo

Given the number and sizes of the studies, a random effects model was employed. The 

pooled estimate (-7.5) and its 95% confidence interval (-14.5 to -0.4) are represented by the 

diamond at the bottom of Figure 5. While the estimate of precision was large, the model 

revealed significant benefit accruing to a 2 g/d EPA dose.87 The 1 g/d estimate from the Peet et 

al. study87 is shown as an open circle because it was not included in the pooled estimate; the 

estimate for the 2 g/d dose shares the same placebo group. Statistical heterogeneity was not 

significant between the two pooled studies (chi-square statistic 0.66 on 1 degree of freedom, 

p=0.42). 
142 

Figure 6. Estimates of the difference in total PANSS score between high dose (3 g/day or greater) EPA and 

placebo groups. Percentage weights contributed by each study to the pooled estimate are shown on the 

right-hand side. 

Difference in mean total PANSS score

-10 -5 0 5 10

Emsley

Peet

Fenton

2002

2002

2001

3

4

3

Dose

(g/d)

12

12

12

Followup

(wks)

40

58

87

n

32%

31%

37%

Random effects

pooled estimate

← → Favors EPA Favors placebo

Looking at high doses of at least 3 g/d EPA, the pooled estimate (-1.5) and its 95% 

confidence interval (-8.0 to 4.9) are represented by the diamond at the bottom of Figure 6. No 

significant benefit was observed in association with high-dose EPA. Statistical heterogeneity 

between the studies was significant at the 0.10 level (chi-square statistic 4.9 on 2 degrees of 

freedom, p=0.09). 

Impact of Covariates and Confounders 

From these preliminary analyses, only 2 g/d, or low-dose, EPA produced a significant 

benefit. Only one trial employed a 1 g/d dose and hence this definition of a low dose could not 

be subjected to quantitative synthesis. Since only data from the UK trials were combined 

statistically in the meta-analysis of low-dose EPA, possible confounding from differences in the 

background diet was minimized, or even eliminated, in a way that likely would not have 
143 

occurred if data from the South African study of Emsley et al. or the American RCT of Fenton et 

al. had been included in this meta-analysis. It must also be recalled that, in Peet and colleagues’ 

RCT, only those receiving clozapine as primary treatment exhibited a significant benefit 

associated with E-EPA supplementation.87 

Is Omega-3 Fatty Acid Intake, Including Diet and/or 

Supplementation, Associated With the Onset, Continuation 

or Recurrence of Schizophrenia? 

As observed in Summary Tables 37 through 39 (below), derived from Evidence Tables 2 and 

3 (Appendix E*

), six observational studies and three cross-national ecological analyses met 

eligibility criteria. Two of the latter have already been described in this report, and so some of 

their details are not repeated. Since it investigated a single group of patients, the Mellor et al. 

study did not qualify to address either basic question 1 (i.e., interventional focus) or 3 (i.e., fatty 

acid content of biomarkers).91 It did, however, meet eligibility criteria to address the present 

question. The nine studies were published between 1988 and 2004.

Overview of Relevant Studies 

Mother’s milk is considered an important dietary source of omega-3 fatty acids, which are 

essential for the development of the brain.176 It is thought that schizophrenia may be linked to 

early brain development,55 and therefore it is not surprising that the relationship between the 

early intake of omega-3 fatty acids and the risk of developing schizophrenia has been explored. 

Peet et al. conducted a case-control study comparing the infant feeding histories (breastfed vs 

formula-fed) of DSM-IV diagnosed schizophrenic patients (n=55) and nonpsychiatric controls 

(n=55) matched for age (mean: 34 years), sex (47 males) and socioeconomic status.92

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
144 

Summary Table 37: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

schizophrenia (observational studies) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Peet, 1997, 

UK: 

case-control 

study92

schizophrenic 

pts 

(n=55) 

matched 

nonpsychiatric 

controls 

(n=55) 

Schizophrenic pts less 

likely to have been 

breastfed;+ breastfeeders 

of >4 wk less frequent in 

schizophrenic pt grp+

Total 

quality: 3 

[Grade: C] 

II 

McCreadie, 

1997, UK: 

case-control 

study143

schizophrenic 

pts 

(n=45) 

siblings 

(n=92)/ 

national 

survey data 

from Scotland 

(n=1,648 & 

n=1,718) & 

Great Britain 

(n=13,687) 

NS lesser breastfeeding in 

schizophrenic pts than 

siblings; most pts born in 

1940s & 1950s, with 

breastfeeding incidence in 

these decades < Scottish 

national surveys in 

1946+++ & 1958;+

 nonbreastfed pts had more 

schizoid & schizoptypal 

traits+++ in childhood than 

siblings, including poorer 

social adjustment;++++ NS 

correlations bet 

breastfeeding length & 

adjustment 

Total 

quality: 4 

[Grade: B] 

II 

Leask, 2000, 

UK: 

case-control 

study142

those 

developing 

schizophrenia 

in 2 national 

birth cohorts 

(1946: 

n=5,362; 1958: 

n=18,856) 

those who do 

not develop 

schizophrenia 

in these 2 

national birth 

cohorts 

In both birth cohorts: NS 

feeding histories of 

schizophrenic pts & 

controls, with or without 

adjustment for offspring’s 

sex & father’s social class 

Total 

quality: 5 

[Grade: B] 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; Length = intervention length; Design = 

research design; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; 

n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = 

decrease(d)/reduction/lower 

In McCreadie et al.’s case-control study, mothers of patients with schizophrenia (n=45; 29 

males) completed a questionnaire about whether, and for how long, their offspring, including all 

siblings (n=92), had been breastfed.143 A census in 1989 identified 146 schizophrenic patients, 

61 of whom had living mothers. From these, 51 mothers were interviewed regarding the birth of 

their children and their subsequent adjustment. The current mental health status of the patients 

was also assessed (details published elsewhere). In 1995, a questionnaire was sent to the 

mothers to determine their offspring’s breastfeeding history, including its duration. National 

survey data for Great Britain (1946: n=13,687), Scotland (1958: n=1,648) and Scotland (1980: 

n=1,718) were used to establish various reference standards. 

Leask et al. analyzed prospective data separately from two UK national birth cohorts (1946: 

n=5,362; 1958: n=18,856) using a nested case-control approach.142 They compared the feeding 

histories (including duration) of those individuals who later developed schizophrenia with the 

rest of the population. The 1946 British National Survey of Health and Development was 
145 

devised to survey all births in mainland Britain. A random sample, stratified by social class, 

comprised a cohort (n=5,362) who were followed up on many occasions (i.e., 20 followups by 

age 43). The 1958 National Child Development Study included 98% of the births in mainland 

Britain, and had five followups, ending when individuals were 33 years of age. Mothers 

provided details about perinatal feeding by interview (1946: when child was age 2; 1958: when 

child was age 7). 

Sasaki et al. examined feeding patterns during the infancy of inpatients and outpatients with 

schizophrenia (n=100; 60 males; age=32+9 years), their healthy siblings (n=37; 22 males; 

age=34.6+8.4 years) and age-matched healthy controls (n=200; 92 males; age=31+10 years) 

(Summary Table 38).144 Mothers of controls were primarily recruited from hospital staff and a 

few physicians. 

Summary Table 38: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

schizophrenia (observational studies) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Sasaki, 2000, 

Japan: 

case-control 

study144

schizophrenic 

inpts & outpts 

(n=100) 

healthy 

siblings 

(n=37)/ 

matched 

healthy 

controls 

(n=200) 

no evidence for lesser 

likelihood of breastfeeding 

in infancy of patients at 1 

or 3 mo 

Total 

quality: 5 

[Grade: B] 

III 

Amore, 2003, 

Italy: 

case-control 

study141

hospital 

admitted 

schizophrenic 

pts 

(n=113) 

siblings 

(n=140)/ 

normal 

controls 

(n=113) 

adjusting for age, sex, 

birth weight, disease 

severity & birth order, NS 

breastfeeding incidence; 

NS age of onset for 

exclusively breastfed vs 

others; breastfeeding 

duration positively 

correlated with age of 

onset+

 

Total 

quality: 6 

[Grade: B] 

III 

Mellor, 1996, 

England: 

1 wk single 

prospective 

cohort study as 

baseline for a 

noncomparative 

before-after 

study91

schizophrenic pts 

(n=20) 

EPA intake negatively 

associated with total 

psychopathology;+

 

negative correlations for 

positive symptoms & ALA 

intake+

 & total n-3 fatty 

intake.+ Multiple 

regression: EPA intake 

inversely related to total 

PANSS;+

 total n-3 intake 

negatively related to 

positive symptoms+

 

Total 

quality: 4 

[Grade: B] 

II 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; Length = intervention length; Design = 

research design; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; 

n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; 

PANSS = Positive and Negative Symptoms Scale; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 
146 

Amore et al. conducted a case-control study to compare the incidence and length of 

breastfeeding in patients with schizophrenia (n=113; n=58 inpatients), their siblings (n=140) and 

normal (i.e., nonschizophrenic) controls (n=113).141 The goal was to examine the relationship 

between the duration of breastfeeding and age of onset of schizophrenia. Schizophrenic patients 

who were either consecutively admitted to a psychiatric ward or attending an outpatient 

community health center were enrolled in Bologna. For each patient, a control was selected 

from the Bologna birth register. The latter were matched for age, sex, singleton status and 

residential district. 

Mellor et al. examined the possible association of both dietary intake and RBC fatty acid 

status with schizophrenic symptoms in a cohort of schizophrenic patients (mean age: 56.1 years; 

13 males) who, after providing prospective data concerning dietary intake, then went on to 

receive supplementation in a noncomparative before-after study.91 All patients were receiving 

neuroleptic medication. 

Christensen and Christensen described the statistical association between the course and 

outcome of schizophrenia using data from eight national centers involved in the WHO’s 2-year 

followup study (Denmark, India, Colombia, Nigeria, UK, the former USSR, US and the former 

Czechoslovakia), and data regarding the dietary intake of fats from various food sources, 

including fish and seafood (Summary Table 39).145 The latter data were obtained from the same 

FAOSTAT source consulted by Peet in his cross-national ecological analysis.109 

Summary Table 39: Association between omega-3 fatty acid intake and onset, continuation or recurrence of 

schizophrenia (cross-national ecological analyses) 

Study groups1

 

Author, Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Christensen, 

1988, 

8 countries: 

cross-national 

ecological 

analysis145

n=8 countries high intake of saturated fat 

associated with unfavorable 

schizophrenia course and 

outcome+- +++ NS relationship bet 

intake of unsaturated fat, including 

PUFAs, & schizophrenia course or 

outcome

Total 

quality: 3 

[Grade: C] 

III 

Noaghiul, 2003, 

14 countries: 

cross-national 

ecological 

analysis90

n=14 countries seafood consumption did not 

predict lifetime prevalence rates

Total 

quality: 4 

[Grade: B] 

III 

Peet, 2004, 

12 countries: 

cross-national 

ecological 

analysis109

n=12 countries fish consumption not associated 

with specific schizophrenia course 

or outcome variables 

Total 

quality: 3 

[Grade: C] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; Length = intervention length; Design = research 

design; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not 

applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; wt = weight; ∆ = change; +

p<.05 or 

significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = 

decrease(d)/reduction/lower 

Lifetime prevalence rates for schizophrenia, from seven countries, were obtained by 

Noaghiul and Hibbeln from the Cross-National Collaborative Group epidemiological study in 
147 

their cross-national ecological analysis.90 To these were added prevalence data from seven 

additional countries (Spain, Israel, Iceland, Australia, UK, Greece and Hong Kong). All rates 

were reported as cases per 100,000 population. Prevalence rates drawn from the Cross-National 

Collaborative Group epidemiological study were standardized at each site, with a weight 

calculated per subject, and stratified for age and sex. Data from other sources could not be 

weighted in this manner since primary data were unavailable. Socioeconomic status and 

educational level were not taken into consideration. The female-to-male ratio (age=18-64 years) 

was roughly equal at all sites, with slightly higher rates seen for Canada, Puerto Rico, Korea and 

New Zealand. National seafood consumption data, measured as apparent seafood consumption 

(lb/person/y), were obtained from the National Marine Fisheries Service and the WHO’s 

FAOSTAT database. As a measure of the disappearance of seafood from the economy per year, 

apparent seafood consumption (lb/person/y) was once again calculated as total catch plus imports 

minus exports. 

Peet’s ecological analysis focused on international variations in the prevalence of depression 

and the outcome of schizophrenia, and their possible prediction by patterns of omega-3 fatty acid 

intake.109 Data on food use were taken from the FAOSTAT database, and reflect apparent 

national food consumption. Two-year outcome data relating to schizophrenia were drawn from 

the WHO’s International Pilot Study of Schizophrenia (IPSS). A second source of schizophrenia 

outcome data was the Determinants of Outcome of Severe Mental Disorders (DOSMED) study. 

Additional references to the sources of these data are included earlier in this report. 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. Of the five case-control studies, only Peet et al.’s abstract92 failed to 

give adequate descriptions of eligibility criteria. Mellor et al.’s description of their patient cohort 

was sparse.91 All three cross-national ecological analyses provided sufficient amounts of detail 

to determine their methods.90,109,145 While the latter each included data from multiple countries, 

the observational studies were conducted in Italy,141 Japan144 and the UK.91,92,142,143 

Population characteristics. Given the heterogeneous nature of the included studies’ 

populations it made little sense to synthesize some of the population characteristics such as age 

or percent male composition. On two occasions, inpatients and outpatients were described as the 

source of the study population.141,144 Mellor et al.’s schizophrenic patients had been, or were, 

longterm inpatients.91 The remaining reports did not provide similar details.90,92,109,142,143,145 

Diagnoses of schizophrenia were assigned using DSM-IV criteria,92,141,144 the ICD-9143 or DSMIII-R for Leask et al.’s 1946 birth cohort and CATEGO criteria for their 1958 birth cohort.142 

Mellor et al. also employed DSM-III-R criteria.91 Most of Sasaki et al.’s patients had been 

chronically ill, had had several episodes of exacerbation and had histories of admission to 

hospital.144 Other than this case-control study report, none of the other reports described a 

method used to rule out schizophrenia or other psychopathology from control groups. 

Comparison subjects and their mothers, in addition to unaffected siblings, were interviewed by 

Sasaki et al.’s clinicians to establish that none were experiencing major psychoses or other 

psychiatric disorders. The WHO’s international followup study, using its own diagnostic 

criteria, were implicated in all three cross-national ecological analyses.90,109,145 

Each observational study report failed to present ethnicity/racial data although Sasaki et al.’s 

likely involved Asian participants.144 The cross-national ecological analyses included, by 

definition, mixed ethnicities/races.90,109,145 Some active attempts to match controls and patients 
148 

were made. Amore et al. matched their groups by age, sex, singleton status and residential 

district.141 Peet et al. matched groups based on age, sex and socioeconomic status.92 The social 

class of the father at birth, and sex of the child were taken into consideration as potential 

confounders in Leask et al.’s study.142 In Amore et al.’s study, the only significant betweengroup differences were that more patients than siblings were male, and more patients than 

controls were second-born or more.141 No significant differences were observed for age of 

offspring, age of mothers at birth, or age of fathers at birth. Amore et al. divided their patients 

with schizophrenia into those who had been solely breastfed for at least the first four months of 

life, those having exclusively received formula, or those having received a mixed feeding within 

the first four months of life.141 

Intervention/exposure characteristics. Typically, interviews were employed in casecontrol studies to gather data concerning the feeding method,92,142 with some investigators also 

inquiring about the duration of feeding practices.141,143 Sasaki et al. employed a written 

questionnaire to collect their data.144 Leask et al.’s breastfeeding data were collected from the 

two cohorts in the same way: prospectively from UK birth registries.142 Data were not provided 

in any report on the possible intake of omega-3 fatty acids by mothers during pregnancy or 

breastfeeding. Mellor et al. collected meal intake data prospectively for one week using a 7-day 

weighed intake approach.91 Diet history diary data were also requested to keep track of betweenmeal intake. Exposure data for all three cross-national analyses were extracted from the United 

Nations’ FAOSTAT database.90,109,145 

Outcome characteristics. Two case-control studies assessed outcomes pertaining to the 

course and outcome of schizophrenia.109,145 Amore et al. evaluated the age of onset of 

schizophrenia.141 McCreadie assessed a number of scores based on instruments evaluating 

adjustment, including the PANSS.143 Mellor et al. employed the PANSS, AIMS and Research 

Diagnostic Criteria concerning tardive dyskinesia.91 All other studies focused on the prevalence 

of schizophrenia. 

Study quality and applicability. The five case-control studies received a mean quality 

score of 4.6, with three studies assigned an applicability rating of II,92,142,143 and another two 

studies receiving an applicability rating of III.141,144 The single prospective cohort study attained 

a quality score of 4 and an applicability rating of II.91 The mean quality score received by the 

three cross-national ecological analyses was 3.3, and each attained an applicability rating of 

III.90,109,145 
149 

Summary Matrix 15: Study quality and applicability of evidence regarding the association between omega-3 

fatty acid intake and onset, continuation or recurrence of schizophrenia 

Study Quality

A B C 

Author Year n Author Year n Author Year n I 

Author Year n Author Year n Author Year n

II 

McCreadie 

Leask 

Mellor 

1997 

2000 

1996 

>13k 

>23k 

20 

Peet 1997 110 

Author Year n Author Year n Author Year n

Applicability 

III 

 Sasaki 

Amore 

Noaghiul 

2000 

2003 

2003 

337 

363 

14C 

Christensen 

Peet 

1988 

2004 

8C 

12C 

n = number of allocated/selected participants; C = Countries; k = 1,000’s 

Qualitative Synthesis of Individual Study Results 

Peet et al. found that, compared with nonpsychiatric controls (78%), schizophrenic patients 

(60%) were less likely to have been breastfed.92 Additional analysis of those individuals who 

had been breastfed for more than 4 weeks indicated that there were fewer of these individuals in 

the schizophrenic group (44%) compared with the control group (67%).

McCreadie reported that the incidence of breastfeeding (i.e., breastfed at least once) was 

lower in schizophrenic patients (29%) than in their siblings (38%).143 This difference was not 

statistically significant. Neither mother’s age at birth, nor birth order, distinguished between 

patients and their siblings. Most of the patients had been born in the 1940s and 1950s, with the 

incidence of breastfeeding in these decades being significantly lower than what was observed in 

Scottish national surveys in 1946 (33% vs 81%) and 1958 (26% vs 51%), respectively. Those 

patients who had not been breastfed exhibited more schizoid and schizotypal personality traits 

(Scale for Assessment of Premorbid Schizoid and Schizotypal Traits) in childhood than did their 

siblings, including poorer social adjustment (Premorbid Social Adjustment Scale). Breastfed 

patients did not differ in these ways from their siblings. No significant correlations were 

observed between length of breastfeeding and any indices of adjustment, including the negative 

PANSS. 

Leask et al. did not find significant differences in the feeding histories of patients with 

schizophrenia and controls, with or without adjustment for offspring’s sex and father’s social 

class.142 In the 1946 birth cohort, 30 cases of schizophrenia or schizoaffective disorder (n=20 

males) had manifested by age 43 years, with 24.1% of cases and 23.6% of controls having 

exclusively been formula-fed. In addition, 17.3% of cases and 12.3% of controls had been 

breastfed for less than 1 month. Corresponding data for those breastfed more than one month 

were 58.6% and 64.1%, respectively. In the 1958 birth cohort, 40 cases of “narrow 

schizophrenia” (n=14 males) had emerged by age 28 years. Of these, 24.1% of cases had been 

solely bottle-fed compared with 31.7% of controls. The figures for those breastfed for less than 

1 month were 27.6% and 24.9%, respectively. Data for those breastfed longer than 1 month 

were 48.3% and 43.3%, respectively. 

Sasaki et al. found no evidence for a lesser likelihood of schizophrenic patients having been 

breastfed, either at 1 month or 3 months post-birth (no statistics reported).144 Nor was there 
150 

evidence that a decrease in breastfeeding had occurred during the infancy of schizophrenic 

patients (no statistics reported). 

Amore et al. divided their schizophrenic patients into those who had been solely breastfed for 

at least the first 4 months of life, those who had exclusively received formula, or those having 

received “mixed” feeding within the first 4 months of life.141 Adjusting for age, sex, birth 

weight, disease severity and birth order, they found no significant between-group differences in 

the incidence of breastfeeding. As well, there were no between-group sex differences in the 

type of feeding. Siblings had been breastfed longer than normal controls. Age of onset was later 

in those exclusively breastfed (22.1+6.3 years) compared with all others (20.8+4.9 years), yet 

this difference was not statistically significant. However, the duration of breastfeeding was 

positively and significantly correlated with the age of onset of schizophrenia.141 

Mellor et al. observed that dietary EPA intake was significantly and negatively associated 

with PANSS total psychopathology.91 Significant and negative correlations were likewise found 

for positive symptoms and both ALA dietary intake and total omega-3 fatty acid intake. Dietary 

EPA intake was also significantly and negatively associated with tardive dyskinesia scores on the 

AIMS. Multiple regression revealed that EPA intake was significantly and inversely related to 

PANSS total scores and to tardive dyskinesia ratings, and that total omega-3 fatty acid intake 

was significantly and negatively related to PANSS positive symptoms. While these results do 

not come from a controlled study, RBC total omega-3 fatty acid content was significantly and 

positively correlated with PANSS negative symptoms.

In their cross-national ecological analysis Christensen and Christensen found that a high total 

intake of saturated fat was significantly associated with ratings of an unfavorable schizophrenia 

course and outcome. To be exact, both the percentage energy derived from fat, including 

saturated fat, and the percentage energy derived predominantly from land animals and birds, 

containing saturated fat, were: a) significantly and positively associated with the mean 

percentage of followups spent in psychotic episodes, the percentage of patients with severe social 

impairment and total overall outcome score; and b) significantly and negatively associated with 

mean days spent outside hospital. The percentage of energy derived from sources with a 

relatively high content of unsaturated fat, including PUFAs (i.e., vegetables, fish and seafood), 

was not significantly associated with any of the aformentioned mental health parameters. 

Multiple regression revealed that only total outcome score was significantly predicted by both 

the percentages of intake of saturated (positive correlation) and unsaturated fats (negative 

correlation). Countries obtaining more of their dietary fat from land animals and fowl and less 

from vegetable or marine sources exhibited a worse schizophrenia outcome. This scenario 

accounted for 97% of the variance in outcome between countries. However, the evidence did not 

exhibit a significant direct relationship between intake of unsaturated fat, including PUFAs, and 

schizophrenia course or outcome. 

Using linear and nonlinear regression models, Noaghiul and Hibbeln found that seafood 

consumption did not significantly predict lifetime prevalence rates (no data reported).90 Peet 

reported that fish consumption was not significantly associated with specific schizophrenia 

course or outcome variables, including mean days out of hospital, percentage of patients with 

severe social impairment, total outcome score, hospitalization status, percentage of patients with 

little social impairment, or total “best outcome” score. 
151 

Quantitative Synthesis 

Meta-analysis was not considered because of the variability in the study designs (case-control 

vs single prospective cohort study vs cross-national ecological analysis), the schizophreniarelated outcomes (incidence vs prevalence vs course vs outcome) as well as in the sampling 

strategies, methods assessing breastfeeding practices and the definitions of cases or controls 

employed in the case-control studies. 

Impact of Covariates and Confounders 

The mix of study designs and study outcomes, in addition to the failure of studies to try to 

experimentally or statistically control for variables with the potential to influence clinical 

outcomes, made it impossible to assess the impact of extra-exposure factors on study outcomes. 

At the same time, few studies yielded results indicating a significant association between omega3 fatty acid intake and the onset, continuation or recurrence of schizophrenia; and, no variables 

were noted as being potentially responsible for determining this pattern of findings. 

Is the Onset, Continuation or Recurrence of Schizophrenia 

Associated With Omega-3 or Omega-6/Omega-3 Fatty Acid 

Content of Biomarkers? 

As observed in Summary Tables 40 through 44 (below), derived from Evidence Table 2 

(Appendix E*), 14 cross-sectional studies published between 1979 and 2003 were included.114,146-

158 Two of these studies were conducted at baseline in prospective cohort studies.157,158 

Overview of Relevant Studies 

Obi and Nwanze assessed the RBC and plasma fatty acid compositions of schizophrenic 

patients (n=6; 30-50 years) compared to age-matched (22-45 years) healthy controls (n=6) drawn 

from hospital staff and students in Nigeria (Summary Table 40).153 Horrobin et al. evaluated the 

fatty acid content in plasma phospholipids in an heterogeneous population of schizophrenic 

patients from three different cities (n=84; mean age: 40.8 [20-71] years; 72.6 % male), compared 

with younger healthy controls (n=119; mean age: 35.7 [19-66] years; 51.3 % male).152 Kaiya et 

al. examined the plasma fatty acid composition in medicated Japanese schizophrenics (n=59; 

mean age: 35.7 years; 61% male), patients with an affective or paranoid disorder (n=24; mean 

age: 36.3 years; 37.5% male) and healthy volunteers recruited from hospital personnel (n=24; 

mean age: 36.3 years; 37.5% male).151

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
152 

Summary Table 40: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of schizophrenia 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Obi, 1979, 

Nigeria: 

multiple-group 

crosssectional 

study153

schizophrenic 

pts 

(n=6) 

healthy 

controls 

 (n=6) 

Ï % of LA in schizophrenic 

pts+ Total 

quality: 1 

[Grade: C] 

III 

Horrobin, 

1989, England, 

Scotland, 

Ireland: 

multiple-group 

crosssectional 

study152

adult male & 

female 

schizophrenic 

pts (n=84) 

adult male 

& female 

controls 

(n=119) 

Ð total n-6 levels in pts;+ Ï n-3 

levels in pts;+ Ð n-6/n-3 in 

pts;+ Ð LA & AA in pts;+ Ï

DHA in pts (England & 

Ireland);++ NS EPA bet grps

Total 

quality: 2 

[Grade: C] 

II 

Kaiya, 1991, 

Japan: 

multiple-group 

crosssectional 

study151

adult male & 

female 

schizophrenic 

pts 

(n=59) 

adult male 

& female 

affective or 

paranoid 

disorders 

(n=24)/ 

adult male 

& female 

controls 

(n=24) 

NS total n-3 FA; Ï DGLA in 

schizophrenic pts;+

Ð LA in 

schizophrenic pts;+ Ï EPA in 

schizophrenic male pts vs 

female pts;++ in cholesterol 

fraction, NS bet schizophrenic 

pts >40 & <40 y; Ï AA in inpts 

vs outpts+

Total 

quality: 3 

[Grade: C] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = 

nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = 

month; ∆ = change; RBC = red blood cells; PL = phospholipid; +p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = decrease(d)/reduction/lower 

Fischer et al. analyzed the fatty acid content in platelets from: German schizophrenic patients 

treated with “high dose” (n=9; age: 24-42 years, inpatients) or “low dose” (n=7; age: 35-53 

years, outpatients) monotherapy of neuroleptic drug (phenothiazine and thioxanthene); untreated 

schizophrenic patients (n=2); and, untreated healthy controls (n=6; 100% male) (Summary Table 

41).150 Peet et al. examined the RBC fatty acid content in medicated schizophrenic inpatients 

(n=23; mean age: 55 years; 69.5% male) and in age- and sex-matched healthy controls (n=16).149 

Vaddadi et al. examined the RBC fatty acid content in hospitalized and non-hospitalized 

medicated schizophrenic patients with or without tardive dyskinesia (n=72), in addition to 

patients with schizophrenia or schizoaffective disorders (n=72; mean age: 35.4 [18-64] years; 

75% male) and age-matched healthy controls (n=39).157 
153 

Summary Table 41: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of schizophrenia 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Fischer, 1992, 

Germany: 

multiple-group 

crosssectional 

study150

“high dose” 

inpts 

(n=9)/ 

control 

males 

(n=6) 

“low dose” 

outpts 

(n=7)/ 

untreated pts 

(n=2) 

Ð LA, AA & DHA “high-dose” 

vs “low dose” & controls;++; 

Ð LA, AA & DHA in ”low 

dose” vs untreated;+ Ï ratio 

of SFA/PUFA in “high dose” 

vs “low dose” & controls+

Total 

quality: 1 

[Grade: C] 

III 

Peet, 1995, 

UK: 

multiple-group 

crosssectional 

study149

medicated 

inpts (n=23) 

age & sexmatched 

healthy 

controls 

(n=16) 

Ð EPA & DHA in pts;+++ Ð

LA & AA in pts;+++ NS 

correlation bet neuroleptic 

dosage & FA levels

Total 

quality: 3 

[Grade: C] 

III 

Vaddadi, 1996, 

Australia: 

multiple-group 

crosssectional 

study at 

baseline of 

multiple 

prospective 

cohort study157

adult male & 

female 

schizophrenic 

pts with 

tardive 

dyskinesia 

(n=32) 

adult male & 

female 

schizophrenic 

pts without 

tardive 

dyskinesia 

(n=40)/ 

 normal 

controls 

(n=39) 

Ð LA pts severe TD vs pts 

without TD;++ Ð LA pts 

without TD vs control 

group;++ Ï (n-3-)DPA pts vs 

controls;+ followup at 4.5 y: 

Ï RBC 

(n-6-)DGLA in both pt grps 

vs controls++

Total 

quality: 1 

[Grade: C] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 FAs; n-6 = omega-6 FAs; 

ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant statistical 

difference; n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; ∆ = change; RBC 

= red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine phosphoglycerides; +

p<.05 

or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = 

decrease(d)/reduction/lower; SFA = saturated fatty acids; TD = tardive dyskinesia 

Mahadik et al.’s sample of 12 schizophrenic patients (n=8 drug-naïve and first episode) and 

six patients with bipolar mood disorder (n=2 manic first episode) were compared to eight sexmatched control subjects with respect to their fatty acid content in cells extracted from skin 

biopsies (Summary Table 42).114 Assies et al. evaluated the RBC fatty acid content in 

schizophrenics (n=16), one patient with psychoaffective disorder, one with bipolar disorder and 

one with a brief psychotic disorder according to DSM-IV diagnostic criteria (n=19; mean age: 

21.2 years; 89% male), compared with age, sex, height and weight-matched healthy controls 

(n=14; mean age: 20.9 years; 85.7% male).148 Yao et al. examined the correlation between RBC 

fatty acid content and in vivo membrane phospholipid metabolites in first-episode, drug-naïve 

schizophrenics (n=11; mean age: 26 [17-44] years; 54.5% male) compared to age-, sex- and racematched normal controls (n=11; mean age: 26 [19-39] years; 54.5% male).154
154 

Summary Table 42: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of schizophrenia 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Mahadik, 1996, 

US: 

multiple-group 

crosssectional 

study114

male & female 

schizophrenic 

pts (n=12) 

male & 

female 

bipolar pts 

(n=6)/ 

controls 

(n=8) 

Ð DHA in cell lines of 

schizophrenic pts vs bipolar pts & 

controls;+ NS DHA bet bipolar & 

controls; Ð AA in schizophrenia 

vs bipolar pts+

Total 

quality: 

5 

[Grade: 

B] 

I 

Assies, 2001, 

Holland: 

multiple-group 

crosssectional 

study148

schizophrenia 

& other 

diagnoses in 

young adults 

(n=19) 

matched 

controls 

(n=14) 

Ð DHA & (n-3-)DPA in pts;++ Ð

total n-3 in schizophrenic pts;+++ 

NS n-6 bet grps; Ð DHA/AA 

ratio in pts;+

 NS AA/EPA, 

DPA/DHA & n-6/n-3; positive 

correlation bet CPZ equivalents 

& AA/EPA;+

 negative correlation 

for EPA & CPZ dosage;+

 Ð n6/n-3 in cannabis users vs 

nonusers; 

no consistent pattern of 

correlations of FA content & 

symptomatology 

Total 

quality: 

2 

[Grade: 

C] 

III 

Yao, 2002, US: 

multiple-group 

crosssectional 

study154

drug-naïve, 

first episode 

schizophrenic 

pts (n=11) 

normal 

controls 

(n=11) 

Ð AA in pts;+

 NS bet-grp 

differences for rest of FA;

positive correlation bet peripheral 

biomarkers & PLs only in 

prefrontal brain++ 

Total 

quality: 

3 

[Grade: 

C] 

I 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 FAs; n-6 = omega-6 FAs; 

ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant statistical 

difference; n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; ∆ = change; RBC 

= red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine phosphoglycerides; +

p<.05 

or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = 

decrease(d)/reduction/lower;SFA = saturated fatty acids; CPZ = chlorpromazine 

Khan et al. enrolled drug-naïve, first episode schizophrenic patients (n=22) drawn from the 

Army Medical Center in United States, chronically medicated schizophrenic patients from an 

outpatient clinic (n=30) and age- and sex-matched healthy volunteers (n=16) (Summary Table 

43).147 This study measured plasma and RBC fatty acid contents and their metabolites from 

peroxidation. 

The first Arvindakshan et al. study examined the RBC and plasma fatty acid compositions in 

medicated schizophrenic patients in India (n=28; mean age: 29.6 years; 64.3% male) and in ageand sex-matched healthy volunteers (n=45; mean age: 30 years; 67% male).155 This was a 

before-after study, where only the patients received an intervention (i.e., omega-3 fatty 

supplementation) for 24 weeks. We assessed the cross-sectional baseline data from 

schizophrenics and controls. Because the intervention part of the study was uncontrolled, clinical 

efficacy data were not eligible for inclusion in this review. Arvindakshan et al.’s second study 

evaluated the RBC membrane content in drug-naïve, first episode schizophrenics (n=20; mean 

age: 29.4 years; 60% male), medicated patients (n=32; mean age: 31.3 years; 65.6% male) and 

age-, sex -and race-matched healthy controls (n=45; mean age: 29.2 years; 55.6% male).146
155 

Summary Table 43: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of schizophrenia 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Khan, 2002, 

US: 

multiple-group 

cross-sectional 

study147

drug-naïve, 

first episode 

schizophrenic 

pts (n=22) 

chronic 

medicated 

schizophrenic 

pts (n=30)/ 

healthy 

controls 

(n=16) 

Ð LA, AA & DHA were lower 

in FE vs chronic pts;+++ Ð

LA, AA & DHA in FE & 

chronic pts vs controls;+++ 

Larger Ð PUFA levels 

associated with greater 

severity of psychosis, 

indicated by Ï clinical 

scores in FE pts vs chronic 

pts; ∆ did not seem to be 

related to age or smoking 

Total 

quality: 3 

[Grade: C] 

I 

Arvindakshan, 

2003, India: 

multiple-group 

cross-sectional 

study at 

baseline of 

before-after 

study155

medicated 

schizophrenic 

pts (n=28) 

healthy 

controls 

(n=45) 

Ð EPA & DHA in pts (at 

baseline);+++ NS in LA or AA 

content (at baseline)

Total 

quality: 4 

[Grade: B] 

III 

Arvindakshan, 

2003, India: 

multiple-group 

cross-sectional 

study146

drug-naïve, 

first episode 

schizophrenic 

pts (n=20) 

medicated 

schizophrenic 

pts (n=32)/ 

healthy 

controls 

(n=45) 

ÐAA, DHA, total n-6 & n-3 

FA in FE & MS vs 

controls;+++ NS AA & DHA 

bet MS vs controls; Ð AA, 

DHA, total n-6 & n-3 in FE 

vs MS;+++ negative 

correlation bet AA & BPRS;+ 

negative correlation bet 

DHA & PANSS negative 

symptoms+++

Total 

quality: 2 

[Grade: C] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source;3 biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 FAs; n-6 = omega-6 FAs; 

ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic acid; E-EPA 

= ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant statistical 

difference; n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = month; ∆ = change; RBC 

= red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine phosphoglycerides; +

p<.05 

or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase(d)/higher; Ð = 

decrease(d)/reduction/lower; FE = first episode; MS = medicated schizophrenics; SFA = saturated fatty acids; BPRS = 

Brief Psychiatric Rating Scale; PANSS = Positive and Negative Symptom Scale 

Evans et al. assessed the RBC fatty acid content in patients with first-episode schizophrenia 

(n=16) and healthy volunteers (n=25), although the latter group was significantly older and were 

more highly educated than the schizophrenic group (Summary Table 44).158 Ranjekar et al. 

measured the RBC and plasma fatty acid content, as well as the lipid oxidative products, in 

medicated schizophrenic patients (n=31; mean age: 37.3 years), patients with bipolar mood 

disorder (n=10; mean age: 40.8 years), and age-, sex- and race-matched healthy controls 

(n=31).156
156 

Summary Table 44: Association between omega-3 or omega-6/omega-3 fatty acid content of biomarkers and 

onset, continuation or recurrence of schizophrenia 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Evans, 2003, 

US: 

multiple-group 

crosssectional study 

at baseline of 

single 

prospective 

cohort study158

first episode 

schizophrenic 

pts (n=16) 

healthy 

controls 

(n=25) 

Ð (n-3-)DPA & DHA in FE vs 

controls;+ NS AA & LA levels 

bet grps 

Total 

quality: 1 

[Grade: 

C] 

I 

Ranjekar, 2003, 

India: 

multiple-group 

crosssectional 

study156

adult male 

schizophrenic 

pts (n=31) 

bipolar 

adult 

males 

(n=10)/ 

healthy 

controls 

(n=31) 

Ð SOD, CAT & GPx in 

schizophrenic pts vs controls;++ 

Ð ALA, DHA & EPA in pts vs 

controls;+ Ð SOD, CAT in 

bipolar pts vs controls;+ 

Total 

quality: 4 

[Grade: 

B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; FA = fatty acids; n-3 = omega-3 FAs; n-6 = 

omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = 

nonsignificant statistical difference; n/a = not applicable; pb = placebo; bet = between; grp = group; wk = week(s); mo = 

month; ∆ = change; RBC = red blood cells; PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine 

phosphoglycerides; +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = 

increase(d)/higher; Ð = decrease(d)/reduction/lower;SOD = superoxide dismutase; CAT = catalase; GPx = glutathione 

peroxidase; PE = phosphatidylethanolamine 

Qualitative Synthesis of Relevant Studies’ Key Characteristics 

Study characteristics. Fourteen included studies had cross-sectional designs involving at 

least two groups.114,146-158 Six studies did not report inclusion criteria,147,148,150,151,153,155 and 

seven did not report exclusion criteria.147,149-153,158 Study sizes ranged from 12153 to 203 

participants.152 Countries where the studies were conducted included: India,146,155,156 Holland,148

Nigeria,153 Japan,151 Germany,150 Australia,157 the US 114,147,154,158 and the UK.149,152 

The Arvindakshan et al. studies were supported by the Council of Scientific and Industrial 

Research, M.L. Vasa, Laxmichand Dayabhai NIH/Fogarty International Center, Interactive 

Research School for Health Affairs and the Vasa Heart Foundation (India).146,155 Evans et al. 

and Khan et al.’s funding source was the NIH/NCCAM147,158 and the Stanley Foundation.158 

Ranjekar et al.’s work was supported by Mr. M.L. Vasa, Laxmichand Dayabhai (Export) Co.156

and Vaddadi et al.’s study was funded by Scotia Pharmaceuticals Ltd. (UK).157 Yao et al.’s 

study was supported by the NIMH, an NARSAD Young Investigator Award, the Office of 

Research and Development, Department of Veteran Affairs and Highland Drive Veteran Affairs 

Pittsburgh Healthcare System.154 Seven studies did not report a funding source.114,148-153

Population characteristics. Studies included only adult participants. Horrobin et al.’s 

controls were younger than their schizophrenic participants and were not fully sex-matched, 

although the difference was not significant.152 Obi and Nwanze’s schizophrenic patients were 

likely well-matched by age (30-50 years).153 Kaiya et al.’s subjects were matched by age.151 In 

Fischer et al.’s study the low-dose antipsychotic therapy group was slightly older than the other 
157 

groups.150 Peet et al. and Assies et al.’s samples were well-matched by age and sex.149 Vaddadi 

et al.’s study groups were well-matched by age (18-64 years).157 Mahadik et al.’s schizophrenic 

and bipolar patients were well-matched by age and sex, with a preponderance of males taking 

part in their project.114 Yao et al.’s work included participants who were matched by age, sex 

and race.154 Only Khan et al.’s first-episode psychotic patients and their controls were matched 

by age.147 Their chronically medicated-schizophrenics were older. For both of Arvindakshan et 

al.’s studies, between-group differences were not observed for age or sex.146,155 Evans et al.’s 

controls were significantly older than their schizophrenic patients.158 Ranjekar et al.’s study 

groups were well-matched by age; and, only males with the same racial origin were included.156 

Few studies described the ethnicity/race of their participants. Three studies included east Indian 

patients146,155,156 and one study included Japanese participants.151 

All studies involved inpatients and/or outpatients with acute and/or chronic schizophrenia of 

varying degrees of severity and ages of onset. Some studies included heterogeneous subtypes of 

schizophrenia, namely schizoaffective disorder,146,148,151,154,157 severe bipolar mood 

disorder,114,148,156 schizophreniform disorder146,154,158 and paranoid disorder.151 Five studies 

included neuroleptic-naïve, first episode schizophrenic participants.114,146,147,154,158 Diagnoses 

were made on the basis of DSM-III-R114,149,151,152,157 or DSM-IV diagnostic criteria.146-148,154-

156,158 Only two studies failed to report this information.150,153 Horrobin et al. also used the 

Research Diagnostic Criteria for schizophrenia.152 Assies et al. as well as Khan et al. employed 

the PANSS.147,148 Assies et al. utilized the MADRS to identify depressive symptomatology 

within the context of bipolar mood disorder.148

The control groups were composed of “healthy volunteers” who were sometimes screened 

for mental disorders using the nonpatient version of the SCID.114,146,154-156 Healthy controls were 

excluded from four studies if they had a personal or family history of psychiatric disorder, 

medication use and/or substance abuse.154-156 Exclusion criteria pertaining to healthy controls 

were not described in most study reports.

In order to control for possible confounding factors, some studies established exclusion 

criteria. Vaddadi et al. excluded any subject with a history of established neurological illness, 

developmental handicap or currently receiving nonsteroidal anti-inflammatory drugs.157 

Mahadik et al.’s patients were excluded if they had a history of substance abuse or dependence, 

seizure disorder, head injury with loss of consciousness, or positive family history of 

Huntington's Disease, dementia, or mental retardation in first degree relatives.114 Assies et al. 

did not include subjects with a major medical illness, mental retardation, endocrine disorders, or 

a cholesterol-lowering diet or medication.148 Yao et al. excluded patients with significant drug or 

alcohol use within one month of the initial assessment, a history of significant medical illness, 

hyperlipidemia at baseline, obesity, starvation in the previous two weeks, neurologic disorders, 

history of psychosis longer than two years, or comorbidity involving a DSM-IV Axis I 

diagnosis.154 Both of Arvindakshan et al.’s studies, as well as that conducted by Ranjekar et al., 

excluded patients with WAIS-R full-scale IQ<80, high levels of dietary supplement use, severe 

under- or malnourishment, seizure disorder, head injury with loss of consciousness, alcohol and 

substance abuse or dependence, excessive smoking, type II diabetes, lipid disorders, 

cardiovascular disease, hypertension or obesity.146,155,156 

Intervention/exposure characteristics. Thirteen studies did not involve an intervention or 

exposure. Only one of the Arvindakshan et al.’s studies employed supplementation155, and 

Assies et al. assessed dietary intake of omega-3 fatty acids using a questionnaire.148 Kaiya et al. 

described the use of a typical Japanese diet rich in rice and seafood by their inpatients residing in 
158 

a Geriatric Hospital.151 No other studies controlled statistically for background diet in their 

analysis. No study reported inappropriate methods by which lipids were extracted, prepared, 

stored or analyzed. 

Cointervention characteristics. One of the most relevant confounders is the use of 

medication for the treatment of schizophrenia. Obi and Nwanze did not report the medication 

used by their participants.153 Horrobin et al.’s sample from England and Scotland were using 

neuroleptic drugs.152 Kaiya et al.’s schizophrenic patients used neuroleptic drugs (i.e., 

haloperidol), while the participants with affective or paranoid disorders were taking 

antidepressants.151 Fischer et al.’s patients were receiving neuroleptics such as phenothiazines 

(i.e., perazine) or thioxanthenes (i.e., flupentixol).150 The reports of Peet et al. and Vaddadi et al. 

mentioned the use of neuroleptic medication by all their patients, but did not provide additional 

details.149,157 Assies et al.’s subjects were taking olanzapine (n=11), pimozide (n=4), risperidone 

(n=3) or clozapine (n=1), combined with other medications such as paroxetine, fluvoxamine, 

oxazepam, temazepam, alprazolam, biperideen, trihexyfenidyl, dexetimide or lithium 

carbonate.148 Some studies also described the use of atypical antipsychotics (i.e., 

risperidone).146,147,155,156,158 Ranjekar et al.’s sample took antidepressants as well.156 In a small 

number of studies, particularly those including cases of first-episode schizophrenia, the 

participants did not receive any type of drug prior to the study or during the study assessment 

period.114,146,154

Outcome characteristics. Outcomes included all types of fatty acid, from various sources, 

and were expressed either as percentages, or fractions (i.e., composition), or concentrations. 

Study quality and applicability. The fourteen cross-sectional studies received a mean 

quality score of 2.5, with all but five studies achieving an applicability rating of III.146,148-

151,153,155-157 Four studies received an applicability rating of I,114,147,154,158 and one study attained a 

rating of II.152

Summary Matrix 16: Study quality and applicability of evidence regarding the association between the 

omega-3 or omega-6/omega-3 fatty acid content of biomarkers and onset, continuation or recurrence of 

schizophrenia 

Study Quality

A B C 

Author Year n Author Year n Author Year n 

I 

Mahadik 1996 26 Yao 

Evans 

Kahn 

2002 

2003 

2002 

22 

41 

68 

Author Year n Author Year n Author Year n

II Horrobin 1989 203 

Author Year n Author Year n Author Year n

Applicability 

III 

 Arvindakshan 

Ranjekar 

2003 

2003 

73 

72 

Obi 

Kaiya 

Fischer 

Peet 

Vaddadi 

Assies 

Arvindakshan 

1979 

1991 

1992 

1995 

1996 

2001 

2003 

12 

97 

24 

39 

111 

34 

97 

n = number of allocated/selected participants 
159 

Qualitative Synthesis of Individual Study Results 

In Obi and Nwanze’s study, a significantly higher proportion of LA was found in 

schizophrenic patients compared with controls.153 The difference was observed in both the 

neutral lipids and the phospholipids extracted from plasma and RBCs. 

In Horrobin et al.’s study, a separate analysis was performed for data from each of the three 

countries.152 There were no significant differences between patients and controls in the total 

amount of plasma phospholipid present. At all three sites, patients had significantly reduced 

total omega-6 fatty acid levels compared with controls. The levels of omega-3 fatty acid were 

significantly increased in the schizophrenic groups. The omega-6/omega-3 fatty acid ratio was 

significantly reduced in all three patient groups. LA and AA were significantly reduced in all 

three groups of patient, and DGLA was reduced in two of them. DHA was significantly 

increased in the schizophrenic patients of England and Ireland compared with controls. EPA 

levels were not significantly different between groups. 

Kaiya et al. found that, with the exception of DGLA which was significantly above normal in 

the schizophrenic patients, the levels of omega-3 fatty acid in plasma phospholipids were not 

significantly different between normal Japanese subjects and schizophrenic patients or patients 

with affective or paranoid disorders.151 From the analysis of fatty acids in plasma cholesterol 

esters, LA was significantly lower in schizophrenic patients compared with controls, but not in 

patients with affective or paranoid disorders. In plasma phospholipids, EPA was significantly 

higher in schizophrenic males compared with schizophrenic females. In the cholesterol fraction, 

there were no significant differences between schizophrenics over and under 40 years of age. 

When data from hospitalized schizophrenics were contrasted with that from outpatients, AA was 

significantly higher in the inpatients. 

Fischer et al. analyzed data regarding the total fatty acid composition of platelets. LA, AA 

and DHA were significantly lower in schizophrenic patients using high-dose neuroleptics 

compared with those taking low-dose neuroleptics or with untreated healthy controls.150 LA, AA 

and DHA were significantly lower in the group of low dose patients compared to two untreated 

schizophrenic patients. In general, the ratio of SFAs to PUFAs was significantly higher in the 

high-dose group compared with the low-dose group or with healthy controls. This ratio was also 

significantly higher in the low dose group than in the controls. 

The medicated and hospitalized schizophrenic patients included in the Peet et al. study 

exhibited significantly lower RBC EPA and DHA levels compared to healthy controls.149 LA 

and AA were also significantly lower than in controls. There was no significant correlation 

between neuroleptic dosage, expressed as chlorpromazine equivalents, and any of the measures 

of fatty acid level. Plasma levels of total free fatty acids did not differ between groups. 

Based on Vaddadi et al.’s initial assessment, schizophrenic patients were grouped according 

to their tardive dyskinesia status.157 The RBC fatty acid compositions from four groups were 

compared. Patients with severe tardive dyskinesia had significantly lower LA compared to 

patients without tardive dyskinesia, who in turn had lower levels compared to the control group. 

All patients had elevated levels of omega-3 fatty acids, but only (omega-3-)DPA was 

significantly higher when compared to controls. Half of the patients were assessed 4.5 years 

later, when only RBC (omega-6-)DGLA was found to be significantly elevated, relative to 

controls, in schizophrenics with and without tardive dyskinesia. 

Given that the cell membrane distributions of AA and DHA did not differ in cultured skin 

fibroblasts from patients with chronic schizophrenia and patients with first-episode 
160 

schizophrenia, Mahadik et al. combined data from these two patient groups for analyses.114 

These data were then compared to those obtained from patients with recurrent bipolar mood 

disorder and sex-matched controls. The DHA composition was found to be significantly lower 

in cell lines of schizophrenic patients compared with cell lines obtained from either bipolar 

patients or normal subjects. Data from the two latter groups did not differ. The percent 

distribution of AA in the cell lines of schizophrenic patients was significantly lower than that in 

bipolar patients, but the percent distribution of AA from either group did not differ significantly 

from that seen in normal controls. 

In the study of Assies et al., no significant differences were found between schizophrenic 

patients and normal controls in terms of age, sex, BMI or dietary intake of lipids at baseline in 

Assies et al.’s study.148 DHA content and that of its precursor (n-3-)DPA were each significantly 

reduced in the RBCs of schizophrenic patients compared with controls. Between-group 

differences for the other omega-3 fatty acids were not observed. Total omega-3 fatty acid 

content was significantly reduced in the schizophrenic group. No significant between-group 

differences were found for any of the omega-6 fatty acids. The DHA/AA ratio was lower in 

schizophrenic patients than in control subjects. The study groups’ AA/EPA, DPA/DHA and 

total omega-6/omega-3 fatty acid content ratios did not differ. There was a significant positive 

correlation between chlorpromazine equivalents and the AA/EPA ratio. A significant negative 

correlation linked EPA content and chlorpromazine dosage. By subgroup analysis, the omega6/omega-3 fatty acid content ratio was significantly lower in cannabis users compared with 

nonusers. There was no consistent pattern of correlations involving fatty acid contents and 

measures of symptomatology. 

Yao et al.’s population of first-episode, untreated schizophrenics had a significantly lower 

RBC AA concentration than did normal controls.154 The remaining fatty acid contents did not 

differ significantly between groups. There was a significant correlation between the levels of 

peripheral biomarkers and the level of free phospholipids in the prefrontal region of the brain, as 

assessed by 31P Spectroscopy. 

Khan et al.’s heterogeneous sample of active army personnel consisted of drug-naïve firstepisode schizophrenics, chronic medicated schizophrenics and healthy controls. The fatty acid 

contents of their RBC membranes were compared.147 The levels of LA, AA and DHA were 

significantly lower in first episode patients than in chronic patients. Levels were also lower in 

first-episode patients and in chronic patients compared with controls. The larger reductions in 

PUFA levels were associated with a greater severity of psychosis assessed in drug-naïve, firstepisode patients, compared with chronic medicated schizophrenics, as assessed using the Brief 

Psychiatric Rating Scale (BPRS), negative PANSS and positive PANSS. These changes did not 

appear to be related to age or to smoking. 

The first Arvindakshan et al. study showed that the schizophrenic patients had a significantly 

lower RBC membrane concentration of EPA and DHA compared to healthy controls.155

Significant between-group differences were not observed for LA or AA content. 

In the second Arvindakshan et al. study, the RBC membrane AA, DHA, total omega-6 and 

total omega-3 fatty acid contents were each significantly lower in both patient groups, 

(medicated and never medicated) when compared to healthy controls.146 The differences 

remained significantly different when the never-medicated patients were compared to the normal 

controls, but neither the AA nor the DHA contents were significantly different when medicated 

schizophrenics and controls were compared. The AA, DHA, total omega-6 fatty acids and total 

omega-3 fatty acid levels in RBCs were significantly lower in never medicated patients 
161 

compared to medicated schizophrenics. The psychopathologic measures in never medicated 

subjects were examined for their relationship to PUFA levels. Significantly negative correlations 

were found for AA levels and BPRS scores, and for DHA levels and PANSS negative 

symptoms. Never medicated patients appeared to exhibit more severe psychopathology than 

medicated patients. 

Evans et al. showed that RBC (omega-3-)DPA and DHA levels were significantly lower in 

first episode, untreated schizophrenics compared with controls.158 Significant between-group 

differences were not observed for AA or LA levels. RBC antioxidant enzymes were assessed 

and it was found that the level of superoxide dismutase (SOD) was significantly lower in 

schizophrenic patients than controls, and catalase (CAT) was significantly elevated in these 

patients. 

Ranjekar et al. evaluated the possible association of levels of RBC antioxidant enzymes (i.e., 

SOD, CAT, glutathione peroxidase [GPx]), as key indices of oxidative stress, with RBC fatty 

acid contents for schizophrenics, bipolar mood disorder patients and normal controls.156 These 

enzymes were significantly lower in schizophrenics compared with controls. ALA, DHA and 

EPA levels were also significantly lower in patients compared to controls. When these analyses 

included data from bipolar patients, only two enzymes—SOD and CAT—were reduced 

significantly relative to control subjects. 

Four studies measured the products of membrane lipid peroxidation utilizing blood levels of 

thiobarbituric acid reactive substances (TBARS).146,147,149,155 The results were inconsistent when 

data from schizophrenics and healthy controls were compared. These data are not reviewed in 

more detail here since they lie beyond the scope of our report. 

Quantitative Synthesis 

Although all of the included studies were controlled, only one had a formal followup that 

included controlled data. Thus, a meta-analysis was not considered. 

Impact of Covariates and Confounders 

Studies were distinguishable on the basis of whether the sample of schizophrenic patients 

was currently, or ever had been, medicated with neuroleptics. Comparing the results obtained 

from studies where patients were, or were not, receiving medication could illumine one possible 

source controlling variation in biomarker outcomes. All comparisons presented here involve 

healthy controls; the use of any other types of control was too infrequent and idiosyncratic to 

specific studies to afford generalization. 

In the five studies where at least one set of analyses involved a comparison between patients 

not on medication and healthy controls,114,146,147,154,158 all assessed RBC fatty acid content data, 

four revealed reductions in DHA,114,146,147,158 three showed reductions in AA content,146,147,154

one highlighted a reduction in LA,147 one noted a reduction in (omega-3-)DPA158 and one found 

significantly lower levels of total omega-6 fatty acids and total omega-3 fatty acids in nevermedicated schizophrenic patients.146 In this last study, when data from patients who had never 

been medicated were compared with data from patients who were currently medicated, levels of 

AA, DHA, total omega-6 fatty acids and total omega-3 fatty acids were significantly lower in 

never-medicated patients.146 
162 

In studies where patients were medicated, and RBC data were again compared with those 

from healthy controls, significant reductions in DHA,148,149,155,156 AA,149 LA,149,157 (omega-3-

)DPA,148 ALA,156 total omega-3 fatty acids,148 DHA/AA148 and EPA149,155,156 were observed in 

schizophrenic patients. While there is considerable overlap when these results are contrasted 

with those from studies where schizophrenic patients were not receiving medication, one notable 

difference is that, compared to controls, medicated patients were more likely to show reduced 

levels of EPA in RBCs. Thus, medication status may have an influence on between-group 

differences in RBC fatty acid content when the comparator is healthy controls. 

As with RBC data, when plasma phospholipids were examined, Horrobin et al. reported 

significantly lower levels of total omega-6 fatty acid content, LA and AA in schizophrenic 

patients compared with controls.152 Kaia et al. revealed that LA was significantly reduced in 

plasma choleterol esters.151 When Fischer et al. assessed the total fatty acid content of platelets 

they found that significant reductions in DHA, AA and LA were associated with medicated 

patients compared with controls as well as with patients receiving high-dose versus low-dose 

neuroleptic medication.150 Patients on low dose medication also exhibited significantly lower 

levels of LA, AA and DHA compared with controls. Those taking high doses of medication also 

displayed a higher SFA/PUFA value compared with those receiving lower doses. These data 

suggest that, as with studies investigating RBC content, medication appears to have an impact on 

biomarker outcomes that may be independent of the disease process. 

However, other biomarker data gleaned from a minority of studies provided a picture of 

effects that are inconsistent with what was found for RBCs. Vaddadi et al. reported that all RBC 

omega-3 fatty acid levels were significantly higher in schizophrenic patients compared with 

healthy controls.157 Horrobin et al. noted the same difference albeit in plasma phospholipids.152 

One final study showed that LA content in either RBCs or plasma phospholipids was actually 

increased significantly in schizophrenic patients compared with controls.153

Is the Onset, Continuation or Recurrence of Autism 

Associated With Omega-3 or Omega-6/Omega-3 Fatty Acid 

Content of Biomarkers? 

As observed in Summary Table 45 (see below), derived from Evidence Table 2 (Appendix 

E*

), a single cross-sectional study published in 2001 met eligibility criteria. 

Overview of Relevant Study’s Characteristics and Results 

Vancassel et al.’s study was supported by INRA, INSERM U316, INSERM Network and the 

Fondation France Telecom.159 It compared the plasma phospholipid fatty acids of mentally 

retarded children (n=18; 72.2% male; mean age: 8.7 years) and in children having received a 

diagnosis of autism (n=15; 73.3% male; mean age: 8.3 years), who were attending the Child 

Psychiatry Day Care Unit in a hospital in France. The diagnoses of autism and mental 

retardation were based on DSM-III-R and DSM-IV criteria. The entire study population 

 

∗

Note: Appendixes and Evidence Tables cited in this report are provided electronically at 

http://www.ahrq.gvo/clinic/tp/o3menttp.htm.
163 

participated in day care and received the same diet over a 12-hour period. There were no 

significant between-group differences for height or weight. The aim of the study was to compare 

the study groups’ plasma fatty acid content. No notable inappropriate methods to extract, 

prepare, store or analyze lipids were described. 

Summary Table 45: Association between omega-3 and omega-6/omega-3 fatty acid content of biomarkers 

and onset, continuation or recurrence of autism 

Study groups1

 

Author, Year, 

Location: 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n) Notable associations

Internal 

validity Applicability 

Vancassel, 

2001, France: 

multiple-group 

cross-sectional 

study159

autistic 

children 

(n=15) 

mentally 

retarded 

children 

(n=18) 

NS plama LA, AA bet grps; NS 

plasma DHA, ALA; Ð total n-3 

in autism; Ï n-6/n-3 in autism 

Total 

quality: 4 

[Grade: B] 

III 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; n-3 = omega-3 fatty acids; n-6 = omega-6 

fatty acids; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = arachidonic 

acid; E-EPA = ethyl eicosapentaenoate; n = sample size; pts = study participants; NR = not reported; NS = nonsignificant 

statistical difference; N/A = not applicable; pb = placebo; grp = group; wk = week(s); mo = month; RBC = red blood cells; 

PL = phospholipid; CPG = choline phosphoglycerides; EPG = ethanolamine phosphoglycerides; Jadad total = Jadad total 

quality score: reporting of randomization, blinding, withdrawals/dropouts (/5); Schulz = reporting of adequacy of 

allocation concealment (adequate, inadequate, unclear); +

p<.05 or significant with 95% confidence interval; ++p<.01; +++p<.001; ++++p<.0001; Ï = increase; Ð = decrease/reduction 

The results showed that there were no significant between-group differences in the plasma 

content of omega-6 fatty acids or in ALA and DHA.159 Yet, autistic children had a significantly 

lower total omega-3 fatty acid level and a significantly higher omega-6/omega-3 fatty acid ratio 

compared to the mentally retarded children. This study received an applicability rating of II and 

a total quality score of 4. 

What is the Evidence That, in Review-Relevant Studies 

Concerning Mental Health, Adverse Events (e.g., Side 

Effects) or Contraindications are Associated With the Intake 

of Omega-3 Fatty Acids? 

Adverse events are often underreported in study reports; therefore, failure to report any does 

not constitute evidence that none occurred. That said, a number of study reports explicitly stated 

that no exposure-related events had been observed;97-99,115,120,122,131,139,140 since the focus here is 

on exposure-related events, we had to include event data (e.g., type, consequence) in Summary 

Tables 46 through 48 when it was unclear as to which circumstances these events could be 

attributed. On one occasion, a failure of study authors to state that certain events were not 

directly linked to the expoure did not prevent our review team from suggesting that they were 

likely related to the disorder and not the exposure (i.e, self-harm [e.g., wrist scratching] in two 

active treatment patients and one control patient, respectively).139 At the same time, Peet et al. 

did not identify the patients or study groups from whom adverse event data were collected.58 
164 

Finally, multiple adverse events can be experienced concurrently or at different points in time 

over a study by a single patient. On occasion, included reports failed to explicitly identify these 

scenarios whereby a small number of study participants contributed many or most of the adverse 

event data. 

Eight treatment RCTs provided some adverse event data.53,58,87,89,95,96,112,119 Two of the three 

intervention studies looking at the possible protective effects of omega-3 fatty acids in healthy 

volunteers also reported safety data.129,130 The treatment trials included two of the three RCTs 

and the only RCT investigating the supplemental and primary treatment of depression, 

respectively. Three of four trials investigating the supplemental treatment of schizophrenia 

yielded adverse event data.58,87,89 

Summary Table 46: Studies reporting adverse events (e.g., side effects) or contraindications

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Safety data 

DEPRESSION

Marangell, 

2003, 

US: 

6 wk 

parallel 

RCT95

2g/d 

DHA 

(n=18) 

pb 

(source 

undefined) 

(n=18) 

2g/d DHA (source undefined): fishy aftertaste (n=14 events), 

belching (n=3), lightheadedness or dizziness (n=3), loose stools 

(n=2), headache (n=2), insomnia (n=1), continued (n=18/18); pb 

(source undefined): fatigue (n=3 events), insomnia (n=1), loose 

stools (n=1), continued (n=18/18) 

Peet, 2002, 

England & 

Scotland: 

12 wk 

parallel 

RCT53

4g/d 

E-EPA 

(n=17)/ 

liquid 

paraffin pb 

(n=18) 

2g/d E-EPA 

(n=18)/ 

1g/d E-EPA 

(n=17) 

Musculoskeletal system: 4g/d E-EPA (source undefined) (n=1); 

2g/d E-EPA (n=2); central & peripheral nervous system: 4g/d EEPA (n=1); 1g/d E-EPA (n=1); pb (liquid paraffin) (n=3); visual 

system: pb (n=1); psychiatric event: 2g/d E-EPA (n=2); 1g/d EEPA (n=4); pb (n=2); gastrointestinal: 4g/d E-EPA (n=5); 2g/d EEPA (n=8); 1g/d E-EPA (n=7); pb (n=4); metabolic: 1g/d E-EPA 

(n=2); pb (n=2); endocrine: 4g/d E-EPA (n=1); respiratory system: 

4g/d E-EPA (n=1); 2g/d E-EPA (n=2); 1g/d E-EPA (n=1); pb (n=2); 

white blood cells: pb (n=1); reproductive system: 2g/d E-EPA 

(n=1); pb (n=2); whole body: 4g/d E-EPA (n=3); 2g/d E-EPA (n=6); 

1g/d E-EPA (n=1); pb (n=4); infections: 4g/d E-EPA (n=3); 2g/d EEPA (n=3); 1g/d E-EPA (n=2); pb (n=2); diarrhea: 1g/d E-EPA 

(n=1) 

Su, 2003, 

China: 

8 wk 

parallel 

RCT96

4.4g EPA + 

2.2g/d DHA 

(n=14) 

olive oil ethyl 

ester pb 

(n=14) 

4.4g EPA + 2.2g/d DHA (fish oil): mild excitement (n=1), continued 

(n=1/1); mild diarrhea (n=1), continued (n=1/1); pb (olive oil ethyl 

esters): insomnia (n=1), continued (n=1/1) 

BIPOLAR DISORDER

Stoll, 1999, 

US: 

4 mo 

parallel 

RCT112

9.6g/d 

EPA+DHA 

(6.2g/d EPA, 

3.4g/d DHA) 

(n=~22) 

olive oil ethyl 

ester pb 

(n=~22) 

Gastrointestinal (mild): 9.6g/d EPA+DHA (fish oil) (n=8), continued 

(n=8/8); pb (olive oil ethyl ester) (n=8), continued (n=8/8) 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; *No explicit description that adverse events 

specifically linked to exposure, only that associated with participants in a specific study group; FA = fatty acids; n-3 = omega3 FAs; n-6 = omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; 

pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; grp 

= group; wk = week(s); mo = month 
165 

In Peet et al.’s supplemental treatment study of depression, no adverse events were reported 

by placebo group participants, whereas 20 of 52 individuals receiving E-EPA had at least one 

mild adverse event.53 One patient dropped out due to a gastrointestinal event (severity 

undefined). According to the authors, all events in the E-EPA groups were linked to the 

ingestion of an oily subtance, not the omega-3 fatty acids per se. Adverse event types were 

evenly distributed across the E-EPA groups. The fewest number of events occurred in the 2 g/d 

E-EPA group. The exact meaning of some of the events was not transparent to our review team, 

however. Likely using the same methodology, and again failing to adequately define some of 

their adverse events, Peet et al.’s study of the supplemental treatment of depression revealed that 

none of the nine patients withdrawn due to an adverse event (4 g/d E-EPA [n=2]; 2 g/d E-EPA 

[n=2]; 1 g/d E-EPA[(n=4]; placebo [n=1]) left because of the exposure per se.87 No betweengroup difference was observed for exposure-related adverse events. The most common events 

were mild and transient (i.e., diarrhea, nausea), and only one control patient withdrew for these 

reasons. It is conceivable that greater numbers of adverse event were reported in these two 

studies because the investigators used a more comprehensive approach to solicit these data. 
166 

Summary Table 47: Studies reporting adverse events (e.g., side effects) or contraindications

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Safety data 

SCHIZOPHRENIA

Peet, 2001, 

England: 

3 mo 

parallel 

RCT58

2g/d EPA 

enriched fish 

oil (n=15 

completers) 

2g/d DHA 

enriched oil 

(source 

undefined) 

(n=16 

completers)/ 

corn oil pb 

(n=14 

completers) 

Study 1: (full sample, n=55) felt ill and forgetful (n=1), dropped out 

(n=1/1); nausea, irritable bowel, indigestion (n=3), dropped out 

(n=3/3) 

Fenton, 

2001, US: 

16 wk 

parallel 

RCT89

3g/d E-EPA 

(n=45) 

mineral oil 

pb 

(n=45) 

3g/d E-EPA (source undefined): upper respiratory infection (n=8), 

continued (n=8/8); diarrhea (n=8), continued (n=8/8) 

Peet, 

2002, 

England: 

12 wk 

parallel 

RCT87

4g/d E-EPA 

(n=27)/ 

liquid 

paraffin pb 

(n=31) 

2g/d E-EPA 

(n=32)/ 

1g/d E-EPA 

(n=32) 

Body as a whole: 4g/d E-EPA (source undefined) (n=2); 2g/d EEPA (n=1); 1g/d E-EPA (n=2); placebo (liquid paraffin) (n=6); 

cardiovascular/heart: 4g/d E-EPA (n=1); 1g/d E-EPA (n=1); pb 

(n=1); central & peripheral nervous system: 4g/d E-EPA (n=2); 

2g/d E-EPA (n=3); pb (n=3); diarrhea: 4g/d E-EPA (n=3); 2g/d EEPA (n=1); 1g/d E-EPA (n=7); pb (n=7); nausea: 4g/d E-EPA 

(n=2); 2g/d E-EPA (n=3); 1g/d E-EPA (n=1); liver & biliary tract: 

1g/d E-EPA (n=1); metabolic: 4g/d E-EPA (n=3); 2g/d E-EPA 

(n=1); 1g/d E-EPA (n=1); pb (n=1); musculoskeletal: pb (n=1); 

psychiatric: 4g/d E-EPA (n=6); 2g/d E-EPA (n=2); 1g/d E-EPA 

(n=4); reproductive: 4g/d E-EPA (n=2); pb (n=1); infections &

respiratory system: 4g/d E-EPA (n=3); 2g/d E-EPA (n=1); 1g/d EEPA (n=5); pb (n=5); skin: 4g/d E-EPA (n=1); 2g/d E-EPA (n=1); 

1g/d E-EPA (n=2); urinary: 1g/d E-EPA (n=2); pb (n=1); vision: 

1g/d E-EPA (n=1); pb (n=1); white cells: 4g/d E-EPA (n=1); pb 

(n=1); other: 4g/d E-EPA (n=3); 2g/d E-EPA (n=1); 1g/d E-EPA 

(n=2) 1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; *No explicit description that adverse events 

specifically linked to exposure, only that associated with participants in a specific study group; FA = fatty acids; n-3 = omega3 FAs; n-6 = omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; 

pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; grp 

= group; wk = week(s); mo = month 

Stoll et al. indicated that side effects were associated with their omega-3 fatty acid 

exposure.112 Their study delivered, by far, the largest dose of omega-3 fatty acids as an 

intervention (9.6 g/d). Three patients had to decrease their daily dose from seven capsules twice 

a day to a minumum of five capsules twice a day from seven capsules twice a day. At the same 

time, while there was no variability in the types of reported adverse event (i.e., gastrointestinal 

disorder), at least a third of study participants from each study group experienced gastrointestinal 

problems. This suggests that the omega-3 fatty acid dose and/or the amount of oil required to 

deliver it may have been too high. While Su et al.’s omega-3 fatty acid dose was high by 

standards established earlier, their participants described very few adverse events.96
167 

Summary Table 48: Studies reporting adverse events (e.g., side effects) or contraindications

Study groups1 Author, 

Year, 

Location: 

Length & 

Design 

Group 1 

(n)/ 

Group 4 

(n)

Group 2 

(n)/ 

Group 3 

(n)

Safety data 

TENDENCIES OR BEHAVIOR WITH THE POTENTIAL TO HARM OTHERS 

Hamazaki, 

1996, 

Japan: 

3 mo 

parallel 

RCT130

1.5-1.8g/d 

DHA (+ 

some EPA) 

(n=27) 

oil capsules 

(97% 

soybean oil 

+ 3% fish oil) 

pb 

(n=26) 

1.5-1.8g/d DHA (fish oil): trend toward obesity (n=1), continued 

(n=1/1); pb (97% soybean oil + 3% fish oil): acne (n=2), continued 

(n=2/2); itching (n=1), continued (n=1/1) 

Hamazaki, 

1998, 

Japan: 13 

wk 

parallel 

RCT129

1.5g/d DHA 

(n=29) 

oil capsules 

(97% 

soybean oil 

+ 3% fish oil) 

pb 

(n=30) 

Pb (97% soybean oil + 3% fish oil): gastrointestinal disorder (n=1), 

dropped out (n=1/1) 

ATTENTION DEFICIT/HYPERACTIVITY DISORDER 

Richardson, 

2002, UK: 

12 wk 

parallel 

RCT119

186 mg/d 

EPA, 

480mg/d 

DHA, 

96mg/d 

GLA, 864 

mg/d cislinolenic 

acid, 42 

mg/d AA & 

8mg/d thyme 

(n=22) 

olive oil pb 

(n=19) 

186mg/d EPA & 480mg/d DHA (source undefined): digestive 

upset (n=1), dropped out (n=1/1); swallowing problems (n=1), 

dropped out (n=1/1); pb (olive oil): digestive upset (n=1), dropped 

out (n=1/1) 

1

Proceeding from highest omega-3, or lowest omega-6/omega-3, fatty acid content of intervention/exposure; 2biomarker 

source; 3

biomarkers = EPA, DHA, AA, AA/EPA, AA/DHA, AA/EPA+DHA; *No explicit description that adverse events 

specifically linked to exposure, only that associated with participants in a specific study group; FA = fatty acids; n-3 = omega3 FAs; n-6 = omega-6 FAs; ALA = alpha linolenic acid; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; AA = 

arachidonic acid; E-EPA = ethyl eicosapentaenoate; Length = intervention length; Design = research design; n = sample size; 

pts = study participants; NR = not reported; NS = nonsignificant statistical difference; n/a = not applicable; pb = placebo; grp 

= group; wk = week(s); mo = month 

Fenton et al. noted that two types of adverse event occurred among more than 5% of the 

EPA-treated patients.89 Marangell et al. identified the largest number of patients describing a 

fishy aftertaste or problems related to belching.95 However, these complaints were not 

associated with studies using E-EPA, a largely purified exposure with relatively minimal odour 

and taste.53,87,89 

In Richardson and Puri’s trial examining the primary treatment of children identified with 

AD/HD and learning difficulties, two active treatment group subjects and one placebo group 

participant left the study due to adverse events. However, the authors did not report on the 

seriousness of these events.119 It is likely not surprising that, of the ten studies that reported 

adverse events, only the study that included children identified problems with swallowing the 

capsules, which led to a discontinuation. 

Ten subjects from each of the two study groups in Hamazaki et al.’s first trial with healthy 

volunteers complained of transient and minor adverse effects (no data reported).130 Of the others 

noted by the investigators (see Summary Table 46), none were sufficiently serious to warrant 
168 

discontinuation from the study. In their second RCT, a gastrointestinal difficulty required that a 

single volunteer withdraw from the control group.129
169 

Chapter 4. Discussion 

Overview 

A total of 86 reports, describing 79 unique studies, investigated questions pertinent to this 

systematic review of the evidence concerning the effects of omega-3 fatty acids on mental 

health. Not all of the mental health disorders or conditions included in this review had evidence 

addressing all of the first three basic questions posed in this review—primary or supplemental 

treatment with omega-3 fatty acids (Question 1), or the association between the onset, 

continuation or recurrence of the disorder or condition and either the intake of omega-3 fatty 

acids (Question 2) or the omega-3 or omega-6/omega-3 fatty acid content of biomarkers 

(Question 3). Schizophrenia (n=28 studies) and depression (n=22 studies) were, by far, the most 

frequently investigated psychiatric disorders. Many possible explanations likely exist for why 

these two disorders have received the most attention, including the prevalence of depression and 

the presumed intractability of schizophrenia. 

Of the collections of studies on schizophrenia and depression, 50% (n=14/28) and 36.4% 

(n=8/22) examined the possible association of schizophrenia and depression outcomes, 

respectively, with the omega-3 or omega-6/omega-3 fatty acid content of biomarkers. These two 

clinical areas (i.e., schizophrenia and depression) have produced an abundance of animal studies, 

as well as both animal and human models concerning the etiology of these disorders.55 This may 

help explain why we found many more human studies examining biomarkers data (Question 3), 

as well as the possible association between omega-3 intake and clinical outcomes (Question 2), 

than studies investigating the treatment of these disorders or conditions (Question 1). It is 

conceivable that the research community has assumed it was necessary to first use biomarkers 

and epidemiological data to demonstrate the plausibility of treating these clinical entities with 

omega-3 fatty acids. Only recently have studies been published concerning the primary or 

supplemental treatment of depression (n=4 RCTs: 2002 or 2003) or schizophrenia (n=5 RCTs: 

2001 or 2002), and this may signal a trend towards an increased emphasis on treatment 

investigations. 

While this review was not initiated to test the specific deficiency hypotheses relating to the 

etiology of depression or schizophrenia, below we have, nonetheless, examined the evidence to 

address the possible soundness of these positions. The justification for the study of the 

remaining psychiatric disorders or conditions for which we reviewed evidence ranged from the 

view that certain types of individual (e.g., bipolar disorder patients) may also suffer from 

deficiencies in “mood-regulating” omega-3 fatty acids, to little or no justification based on 

human or animal models or data (e.g., obsessive-compulsive disorder). Nonetheless, a study was 

included if it met our eligibility criteria. 

For each psychiatric topic, in turn, we present a synthesis of the key findings with respect to 

each of the first three basic questions. This includes a critical appraisal of the individual studies 

from which the results were drawn. Attention is paid to the numbers, size, quality and 

applicability (i.e., to relevant North American populations) of studies in trying to ascertain larger 

patterns of result. The broader implications of these findings, including potential future research, 

are highlighted. We begin with the cross-cutting issue of safety. 
170 

Evidence Synthesis and Appraisal 

Only interventional studies employing omega-3 fatty acids as supplementation provided 

safety data. Some interventional studies, which employed various populations, 

interventions/exposures and followup durations, did not report either having solicited adverse 

effects data from study participants or having received such reports. Results from these studies 

suggest that omega-3 fatty acid exposures were, for the most part, well tolerated. In spite of a 

small number of discontinuations presumed to have been instigated by an adverse event, it is 

unlikely that moderate or severe side effects were ever observed in relation to an omega-3 fatty 

acid exposure. Occasionally, adverse events were linked to the intake of oily substances, rather 

than to the omega-3 fatty acid contents in the oils. 

Reported difficulties tended to be mild and transient, often involving gastrointestinal upset or 

nausea. Aside from the minor adverse effects associated with Stoll et al.’s very high dose of 

omega-3 fatty acids (i.e., 3 patients had to decrease the number of capsules swallowed per day, 

yet with none required to discontinue),112 no other discernible patterns were seen regarding the 

impact of dose, type (e.g., DHA vs EPA) or source (e.g., marine, plant, nut) of omega-3 fatty 

acids on safety. In the study by Richardson and Puri, one AD/HD child in the active treatment 

group had to leave the study due to problems swallowing the capsules.119 Few of the events 

described in two trials by Hamazaki et al., which enrolled healthy volunteers, suggested that the 

adverse effects had been directly related to the exposure.129,130 The ability of purified forms of 

EPA (i.e., E-EPA) to maintain blinding, due in large part to the oil’s minimal fishy taste and 

odor, could not be evaluated because there were too few studies with which to construct 

meaningful comparisons. 

Four RCTs addressed the questions concerning the primary or supplemental treatment of 

depression. One addressed primary treatment,95 whereas three investigated supplemental 

treatment.53,96,97 Marangell et al. found no benefit related to 2 g/d DHA employed as primary 

treatment despite an increase in the absolute RBC levels of DHA in the active treatment group.95 

Reasons for this null result could include the use of too small a dose, too short an intervention 

period, the “wrong” omega-3 fatty acid, broken blinding (i.e., unidentified by group, 14 patients 

experienced a fishy aftertaste) or failure to modify background omega-6 fatty acid intake at the 

same time. Clearly, more than a single, likely underpowered trial of low quality (i.e., internal 

validity) and undetermined applicability is required to ascertain the value of omega-3 

supplementation as primary treatment for depression. Data from two of the supplemental 

treatment studies that included a few patients who were not receiving medication could not be 

used to address the question concerning primary treatment because the study reports did not 

provide these individuals’ results separately.96,97

Peet et al.’s dose-ranging study of E-EPA as supplemental treatment for depression found 

that only 1 g/d for 12 weeks had a significant impact on various clinical outcomes.53 Two trials 

of shorter duration also showed significant benefits associated with 2 g/d E-EPA and 6.6 g/d of 

EPA+DHA, respectively;96,97 the significant clinical effect reported by Su et al. was associated 

with a significant increase in RBC EPA exclusively in the active treatment group.96 However, it 

was decided to forego meta-analysis due to: variations in dose both within and between studies; 

variation in the definition of the omega-3 fatty acid interventions; different followup lengths; 

and, the use of different sources of placebo material. In addition, unlike the other two 

supplemental treatment trials, Peet et al.’s did not formally identify patients with a depressive 
171 

disorder.53 This last observation may account for Peet et al.’s finding that 1 g/d E-EPA had a 

beneficial effect on depressive symptomatology.53 It is conceivable that this low dose would not 

have helped the treatment-resistent depressive disorders investigated in the other trials. Yet, this 

likely cannot explain why Peet et al.’s higher doses (2 g/d, 4 g/d) did not likewise ameliorate 

depressive symptoms, or why more responders (i.e., 50% improvement) were found in the 

placebo group than in the 2 g/d E-EPA group. It is possible that the study by Su et al. was 

confounded by uncontrolled combinations of medication.96

There were too few included studies to reliably ascertain the impact of extra-interventional 

variables with the potential to influence clinical results, or the possible covariation of clinical and 

biomarker effects. Overall, in spite of the sound internal validity of the three included trials, this 

study collection is too small to permit us to determine whether omega-3 fatty acid 

supplementation is efficacious as a supplemental treatment for depressive disorders or 

symptomatology. Moreover, the three studies exhibited weak applicability to even a 

predominantly female North American population. Yet, these preliminary findings suggest there 

may be promise in pursuing investigations into the use of omega-3 fatty acids as a supplemental 

treatment for depression. 

All 12 of the studies addressing the question concerning the possible association between 

depression outcomes and omega-3 fatty acid intake could be construed as focusing on whether 

(foods containing) omega-3 fatty acids might protect against the onset of depressive disorders or 

symptomatology. No study investigated subquestions relating omega-3 fatty acid intake to either 

the continuation or recurrence of depressive disorders or symptoms. 

The types of research design providing evidence relating to onset varied in terms of their 

inherent ability to meaningfully investigate this question. Best suited to address this question 

were three controlled prospective studies; yet, these constituted a minority. Of these three 

RCTs,98-100 the study by Wardle et al. merely assessed the impact of diets without distinguishing 

the exact nature of the role played by oil fish intake within the Mediterranean diet;99 and, the data 

generated by Ness et al. confirmed the assumption that advice to eat fish will not guarantee the 

compliance of study participants.100 Thus, the results of both “intervention” studies could not 

meaningfully shed light on the question of onset.100 The RCT of Llorente et al. examined the use 

of supplementation to prevent postpartum depression. While well-designed, the study included a 

narrowly defined population (i.e., breastfeeding women) and did not reveal a significant clinical 

benefit related to omega-3 fatty acid intake, despite a significant increase in plasma phospholipid 

DHA. Moreover, most of the women in Llorente et al.’s trial exhibited, at worst, minimal 

depressive symptomatology. Therefore, in spite of their RCT designs, these three studies did not 

constitute the best tests of the possibility that omega-3 fatty acids might protect against the onset 

of depressive disorders or symptomatology. 

The observational studies did not contribute much to resolving the question of onset, despite 

their somewhat consistent picture of a lack of association. The reason is that their designs also 

did not constitute the best tests of omega-3 fatty acids’ protective potential. The 36-month single 

prospective (uncontrolled) cohort study by Woo et al. found no significant, adjusted association 

between fish intake and depressive symptoms in an elderly Chinese population.110 Hakkarainen 

et al.’s prospective cohort study observed no significant, adjusted association between fish 

consumption or (calculated) omega-3 fatty acid intake and indices of depression.111 Edwards et 

al.’s multiple-group cross-sectional study revealed that none of the dietary omega-3 or omega-6 

fatty acid variables were significant predictors of depressive symptomatology.48 Two single 

population cross-sectional surveys completed by Tanskanen and colleagues in Finland each 
172 

described a significant association between the frequency of fish consumption and depressive 

symptomatology in females,81 and in both males and females.80 It is unclear why the first 

significant association was observed only for females.81 Tanskanen et al. employed a single 

question to assess the exposure, and perhaps a food frequency questionnaire would have been 

better.81 Suzuki et al.’s single population cross-sectional survey revealed a nonsignificant 

association between depression and the intake of fish or seafood despite observations that ALA 

and total omega-3 fatty acid intake were inversely related to the likelihood of depressive 

symptomatology.107 

In cross-sectional designs, the absence of a meaningful temporal separation between the 

measurement(s) of the exposure (e.g., intake of fish or specific omega-3 fatty acids) and the 

clinical outcome (e.g., onset of depression) prevents the possible observation of cause and effect, 

which thereby precludes drawing causal inferences concerning the impact of the exposure on the 

(likelihood of the) clinical outcome. Cross-sectional surveys are also limited by recall bias. At 

the same time, five of the six observational studies exhibited the weakest applicability to a North 

American population.80,81,107,110,111 Each study took place either in Finland or Asia, where 

dietary fish intake is considerably higher than it is in North America. It is likely that greater fish 

intake yields a lower omega-6/omega-3 fatty acid intake ratio in the background diet. 

The most consistent picture of an inverse relationship between the exposure and clinical 

outcomes was observed in the type of study providing the weakest evidence: cross-national 

ecological analyses.47,108,109 These provide possible evidence of the covariation of exposure 

(e.g., apparent national seafood consumption) and outcome (e.g., prevalence of depression) from 

often large samples of data derived invariably from non-overlapping sources, that is, where a 

given sample of individuals does not provide both exposure and outcome data. Thus, individualor patient-level inferences cannot be drawn. Exposure data are at best crude indices of intake, 

failing to reflect the dietary practices of individuals or even population subgroups;109 and, these 

types of study are readily confounded by cultural, economic, social and other factors.47 An 

additional barrier to drawing conclusions based on these findings is that their cross-national 

focus precludes generalization to the North American population of subjects who may be at risk 

of developing depressive disorders or symptomatology. 

Taken together, the inconsistent results, as well as the limitations of both the inherently 

stronger (i.e., prospective controlled studies) and weaker designs having produced them, suggest 

that there is currently insufficient evidence to decide whether or not omega-3 fatty acid intake 

can protect individuals—with or without known predispositions—from developing either 

depressive disorders or symptomatology. The observation that the risk of depressive 

symptomatology is inversely related to fish/seafood consumption or omega-3 fatty acid intake 

was less likely to be produced by research designs that more appropriately permit the drawing of 

causal inferences regarding the etiologic role of exposure to omega-3 fatty acids in the 

development of depressive disorders or symptoms. Studies that are prospective, controlled and 

focused on subject-level data were less likely to demonstrate evidence for a significant protective 

relationship. Having identified too few of these stronger study designs also made it 

inappropriate to conduct a quantitative synthesis and impossible to comprehensively assess the 

possible influence, on clinical outcomes, of extra-exposure variables (i.e., covariates, 

confounders). As well, too few studies produced results that could be meaningfully extrapolated 

to North Americans. 

Eight controlled studies were identified that had the potential to address Question 3 

concerning the possible association between biomarkers data and the onset of depressive 
173 

disorders or symptomatology.

48,98,101-106 However, only one study was prospective by design.98 

The other seven were multiple-group cross-sectional designs. Therefore, it was impossible to 

draw causal inferences concerning the onset of depression from the results of the seven weaker 

designs, or to consider meta-analysis. With respect to the multiple-group cross-sectional studies, 

we focused solely on comparisons between groups of patient diagnosed with depression and 

controls, with the latter typically identified as “healthy” and sometimes matched by age and sex. 

For each study, this contrast established the sharpest differentiation possible between study 

groups, even though only a few of the study reports described the methods by which they had 

formally ruled out the presence or risk of depressive disorders or symptomatology in their 

control subjects. Results are described as they appeared in the literature, with the data from the 

strongest design (i.e., RCT)98 providing, at best, a very limited answer to the research question. 

The two earliest publications included in the review—one by Ellis and Sanders105 and the 

other by Fehily et al.106—revealed a pattern of findings that has since been disconfirmed. Each 

study reported that plasma CPG EPA and DHA levels were higher in those with a diagnosis of 

endogenous depression than in healthy controls. They also noted that similar between-group 

differences in RBC CPG levels of EPA, DHA and AA existed although they were less 

pronounced (no data reported). These results would disconfirm the omega-3 fatty acid 

deficiency hypothesis introduced in Chapter 1. However, unlike virtually all subsequent studies, 

their “endogenously depressed” populations exhibited substantial diagnostic heterogeneity to the 

extent that it would likely be impossible to find the appropriate populations to which the results 

of these two studies might be meaningfully generalized. 

Arguably the two best controlled cross-sectional studies were conducted by Maes and 

colleagues in Belgium.101,103 A priori they excluded many potential confounders (e.g., 

background diet, alcohol use, heavy smoking, medications at assessment, comorbid conditions) 

in addition to matching for age and sex. Also, like few other other studies,104 they explicitly 

described having excluded from the control group, those subjects with notable psychopathology. 

Maes et al.’s results are thus likely more reliable, but not solely because they were less prone to 

confounding. They also employed formal research diagnostic criteria. To draw one comparison, 

Fehily et al.106 combined data from unipolar, bipolar and adjustment disorder subjects, whereas 

Maes et al. excluded subjects with bipolar diagnoses and distinguished between subjects with 

minor and major depression. Peet et al.’s study was less tightly-controlled experimentally yet 

they also attempted to rule out psychopathology in controls while noting the absence of 

significant between-group differences for smoker status.102 Most studies did not control for the 

likely confounding effects of stress, smoker status or diet.177 Both studies by Maes et al., as well 

as the study by Tiemeier et al., admitted patients to hospital to establish a highly controlled 

environment.101,103,104 

Maes et al.’s first set of results indicated that levels of ALA, total omega-3 fatty acids and 

EPA in serum cholesteryl esters, as well as EPA in serum phospholipids, were significantly 

lower in major depressed patients compared with healthy volunteers.103 As well, AA/EPA in 

both cholesteryl esters and phospholipids were significantly higher in the major depressed patient 

group compared with controls. ALA, EPA and DHA levels collectively discriminated between 

these two study groups as well as distinguished minor depressed individuals. 

Peet et al.102 reported that the picture of depleted omega-3 fatty acids in serum cholesteryl 

esters described by Maes et al.103 was observed in the RBC total omega-3 fatty acids and DHA of 

drug-free patients compared with healthy controls.102 Yet, Peet et al. pointed out that the 

difference in the number of current smokers across their two study groups (i.e., compared with 
174 

controls, all but two depressed patients were nonsmokers) constituted a possible source of 

confounding.102 They also acknowledged that there may have been prestudy medication in cell 

membranes, which likewise may have confounded study outcomes. Nevertheless, Edwards et al. 

reported similar findings of significantly lower RBC total omega-3 fatty acids, DHA and EPA in 

medicated depressed patients compared with matched healthy controls.48 Controlling for stress 

and smoker status had no effect on RBC values in Edwards et al.’s study.48 

Maes et al.’s second study revealed significantly lower fractions of EPA, DHA, AA and total 

omega-3 fatty acids in the serum phospholipids of major depressed patients compared with 

healthy volunteers.101 As in their first study, they also reported higher AA/EPA fractions in the 

patient group.101 Significantly lower fractions and concentrations of ALA, EPA and total 

omega-3 fatty acids were observed in the serum cholesteryl esters of these patients.101 

Significantly higher AA/EPA and total omega-6/omega-3 fractions were observed in the patient 

group as well.101 Tiemeier et al. found that percentages of AA, AA/DHA and total omega6/omega-3 in plasma phospholipids were significantly higher in depressed patients compared 

with controls.104 The percentage of DHA was lower in the depressed patient group. 

Correlational data showed significant negative relationships between: HDRS scores and EPA 

in serum cholesteryl esters103 or other PUFAs;101 BDI scores and RBC ALA, DHA and total 

omega-3 fatty acids, although multiple regression revealed that only ALA levels predicted BDI 

scores;48 and, between plasma phospholipid DHA and results on the BDI, EPDS or SCID.98 

These last findings were obtained from Llorente et al.’s RCT.98 Significant positive relationships 

defined HDRS scores and both AA/EPA and total omega-6/omega-3 fatty acid levels in the 

plasma phospholipids of major depressed patients.103

Collectively, the between-group differences suggest a possible balance of PUFAs such that 

significantly decreased levels of omega-3 fatty acid content coexist with increases in some 

omega-6 fatty acid levels and in some omega-6/omega-3 fatty acid ratios. Medication status did 

not appear to modify this picture.101 For example, EFA levels were not affected in those of 

Edwards et al.’s patients who had antidepressants added prior to a second assessment of their 

EFA status.48 Peet et al. reported that, after six weeks of treatment with antidepressants in ten 

depressed patients, PUFA levels did not change significantly (no data reported).102 

However, these results were obtained from cross-sectional studies from which causal 

inferences relating to onset cannot be drawn. Selection bias can also influence study outcomes in 

these designs. In addition, PUFA status in studies of mental health is likely determined by 

multiple factors, suggesting that any between-group differences in PUFA content observed in 

this review may not simply reflect the disease process itself. Other influences include: age; sex; 

the dietary intake, metabolism and incorporation into cell membranes of various types and 

amounts of both omega-3 and omega-6 fatty acid content (given their competitive relationship 

with respect to enzymes, for example); the disease process underlying any possible comorbid 

conditions; the efficiency of the PUFA metabolic processes, including the availability and 

effectiveness of enzymes implicated in the processes of desaturation and elongation; the longlasting effects of psychotropic medication (e.g., mood stabilizers, antipsychotics) on cell 

membranes; and the ability of protective mechanisms to deal with degradation from oxidation 

and other sources (e.g., smoking, alcohol consumption).48,101-103,178-180

Differences in RBC PUFA content can be attributed to the mechanisms of action of mood 

stabilizers (i.e., postsynaptic signal transduction processes) or the abnormal psychoimmunology 

of patients with bipolar disorder.113 Mood stabilizers can reduce the AA turnover rate;181 and, 

smoking has been observed to deplete PUFAs from cell membranes (e.g., DHA, [omega-3-
175 

]DPA, omega-6 fattty acid series).182 Given that these variables have been highlighted as 

influences on EFA status requires that they be controlled for experimentally or statistically in 

studies assessing the possible association between the fatty acid content of biomarkers and 

clinical outcomes (e.g., onset of depression). 

Thus, with only cross-sectional evidence available to address the question of onset there 

exists the need for more appropriate tests of the deficiency hypothesis. Ideally, these would 

employ controlled prospective study designs. The available results, at best, suggest the possible 

definition of the EFA profile that future research might identify as being responsible for the 

development of depression. Until then we can only speculate that “it is more likely that changes 

in fatty acid intake in the population influence depression prevalence than vice versa.”53 The 

possible role played by omega-3 fatty acid intake or the omega-3 or omega-6/omega-3 fatty acid 

content of biomarkers in the continuation or recurrence of depression could not be assessed given 

no studies with these foci were identified. Whether PUFAs’ influence on mental health also 

entails, for example, the activation of the inflammatory response system, including the 

production of eicosanoids, remains to be determined. 

Only Question 2 could be addressed with respect to suicidal ideation or behavior. 

Hakkarainen et al. reported no significant associations between either intake of fatty acids or fish 

consumption and successful suicides.111 Tanskanen et al. noted that the adjusted risk of suicidal 

ideation decreased significantly in frequent fish consumers.80 The evidence base is thus too 

small, and the designs less than optimal, to permit us to conclude anything with respect to the 

possible association between omega-3 fatty acid intake and the onset of suicidal ideation or 

behavior. Their applicability is limited by the fact that both studies were conducted in Finland. 

Two controlled studies investigated the supplemental treatment of bipolar disorder with 

omega-3 fatty acid supplementation,93,112 although only one report gave us an opportunity to 

systematically assess its study parameters and results. While the Stoll et al. trial had to be 

stopped prematurely, their very high dose of 9.6 g/d EPA+DHA produced a significantly longer 

period of remission in the active treatment group compared with controls.112 Medication status 

did not alter this finding. Rating scale results, including depressive symptomatology, showed 

greater improvement in the omega-3 fatty acid intervention group compared with controls. 

While these pilot observations appear to be promising, there was also evidence that the blind had 

been broken. Almost 90% of active treatment patients correctly guessed that they had received 

fish oil capsules, with data from patients indicating that both the clinical response and a fishy 

aftertaste contributed to their deduction. For the sake of both its promising findings regarding 

the impact on a subacute course of bipolar disorder, and its limitations (i.e., its loss of power 

because of its stoppage; broken blind), this study requires replication. It might also be useful to 

use a lower dose even though the present one did not produce even moderately severe side 

effects. A lower dose might also better control the fishy aftertaste. At present, the evidence base 

is too limited to definitively conclude anything about the potential of omega-3 fatty acids as 

supplemental therapy for bipolar disorder. 

The same must be said with respect to the capacity of omega-3 fatty acids to prevent the 

onset of bipolar disorder (Question 2). Evidence suggesting the possibility that seafood 

consumption plays a protective role was identified by a single, cross-national ecological 

analysis.90 Yet, while the investigators employed stratifications for both age and sex, they did 

not control for socioeconomic status, urban/rural ratio, educational level, marital status, alcohol 

consumption, smoker status or family history. These are likely significant omissions given that 

these risk factors can predict the onset of bipolar illness.90 The authors also recognized that these 
176 

data cannot shed light on whether the lifetime risk for bipolar disorder was affected by low 

seafood consumption in adulthood and/or by nutritional insufficiency in early neurological 

development.90 Nutrient deficiencies during the second and third trimester of pregnancy can 

increase the risk of developmental affective disorders in children.183 Noaghiul and Hibbeln’s 

results,90 while parallelling observations obtained from the above-noted cross-national ecological 

analyses regarding depression, likewise exhibit limited applicability to individuals/patients and 

to the North American population. 

The results from two multiple-group cross-sectional studies did not agree on whether a 

diagnosis of bipolar disorder was associated with a specific biomarker profile when compared 

with data from controls (Question 3). This divergence may be attributable to the fact that the two 

studies obtained their PUFA samples from different biomarker sources. Chiu et al. noted 

significant between-group differences in AA and DHA from RBC membranes.113 Adding 

medication did not appreciably change the EFA levels in Chiu et al.’s bipolar patients. They did, 

however, fail to control for diet. Mahadik et al. assessed AA and DHA compositions of cultured 

skin fibroblasts, finding no significant between-group differences for small numbers of bipolar 

patient and controls.114 Although Mahadik et al. controlled for dietary intake as one key 

influence on RBC and brain PUFA levels,114 PUFA levels from skin fibroblasts may not reflect 

brain PUFA levels.113 Moreover, the clinical status of their patients (i.e., duration of illness, 

mood state [mania, depression, mixed], symptom severity) was poorly defined and controlled 

for; and, no data were reported indicating patterns of mood stabilizer or antipsychotic medication 

use, which have been found to influence PUFA levels (see above). The studies were conducted 

in countries varying in terms of their background diet, and likely their omega-6/omega-3 fatty 

acid content intake ratio, and this factor may have also influenced the results. In any event, the 

fact that both efforts employed cross-sectional designs precludes deriving casual inferences 

regarding the onset of bipolar disorder. 

Two RCTs yielded data investigating the possible protective influence (Question 2) of 

omega-3 fatty acid intake and the onset of symptoms but not disorders of anxiety.

99,100 Both the 

Wardle et al. and Ness et al. studies failed to find a significant association. As noted with 

regards to the subject of depression, neither RCT constituted an appropriate assessment of this 

question. 

Fux et al.’s results indicated that E-EPA was ineffective as a supplemental treatment for

obsessive-compulsive disorder.

115 However, nothing definitive can be concluded from a single, 

underpowered crossover study, which failed to describe a washout period. 

Two cross-sectional studies investigating the possible association between the onset of 

anorexia nervosa and the fatty acid content of biomarkers analyzed plasma phospholipid 

data.116,117 Their observations concurred that both ALA and total omega-6 fatty acid levels were 

significantly lower in anorexic patients than in controls. However, their findings differed in that 

Holman et al.116 noted a similar reduction in DHA in anorexic patients while Langan and Farrell 

found that DHA levels were significantly reduced in controls.117 Holman et al.116 noted a 

significantly lower level of EPA in patients, and Langan and Farrell117 reported a reduction of 

LA in these patients compared with controls. Only Holman et al. evaluated the contents of 

plasma cholesteryl esters, with respect to which they observed no significant between-group 

differences. However, in plasma triglyceride fractions they did find significantly reduced total 

omega-3 fatty acid content in their patients. Irrespective of these results, these small studies 

utilized a design preventing the drawing of causal inferences regarding etiology. 
177 

Notwithstanding the noncomparability of interventions, comparators and populations (i.e., 

with118,120,121 or without a formal diagnosis of AD/HD;119 with120 or without significant 

comorbidity119,121), the results of the three RCTs118-120 and the comparative before-after study121

addressing the question about the primary treatment of AD/HD were inconsistent at best. They 

did not show uniform improvement in clinical outcomes, and in some cases, significant 

improvements were observed only for control children.120 The studies by Hirayama et al.120 and 

Harding et al.121 failed to report any significant between-group clinical differences. These are 

the only two studies which clearly distinguished omega-3 fatty acids as the “intervention.” 

Moreover, Harding et al.’s results are likely unreliable given the selection bias that results from 

having parents chose which intervention their child will receive. 

Each of the two studies exhibiting a few significant clinical effects had used a “cocktail,” 

which included much more than omega-3 fatty acids; and the nature of the synergies involving 

the components comprising the respective “cocktails” was not evaluated.118,119 In one of these 

two studies, the research design did not allow the researchers to tease out the possible specific 

benefit of omega-3 fatty acids.119 None of the studies employing DSM-IV to identify AD/HD 

actually distinguished their populations by AD/HD subtype (e.g., Inattentive vs 

Hyperactive/Impulsive vs Combined), which is an important source of clinical heterogeneity. 

The different subtypes entail dissimilar clinical pictures given the various clusters of symptom or 

behavior required to identify their presence.13 

With respect to the supplemental treatment of AD/HD, Voigt et al. observed only 

nonsignificant between-group clinical differences.122 These observations were associated with 

increased plasma phospholipid DHA levels observed exclusively in the DHA study group. 

Stevens et al. found almost no evidence of clinical benefit for their “cocktail” exposure 

compared with a very high dose of olive oil as placebo.123 This was accompanied by 

observations of no significant between-group differences for fatty acid content in plasma 

phospholipids. Participants in the Stevens et al. trial were also entered into the study based 

merely on parental, not professional, confirmation of an AD/HD diagnosis. The clinical features 

of AD/HD can exist as isolated clusters of symptom insufficient to merit a formal diagnosis of 

AD/HD and so, there is no guarantee that all children would have received a DSM-IV diagnosis 

of AD/HD. Brue et al. reported a benefit for problems of inattentiveness yet not for 

hyperactivity and impulsivity.118 

Overall, these supplemental treatment RCTs may have employed intervention lengths that 

were too short. Primary treatment trials lasted longer. It is also conceivable that weightadjusting doses of omega-3 fatty acids would have produced a different picture of the efficacy of 

these primary or supplemental interventions, although all elements of the sometimes complex 

interventions would likely have required similar adjustments.118,119,123 

While the results of the supplemental treatment studies are more uniformly generalizable to 

the North American population than those generated by primary treatment studies of AD/HD, 

there were too few studies whereby the specific effects of omega-3 fatty acids could be isolated, 

thereby preventing us from concluding one way or the other about the specific efficacy of 

omega-3 fatty acids as a primary or supplemental treatment.118,119,123 The only consistent 

observation is that, contrary to the situation in the trials of depression, where the majority of 

subjects were female, most of the participants in the two collections of AD/HD study were male. 

This is not surprising given what has often been observed in clinical practice. 

Yang et al.’s multiple-group cross-sectional design was not concerned with trying to 

establish a link between omega-3 fatty acid intake and the onset of AD/HD.94 At best, the results 
178 

from this study might hint at the possible conditions maintaining AD/HD, although controlled 

prospective designs are required to determine causality. Nevertheless, Yang et al. found that, 

relative to healthy controls, AD/HD children consumed significantly lesser amounts of LA and 

ALA. These observations, while requiring replication, could be suggestive if it turns out that 

lower LA and ALA content in biomarkers also distinguishes those individuals with AD/HD and 

healthy controls.

In their first study Mitchell et al. failed to observe any univariate between-group differences 

for RBC fatty acid content, although multivariate analysis revealed that levels of ALA and AA, 

along with a few other fatty acids, distinguished hyperactive and control children.126 Stevens et 

al. also found significantly lower AA levels in hyperactive boys.124 In their second study, 

Mitchell et al. reported that levels of DHA, AA and DGLA in serum phospholipids were 

significantly reduced in formally diagnosed hyperactive children.125 Stevens et al. also found 

significantly reduced AA, EPA, DHA and total omega-3 fatty acids in the plasma phospholipids 

of hyperactive boys.124 However, Stevens et al.’s study did not confirm this observation.124 

They noted higher PUFA intake in the diet of hyperactive boys. More work is needed to resolve 

this divergence of findings. 

Only the second Mitchell et al. study employed formal diagnostic criteria (i.e., DSM-III) to 

identify their hyperactive subjects.125 However, none of these biomarker studies formally ruled 

out the presence of psychopathology in the control subjects. The use of cross-sectional designs 

by so few studies necessitates additional empirical work. 

Based on a single observational study, which controlled for age, income, smoking, alcohol 

consumption and eating patterns, mental health status was observed to be lower in those 

consuming no fish.127 However, this cross-sectional design precludes inferring that the onset of 

mental health diffulties is related to fish consumption. 

Seven studies, including three RCTs enrolling healthy volunteers, investigated the 

relationship between omega-3 fatty acid intake and tendencies or behaviors with the potential to 

harm others. All but Gesch et al.’s study were designed to address the relationship of intake and 

the onset of these tendencies or behaviors.131 Gesch et al.’s trial investigated the possibility of 

using an exposure to prevent the recurrence of antisocial behavior (i.e., secondary prevention). It 

is difficult to discern any reliable, significant patterns, or lack thereof, across the various 

outcomes, populations and designs, however. 

Hamazaki et al.’s work with university students showed that, when a stressor was applied, 

DHA supplementation provided some protection against aggression directed at the external 

world;130 however, a subsequent study, involving no stressor component, showed that control oil 

capsules had a similar beneficial impact on aggression in control subjects.129 The first 

observation was associated with no between-group differences for DHA, EPA or AA content in 

serum phospholipds. The behavioral finding in their second study, in favor of the control 

subjects, was coupled with significant increases in RBC EPA and DHA content in the DHA 

group, and a significant increase in RBC LA content in the control group. For Hamazaki et al.’s 

elderly Thai population, some benefit related to the prevention of extraaggression was observed 

for university employees yet not for villagers.128 Appropriate between-group analyses of RBC 

content data were not performed. No reliable patterns relating clinical and biomarker effects 

could be discerned across Hamazaki et al.’s trials. 

Enrolling very different populations, yet focused on trying to see if omega-3 fatty acid 

exposures prevent the onset of tendencies or behavior with the potential to harm others, Wardle 

et al.’s RCT observed no significant benefits for anger/hostility associated with special diets,99
179 

Iribarren et al.’s cross-sectional survey found that high intake of DHA and the consumption of 

fish rich in omega-3 fatty acids may be related to a lesser likelihood of high levels of hostility in 

young adults,132 and Hibbeln’s cross-national ecological analysis revealed that lower apparent 

seafood consumption was associated with higher rates of death due to homicide.133 Gesch et 

al.’s “cocktail” supplementation provided young adult prisoners with some (secondary) 

protection against committing new offences.131 

Overall, these findings are sufficiently inconsistent and involve too few research designs 

permitting the drawing of causal inferences (i.e., cross-sectional survey,132 cross-national 

ecological analysis133) and too many different definitions of the exposure, population and 

outcome99,128-133 for us to be able to derive an individual/patient-level conclusion regarding the 

protective benefits of omega-3 fatty acid intake when it comes to tendencies or behavior with the 

potential to harm others. Moreover, as a whole, the generalizability of their findings to North 

Americans is limited. 

Very few significant between-group differences were observed in the three included studies 

addressing the biomarkers question with respect to the onset of tendencies or behavior with the 

potential to harm others;

134-136 and, given the differences in the investigated populations, 

generalizations cannot be made. That said, Hibbeln et al. reported no significant between-group 

differences for PUFA content when violent and non-violent subjects were compared.134 The 

only observation identified in more than one study entailed lower DHA levels in the plasma 

phospholipids of patients with antisocial personality compared with healthy controls,135 and in 

the plasma phospholipids of aggressive cocaine addicts compared with nonaggressive cocaine 

addicts.136 However, only the Hibbeln et al. study did not include a small number of 

participants.134 The exclusive use of cross-sectional designs precludes drawing any inferences 

regarding etiology. 

The conflicting results regarding reduced PUFA content in alcoholic patients reported by 

Alling et al.138 and Hibbeln et al.137 may not simply be attributable to the different biomarker 

sources that were investigated. The lower levels of LA, DHA, DGLA and AA found by Alling 

et al.137 in male chronic alcoholics, compared with healthy male controls, could have been 

caused by the consumption of alcohol itself.60 Yet, the fact that Hibbeln et al.’s abstinent 

alcoholics exhibited higher PUFA concentrations, while also having smoked many more 

cigarettes per annum than did healthy controls, is not easily explained. Whatever the correct 

explanation, findings linked to cross-sectional designs again preclude drawing any inferences 

regarding the etiology of alcoholism. 

Zanarini et al.’s RCT examined E-EPA as a primary treatment for borderline personality 

disorder and found that there were significant clinical effects over the course of the study, as the 

E-EPA group had, at study end, significantly lower mean scores on both the MADRS and 

MOAS compared with the placebo group.139 Notwithstanding its strong applicability to the 

North American population, this was a small study requiring replication. 

While the results of the Peet et al. trial58 indicated placebo-controlled benefits accruing to 

omega-3 fatty acid supplementation as primary treatment for schizophrenia, this was a small and 

methodologically adequate pilot trial with little applicability to the North American population. 

More work is required before we can decide anything about omega-3 fatty acids’ promise in this 

context. Considerably more can be said about their role as supplemental treatment for 

schizophrenia. 

Four recently published RCTs, exhibiting sound internal validity, examined omega-3 fatty 

acids as supplemental treatment for schizophrenia.

58,87,89,140 Three of them reported significant 
180 

clinical effects in favor of EPA using total PANSS scores,58,87,140 although Peet et al.’s study 

observed this effect only for those receiving clozapine as primary treatment.87 Emsley et al.’s 

RCT also found that the reduction in PANSS total scores associated with E-EPA 

supplementation was greater in patients taking conventional antipsychotic medications when 

compared with those taking clozapine.140 EPA did not significantly ameliorate negative 

(PANSS) symptoms in any study, and improvements were rarely seen for positive (PANSS) 

symptoms.58 General psychopathology (PANSS) scores were seldom improved significantly 

(i.e., by E-EPA140). In Emsley et al.’s trial, tardive dyskinesia was ameliorated using 3g/d EEPA.140 The only study employing DHA as an intervention showed nonsignificant benefits 

when compared with placebo or EPA.58

Results of our meta-analysis of PANSS total data revealed that dose influenced outcome. A 

significant placebo-controlled effect was identified for 2g/d EPA yet not for doses of at least 

3g/d EPA. However, the significant result demonstrated somewhat limited applicability to the 

North American population although the inclusion of two UK studies meant that the potentially 

confounding influence of background diet was controlled for. While these findings are 

suggestive, they are not definitive given that the results subjected to meta-analysis were derived 

from a small number of trials involving a small number of patients with schizophrenia. 

Moreover, the effect might have been more pronounced had the data entered into meta-analysis 

come exclusively from patients taking clozapine as primary treatment. Peet et al. did not 

distinguish their results by type of primary treatment,58 and we did not enter data exclusively 

from patients receiving clozapine in Peet et al.’s second trial.87 

Peet et al.’s patients who received clozapine were typically switched to this medication 

because existing pharmacotherapies had failed.87 This suggests that these patients, for whom a 

placebo effect was far less likely than for patients receiving other antipsychotic medication, were 

more impaired than those patients receiving the other pharmacotherapies. Moreover, patients 

taking clozapine were at best partial responders to this agent given that they still exhibited 

PANSS total scores of at least 50 at the start of the RCT. Thus, patients on clozapine likely 

exhibited more “room for improvement” than did patients receiving the other drugs. That said, 

the positive response to E-EPA in this exploratory trial is quite interesting, and suggests the need 

to replicate this finding in an adequately-powered trial, which at minimum would need to enrol 

patients stratified by type of antipsychotic medication. Yet, the Emsley et al. study found a 

nonsignificant trend towards greater reduction in total PANSS scores in participants taking 

typical antipsychotic medication, compared with those receiving clozapine.140 

The overall outcome—a significant impact of low-dose EPA and a nonsignificant effect of 

high-dose EPA—may have been different if both of Peet et al.’s studies had used E-EPA. 

Compared with unpurified EPA,58 E-EPA’s processing minimizes its odour and flavor,87 and 

this, in turn, should better preserve blinding. Another possible influence on the results relates to 

Peet et al.’s use of “uncontrolled dosing,” which involved pourable oils.58 That is, the exposure 

was not delivered via capsules containing controllable amounts of exposure, but rather via 

prescribed amounts of oil poured from bottles onto or into foods on a daily basis. Uncontrolled 

dosing might have produced variability both in the daily and the full study intake of omega-3 

fatty acids in the active treatment group and/or in the daily and the full study intake of corn oil in 

the placebo group. This could lead to confounding stemming from changes in the planned, 

constant between-group difference in omega-3 fatty acid intake and in the planned, constant 

between-group equivalence for energy/caloric intake. Controlled dosing likely would have 

substantially improved the experimental control in Peet et al.’s RCT.58 Other potential 
181 

influences on study results were the short intervention periods, small sample sizes and the use of 

different placebo sources (i.e., liquid paraffin87 vs corn oil58). More evidence is required to 

replicate these findings. 

Having more studies to systematically review might eventually facilitate comprehensive 

assessments of the possible role of key covariates or confounders (e.g., current smoker status). 

Biomarker data were not meta-analyzed given the exploratory purpose underlying the inclusion 

of these observations from treatment studies. Baseline RBC EPA level predicted clinical 

improvement in response to EPA supplementation, for example.58

A completed Cochrane review of PUFA supplementation for schizophrenia did not conduct 

meta-analysis in the way that we undertook ours, despite the fact that they identified the same 

placebo-controlled trials investigating the impact of omega-3 fatty acids.61 They did not evaluate 

the impact of dose on total PANSS scores in the same fashion; and, they combined data obtained 

from patients in placebo-controlled RCTs investigating omega-3 fatty acid supplementation as 

either primary or supplemental treatment. In our view, their approach compromised the 

meaningful interpretation of their observed effect in favor of omega-3 fatty acids even though 

this finding parallels what we observed exclusively with respect to a 2g/d dose of omega-3 fatty 

acids. No other completed systematic reviews investigating the benefits of omega-3 fatty acids 

in mental health were identified by our review. 

As an aside, uncontrolled studies of the effect of omega-3 fatty acid supplementation have 

shown that 10 g/d of concentrated fish oil (MaxEPA®), including 1.7 g/d EPA and 1.1 g/d DHA, 

over 6 weeks improved schizophrenic symptoms and tardive dyskinesia in schizophrenic patients 

(n=20) taking their regular antipyschotic medication.91 However, Rudin et al. failed to identify a 

clinical benefit when linseed oil was given as a source of ALA (50% ALA) to a handful of 

patients with schizophrenia (n=5).184 

Research designs, which because of their prospective and controlled nature, are most 

appropriate for addressing the question of the possible intake of omega-3 fatty acids and the 

onset of schizophrenia were not found. Thus, there is little that can be said with confidence with 

regards to this subject. The only prospective study was not controlled, and its followup was very 

short.91 This, along with the observation that the diagnosis of schizophrenia had already been 

assigned in this study, indicates that its attempt to correlate dietary intake data with 

schizophrenia symptom scores could not be used to illumine the question of etiology. As well, 

data indicating a significant inverse association of EPA intake over 1 week with total 

psychopathology, or a similar, inverse relationship involving both ALA and total omega-3 fatty 

acid intake with positive symptom scores, do not allow us to respond meaningfully to the 

question of the exposure’s possible impact on the disorder’s continuation.91 

The results from five case-control studies do not permit us to conclude that there is a reliable 

association between omega-3 fatty acid intake and the onset, course or outcome of 

schizophrenia. While Peet et al. noted that schizophrenic patients were significantly less likely 

to have been breastfed,92 findings from three other studies did not support this observation;142-144

and, Amore et al.’s only statistically significant association indicated that the longer infants were 

breastfed, the later was the onset of schizophrenia.141 

Differences in national or regional feeding patterns might account for differences among 

studies. At the same time, Sasaki et al. did not adjust or match for key confounders such as sex, 

maternal age or socioeconomic status.144 McCreadie143did not have access to stratified sampling 

data whereas Leask et al. did,142 perhaps leading to differences in observed patterns of 

breastfeeding. Moreover, less bias may have been associated with Leask’s study142 since their 
182 

cases and controls came from the same population at risk, with equal baseline risk of inclusion. 

Another factor potentially distinguishing the Leask et al. and McCreadie et al. studies is that the 

former’s outcomes142 were incident cases while the latter obtained prevalence data,143 which can 

be biased towards chronic illness. Leask et al.’s finding was likely more reliable for these 

reasons, although their analyses may have lacked statistical power. In any case, the studies 

suggested the absence of a significant association. 

As well, likely only one case-control study adequately ruled out the possible impact of recall 

bias. Leask et al. analyzed breastfeeding data from mothers when their children were either two 

or seven years of age.142 Mothers in the other studies had to recall events 20-50 years in the past. 

Some studies have shown that while long-term recall of whether an infant was breastfed is good, 

the duration of breastfeeding or the timing when other milk products were initiated are recalled 

less well.185-187 

While cross-ecological analyses do not highlight data indicating individual/patient-level 

covariations of exposure and outcome, they nevertheless failed to demonstrate either a 

significant association of seafood consumption and lifetime prevalence rates of schizophrenia90

or a significant relationship between fish consumption,109 or UFA intake,145 and the course or 

outcome of schizophrenia. That said, none of these studies attempted to rule out the possibility 

that (the nature of) early mother-infant contact might just as easily explain any possible 

association between breastfeeding and schizophrenia. 

While medication status may have had somewhat of an influence on between-group 

differences in RBC or plasma phospholipid fatty acid content when the comparison group was 

healthy controls, because these data were obtained from cross-sectional studies, no meaningful 

possibility exists to permit drawing causal inferences regarding patterns of PUFA content and 

the onset of schizophrenia. The same criticism applies to the single study examining biomarkers 

data with respect to autism.

Clinical Implications 

Omega-3 fatty acids in the present review’s collection of interventional studies were not 

associated with moderate or severe adverse events. Supplementation was well-tolerated, with 

some mild, mostly gastrointestinal events occurring occasionally. Even the highest doses of 

omega-3 fatty acids did not produce significant side effects requiring patients to withdraw. The 

lack of variety in the types of omega-3 fatty acid employed in these studies means that this safety 

profile refers almost exclusively to the intake of either purified (i.e., E-EPA) or unpurified EPA. 

The picture pertaining to the remaining evidence is essentially just as unequivocal. For each 

psychiatric disorder or condition whose evidence we evaluated, it is impossible to definitively 

conclude anything with respect to omega-3 fatty acids’ efficacy as a therapy or prevention. The 

existing evidence is therefore insufficient to support clinical recommendations regarding the use 

of omega-3 fatty acids for the treatment or prevention of any specific mental health condition. 

Although some individual studies have reported some favorable results, trials have tended to be 

small, results have often been inconsistent, and study quality has been limited. It is likewise 

impossible to take existing biomarkers data as constituting reliable predictors of the onset, 

continuation or recurrence of any psychiatric disorder or condition. Too few large, wellcontrolled prospective studies employing research designs with the greatest inherent potential to 
183 

address each of the first three basic research questions were identified in this systematic review. 

Yet, given their reasonable safety profile, it is likely that the use of (foods containing) omega-3 

fatty acids to influence mental health is unlikely to produce notable adverse effects. 

While little is known about the primary treatment of schizophrenia, more can be said about 

its supplemental treatment. A low dose of 2g/d EPA may, in the shortterm, ameliorate symptoms 

of schizophrenia. High dose (at least 3g/d) EPA did not provide a similar benefit. However, 

these observations require replication from much larger, longer term studies that also exercise 

specific experimental and statistical controls. These refinements are described in the next 

section. Until these studies are conducted we will not feel confident that 2g/d EPA, or any other 

dose or type of omega-3 fatty acid, can or cannot produce even reliable shortterm symptom 

improvement in schizophrenia. Similarly, until more appropriate research designs are employed, 

the existing evidence does not allow us to conclude that either specific patterns of omega-3 fatty 

acid intake or particular PUFA levels in biomarkers reliably predict the onset, continuation or 

recurrence of schizophrenia. It is therefore doubtful that the latter observations can be used to 

unequivocally confirm the PUFA deficiency facet of the membrane phospholipid hypothesis 

concerning the etiology of schizophrenia.55 

It has also been suggested that smoker status alone may account for the results indicating 

between-group differences in PUFA content,60 although other factors can influence PUFA status 

as well (e.g., medication use, alcohol consumption: see above). Hibbeln et al.’s additional 

analysis60 of RCT data from their investigation of the effect of omega-3 fatty acids as 

supplemental treatment for schizophrenia89 revealed some important observations that may raise 

doubts about the validity of some of the data presumed to support the membrane phospholipid 

hypothesis regarding the etiology of schizophrenia.55 They have suggested that failing to 

account for current smoker status in studies examining the possible depletion of PUFA content 

may have confounded numerous, if not most, of the results of cross-sectional studies thought to 

support the hypothesis.60 Their observations are summarized below. 

Peet et al.’s demonstration of the superiority of EPA over DHA as supplemental treatment 

for schizophrenia was not expected.58,188,189 The investigators had assumed that DHA’s 

prominent role in neuronal membrane phospholipids, via their capacity to affect the 

configuration and function of neurotransmitters (e.g., dopamine), might contribute to the 

amelioration of symptoms. (Others have suggested that DHA has mood stabilizing effects 

because of its action on serotenergic neurotransmission, altered membrane fluidity and 

suppressed phosphatidylinositol and protein kinase C signal transduction.113,188-190) Peet et al. 

also expected that EPA’s lesser representation in neuronal membranes would mean that it would 

play a less important role. They argued that any positive clinical effect of EPA would have to 

occur independent of its direct incorporation into neuronal membrane phospholipids.58 

That said, they found that schizophrenic patients with the lowest RBC EPA levels exhibited 

the weakest response to treatment, an observation, they argued, that would not be predicted if 

EPA treatment merely entailed correcting a membrane deficiency.58 Given their earlier findings 

of a bimodal distribution of PUFA levels in schizophrenic patients (i.e., very low vs moderately 

low EPA reductions when compared with healthy controls149), the group with very low EPA 

levels in their treatment study may have had a more serious metabolic problem that was less 

amenable to modification by EPA supplementation. On the other hand, further analyses of 

biomarker data from Fenton et al.’s supplemental treatment RCT89 found no evidence of baseline 

bimodal distributions of RBC EPA, DHA or AA compositions in schizophrenic patients.60 
184 

Mechanisms potentially leading to EPA being more effective than DHA in depression have 

been reviewed briefly by Peet et al.53 In depression, the production of PGs from AA by the 

cyclooxygenase system appears to be elevated; and, EPA but not DHA has been observed to be 

an effective substrate for cyclooxygenase, and can compete with AA at this point in the 

metabolic pathway. Also, in some phospholipase A2 assays, EPA but not DHA has been seen to 

be an effective inhibitor. Work investigating EPA’s possible mode of action has also suggested 

the possible role of increased phospholipase A2 enzyme in the etiology of schizophrenia.55 

Although the modulation of background drug pharmacokinetics cannot be ruled out as the 

mechanism of action of E-EPA, Peet and Horrobin have suggested that it is more likely that its 

action is on cell membranes and signal transduction systems.53,190 These different effects of EPA 

and DHA, which may be characterized both by synergism and antagonism, suggest that the 

biological effects of fish oils, which contain both EPA and DHA in highly variable proportions, 

may be difficult to predict.53 

Overall, we agree with Peet et al. that the biomarkers (Question 3) and intake-outcome 

association data (Question 2) are likely suggestive enough to justify the conduct of more 

intervention studies pertaining to schizophrenia and depression.58 We provide a few details in 

the next section. 

Until data are obtained from more appropriate research designs (i.e., well-controlled 

prospective designs collecting individual/patient-level data), it is likely impossible to conclude 

with great confidence that an omega-3 fatty acid deficiency is responsible for the onset of 

depression (Question 3); or, that these findings, together with data presumed to reflect the 

“protective potential” of omega-3 fatty acid intake (Question 2), can readily be taken to justify 

the use of omega-3 fatty acids as either prevention or therapy. Testing the omega-3 fatty acid 

deficiency hypothesis also requires control of variables with the potential to influence PUFA 

status. Suggestive results from the small number of typically underpowered RCTs likely cannot 

be used to confirm or disconfirm the value of using omega-3 fatty acids as a primary or 

supplemental therapeutic for depressive disorders or symptomatology (Question 1). More 

evidence is required. 

Even less, or nothing, can be concluded about the value of omega-3 fatty acids as (primary or 

supplemental) treatment or (primary or secondary) prevention for bipolar disorder, suicidal 

ideation or behavior, symptoms of anxiety, obsessive-compulsive disorder, anorexia nervosa or 

other eating disorders, AD/HD, tendencies or behavior with the potential to harm others, 

alcoholism, borderline personality disorder, autism and mental health difficulties in general. The 

same may be said about the value of PUFA biomarker profiles as reliable predictors of the onset, 

continuation or recurrence of these disorders. Even if apparently consistent findings were noted, 

for example when a greater intake of (foods containing) omega-3 fatty acids was associated with 

lower prevalence rates of both depression and bipolar disorder, these observations came from 

designs exhibiting the weakest ability to illumine individual/patient-level associations (i.e., 

cross-national ecological analyses). Furthermore, much of the included research evidence lacked 

strong applicability to North Americans. Recommendations for further research stem from the 

identication of limitations characterizing existing studies and are highlighted in the next section. 
185 

Research Implications and Directions 

One overarching finding revealed by our review is that not all psychiatric disorders have 

been investigated for their clinical response to primary or supplemental treatment with omega-3 

fatty acids (Question 1) or for their possible association (e.g., prevention) with either omega-3 

fatty acid intake (Question 2) or the omega-3 or omega-6/omega-3 fatty acid content of 

biomarkers (Question 3). Some studies have also focused exclusively on psychiatric conditions 

(e.g., symptoms of anxiety) that are necessary yet insufficient to merit a formal clinical 

diagnosis. 

The primary targets of mostly recent research endeavors have been schizophrenia and 

depression. Studies examining the association between these psychiatric disorders or conditions 

and the PUFA content in biomarkers (Question 3) have outnumbered those investigations 

evaluating their association with the intake of omega-3 fatty acids (Question 2), and have far 

outnumbered studies assessing treatment of these disorders or conditions with omega-3 fatty 

acids (Question 1). In intervention studies, the emphasis has been almost exclusively on the 

supplemental treatment of these disorders or conditions. 

The lack of studies pertaining to some psychiatric disorders or conditions (e.g., eating 

disorders other than anorexia nervosa) means that nothing can be concluded other than the need 

for multiple research investigations, employing appropriately-controlled designs of sufficient 

size (i.e., to afford detection of a meaningful effect/association) and incorporating sound 

methodologies (e.g., reliable and valid outcome measurements). For those psychiatric disorders 

or conditions for which fewer than all of the first three basic questions were found to have been 

examined with empirical evidence (e.g., borderline personality disorder), the unstudied questions 

likewise require research embodying multiple, appropriately-controlled designs of sufficient size, 

and implementing sound methodologies. 

Yet, even for those questions investigated by numerous studies (i.e., associations between the 

PUFA content of biomarkers or the intake of omega-3 fatty acids and schizophrenia or 

depression), limited sample sizes, designs (e.g., cross-sectional studies examining associations 

between biomarkers and the onset of schizophrenia or depression) and methodologies (e.g., using 

apparent seafood consumption to measure intake of sources containing omega-3 fatty acids in 

cross-national ecological analyses) highlight the need for studies incorporating modifications to 

each of these study parameters. Finally, for those few topic areas where studies implementing 

appropriately-controlled research designs and sound methodologies yielded somewhat suggestive 

(i.e., supplemental treatment of schizophrenia) or potentially promising results (i.e., 

supplemental treatment of depression), more, similarly well-designed studies need to be 

completed, which enroll/allocate larger sample populations and implement additional or refined 

research design or methodologic characteristics (e.g., account more extensively for covariates 

and confounders). Given that only minor safety issues were noted in the included studies—

despite their likely under-reporting— treatment and prevention trials are justifiable. We now 

highlight some of the possible directions these investigations might take. While we focus 

considerable attention on schizophrenia and depression, given their prominence in our review, 

many of the basic issues apply equally to other psychiatric disorders or conditions. 

One possible approach to developing future research avenues is to encourage the collection 

of data (e.g., animal or human) and the construction of models (e.g., mechanisms of action) 

suggesting the (e.g., biological) plausibility of clinical treatment effects associated with omega-3 
186 

fatty acid supplementation before needlessly embarking upon the expense of studies examining 

the utility of these treatments for mental health problems (Question 1). From this vantage point, 

it could be argued that, for those psychiatric disorders or conditions for which few or no 

empirical treatment data have yet been obtained, the next step would be to establish some degree 

of plausibility regarding treatment based on empirical evidence addressing other, purportedly 

more “basic” research questions. 

Two such questions, albeit exclusively focused on human data, were addressed in our review: 

the association between the the onset, continuation or recurrence of psychiatric disorders or 

conditions and the intake of omega-3 fatty acids (Question 2), or their association with the 

omega-3 or omega-6/omega-3 fatty acid content of biomarkers (Question 3). Empirical answers 

to these two questions could suggest important roles (e.g., risk factors) for omega-3 fatty acid 

contents in mental health, observed in terms of their dietary intake and/or their levels (e.g., 

composition, concentration) present within blood lipid biomarkers. In turn, these data could 

serve to justify the use of omega-3 fatty acids as a treatment. 

In the present collection of studies, answers to Questions 2 and 3 were too limited, either 

design-wise or methodologically, to provide support for the deficiency hypotheses relating to 

either depression or schizophrenia. For the reasons described earlier, both cross-sectional studies 

and cross-national ecological analyses cannot produce answers that meaningfully identify those 

omega-3 fatty acid intake or biomarker profiles that may influence the onset of depression or 

schizophrenia. As well, studies employing other designs did not provide unequivocal support for 

these hypotheses. Thus, investigators in the domain of inquiry of interest to the present 

systematic review have at least two options: either wait for these “basic” data to be collected 

before conducting treatment studies, or find some other rationale supporting the design of new 

treatment trials. One such raison d'être might be to improve upon the designs and methodologies 

of studies that have already been completed. We suggest that this option may be especially 

relevant with regards to the foci of schizophrenia and depression. Moreover, it has also been 

said that data from epidemiological studies observing the association between fish consumption 

and psychiatric disorders (e.g., depression), or data from cross-sectional studies observing the 

association between the PUFA content of biomarkers and clinical outcomes (e.g., 

presence/absence of a diagnosis of major depressive disorder), each constitute, at best, indirect 

lines of evidence supporting a role for omega-3 fatty acids in the etiology, pathogenesis and 

treatment of such disorders.191

What, then, are the directions that these treatment studies might take? After we focus on this 

question, we highlight briefly some avenues that studies addressing the other two basic questions 

(i.e., intake, biomarkers) might follow. Many of the issues we raise are pertinent to all questions, 

given that they reflect the need to exercise tighter control of variables (e.g., population) with the 

potential to confound results. At present, despite the suggestive picture of efficacy of a 2g/d 

dose as supplemental treatment for schizophrenia, nothing conclusive can be said about the 

nature of the impact of any of the confounders (e.g., smoking; alcohol use; omega-3 fatty acid 

dose) on clinical or biomarker outcomes with respect to any of the questions or 

disorders/conditions whose studies we systematically reviewed. 

With respect to the question of the efficacy of omega-3 fatty acids as primary or 

supplemental treatment for any psychiatric disorder or condition, there have been too few wellcontrolled RCTs of sufficient size and intervention length to permit drawing any meaningful 

conclusions about shortterm symptom relief. Moreover, only one study each examined the 

primary treatment of depression or schizophrenia. More, larger and adequately powered studies 
187 

are required.53 As well, three months of omega-3 fatty acid supplementation in the life of a 

patient with schizophrenia or with treatment-resistant depression likely cannot be considered, in 

clinical terms, to be a shortterm intervention. Intervention lengths in the studies investigating the 

supplemental treatment of depression or schizophrenia lasted no longer than 13 weeks; often, 

patients seen in clinical practice with either of these disorders will receive medication for years 

or even decades. 

Therefore, especially because of the somewhat suggestive evidence pertaining to 2g/d EPA 

as supplemental treatment for schizophrenia, additional studies need to replicate this shortterm 

finding over longer investigative periods. These studies should resolve whether or not omega-3 

fatty acid supplementation, when provided as a supplemental intervention, can provide (e.g., 

additional) shortterm and longer term symptom relief. Then, if ever reliable longterm symptom 

relief is demonstrated, future studies could be conducted to see whether omega-3 fatty acid 

supplementation can alter the progression of psychiatric disorders or conditions. The effects of 

certain conditions associated with schizophrenia and/or the medications given to schizophrenic 

patients might be lessened, or even prevented. One focus could be tardive dyskinesia, whose 

incidence, severity or progression could be studied as potentially modifiable outcomes. 

Likewise, for some patients diagnosed with major depression, suicidal ideation or behavior may 

become less likely or less intense. Dysphoric feelings might also be “prevented” from becoming 

full-fledged disorders. In addition, patients with “rapid cycling” forms of bipolar disorder could 

experience a lengthening of the time between major shifts in mood. 

To return to the topic of schizophrenia, if ever its symptoms or clinical course are 

demonstrated to be improved by omega-3 fatty acid supplementation, especially in the longterm, 

then “medication-sparing” research designs could be used to test whether adding a specific dose 

of omega-3 fatty acids—which typically exhibits a relatively benign safety profile—to a lowerthan-usual dose of antipsychotic medication can maintain at least the same level of clinical 

improvement (e.g., symptom control) typically associated with a traditional dose of this 

antipsychotic medication. This is potentially clinically significant since, at full-dose, 

antipsychotic medications often exhibit a notable safety profile (i.e., moderate-to-severe adverse 

effects). In this way, patients might be “spared” the likelihood, or a particular intensity, of side 

effects associated with their regular antipsychotic medication (e.g., extrapyramidal 

symptoms).140 This type of study design is often employed in studies examining health problems 

(e.g., asthma) where it may be best to reduce doses of medication (e.g., oral corticosteroids), 

which especially in the longterm, can have negative health consequences. 

In such a dose-sparing study, the exact amount of the (absolute or percent) dose reduction 

could be defined either before the RCT begins or established during the course of the study. In 

either design, patients selected would include those schizophrenic individuals whose symptoms 

are well-controlled by their regular antipsychotic medication. If these participants vary on the 

basis of the type of prestudy medication, stratification by medication type could be undertaken. 

The types and severities of prestudy adverse effect related to their antipsychotic medication 

would be noted prior to the commencement of the trial. 

In the type of RCT where the dose reduction is defined before the study begins, patients 

would be randomized to one of two conditions: a) an (absolute or percent) reduction in the dose 

of their regular antipsychotic medication in addition to receiving a daily dose of omega-3 fatty 

acid supplementation; or b) continuing to receive their regular antipsychotic medication in 

addition to a placebo to control for the other group’s receipt of supplementation. While other 

design or analytic controls would be required (e.g., adding placebo material to the first group’s 
188 

antipsychotic medication in order to mask the dose reduction; determining whether the degree of 

symptom control at study baseline for both groups was indeed the same), the outcomes of 

interest would be whether or not: a) the same degree of symptom control (e.g., PANSS total) was 

observed in both groups; and b) adverse effects related to the antipsychotic medication occurred 

less often, or were less severe, in the dose reduction group. 

In the second type of RCT, dose reduction in one of the study groups would be conducted on 

a patient-by-patient basis, and in a predefined and uniformly stepwise fashion, until evidence for 

a loss of symptom control would signal a halt to the reductions. While implementing all of the 

aforementioned controls, the outcomes of interest would be: a) the mean (or maximal) percent 

dose reduction that permits symptom control; and, b) the pattern (i.e., frequency or severity) of 

adverse effects. 

These studies might identify, in empirical fashion, the specific types(s) of patient or 

medication for which dose reductions are beneficial on the basis of both outcomes. The first 

type of RCT would typically precede conduct of the second type. A final followup would need 

to take place no earlier than at six months, to be able to establish the stability of any benefits. 

For each disorder or condition, including schizophrenia and depression, much more work 

needs to be done to identify the exact sources (e.g., marine), types and doses of omega-3 fatty 

acids, and combinations thereof, which reliably produce clinical effects. Both DHA and ALA 

were underrepresented in the present evidence base. Whether or not specific doses of EPA and 

DHA should be combined, and how, and for which disorders or conditions, remains to be 

determined. Whether or not different types and doses of omega-3 fatty acid are required to treat 

disorders (e.g., major depressive disorder), compared with psychiatric conditions (e.g., feelings 

of dysphoria), is unknown. Likewise, whether or not different types and doses of omega-3 fatty 

acid are required to treat disorders of varying degress of severity, or associated with various 

types (and severities) of comorbid condition, are unresolved questions. Additionally, with 

respect to each of these questions, there remains the issue of which combinations of omega-3 

fatty acid types and doses are both efficacious and safe, that is, where they minimize the 

likelihood of even mild, transient adverse events. 

There are also a number of questions that need to be addressed further regarding dosage. For 

example, is one RCT enough to determine that 1 g/d E-EPA yields significant clinical 

improvement in populations experiencing depressive symptomatology?53 Would such a low 

dose produce the same kind of effect in those formally diagnosed with a depressive disorder? It 

is our view that we need more research evidence before we can conclude anything about the 

utility of this dose for any psychiatric disorder or condition, not just for those individuals 

exhibiting depressive symptomatology. 

At the same time, is 9.6 g/d EPA+DHA too high a dose for patients with bipolar disorder112

or any other disorder? Stoll et al. did not report even moderate adverse events associated with 

this dose.112 Again, we likely need more than a single study (which was stopped prematurely) 

before we can conclude anything about this dose’s clinical utility. Additional research might 

reveal that the definition of an “effective dose” is disorder-specific, that doses should be weightadjusted especially in studies with children, or that doses should be adjusted to fit individuals, 

and not vice versa.53,190 

While dose-ranging studies may be helpful in determining answers to some of these 

unresolved issues, it may be wise, however, to avoid situations such as those encountered in the 

two supplemental treatment RCTs conducted by Peet and colleagues. By having four levels 

define their intervention (i.e., 4g/d vs 2g/d vs 1g/d vs placebo) in studies examining depression53
189 

and schizophrenia,87 these investigators made it difficult to power each study sufficiently to 

afford detection of significant clinical effects. It may be better to design less complicated studies 

with respect to levels of the intervention, while instead instituting greater experimental control of 

variables with the potential to confound clinical outcomes. More about this topic is discussed 

below. 

That said, in designing future trials, we will likely need to select doses which allow us to 

make sense of why only patients receiving a low dose (1g/d) E-EPA in Peet et al.’s investigation 

of the supplemental treatment for depression benefited clinically.53 The investigators themselves 

offered no cogent explanation, yet we suggest that the effect might eventually be found to have 

been produced by hormesis, or to have been influenced by certain changes—which were 

unrelated to the intervention—in the clinical status or background diet (e.g., omega-6/omega-3 

fatty acid intake ratio) of patients receiving the 1g/d dose of E-EPA. 

If the goal is to be able to readily interpret study results aimed at determining the clinical 

utility of omega-3 fatty acids as an intervention, researchers likely need to satisfy a number of 

requirements. Studies should likely avoid using uncontrolled dosing methods (e.g., oils poured 

from bottles), since this approach makes it difficult for studies employing controlled research 

designs to achieve two key controls typically preferred in supplementation studies; each control 

is intended to minimize the influence of confounding. For example, requests to pour specific 

amounts (or ranges) of oil from bottles on a per-meal or a per-day basis, can make it difficult to 

assure that study subjects consistently pour the prespecified amounts of oil and thereby maintain 

the planned on-study between-group difference in the intake of omega-3 fatty acids (e.g., 3 g/d 

EPA vs 0 g/d EPA) as well as the planned on-study between-group equivalence of energy/caloric 

intake (e.g., 3g/d of oil for each study group).58 Failure to maintain these two between-group 

constants would confound study results.72 Then, at the end of the study, when clinical results 

following uncontrolled dosing require interpretation, it may be impossible to specify, with much 

precision or confidence, the “daily dose” to which a significant or nonsignificant between-group 

difference might be attributed. 

Uncontrolled interventional studies can also be plagued by this consequence of uncontrolled 

dosing. It is likely easier to control “doses” when the exposure is delivered via prespecified 

numbers of swallowable capsules containing finite amounts of omega-3 fatty acid content. 

Compliance data may someday help to evaluate the present hypothesis regarding the benefits of 

controlled dosing. For now, the nature of the impact of Peet et al.’s uncontrolled dosing 

scheme58 on the significant clinical effect identified by our meta-analysis, assessing the value of 

low-dose EPA as a supplemental treatment for schizophrenia, remains unknown. 

If the goal is to be able to readily interpret study results aimed at determining the clinical 

utility of omega-3 fatty acids as an intervention, it is also likely wise to avoid using complex 

interventions, or “cocktails,” which contain omega-3 fatty acids combined with many other 

active ingredients. Otherwise, it will be impossible to account for the exact contribution of 

omega-3 fatty acids to any clinical effects. The issue of complex exposures is discussed further 

below. 

One type of ingredient in omega-3 fatty acid exposures that is likely useful is one which can 

maintain the freshness of the exposure and thereby prevent the type of rancidity that would allow 

patients to determine, from the increasingly strong taste or odour of especially fish oils 

especially, which exposure they are receiving.190,191 Failure to maintain freshness can jeopardize 

blinding. Several interventional studies added, for example, the antioxidants tertiary 

butylhydroquinone and tocopherals, to what all study groups received as their exposure so as to 
190 

maintain the exposure’s freshness, but also to avoid any possible confounding were these 

ingredients ever found to have a psychoactive effect.96,192 Other studies added flavoring to what 

all study groups received, or even vacuum-deodorized the exposures in order to maintain 

blinding.96,191 Still others employed purified EPA, or E-EPA, which purportedly eliminates 

much of an oil’s original taste and odour.53,87,115,139 

Future research probably needs to carefully examine the impact of using E-EPA, compared 

with EPA, both to maintain blinding and to influence study outcomes. Processing EPA may 

change its therapeutic (or preventive) potential, but research assessing its role in mental health is 

needed to ascertain this possibility. At the same time, the actual purity of all exposures should 

likely be established.191 Otherwise, unknown elements already contained within fish oil, for 

example, might somehow mitigate the effects of the oil itself. Only studies that employed EEPA even broached this subject, meaning that the exposures in the other interventional studies 

could have included agents that potentially affected their therapeutic (or preventive) value. No 

study report addressing any of the basic questions described having assessed the possible 

presence of, or having eliminated, methylmercury from marine sources of omega-3 fatty acids. 

The choice of placebo may also affect study results. While the need for a standard placebo 

format in research on the therapeutic or preventive role of omega-3 fatty acids in mental health 

has yet to be established, there is preliminary evidence suggesting that investigators might want 

to consider steering away from the use of olive oil as a placebo in interventional studies of 

mental health.119,120 Olive oil is a source of oleic acid, from which the psychoactive lipid 

oleamide can be biosynthesized in mammals;193 and, oleamide has psychoactive properties, 

including the induction of sleep and the modulation of serotonin receptor-mediated signaling.194 

Thus, olive oil may actually affect mood disorders, which might diminish between-group 

differences in certain clinical outcomes.195 Stevens et al. has recommended that liquid paraffin 

oil be used as placebo in supplementation studies.123 Liquid paraffin oil was the choice of 

various intervention studies reviewed in our report.53,87,115,140 Whatever the true influence of 

placebo contents on clinical outcomes turns out to be, it has been recommended that one way to 

minimize the placebo response seen on a few occasions in our review may be to include a 2-

week placebo run-in period in trials.88

To revisit the subject of complex interventions, given the primarily competitive interrelationships between omega-3 and omega-6 fatty acids, and their respective metabolites—both 

within the metabolic pathway and within membranes—future research could potentially end up 

identifying that specific types and quantities of both omega-3 and omega-6 fatty acids require 

simultaneous modification to reliably produce clinical benefits for some or all psychiatric 

disorders or conditions. This research might also point out that these significant clinical effects 

are brought about by changes in levels of specific types of PUFA in specific biomarker sources 

(e.g., RBCs). That is, significant clinical benefits could result from the subtraction, from the 

background diet, of specific types and amounts of omega-6 fatty acids, concomitant with the 

addition of omega-3 fatty acid content. This strategy could essentially lower the omega6/omega-3 fatty acid intake ratio. It might also decrease the omega-6/omega-3 fatty acid content 

ratio in certain biomarkers, although, as pointed out earlier, PUFA status has multiple 

determinants. However, no study identified by our review employed this dual approach. 

Given that a high omega-6/omega-3 fatty acid intake ratio has been thought to be associated 

with patterns of disease,33-45 the possible success of a strategy to reduce the omega-6/omega-3 

fatty acid ratio might not be unexpected. Variables such as the magnitude of the change in each 

PUFA’s content, the intake ratio’s actual value, the intervention length, or the timing of these 
191 

changes in (or prior to) a disease process might determine the success of such a therapeutic (or 

preventive) strategy. 

There is some suggestion that the omega-6/omega-3 intake ratio in the background diet may 

predict the likelihood of observing significant clinical effects. It comes not from the present 

review, since there were too few studies per psychiatric disorder or condition with which to 

assess the impact of this possible confounder. Rather, we shared these observations in a recent 

report examining the impact of omega-3 fatty acids in asthma.72 While we did not feel it was 

appropriate to perform a meta-analysis of these results concerning asthma, an impressionistic 

analysis suggested that studies examining the effects of omega-3 fatty acid supplementation 

conducted within Asian countries—where the omega-6/omega-3 fatty acid intake ratio in the 

background diet is considerably reduced compared with the omega-6/omega-3 fatty acid intake 

ratio in the background diet of populations selected from non-Asian countries—were more likely 

to produce significant clinical improvements in respiratory outcomes.72 With less competition 

for enzymes in the metabolic pathway, and for positions in cell membranes, it is conceivable that 

in populations eating considerable amounts of fish or seafood, their lower levels of omega-6 fatty 

acid intake and higher levels of omega-3 fatty acid intake in the prestudy and on-study 

background diets may make it “easier” for additional omega-3 fatty acid supplementation to 

make a clinical difference. This speculation may pertain especially (or exclusively) to DHA, 

given its likely function(s) in cell membranes. Yet, an alternative hypothesis could suggest that 

significant clinical benefits are less likely when the omega-6/omega-3 fatty acid intake ratio is 

already reduced prior to a study because cell membranes already contain “enough” omega-3 fatty 

acid content, and adding typically small amounts of omega-3 fatty acid content via 

supplementation may not make an appreciable difference. 

Whichever hypothesis is confirmed by future research, both perspectives rest on the 

assumption that clinical effects are brought about by changes in the PUFA levels observed within 

blood lipid biomarkers. More research could indicate that this is not the case. While PUFA 

status is influenced by more than just the intake of omega-3 fatty acids, the mechanism 

promoting clinical changes could actually be even more complicated, implicating the availability 

of enzymes to, for example, desaturate or elongate PUFA metabolites, or entailing the production 

or activities of eicosanoids or cytokines. The LC PUFAs especially may be found to directly 

influence synaptic function through effects on membrane structure and/or indirectly through the 

production of eicosanoids (PGs, LTs, TXs) or via immune system/cytokine interactions.122,190 It 

is therefore likely appropriate to continue examining PUFA content levels in biomarkers within 

studies evaluating the impact of omega-3 fatty acids on mental health. 

In the present review, we could not investigate either directly or indirectly (e.g., using the 

country in which a study was conducted as a surrogate measure of the omega-6/omega-3 fatty 

acid intake ratio) the impact on clinical outcomes of the omega-6/omega-3 fatty acid intake ratio 

of: a) the prestudy/baseline background diet, b) the on-study background diet (i.e., excluding the 

supplementation), or c) the complete on-study diet (i.e., background diet plus supplementation). 

Moreover, few investigators conducting interventional studies controlled for this possible 

confounder either by mandating that patients maintain their prestudy/baseline background diet 

during the study or by performing a covariate analysis. 

Researchers in future interventional studies (i.e., treatment, prevention) will likely need to 

account analytically (e.g., covariate analysis), if not experimentally (e.g., subject selection 

criteria; stratification), for prestudy and on-study background definitions of diet, and their 

inherent omega-6/omega-3 intake ratios, if only because they may influence/predict clinical 
192 

outcomes. At the same time, it may be premature to assert that given the likely interrelationships between omega-3 and omega-6 fatty acid contents both in the diet and in blood 

lipid biomarkers, the questions examined in this review could benefit in the future from an 

expanded scope, that is, to include a co-focus on the influence of omega-6 fatty acids in mental 

health. 

Future research also needs to assure full knowledge of the details defining study populations 

so that this source of clinical heterogeneity can be taken into account when analyzing and 

interpreting the results of interventional or observational studies. Many study reports included in 

our review failed to specify many of the details pertaining to population variables with the 

potential to confound study outcomes. These include the possible between-group differences 

observed at study baseline in controlled studies, which relate to the severity and historical course 

of the primary disorder (e.g., age of onset, number of episodes, timing of intervention relative to 

the disease process [e.g., first-episode vs chronic schizophrenia]) or the presence and nature 

(e.g., severity, age of onset) of comorbid conditions (see Chapter 2). Occasionally, full sample 

descriptions of these variables were not provided. Failing to have these details made it 

impossible for us to informally assess their possible impact on study results. 

However, this was not always the case in individual studies. In their RCT examining the 

supplemental treatment of schizophrenia, Hibbeln et al. were concerned that the long duration of 

illness in their patient population, reflected in notable symptoms despite treatment with newer 

neuroleptics (e.g., clozapine), may have contributed to the failure to find a significant clinical 

effect for their full sample.60,88 Patients in other supplemental treatment studies had been 

younger and exhibited a shorter illness duration. However, additional analyses revealed that 

duration of illness was not associated with changes in clinical outcomes or in changes in EPA, 

DHA, AA, or AA/EPA fatty acid contents following EPA supplementation.60 Analytic “control” 

for this possible confounder was achieved, and afforded a clearer interpretation of study 

outcomes. 

Other possible, population sources of confounding may be observed in circumstances where 

on-study life events unrelated to the exposure (e.g., job loss) can influence subjects’ psychiatric 

status and, in turn, their response to treatment. But, these events need to be measured in order to 

to statistically control for them. Seldom did the present collection of interventional studies 

identify the occurrence, or noted absence, of important life events other than those few presumed 

to be the reason for a discontinuation. 

Successful control for population sources of confounding can also be achieved through 

experimental means. For example, an interventional or an observational study might only 

include patients exhibiting a single diagnostic subtype, or a minimal or maximal severity level 

for a particular disorder. They might also exclude patients exhibiting certain types or severities 

of a particular comorbid condition. While such restrictive conditions limit the possible “breadth” 

of the population to which study results can be generalized, these experimental controls 

maximize the specificity of populations to which the evidence can be extrapolated. Ultimately, 

this could benefit the practice of mental health care. 

One final population source of confounding was highlighted in a recent meta-analysis 

investigating the impact of short-acting Ritalin® in the treatment of AD/HD.13 The basic 

premise is that, while patients or populations may share a given diagnostic label (e.g., AD/HD) 

assigned using stringent clinical approaches, even sophisticated diagnostic classification 

approaches (e.g., DSM) can lead to an obfuscation of individual differences when it comes to 
193 

understanding what each of these individuals is experiencing clinically and, in turn, selecting an 

appropriate treatment strategy. We focus here on the first observation. 

To use AD/HD as an example, three major subtypes of AD/HD are identified by DSM-IV 

(i.e., predominantly Inattentive subtye vs predominantly Hyperactive subtype vs Combined 

subtype). Thus, the “AD/HD” label can refer to three different clinical scenarios. In the AD/HD 

studies included in our review, seldom were the exact subtypes specified or was this source of 

clinical heterogeneity controlled for analytically. To compound matters, the method employed to 

assign any one of these subtype diagnoses allows for important variability in the numbers, and 

combinations of symptom that can be taken to indicate the presence of a single diagnostic 

subtype. For example, for problems with inattention, DSM-IV asks clinicians to select 6 of 9 

possible items, and the same request for 6 items is made with respect to 9 possibilities 

concerning problems with hyperactivity/impulsivity. Thus, there are several different 

combinations of symptom referred to by a single diagnostic label; this might be thought of as a 

homogeneous population in an interventional or observational study, when in fact, it is not. 

Individuals could vary widely on the basis of their clinical pictures of symptoms. Furthermore, 

this heterogeneity could influence responses to treatment even in RCTs, where different 

distributions of clinical picture could characterize different study groups. Such uncontrolled 

population variability is likely undesirable, and it is further complicated when and if controls are 

not put in place to deal with similar problems relating to variability in comorbid conditions. 

Finally, as introduced in Chapter 1, one other population source of clinical heterogeneity—

most important when different studies are compared, as is the case in systematic reviews—stems 

from relevant studies having used different diagnostic systems, or even different versions of a 

constantly evolving system (e.g., DSM-III published in 1980, DSM-III-R in 1987 and DSM-IV 

in 1994), to identify their study populations. Since the diagnostic criteria of these systems can 

vary, even slightly, then the study populations, or subpopulations, they identify can also vary.13 

This additional definition of “diagnosis heterogeneity” could account for differences in outcomes 

observed in different studies. Systematic reviews relating to mental health should therefore 

consider evaluating the impact of diagnostic systems on study outcomes. However, in our 

review, having too few studies included per psychiatric disorder prevented us from achieving this 

task. 

Other types of control are likewise required to maximize the interpretability of results of 

interventional or observational studies involving omega-3 fatty acids. Here, we distinguish 

between three types of variable based on their possible influence on outcomes. They include: 

those that have the potential to impact clinical (mental health) outcomes; those that can influence 

the fatty acid content of biomarkers (and which may turn out to be responsible for specific 

clinical effects); and, those that appear to affect both types of outcome. 

There were too few studies per psychiatric disorder or condition to permit the identification 

of the nature or extent of the influences of effect modifiers on clinical outcomes relating to any 

of the basic research questions we investigated. Examples of influences on mental health 

observed in clinical practice include: illicit drug use, general health status, stressors, social 

support, exercise, quality of sleep, marital status, education, income and employment status. In 

both controlled and uncontrolled studies, these factors can independently, or in combination, 

influence mental health outcomes and thereby confound study results. These influences can be 

observed, for example, where their on-study status changes in ways unrelated to the 

intervention/exposure (e.g., an unexpected death in the family). In controlled studies, these 

variables (e.g., disease severity; comorbid conditions) can also affect study outcomes when 
194 

study groups differ in their prestudy/baseline status. Either scenario has the potential to mask or 

artificially inflate the actual benefits of an omega-3 fatty acid intervention/exposure. As a result, 

future studies relating omega-3 fatty acids and mental health should consider controlling, either 

experimentally or analytically, for the possible impact of these variables. 

Influences on PUFA status include: the disease process itself; dietary intake, metabolism and 

incorporation into cell membranes of various types and amounts of both omega-3 and omega-6 

fatty acid content; efficiency of the PUFA metabolic processes, including the availability and 

effectiveness of enzymes implicated in the processes of desaturation and elongation; and the 

ability of protective mechanisms to deal with degradation from oxidation and other sources.48,101-

103,178-180 While the impact of these variables could not be ascertained in our review, future 

studies which assume that beneficial effects on clinical outcomes might be mediated by changes 

in the PUFA status of biomarkers likely need to account for these factors. 

Variables with the potential to influence both clinical (e.g., control of psychiatric 

symptomatology) and PUFA (e.g., omega-6/omega-3 fatty acid content in RBCs) 

status/outcomes include: age; sex; the disease process underlying any possible comorbid 

conditions; psychotropic medication, including type, dose and duration of use; (e.g., 

prestudy/baseline and on-study) background diet; alcohol consumption; and current smoker 

status.60,180 But, other than those data indicating the positive impact of omega-3 fatty acid 

supplementation on symptoms of schizophrenia in patients taking clozapine,87 little can be said 

about the actual roles of these variables within our evidence base. While the impact of 

medication status on the PUFA levels of biomarkers could be informally assessed with respect to 

schizophrenia, little that is meaningful can be concluded since the preponderance of crosssectional designs prevents drawing inferences about etiology. As stated earlier, the impact of 

background diet, or of the country in which the study was conducted as a possible surrogate 

measure of the omega-6/omega-3 fatty acid content thereof, could not be evaluated. 

Overall, there were too few studies per psychiatric disorder or condition to permit the 

identification of the nature or extent of the influences of these or other effect modifiers on 

outcomes relating to any of the basic research questions we investigated. It is therefore difficult 

to definitively rule out the possible impacts that these variables may have had on study 

outcomes. New research should consider routinely accounting for these factors. As was 

presented above, one interventional study did pursue this ideal regarding the variable of “illness 

duration.” 

Hibbeln et al. also argued, based on additional analyses of interventional data,89 that sex and 

current smoking status are important confounders in studies examining the interventional or 

observational relationships between omega-3 fatty acids and schizophrenia outcomes.60 Each 

variable was significantly related to fatty acid compositions. DHA was reduced in smokers 

compared with nonsmokers, and males had lower DHA and EPA fractions compared with 

females. MANOVA revealed that, of all subgroups, nonsmoking women had the highest EPA 

and DHA levels while AA did not vary by smoker status or sex.60 For females, nonsmokers 

exhibited a greater RBC EPA and DHA percentages compared with smokers. For males, no 

significant differences for EPA, DHA or AA were noted when smoker status was evaluated. 

Both EPA and DHA compositions were higher in female nonsmokers compared with male 

nonsmokers. Neither fatty acid compositions nor the number of cigarettes smoked per day 

differed significantly for male and female smokers. Thus, the sex specificity of the smoker 

status effect is likely not attributable to differences in smoking intensity (i.e., daily number of 
195 

cigarettes smoked). Smoking intensity was not significantly associated with either absolute or 

relative amounts of EPA, DHA or AA in RBCs. 

Hibbeln et al. then reported that, when they assessed the effects of sex and smoker status on 

the dietary intake of omega-3 (ALA, EPA, DHA) and omega-6 fatty acids (LA, AA), dietary 

intakes did not differ by sex or current smoker status when data were expressed as absolute 

amounts of daily intake.60 When intake data were observed as percentages of total fat intake, 

nonsmokers consumed more ALA, although no other significant differences were observed. The 

consumption of EPA and DHA, expressed as percentages of total fat intake, were greater in 

females compared with male patients. Differences in AA were not found when either smoker 

status or sex were taken into consideration. Dietary EPA intake (as percentage of total fat 

intake) predicted the RBC EPA composition for all patients, for male patients alone, and for 

nonsmoking males.60 Dietary DHA intake predicted the RBC DHA composition for males and 

for nonsmoking male patients. All correlations were significant and positive. Hibbeln et al. 

concluded that sex and current smoking status should be accounted for in research since they are 

strongly related to the intake of omega-3 fatty acids and to fatty acid compositions.60 Finally, 

while our review could not determine whether PUFA levels indeed reflect the mechanism 

responsible for clinical effects, in no small part because we remain uncertain that reliable or 

robust clinical benefits actually exist for any psychiatric disorder or condition, we believe that 

their possible role in producing clinical benefits behooves researchers to assess their possible 

influences in new studies. 

Turning our attention to the issue of outcomes, investigators conducting future research 

likely need to identify all of the most clinically pertinent outcomes for a given disorder or 

condition. The reason is that significant clinical benefits observed in mental health research can 

be outcome-dependent. A recent meta-analysis demonstrated this with respect to treatment 

studies examining the impact of short-acting Ritalin® on AD/HD.13 Significant clinical benefits 

were seen only for a subset of the central problems defining the presence of various forms of 

AD/HD. This observation suggests that each of the key symptoms defining a psychiatric 

disorder should likely be measured in new research. 

To adequately investigate questions concerning the association between omega-3 fatty acid 

intake or the PUFA content of biomarkers and the onset, continuation or recurrence of 

psychiatric disorders or conditions, many of the controls discussed thus far are indicated. The 

ideal design to permit drawing causal inferences about etiology is a prospective and controlled 

one. 

Primary prevention RCTs may be the best way to examine the possible protective role of 

omega-3 fatty acid intake, although the length of followup required to establish meaningful 

effects may necessitate studies that are exceptionally long and too expensive to conduct. 

Prospective cohort studies investigating the possible association between clinical outcomes and 

omega-3 fatty aid intake or PUFA status of biomarkers are likely a good choice yet they, too, 

might be too costly given the exposure period required to permit the detection of incident cases. 

When it comes to the question relating the intake of omega-3 fatty acids and review-pertinent 

clinical outcomes (e.g., onset), while prevention RCTs could implement precisely defined 

interventions, involving capsule-based supplementation, prospective cohort studies are more 

likely to assess patterns of consumption of foods containing omega-3 fatty acid content. The 

latter studies, while perhaps demonstrating greater ecological validity, nevertheless suffer from 

difficulties in precisely delineating the types and amounts of omega-3 fatty acid content 

associated with clinical outcomes. 
196 

A question that would need to be resolved likely prior to undertaking any of these studies 

relates to the timing of the intervention or exposure period. That is, when should a study with 

either a treatment or prevention focus begin, and end? The answer is likely disorder-specific, 

and should be based on what is known from clinical practice and research regarding the age of 

onset for the disorder. It probably makes little sense to state, without distinction, that these 

studies should all begin shortly after birth, with followups to occur every 2 years, for 20 years or 

more. 

What may be more useful is to think somewhat outside the box. For example, it may make 

some sense to “piggyback” the assessment of mental health outcomes in well-controlled and 

adequately-powered studies that initially aim to assess the impact of omega-3 fatty acid 

supplementation, via formula feeding, on growth, visual, neurodevelopmental or cognitive 

outcomes. With time, and and further assessments of these outcomes, what began as an RCT 

could eventually become a less-expensive, single group observational study designed to identify 

the development of possible problems in mental health. Five-year telephone followups could be 

conducted to assess recent intake of (foods or supplements containing) omega-3 fatty acids and 

mental health status, such that if there is evidence that psychiatric symptoms or disorders may 

have emerged since the last followup, the individual could be seen and assessed formally. What 

this approach could offer is an opportunity to relate the intake of omega-3 fatty acids both early 

and later in life with the development of psychiatric disorders or conditions. Moreover, the interrelationships among the various outcomes assessed in the study could reveal the broadest 

developmental context possible within which to understand, at the very least, the etiology of 

psychiatric disorders or conditions. As in most early intervention studies of formula 

supplementation involving PUFAs, a reference group of breastfed offspring could be followed in 

parallel. Assessments of the fatty acid content of biomarkers could be included in such an 

endeavor, including during pregnancy and at various times post-delivery. 

That said, where the questions regarding the association between the onset, continuation or 

recurrence of psychiatric disorders or conditions and the intake of omega-3 fatty acids or the 

fatty acid content of biomarkers are concerned, it may be sufficient to avoid both cross-sectional 

studies and cross-national ecological analyses. Neither design generates data that allow us to 

resolve either of these questions. Case-control studies constitute an option,109 although this 

design likely better suits the question examining the relationship between omega-3 fatty acid 

intake and the onset, continuation or recurrence of psychiatric disorder or conditions. 

What also needs to be determined via new research is whether patterns of omega-3 fatty acid 

intake or patterns in the fatty acid content of biomarkers can prevent a psychiatric symptom (e.g., 

feelings of dysphoria) from developing into a full-fledged disorder. As well, what remains to be 

seen is whether patterns of omega-3 fatty acid intake or patterns in the fatty acid content of 

biomarkers can predict and perhaps prevent the continuation or recurrence of psychiatric 

disorders or conditions. It is conceivable that additional research could someday illumine the 

secondary preventive value of the intake of omega-3 fatty acids, for example. 

In general, if researchers ever hoped to establish or reinforce the plausibility of employing 

omega-3 fatty acids as a treatment for any psychiatric disorder or condition using evidence from 

studies examining the associations between clinical outcomes and the intake of omega-3 fatty 

acids as well as the fatty acid content of biomarkers, it is our view that this has not been 

achieved. Therefore, the recent publication of treatment studies directed at depression, and 

especially schizophrenia, may suggest either that researchers have interpreted these data in ways 
197 

that diverge greatly from our interpretation or, that they have perceived some other, inherent 

value in undertaking treatment trials. 

Nonetheless, if future research is going to produce data that are unequivocally applicable to 

North Americans, it will likely need to enroll either North American populations or populations 

exhibiting a high omega-6/omega-3 fatty acid intake ratio similar to what has been observed in 

the diet of North Americans. It is our view that the dietary omega-6/omega-3 fatty acid intake 

ratio may eventually be seen to play an important role in the prevention and treatment of 

psychiatric disorders or conditions. 

Limitations of the Review 

While there are some limitations characterizing the present systematic review, almost none 

could likely be considered a serious impediment to the interpretation of the evidence we 

identified and synthesized. Overall, we found too few studies investigating a given question, and 

employing an appropriate research design of sufficient size and sound methodology, to have 

these limitations alter the view that, at present, we cannot conclude anything definitive about the 

disorder/condition-specific or overarching roles of omega-3 fatty acids in mental health. As 

well, the possible roles played by likely covariates and confounders could hardly be evaluated at 

all. We were limited in what we could observe because of the paucity of relevant studies per 

question and because many studies did not specifically investigate the influence of these 

variables. This is unfortunate since alcohol consumption, for example, like current smoker 

status, appears to influence both mental health and PUFA status. 

The only limitations of possible significance concern the meta-analysis conducted with data 

obtained from RCTs investigating the efficacious use of omega-3 fatty acids as supplemental 

treatment for schizophrenia. It was less than ideal to use post-treatment means from Peet et al.’s 

study58 when data indicating changes from baseline in outcomes are preferred. Another study 

report by Peet and colleagues, also used in the meta-analysis, did provide these data.87 

Unfortunately, our request for change from baseline data from the Peet et al. study58 did not yield 

a successful response. Furthermore, what remains unknown at this time are the independent or 

combined impacts of combining data from studies failing to distinguish outcome data from 

patients receiving different primary medications,58,87 and using different interventions (i.e., 

purified87 versus unpurified EPA;58 controlled87 versus uncontrolled dosing58), on the metaanalytic estimate or its precision. It should be recalled that there is, for example, limited 

empirical evidence indicating that low-dose (2 g/d) EPA yielded a clinical benefit solely for 

those patients receiving clozapine.87 Replication efforts are required, however, before we can 

feel confident in the reliability of this observation. 

Knowing, in advance, that data from cross-sectional designs could not possibly permit 

drawing causal inferences about the etiology of psychiatric disorders or conditions, from data 

reflecting either the dietary intake of omega-3 fatty acids or the PUFA content of biomarkers, 

might have afforded a decision to a priori exclude these studies from the review. However, this 

would have left us with few studies to review; and, while the purpose of our review did not 

include testing the deficiency hypotheses regarding the onset of depression or schizophrenia, 

reviewing these studies (or cross-national ecological analyses) nevertheless allowed us to 

highlight the evidence typically used to support these etiologic explanations. 
198 

At the same time, it is unlikely that expanding our focus with respect to PUFA metabolism 

beyond the compositions or concentrations of PUFA metabolites (e.g., to include data regarding 

the possible presence or activity of enzymes involved in the processes of desaturation or 

elongation within the metabolic pathway) would have produced results revealing a less unclear 

picture concerning the association between the PUFA content of biomarkers and the onset, 

continuation or recurrence of a psychiatric disorder or condition. These relationships were 

typically investigated in similarly limited, cross-sectional designs. 

As stated in Chapter 2, in light of the relatively limited details often provided in reports about 

the ways in which lipid samples were extracted, stored and analyzed, we could only readily 

identify situations where investigators described inappropriate methods. It is unclear how this 

state of affairs might have influenced the observations we gleaned from the evidence base 

concerning the role of omega-3 fatty acids in mental health. 

Time constraints made it impossible to complete dual-assessor appraisals of the quality (i.e., 

internal validity) of studies employing designs other than an RCT, or the applicability of all the 

included studies. One experienced quality assessor conducted these evaluations. At the same 

time, we conducted these quality assessments of designs other than RCTs using items we either 

modified from existing instruments or which we had to develop outright because no similar tools 

existed (e.g., cross-national ecological analyses). A design-specific, total quality score was then 

generated for each study, from which a single summary value was derived (i.e., A, B, C). This 

simplification permitted the entry of these values into summary matrices. However, the designspecific cutpoints used to assign these values were established without any validational basis, 

and so their value is likely extremely limited. The applicability indices, while continuing the 

work we did when we systematically reviewed the evidence for the health effects of omega-3 

fatty acids on asthma,72 also did not receive any validational support. Nevertheless, given the 

limited number of studies addressing a specific question, and using a design whose data could 

meaningfully elucidate it, it is unlikely that these shortcomings could have had a meaningful 

impact on the “take home messages” highlighted by our review. Formal statistical assessments 

of the impacts of study quality or applicability on study outcomes could not be conducted. 

Finally, with a very limited number of studies entered into meta-analysis, an examination of the 

possible presence and impact of publiation bias could not be conducted. 

Conclusion 

Studies investigating omega-3 fatty acids employed as an intervention revealed the absence 

of a notable safety profile associated with any type or dose of omega-3 fatty acids represented in 

the review. Only with respect to the supplemental treatment of schizophrenia is the evidence 

even somewhat suggestive of omega-3 fatty acids’ potential as a shortterm intervention. Even 

then, these results pertaining to 2g/d, or low-dose, EPA58,87 need to be replicated using larger 

sample populations, longer investigative periods and instituting various methodologic (i.e., 

experimental or analytic) controls. The observed failure of high-dose (i.e., >3 g/d) EPA 

supplementation to produce a clinical benefit likewise requires replication with similar design 

modifications. 

Data regarding the supplemental treatment of depression suggest a focus where considerable 

additional, clarifying research might eventually reveal the shortterm or longterm therapeutic 
199 

value of omega-3 fatty acid supplementation. One study demonstrating a significant placebocontrolled clinical effect related to 1 g/d E-EPA given, over 12 weeks, to 17 patients with 

depressive symptoms—rather than depressive disorders—cannot be taken to support the view of 

the utility of this exposure as a supplemental treatment for depressive symptomatology or 

disorders.53 Equally inadequate to establish the efficacy of omega-3 fatty acids as a 

supplemental treatment for depression are two other trials,96,97 which lasted 4 or 8 weeks and 

employed active exposures and exposure-placebo contrasts that distinguish them from the study 

which highlighted the efficacy of 1g/d E-EPA.53

Nothing can yet be concluded concerning the clinical utility of omega-3 fatty acids provided 

as a supplemental treatment for any other psychiatric disorder or condition, or as a primary 

treatment for all psychiatric disorders or conditions, examined in our review. Primary treatment 

studies were rare. Much more research is needed before we can begin to ascertain the possible 

utility of (foods or supplements containing) omega-3 fatty acids as a primary prevention for 

psychiatric disorders or conditions. From both an economic and scientific point of view, it might 

be worthwhile to “piggyback” studies of the primary protective potential of omega-3 fatty acids 

in mental health onto controlled, longitudinal studies of their impact on general health and 

developmental outcomes (e.g., growth; neurodevelopment; visual and cognitive development). 

Requisite modifications for treatment or prevention studies include well-defined and 

appropriately sampled populations, followup periods of suitable lengths, key experimental or 

analytic controls (e.g., for confounders) and individual/patient-level data. Overall, almost 

nothing is known about the therapeutic or preventive potential of each source, type, dose or 

combination of omega-3 fatty acids. 

Because of limited study designs, little is known about the relationship between PUFA 

biomarker profiles and the onset of any psychiatric disorder or condition. Studies examining the 

possible association between the intake of omega-3 fatty acids, or the PUFA content of 

biomarkers, and the continuation or recurrence of psychiatric disorders or conditions were 

virtually nonexistent. 

If future research is going to produce data that are unequivocally applicable to North 

Americans, it will likely need to enroll either North American populations or populations 

exhibiting a high omega-6/omega-3 fatty acid intake ratio similar to what has been observed in 

the diet of North Americans. Furthermore, if a reasonable view is that omega-3 fatty acids may 

play a role in mental health, then given the observed or proposed inter-relationships between 

omega-3 and omega-6 fatty acid contents both in the regular diet and in the human biosystem, it 

may behoove researchers to investigate the possible therapeutic or preventive value of the dietary 

omega-6/omega-3 fatty acid intake ratio. 

To this end, interventional studies could concurrently modify the intake of omega-3 and 

omega-6 fatty acids, and thereby manipulate experimentally the omega-6/omega-3 fatty acid 

intake ratio. Prospective observational studies could trace the possible links between the omega6/omega-3 fatty acid intake ratio and the development, course or outcome of psychiatric 

disorders or conditions. Finally, any notable causal or correlational relationships observed 

between the omega-6/omega-3 fatty acid intake ratio and the development, course or outcome of 

psychiatric disorders or conditions might then be “explained” by observed patterns of omega6/omega-3 fatty acid content in peripheral, or even brain, biomarkers. 

 201 

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essential fatty acid metabolism in Sjogren-Larsson 

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predefined mental health outcomes. 

Hibbeln J R, Salem N. Risks of cholesterol-lowering 

therapies. Biol Psychiatry 1996;40(7):686-687. Not a first 

publication of empirical evidence. 

Hills H C. Good food: grain-free, milk-free. undated, 123pp 

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Psychogeriatr 2002;14( 4):331-334. Not a first publication 

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Prog Lipid Res 1981;20( 539):-541. Not a first publication 

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Horrobin D F, Manku M S, Hillman H et al. Fatty acid 

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Biol Psychiatry 1991;30( 8):795-805. Not involving human 

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(intervention/exposure or biomarkers). 
212 

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Schweiz Rundsch Med Prax 2001;90( 12):512-513. Not a 

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autism. Alternative Therapies in Health & Medicine 

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of alcohol. Alcohol & Alcoholism 1984;19( 2):97-99. Not a 

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Lesperance F, Frasure-Smith N. Depression and coronary 

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CMAJ: Canadian Medical Association Journal 2003;168( 

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anorexia in the breast-fed infants. Role of IL-1beta and 

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(intervention/exposure or biomarkers). 

Mahadik S P, Khan M M, Evans D R et al. Elevated plasma 

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Mehta V R. 'Side effects of eicosapentaenoic acid and 

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Minerva. Br Med J 1996;312( 7026):322. Not a first 

publication of empirical evidence. 

Mischoulon D, Rosenbaum J F. The use of natural 

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empirical evidence. 

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Noetzel M, Moser H, Salem N et al. Brain uptake and 

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Roundtable discussion of session 4: The roles of DHA in 

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Omega-3 mania. Healthnews 2004;10( 4):5 Not a first 

publication of empirical evidence. 

Psychoses, neuroses and omega-3 essential fatty acids - 

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213 

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Riles S. New research on the treatment of schizophrenia. 

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empirical evidence. 

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Robinson F. Freedom foods. Food Nutr Bull 2002;27( 

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Ross B M, McKenzie I, Glen I et al. Increased levels of 

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Biol Psychiatry 1981;16( 9):837-848. Not related to 

predefined mental health outcomes. 

Saito H. SHRSP: A novel field of study. Biogenic Amines 

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214 

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Not a first publication of empirical evidence. 

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Not related to predefined mental health outcomes. 

Segarnick D J, Cordasco D M, Rotrosen J. Prostanoid 

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Seung Kim H F, Weeber E J, Sweatt J D et al. Inhibitory 

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Allerg Immunol (Paris) 2000;32( 7):261-271. Not a first 

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215 

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Vaddadi K S. Penicillin and essential fatty acid 

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omega-3 fatty acid focus (intervention/exposure or 

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Wolkin A, Segarnick D, Sierkierski J et al. Essential fatty 

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Alcoholism: Clinical & Experimental Research 1987;11( 

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Woodhouse R J. Report from Great Britain. Pharm Ind 

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evidence. 

Yao J K, Sistilli C G, Van Kammen D P. Membrane 

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predefined mental health outcomes. 

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empirical evidence. 

Young S N. Lifestyle drugs, mood, behaviour and 

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empirical evidence.
 216 

Listing of Excluded Studies at Level 3 Screening 

Adams P B, Lawson S, Sanigorski A et al. Arachidonic 

acid to eicosapentaenoic acid ratio in blood correlates 

positively with clinical symptoms of depression. Lipids 

1996;31 Suppl(S157):-S161. Uncontrolled study. 

Alling C, Aspenstrom G, Dencker S J et al. Essential fatty 

acids in chronic alcoholism. Acta Medica Scandinavica - 

Supplementum 1979;631( 1):-38. Uncontrolled study. 

Assies J, Lok A, Bockting C L et al. Fatty acids and 

homocysteine levels in patients with recurrent depression: 

An explorative pilot study. Prostaglandins Leukotrienes & 

Essential Fatty Acids 2004;70( 4):349-356. Uncontrolled 

study. 

Bell J G, Sargent J R, Tocher D R et al. Red blood cell fatty 

acid compositions in a patient with autistic spectrum 

disorder: A characteristic abnormality in 

neurodevelopmental disorders? Prostaglandins 

Leukotrienes & Essential Fatty Acids 2000;63( 1-2):21-25. 

Uncontrolled study. 

Buydens-Branchey M, McMakin D L, Hibbeln J R. 

Polyunsaturated fatty acid status and relapse vulnerability 

in cocaine addicts. Psychiatry Res 2003;120( 1):29-35. 

Uncontrolled study. 

Chiu C C, Huang S Y, Shen W W et al. Omega-3 fatty 

acids for depression in pregnancy.[erratum appears in Am J 

Psychiatry. 2003 Apr;160(4):810]. Am J Psychiatry 

2003;160( 2):385. Uncontrolled study. 

De Vriese S R, Christophe A B, Maes M. Lowered serum 

n-3 polyunsaturated fatty acid (PUFA) levels predict the 

occurrence of postpartum depression: Further evidence that 

lowered n-PUFAs are related to major depression. Life Sci 

2003;73( 25):3181-3187. Uncontrolled study. 

Holman R T, Johnson S. Changes in essential fatty acid 

profile of serum phospholipids in human disease. Prog 

Lipid Res 1981;20( 67):-73. Uncontrolled study. 

Hummel B, Dittmann S, Forsthoff A et al. Clozapine as 

add-on medication in the maintenance treatment of bipolar 

and schizoaffective disorders. Neuropsychobiology 

2002;45( suppl 1):37-42. Uncontrolled study. 

Johnson S M, Hollander E. Evidence that eicosapentaenoic 

acid is effective in treating autism. Hillside J Clin 

Psychiatry 2003;64( 7):848-849. Uncontrolled study. 

Kinrys G. Hypomania associated with omega3 fatty 

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716. Uncontrolled study. 

Mamalakis G, Tornaritis M, Kafatos A. Depression and 

adipose essential polyunsaturated fatty acids. 

Prostaglandins, Leukotrienes and Essential Fatty Acids 

2002;67( 5):311-318. Uncontrolled study. 

Mellor J E, Laugharne J D, Peet M. Schizophrenic 

symptoms and dietary intake of n-3 fatty acids. Schizophr 

Res 1995;18( 1):85-86. Uncontrolled study. 

Osborne R H, Sinclair A J. Red blood cell polyunsaturated 

fatty acid n-6 to n-3 ratios correlate with anxiety and 

depression in women with breast cancer. Proceedings of the 

Nutrition Society of Australia 1995;19( 53; 8 ref.). 

Uncontrolled study. 

Puri B K, Richardson A J. Sustained remission of positive 

and negative symptoms of schizophrenia following 

treatment with eicosapentaenoic acid. Arch Gen Psychiatry 

1998;55( 2):188-189. Uncontrolled study. 

Puri B K, Counsell S J, Hamilton G et al. Eicosapentaenoic 

acid in treatment-resistant depression associated with 

symptom remission, structural brain changes and reduced 

neuronal phospholipid turnover. Int J Clin Pract 2001;55( 

8):560-563. Uncontrolled study. 

Puri B K, Counsell S J, Richardson A J et al. 

Eicosapentaenoic acid in treatment-resistant depression. 

Arch Gen Psychiatry 2002;59( 1):91-92. Uncontrolled 

study. 

Puri B K, Richardson A J, Horrobin D F et al. 

Eicosapentaenoic acid treatment in schizophrenia 

associated with symptom remission, normalisation of blood 

fatty acids, reduced neuronal membrane phospholipid 

turnover and structural brain changes. Int J Clin Pract 

2000;54( 1):57-63. Uncontrolled study. 

Richardson A J, Cyhlarova E, Ross M A. Omega-3 and 

omega-6 fatty acid concentrations in red blood cell 

membranes relate to schizotypal traits in healthy adults. 

Prostaglandins Leukotrienes & Essential Fatty Acids 

2003;69( 6):461-466. Uncontrolled study. 

Richardson A J, Easton T, Puri B K. Red cell and plasma 

fatty acid changes accompanying symptom remission in a 

patient with schizophrenia treated with eicosapentaenoic 

acid. Eur Neuropsychopharmacol 2000;10( 3):189-193. 

Uncontrolled study. 

Richardson A J, Easton T, Gruzelier J H et al. Laterality 

changes accompanying symptom remission in 

schizophrenia following treatment with eicosapentaenoic 

acid. Int J Psychophysiol 1999;34( 3):333-339. 

Uncontrolled study. 

Shah S, Vankar G, Telang S D, Ramchand C N et al. 

Eicosapentaenoic acid (EPA) as an adjunct in the treatment 
217 

of schizophrenia. Schizophr Res 1998;29( 158):158. 

Uncontrolled study. 

Snyder Dollie C. Orthomolecular, nutritional and EPA 

therapy: A winning combination in the treatment of 

schizophrenia: A parent's testimonial. Journal of 

Orthomolecular Medicine 2003;18( 1):33-40. Uncontrolled 

study. 

Stevens L J, Zentall S S, Abate M L et al. Omega-3 fatty 

acids in boys with behavior, learning, and health problems. 

Physiol Behav 1996;59( 4-5):915-920. Uncontrolled study. 

Su K P, Shen W W, Huang S Y. Omega-3 fatty acids as a 

psychotherapeutic agent for a pregnant schizophrenic 

patient. Eur Neuropsychopharmacol 2001;11( 4):295-299. 

Uncontrolled study. 

Woodbury M M, Woodbury M A. Neuropsychiatric 

development: two case reports about the use of dietary fish 

oils and/or choline supplementation in children. J Am Coll 

Nutr 1993;12( 3):239-245. Uncontrolled study. 

Wright Jonathan. Treatment of chronic anxiety and 

associated physical complaints with niacinamide and 

essential fatty acids: Two cases. Journal of Orthomolecular 

Medicine 1992;7( 3):182-186. Uncontrolled study. 

219

Table of Studies Investigating Each Question: organized by 

the order of presentation in the text 

Question INCLUDED STUDIES (i.e., THE PRIMARY REPORT REFERRED TO IN TEXT) 

• Primary 

Treatment for 

Depression 

• Marangell et al., 2003:95 Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim 

HF, Puryear LJ. A double-blind, placebo-controlled study of the omega-3 fatty 

acid docosahexaenoic acid in the treatment of major depression. Am J 

Psychiatry 2003;160(5):996-998. 

• Supplemental 

Treatment for 

Depression 

• Peet & Horrobin, 2002:53 Peet M, Horrobin DF. A dose-ranging study of the 

effects of ethyl-eicosapentaenoate in patients with ongoing depression despite 

apparently adequate treatment with standard drugs. Arch Gen Psychiatry 

2002;59(10):913-919. 

• Nemets et al., 2002:97 Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 

fatty acid to maintenance medication treatment for recurrent unipolar 

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• Su et al., 2003:96 Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids 

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• Intake 

Associated 

with Onset of 

Depression 

(i.e., Primary 

Prevention) 

• Llorente et al., 2003:98 Llorente AM, Jensen CL, Voigt RG, Fraley JK, Berretta 

MC, Heird WC. Effect of maternal docosahexaenoic acid supplementation on 

postpartum depression and information processing. Am J Obstet Gynecol 

2003;188(5):1348-1353. 

• Wardle et al., 2000:99 Wardle J, Rogers P, Judd P, Taylor MA, Rapoport L, 

Green M et al. Randomized trial of the effects of cholesterol-lowering dietary 

treatment on psychological function. Am J Med 2000;108(7):547-553. 

• Ness et al., 2003:100 Ness AR, Gallacher JEJ, Bennett PD, Gunnell DJ, Rogers 

PJ, Kessler D et al. Advice to eat fish and mood: A randomised controlled trial 

in men with angina. Nutr Neurosci 2003;6(1):63-65. 

• Hakkarainen et al., 2004:111 Hakkarainen R, Partonen T, Haukka J, Virtamo J, 

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• Tanskanen et al., 2001:81 Tanskanen A, Hibbeln JR, Tuomilehto J, Uutela A, 

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• Tanskanen et al., 2001:80 Tanskanen A, Hibbeln JR, Hintikka J, Haatainen K, 

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• Woo et al., 2002:110 Woo J, Ho SC, Yu ALM. Lifestyle factors and health 

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• Edwards et al., 1998:48 Edwards R, Peet M, Shay J, Horrobin D. Omega-3 

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• Hibbeln, 1998:47 Hibbeln JR. Fish consumption and major 

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• Peet, 2004:109 Peet M. International variations in the outcome of schizophrenia 

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ecological analysis. Br J Psychiatry 2004;184:404-408. 

• Biomarker 

Content 

Associated 

with Onset of 

Depression 

• Ellis & Sanders, 1977:105 Ellis FR, Sanders TAB. Long chain polyunsaturated 

fatty acids in endogenous depression. J Neurol Neurosurg Psychiatry 

1977;40(2):168-169. 

• Fehily et al., 1981:106 Fehily AMA, Bowey OAM, Ellis FR, Meade BW. Plasma 

and erythrocyte membrane long chain polyunsaturated fatty acids in 
220

endogenous depression. Neurochem Int 1981;3(1):37-42. 

• Maes et al., 1996:103 Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, 

Meltzer H. Fatty acid composition in major depression: decreased omega 3 

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ratio in cholesteryl esters and phospholipids. J Affect Disord 1996;38(1):35-46. 

• Peet et al., 1998:102 Peet M, Murphy B, Shay J, Horrobin D. Depletion of 

omega-3 fatty acid levels in red blood cell membranes of depressive patients. 

Biol Psychiatry 1998;43(5):315-319. 

• Edwards et al., 1998:48 Edwards R, Peet M, Shay J, Horrobin D. Omega-3 

polyunsaturated fatty acid levels in the diet and in red blood cell membranes of 

depressed patients. J Affect Disord 1998;48(2-3):149-155. 

• Maes et al., 1999:101 Maes M, Christophe A, Delanghe J, Altamura C, Neels H, 

Meltzer HY. Lowered omega3 polyunsaturated fatty acids in serum 

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• Tiemeier et al., 2003:104 Tiemeier H, van Tuijl HR, Hofman A, Kiliaan AJ, 

Breteler MMB. Plasma fatty acid composition and depression are associated in 

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• Llorente et al., 2003:98 Llorente AM, Jensen CL, Voigt RG, Fraley JK, Berretta 

MC, Heird WC. Effect of maternal docosahexaenoic acid supplementation on 

postpartum depression and information processing. Am J Obstet Gynecol 

2003;188(5):1348-1353. 

• Intake 

Associated 

with Onset of 

Suicidal 

Ideation or 

Behavior (i.e., 

Primary 

Prevention) 

• Hakkarainen et al., 2004:111 Hakkarainen R, Partonen T, Haukka J, Virtamo J, 

Albanes D, Lonnqvist J. Is low dietary intake of omega-3 fatty acids associated 

with depression? Am J Psychiatry 2004;161(3):567-569. 

• Tanskanen et al., 2001:80 Tanskanen A, Hibbeln JR, Hintikka J, Haatainen K, 

Honkalampi K, Viinamaki H. Fish consumption, depression, and suicidality in a 

general population.[comment]. Arch Gen Psychiatry 2001;58(5):512-513. 

• Supplemental 

Treatment for 

Bipolar 

Disorder 

• Stoll et al., 1999:112 Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, 

Diamond E et al. Omega 3 fatty acids in bipolar disorder: a preliminary doubleblind, placebo-controlled trial.[comment]. Arch Gen Psychiatry 1999;56(5):407-

412. 

• Akkerhuis & Nolen, 2003:93 Akkerhuis GW, Nolen WA. Lithium-associated 

psoriasis and omega-3 fatty acids. Am J Psychiatry 2003;160(7):1355. 

• Intake 

Associated 

with Onset of 

Bipolar 

Disorder (i.e., 

Primary 

Prevention) 

• Noaghiul & Hibbeln, 2003:90 Noaghiul S, Hibbeln JR. Cross-national 

comparisons of seafood consumption and rates of bipolar disorders. Am J 

Psychiatry 2003;160(12):2222-2227. 

• Biomarker 

Content 

Associated 

with Onset of 

Bipolar 

Disorder 

• Mahadik et al., 1996:114 Mahadik SP, Mukherjee S, Horrobin DF, Jenkins K, 

Correnti EE, Scheffer RE. Plasma membrane phospholipid fatty acid 

composition of cultured skin fibroblasts from schizophrenic patients: comparison 

with bipolar patients and normal subjects. Psychiatry Res 1996;63(2-3):133-

142. 

• Chiu et al., 2003:113 Chiu CC, Huang SY, Su KP, Lu ML, Huang MC, Chen CC 

et al. Polyunsaturated fatty acid deficit in patients with bipolar mania. Eur 

Neuropsychopharmacol 2003;13(2):99-103. 

• Intake 

Associated 

with Onset of 

Anxiety (i.e., 

Primary 

Prevention) 

• Wardle et al., 2000:99 Wardle J, Rogers P, Judd P, Taylor MA, Rapoport L, 

Green M et al. Randomized trial of the effects of cholesterol-lowering dietary 

treatment on psychological function. Am J Med 2000;108(7):547-553. 

• Ness et al., 2003:100 Ness AR, Gallacher JEJ, Bennett PD, Gunnell DJ, Rogers 

PJ, Kessler D et al. Advice to eat fish and mood: A randomised controlled trial 

in men with angina. Nutr Neurosci 2003;6(1):63-65. 

• Supplemental 

Treatment for 

ObsessiveCompulsive 

• Fux et al., 2004:115 Fux M, Benjamin J, Nemets B. A placebo-controlled crossover trial of adjunctive EPA in OCD. J Psychiatr Res 2004;38(3):323-325. 
221

Disorder 

• Biomarker 

Content 

Associated 

with Onset of 

Anorexia 

Nervosa 

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essential fatty acid status of patients hospitalized for anorexia nervosa. Am J 

Clin Nutr 1985;41(5):1054-1060. 

• Holman et al., 1995:116 Holman RT, Adams CE, Nelson RA, Grater SJ, 

Jaskiewicz JA, Johnson SB et al. Patients with anorexia nervosa demonstrate 

deficiencies of selected essential fatty acids, compensatory changes in 

nonessential fatty acids and decreased fluidity of plasma lipids. J Nutr 

1995;125(4):901-907. 

• Primary 

Treatment for 

Attention 

Deficit/ 

Hyperactivity 

Disorder 

• Richardson & Puri, 2002:119 Richardson AJ, Puri BK. A randomized doubleblind, placebo-controlled study of the effects of supplementation with highly 

unsaturated fatty acids on ADHD-related symptoms in children with specific 

learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry 

2002;26(2):233-239. 

• Hirayama et al., 2004:120 Hirayama S, Hamazaki T, Terasawa K. Effect of 

docosahexaenoic acid-containing food administration on symptoms of attentiondeficit/hyperactivity disorder - A placebo-controlled double-blind study. Eur J 

Clin Nutr 2004;58(3):467-473. 

• Brue et al., 2001:118 Brue AW, Oakland TD, Evans RA. The use of a dietary 

supplement combination and an essential fatty acid as an alternative and 

complementary treatment for children with attention-deficit/hyperactivity 

disorder. Sci Rev Altern Med 2001;5(4):187-194. 

• Harding et al., 2003:121 Harding KL, Judah RD, Gant CE. Outcome-based 

comparison of Ritalin versus food-supplement treated children with AD/HD. 

Altern Med Rev 2003;8(3):319-330. 

• Supplemental 

Treatment for 

Attention 

Deficit/ 

Hyperactivity 

Disorder 

• Brue et al., 2001:118 Brue AW, Oakland TD, Evans RA. The use of a dietary 

supplement combination and an essential fatty acid as an alternative and 

complementary treatment for children with attention-deficit/hyperactivity 

disorder. Sci Rev Altern Med 2001;5(4):187-194. 

• Voight et al., 2001:122 Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta 

MC, Heird WC. A randomized, double-blind, placebo-controlled trial of 

docosahexaenoic acid supplementation in children with attentiondeficit/hyperactivity disorder.[comment]. J Pediatr 2001;139(2):189-196. 

• Stevens et al., 2003:123 Stevens L, Zhang W, Peck L, Kuczek T, Grevstad N, 

Mahon A et al. EFA supplementation in children with inattention, hyperactivity, 

and other disruptive behaviors. Lipids 2003;38(10):1007-1021. 

• Intake 

Associated 

with Onset of 

Attention 

Deficit/ 

Hyperactivity 

Disorder (i.e., 

Primary 

Prevention) 

• Yang et al., 1999:94 Yang S-C, Chiu W-C, Chen J-R, Lee J-C, Shieh M-J. 

Dietary intakes of 4-8 years old children with attention-deficit hyperactivity 

disorder. Nutr Sci J 1999;24(2):153-165. 

• Biomarker 

Content 

Associated 

with Onset of 

Attention 

Deficit/ 

Hyperactivity 

Disorder 

• Mitchell et al., 1983:126 Mitchell EA, Lewis S, Cutler DR. Essential fatty acids 

and maladjusted behaviour in children. Prostaglandins Leukot Med 

1983;12(3):281-287. 

• Mitchell et al., 1987:125 Mitchell EA, Aman MG, Turbott SH, Manku M. Clinical 

characteristics and serum essential fatty acid levels in hyperactive children. Clin 

Pediatr (Phila) 1987;26(8):406-411. 

• Stevens et al., 1995:124 Stevens LJ, Zentall SS, Deck JL, Abate ML, Watkins 

BA, Lipp SR et al. Essential fatty acid metabolism in boys with attention-deficit 

hyperactivity disorder. Am J Clin Nutr 1995;62(4):761-768. 

• Intake 

Associated 

with Onset of 

Mental Health 

Difficulties (i.e., 

Primary 

Prevention) 

• Silvers & Scott., 2002:127 Silvers KM, Scott KM. Fish consumption and selfreported physical and mental health status. Public Health Nutr 2002;5(3):427-

431. 
222

• Intake 

Associated 

with Onset or 

Continuation of 

Tendencies or 

Behaviors with 

the Potential to 

Harm Others 

(i.e., Primary or 

Secondary 

Prevention) 

• Hamazaki et al., 1996:130 Hamazaki T, Sawazaki S, Itomura M, Asaoka E, 

Nagao Y, Nishimura N et al. The effect of docosahexaenoic acid on aggression 

in young adults. A placebo-controlled double-blind study. J Clin Invest 

1996;97(4):1129-1133. 

• Hamazaki et al., 1998:129 Hamazaki T, Sawazaki S, Nagao Y, Kuwamori T, 

Yazawa K, Mizushima Y et al. Docosahexaenoic acid does not affect 

aggression of normal volunteers under nonstressful conditions. A randomized, 

placebo-controlled, double-blind study. Lipids 1998;33(7):663-667. 

• Hamazaki et al., 2002:128 Hamazaki T, Thienprasert A, Kheovichai K, 

Samuhaseneetoo S, Nagasawa T, Watanabe S. The effect of docosahexaenoic 

acid on aggression in elderly Thai subjects--a placebo-controlled double-blind 

study. Nutr Neurosci 2002;5(1):37-41. 

• Wardle et al., 2000:99 Wardle J, Rogers P, Judd P, Taylor MA, Rapoport L, 

Green M et al. Randomized trial of the effects of cholesterol-lowering dietary 

treatment on psychological function. Am J Med 2000;108(7):547-553. 

• Iribarren et al., 2004:132 Iribarren C, Markovitz JH, Jacobs Jr DR, Schreiner PJ, 

Daviglus M, Hibbeln JR. Dietary intake of n-3, n-6 fatty acids and fish: 

Relationship with hostility in young adults - The CARDIA study. Eur J Clin Nutr 

2004;58(1):24-31. 

• Gesch et al., 2002:131 Gesch CB, Hammond SM, Hampson SE, Eves A, 

Crowder MJ. Influence of supplementary vitamins, minerals and essential fatty 

acids on the antisocial behaviour of young adult prisoners. Randomised, 

placebo-controlled trial. Br J Psychiatry 2002;181:22-28. [Secondary 

Prevention] 

• Hibbeln, 2001:133 Hibbeln JR. Seafood consumption and homicide mortality: A 

cross-national ecological analysis. 4th Congress of the International Society for 

the Study of Fatty Acids and Lipids (ISSFAL 2000). World Rev Nutr Diet 

2001;88:41-46. 

• Biomarker 

Content 

Associated 

with Onset of 

Tendencies or 

Behaviors with 

the Potential to 

Harm Others 

• Virkkunen et al., 1987:135 Virkkunen ME, Horrobin DF, Jenkins DK, Manku MS. 

Plasma phospholipid essential fatty acids and prostaglandins in alcoholic, 

habitually violent, and impulsive offenders. Biol Psychiatry 1987;22(9):1087-

1096. 

• Hibbeln et al., 1998:134 Hibbeln JR, Umhau JC, Linnoila M, George DT, Ragan 

PW, Shoaf SE et al. A replication study of violent and nonviolent subjects: 

cerebrospinal fluid metabolites of serotonin and dopamine are predicted by 

plasma essential fatty acids. Biol Psychiatry 1998;44(4):243-249. 

• Buydens-Branchey et al., 2003:136 Buydens-Branchey L, Branchey M, McMakin 

DL, Hibbeln JR. Polyunsaturated fatty acid status and aggression in cocaine 

addicts. Drug Alcohol Depend 2003;71(3):319-323. 

• Biomarker 

Content 

Associated 

with Onset of 

Alcoholism 

• Alling et al., 1984:138 Alling C, Gustavsson L, Kristensson-Aas A, Wallerstedt S. 

Changes in fatty acid composition of major glycerophospholipids in erythrocyte 

membranes from chronic alcoholics during withdrawal. Scand J Clin Lab Invest 

1984;44(4):283-289. 

• Hibbeln et al., 1998:137 Hibbeln JR, Linnoila M, Umhau JC, Rawlings R, George 

DT, Salem N, Jr. Essential fatty acids predict metabolites of serotonin and 

dopamine in cerebrospinal fluid among healthy control subjects, and early- and 

late-onset alcoholics. Biol Psychiatry 1998;44(4):235-242. 

• Primary 

Treatment for 

Borderline 

Personality 

Disorder 

• Zanarini et al., 2003:139 Zanarini MC, Frankenburg FR. omega-3 Fatty acid 

treatment of women with borderline personality disorder: a double-blind, 

placebo-controlled pilot study. Am J Psychiatry 2003;160(1):167-169. 

• Primary 

Treatment for 

Schizophrenia 

• Peet et al., 2001:58 Peet M, Brind J, Ramchand CN, Shah S, Vankar GK. Two 

double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the 

treatment of schizophrenia. Schizophr Res 2001;49(3):243-251. 

• Supplemental 

Treatment for 

Schizophrenia 

• Peet et al., 2001:58 Peet M, Brind J, Ramchand CN, Shah S, Vankar GK. Two 

double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the 

treatment of schizophrenia. Schizophr Res 2001;49(3):243-251. 

• Fenton et al., 2001:89 Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable 

M. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) 

supplementation for residual symptoms and cognitive impairment in 
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schizophrenia.[comment]. Am J Psychiatry 2001;158(12):2071-2074. 

• Emsley et al., 2002:140 Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ. 

Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as 

supplemental treatment in schizophrenia. Am J Psychiatry 2002;159(9):1596-

1598. 

• Peet et al., 2002:87 Peet M, Horrobin DF, Study Group E-EM. A dose-ranging 

exploratory study of the effects of ethyl-eicosapentaenoate in patients with 

persistent schizophrenic symptoms. J Psychiatr Res 2002;36(1):7-18. 

• Intake 

Associated 

with Onset of 

Schizophrenia 

(i.e., Primary 

Prevention) 

• Peet et al., 1997:92 Peet M, Poole J, Laugharne J. Infant feeding and the 

development of schizophrenia. Schizophr Res 1997;24:255-256. 

• McCreadie, 1997:143 McCreadie RG. The Nithsdale Schizophrenia Surveys. 16. 

Breast-feeding and schizophrenia: preliminary results and hypotheses. Br J 

Psychiatry 1997;170:334-337. 

• Leask et al., 2000:142 Leask SJ, Done DJ, Crow TJ, Richards M, Jones PB. No 

association between breast-feeding and adult psychosis in two national birth 

cohorts. Br J Psychiatry 2000;177:218-221. 

• Sasaki et al., 2000:144 Sasaki T, Okazaki Y, Akaho R, Masui K, Harada S, Lee I 

et al. Type of feeding during infancy and later development of schizophrenia. 

Schizophr Res 2000;42(1):79-82. 

• Amore et al., 2003:141 Amore M, Balista C, McCreadie RG, Cimmino C, Pisani 

F, Bevilacqua G et al. Can breast-feeding protect against schizophrenia? Casecontrol Study. Biol Neonate 2003;83(2):97-101. 

• Mellor et al., 1996:91 Mellor JE, Laugharne JDE, Peet M. Omega-3 fatty acid 

supplementation in schizophrenic patients. Hum Psychopharm 1996;11(1):39-

46. 

• Christensen & Christensen, 1988:145 Christensen O, Christensen E. Fat 

consumption and schizophrenia. Acta Psychiatr Scand 1988;78(5):587-591. 

• Noaghiul & Hibbeln, 2003:90 Noaghiul S, Hibbeln JR. Cross-national 

comparisons of seafood consumption and rates of bipolar disorders. Am J 

Psychiatry 2003;160(12):2222-2227. 

• Peet, 2004:109 Peet M. International variations in the outcome of schizophrenia 

and the prevalence of depression in relation to national dietary practices: an 

ecological analysis. Br J Psychiatry 2004;184:404-408. 

• Biomarker 

Content 

Associated 

with Onset of 

Schizophrenia 

• Obi & Nwanze, 1979:153 Obi FO, Nwanze EA. Fatty acid profiles in mental 

disease. Part 1. Linolenate variations in schizophrenia. J Neurol Sci 

1979;43(3):447-454. 

• Horrobin et al., 1989:152 Horrobin DF, Manku MS, Morse-Fisher N, Vaddadi KS, 

Courtney P, Glen AI et al. Essential fatty acids in plasma phospholipids in 

schizophrenics. Biol Psychiatry 1989;25(5):562-568. 

• Kaiya et al., 1991:151 Kaiya H, Horrobin DF, Manku MS, Fisher NM. Essential 

and other fatty acids in plasma in schizophrenics and normal individuals from 

Japan. Biol Psychiatry 1991;30(4):357-362. 

• Fischer et al., 1992:150 Fischer S, Kissling W, Kuss HJ. Schizophrenic patients 

treated with high dose phenothiazine or thioxanthene become deficient in 

polyunsaturated fatty acids in their thrombocytes. Biochem Pharmacol 

1992;44(2):317-323. 

• Peet et al., 1995:149 Peet M, Laugharne J, Rangarajan N, Horrobin D, Reynolds 

G. Depleted red cell membrane essential fatty acids in drug-treated 

schizophrenic patients. J Psychiatr Res 1995;29(3):227-232. 

• Vaddadi et al., 1996:157 Vaddadi KS, Gilleard CJ, Soosai E, Polonowita AK, 

Gibson RA, Burrows GD. Schizophrenia, tardive dyskinesia and essential fatty 

acids. Schizophr Res 1996;20(3):287-294. 

• Mahadik et al., 1996:114 Mahadik SP, Mukherjee S, Horrobin DF, Jenkins K, 

Correnti EE, Scheffer RE. Plasma membrane phospholipid fatty acid 

composition of cultured skin fibroblasts from schizophrenic patients: comparison 

with bipolar patients and normal subjects. Psychiatry Res 1996;63(2-3):133-

142. 

• Assies et al., 2001:148 Assies J, Lieverse R, Vreken P, Wanders RJ, Dingemans 

PM, Linszen DH. Significantly reduced docosahexaenoic and 

docosapentaenoic acid concentrations in erythrocyte membranes from 

schizophrenic patients compared with a carefully matched control group. Biol 
224

Psychiatry 2001;49(6):510-522. 

• Yao et al., 2002:154 Yao J, Stanley JA, Reddy RD, Keshavan MS, Pettegrew 

JW. Correlations between peripheral polyunsaturated fatty acid content and in 

vivo membrane phospholipid metabolites. Biol Psychiatry 2002;52(8):823-830. 

• Khan et al., 2002:147 Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, 

Mahadik SP. Reduced erythrocyte membrane essential fatty acids and 

increased lipid peroxides in schizophrenia at the never-medicated first-episode 

of psychosis and after years of treatment with antipsychotics. Schizophr Res 

2002;58(1):1-10. 

• Arvindakshan et al., 2003:146 Arvindakshan M, Sitasawad S, Debsikdar V, 

Ghate M, Evans D, Horrobin DF et al. Essential polyunsaturated fatty acid and 

lipid peroxide levels in never-medicated and medicated schizophrenia patients. 

Biol Psychiatry 2003;53(1):56-64. 

• Arvindakshan et al., 2003:155 Arvindakshan M, Ghate M, Ranjekar PK, Evans 

DR, Mahadik SP. Supplementation with a combination of omega-3 fatty acids 

and antioxidants (vitamins E and C) improves the outcome of schizophrenia. 

Schizophr Res 2003;62(3):195-204. 

• Evans et al., 2003:158 Evans DR, Parikh VV, Khan MM, Coussons C, Buckley 

PF, Mahadik SP. Red blood cell membrane essential fatty acid metabolism in 

early psychotic patients following antipsychotic drug treatment. Prostaglandins 

Leukot Essent Fatty Acids 2003;69(6):393-399. 

• Ranjekar et al., 2003:156 Ranjekar PK, Hinge A, Hegde MV, Ghate M, Kale A, 

Sitasawad S et al. Decreased antioxidant enzymes and membrane essential 

polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. 

Psychiatry Res 2003;121(2):109-122. 

• Biomarker 

Content 

Associated 

with Onset of 

Autism 

• Vancassel et al., 2001:159 Vancassel S, Durand G, Barthelemy C, Lejeune B, 

Martineau J, Guilloteau D et al. Plasma fatty acid levels in autistic children. 

Prostaglandins Leukot Essent Fatty Acids 2001;65(1):1-7. 
225

Abbreviations 

AA (20:4 n-6) Arachidonic acid 

AI Adequate Intake 

ALA (18:3 n-3) Alpha linolenic acid 

cAMP Cyclic adenosine monophosphate 

C5a 

COX 

Complement fragment 5a 

Cyclooxygenase 

DHA (22:6 n-3) Docosahexaenoic acid 

DTS Dense tubular system 

EAR Estimated Average Requirement 

EFA Essential fatty acid 

EPA (20:5 n-3) Eicosapentaenoic acid 

GLA (18:3 n-6) Gamma linolenic acid 

HDL 

IFN 

IgE 

High density lipoprotein 

Interferon 

Immunoglobulin E 

IL Interleukin 

LA (18:2 n-6) Linoleic acid 

LC PUFA Long-chain polyunsaturated fatty acid 

LDL Low density lipoprotein 

LT Leukotriene 

PG Prostaglandin 

PPAR Peroxisome proliferator activated receptor 

PUFA Polyunsaturated fatty acid 

RCT 

RDA 

Randomized Controlled Trial 

Recommended Dietary Allowances 

SREBP Sterol regulatory element binding protein 

Tg Triglycerides 

TNF Tumor necrosis factor 

Tx Thromboxane 

VLDL Very low density lipoprotein 
Appendix A. Search Strategies 

Search Strategy 1 

Ovid interface for Medline, Embase, PsycInfo, Cochrane Central Register of Controlled Trials 

1.exp mental disorders/ 

2. exp mental disease/ 

3. suicide attempt/ 

4. attempted suicide/ 

5. exp suicide/

6. suicid$.mp. 

7. exp Aggression/ 

8. Aggressiveness/ 

9. Aggressive behavior/ 

10. exp Impulsive Behavior/ 

11. Impulsiveness/ 

12. exp Impulse Control Disorders/ 

13. or/1-12 

14. exp fatty acids, omega-3/ 

15. fatty acids, essential/

16. Dietary Fats, Unsaturated/ 

17. linolenic acids/ 

18. exp fish oils/ 

19. (n 3 fatty acid$ or omega 3).tw. 

20. docosahexa?noic.tw,hw,rw. 

21. eicosapenta?noic.tw,hw,rw. 

22. alpha linolenic.tw,hw,rw. 

23. (linolenate or cervonic or timnodonic).tw,hw,rw. 

24. menhaden oil$.tw,hw,rw. 

25. (mediterranean adj diet$).tw. 

26. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or

walnut or mustard seed) adj2 oil$).tw. 

27. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 

28. (fish adj2 oil$).tw. 

29. (cod liver oil$ or marine oil$ or marine fat$).tw. 

30. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 

31. (fish consumption or fish intake or (fish adj2 diet$)).tw. 

32. diet$ fatty acid$.tw. 

33. or/14-32

34. dietary fats/ 

35. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter

study).pt. 

36. random$.tw. 

37. exp clinical trials/ or evaluation studies/ 

38. follow-up studies/ or prospective studies/ 

39. or/35-38

40. 34 and 39

41. (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 

42. (omega 3 or n 3).mp. 

43. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp. 

44. 42 and 43

45. 33 or 40 or 41 or 44 

46. 13 and 45

A-1
Appendix A. Search Strategies (continued) 

Search Strategy 2 

Mental Health with free text supplement

Ovid interface for CDSR 

1. exp mental disorders/ 

2. exp mental disease/ 

3. suicide attempt/ 

4. attempted suicide/ 

5. exp suicide/

6. suicid$.mp. 

7. exp Aggression/ 

8. Aggressiveness/ 

9. Aggressive behavior/ 

10. exp Impulsive Behavior/ 

11. Impulsiveness/ 

12. exp Impulse Control Disorders/ 

13. or/1-12 

14. exp fatty acids, omega-3/ 

15. fatty acids, essential/

16. Dietary Fats, Unsaturated/ 

17. linolenic acids/ 

18. exp fish oils/ 

19. (n 3 fatty acid$ or omega 3).tw. 

20. docosahexa?noic.tw,hw,rw. 

21. eicosapenta?noic.tw,hw,rw. 

22. alpha linolenic.tw,hw,rw. 

23. (linolenate or cervonic or timnodonic).tw,hw,rw. 

24. menhaden oil$.tw,hw,rw. 

25. (mediterranean adj diet$).tw. 

26. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or

walnut or mustard seed) adj2 oil$).tw. 

27. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 

28. (fish adj2 oil$).tw. 

29. (cod liver oil$ or marine oil$ or marine fat$).tw. 

30. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 

31. (fish consumption or fish intake or (fish adj2 diet$)).tw. 

32. diet$ fatty acid$.tw. 

33. or/14-32

34. dietary fats/ 

35. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or

multicenter study).pt. 

36. random$.tw. 

37. exp clinical trials/ or evaluation studies/ 

38. follow-up studies/ or prospective studies/ 

39. or/35-38

40. 34 and 39

41. (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 

42. (omega 3 or n 3).mp. 

43. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp. 

44. 42 and 43

45. 33 or 40 or 41 or 44 

46. 13 and 45

47. remove duplicates from 46 

48. mental health.mp. 

A-2
Appendix A. Search Strategies (continued) 

49. psychiat$.mp. 

50. schizophr$.mp. 

51. bipolar$.mp. 

52. depressi$.mp. 

53. (mania$ or hypomani$).mp. 

54. unipolar$.mp. 

55. (psychotic$ or psychosis$).mp. 

56. (schizoaffective or schizo-affective).mp. 

57. (aggressi$ and behav$).mp. 

58. Aggression.mp. 

59. aggressivity.mp. 

60. impulsiv$.mp. 

61. Impulse Control$.mp.

62. or/48-61

63. 45 and 62

64. 47 or 63

Search Strategy 3 

Mental Health with freetext supplement

Silverplatter interface for CAB Health 

#1. "mental-disorders" in SU

#2. "depression-" in SU 

#3. "neuroses-" in SU 

#4. "mental-health" in SU 

#5. "suicide-" in SU 

#6. mental health in ti,ab,su 

#7. psychiat* in ti,ab,su

#8. schizophr* in ti,ab,su 

#9. bipolar* in ti,ab,su 

#10. depressi* in ti,ab,su 

#11. (mania* or hypomani*) in ti,ab,su 

#12. unipolar* in ti,ab,su 

#13. (psychotic* or psychosis*) in ti,ab,su 

#14. (schizoaffective or schizo-affective) in ti,ab,su 

#15. (aggressi* near10 behav*) in ti,ab,su 

#16. aggression in ti,ab,su

#17. aggressivity in ti,ab,su 

#18. impulsiv* in ti,ab,su 

#19. impulse control* in ti,ab,su 

#20. ("delusory-parasitoses" in SU) or ("psychoses-" in SU) or ("schizophrenia-" in SU) 

#21. ("aggression-" in SU) or ("aggressive-behaviour" in SU) or ("fighting-" in SU) 

#22. #1 or #2, #3, #4, #5, #6, #7, #8, #9, #10, #11, #12, #13, #14, #15, #16, #17, #18, #19, #20, #21 

#23. omega 3

#24. ("essential-fatty-acids" in SU) or ("linolenic-acid" in SU) 

#25. ("docosahexaenoic-acid" in SU) or ("eicosapentaenoic-acid" in SU) 

#26. explode "plant-oils" in SU 

#27. explode "fish-oils" in SU 

#28. "fish-consumption" in SU 

#29. "polyenoic-fatty-acids" in SU 

#30. "polyunsaturated-fats" in SU 

#31. "dietary-fat" in SU 

#32. (n 3 fatty acid* or omega 3) in ti,ab,su 

#33. (docosahexanoic or docosahexaenoic) in ti,ab,su 

A-3
Appendix A. Search Strategies (continued) 

#34. (eicosapentanoic or eicosapentaenoic) in ti,ab,su 

#35. (alpha linolenic)in ti,ab,su 

#36. (linolenate or cervonic or timnodonic) in ti,ab,su 

#37. (mediterranean diet) in ti,ab,su 

#38. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or

walnut or mustard seed or menhaden) and oil*) in ti,ab,su 

#39. (walnut* or butternut* or soybean* or pumpkin seed*) in ti,ab,su 

#40. (fish oil* or cod liver oil* or marine oil* or marine fat*) in ti,ab,su

#41. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov*) in ti,ab,su 

#42. (fish consumption or fish intake) in ti,ab,su 

#43. (diet* fatty acid*) in ti,ab,su 

#44. (ropufa or maxepa or omacor or efamed or resq or epagis or almarin or coromega) in ti,ab,su 

#45. ((omega 3 or n 3) and (polyunsaturated fat* or pufa or dha or epa or long chain or longchain or lc*)) 

in ti,ab,su

#46. "long-chain-fatty-acids" in SU 

#47. (fish and diet) in ti,ab,su 

#48. (explode "essential-oils" in SU) or (explode "olive-oil" in SU) or (explode "palm-oils" in SU) or

(explode "plant-oils" in SU) or (explode "seed-oils" in SU) 

#49. explode "fish-liver-oils" in SU 

#50. ("long-chain-fatty-acids" in SU) or (((omega 3 or n 3) and (polyunsaturated fat* or pufa or dha or epa 

or long chain or longchain or lc*)) in ti,ab,id) or ((ropufa or maxepa or omacor or efamed or resq or 

epagis or almarin or coromega) in ti,ab,id) or ((diet* fatty acid*) in ti,ab,id) or ((n 3 fatty acid* or 

omega 3) in ti,ab,id) or ("dietary-fat" in SU) or ("polyunsaturated-fats" in SU) or ("polyenoic-fattyacids" in SU) or ("fish-consumption" in SU) or (explode "fish-oils" in SU) or (explode "plant-oils" in 

SU) or (("docosahexaenoic-acid" in SU) or ("eicosapentaenoic-acid" in SU)) or (("essential-fattyacids" in SU) or ("linolenic-acid" in SU)) or (omega 3) or ((fish consumption or fish intake) in ti,ab,id) 

or ((salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov*) in ti,ab,id) or 

((fish oil* or cod liver oil* or marine oil* or marine fat*) in ti,ab,id) or ((walnut* or butternut* or 

soybean* or pumpkin seed*) in ti,ab,id) or (((flax or flaxseed or flax seed or linseed or rape seed or 

rapeseed or canola or soy or soybean or walnut or mustard seed or menhaden) and oil*) in ti,ab,id) 

or ((mediterranean diet) in ti,ab,id) or ((linolenate or cervonic or timnodonic) in ti,ab,id) or ((alpha

linolenic)in ti,ab,id) or ((eicosapentanoic or eicosapentaenoic) in ti,ab,id) or ((docosahexanoic or 

docosahexaenoic) in ti,ab,id) or (explode "fish-liver-oils" in SU) or ((explode "essential-oils" in SU) or 

(explode "olive-oil" in SU) or (explode "palm-oils" in SU) or (explode "plant-oils" in SU) or (explode 

"seed-oils" in SU)) or ((fish and diet) in ti,ab,id) 

#51. ((explode "almond-oil" in SU) or (explode "castor-oil" in SU) or (explode "coconut-oil" in SU) or

(explode "cottonseed-oil" in SU) or (explode "groundnut-oil" in SU) or (explode "jojoba-oil" in SU) or

(explode "linseed-oil" in SU) or (explode "maize-oil" in SU) or (explode "melon-seed-oil" in SU) or 

(explode "mustard-oil" in SU) or (explode "palm-kernel-oil" in SU) or (explode "rapeseed-oil" in SU) 

or (explode "rice-oil" in SU) or (explode "safflower-oil" in SU) or (explode "sesame-oil" in SU) or

(explode "soyabean-oil" in SU) or (explode "sunflower-oil" in SU) or (explode "tung-oil" in SU) or

(explode "wheat-germ-oil" in SU)) or (("cod-liver-oil" in SU) or ("menhaden-oil" in SU)) 

#52. #50 or #51 

#53. #22 and #52 

A-4
Appendix B. Letter to Industry Representatives 

Letter to Industry Representatives from the Three EPCs 

Investigating the Health Benefits of Omega-3 Fatty Acids 

May 2, 2003 

Dear _________, 

I am writing on behalf of the Evidence Based Practice Centers at RAND, New England 

Medical Center and the University of Ottawa. We are conducting a systematic review of 

the efficacy and toxicity of omega-3 fatty acids in the prevention and treatment of a 

number of different diseases/conditions. This review is being conducted under a contract 

from the Agency for Healthcare Research and Quality (AHRQ). 

We are contacting you to see if there is any evidence, including unpublished evidence, 

that you want considered. Our focus is on clinical trials of omega-3 fatty acids in 

humans, so animal and chemical studies are not necessary. 

The specific questions that all the EPCs will address are detailed in the attachment to this 

letter. 

Please contact me with any information that you might have. I will be out of town next 

week and will respond to any questions when I get back. If you have any questions that 

you would like addressed before I return, please contact Donna Mead at the address 

above. 

Best regards,

Catherine MacLean, M.D., Ph.D. 

RAND1700 Main Street, M 23-C 

Santa Monica, CA 90407-2138 

Voice: 310 393-0411, x6364 

Fax: 310-451-6930 

maclean@rand.org

B-1
Appendix C. Data Assessment and Data Abstraction Forms 

Relevance Assessment Form 

Please respond to each question.* Use the comments box to identify duplicate reports, a key 

review whose references should be checked, anomalies, etc. 

a. Inclusion criteria: 

1. Does this report describe a study involving human participants?

 YES Can’t Tell NO 

2. Does this study evaluate the role of: a. omega-3 fatty acid intake (diet and/or 

supplementation) as an intervention/exposure; or b. omega-3 or omega-6/omega-3 fatty 

acid content of biomarkers? 

 YES Can’t Tell NO 

3. Is the purpose of the study to investigate: a. the effect (e.g., efficacy, effectiveness) of

omega-3 fatty acid intake (diet and/or supplementation) as (primary or supplemental) 

treatment for --or the association of their intake with the onset, continuation or 

recurrence of-- psychiatric disorders or symptoms/behaviors (e.g., depressive, bipolar, 

anxiety or eating disorders; ad/hd; schizophrenia; anxiety, depression, 

aggression/hostility, impulsivity or suicidal behavior); or b. the association of the omega3 or omega-6/omega-3 fatty acid content of biomarkers with the onset, continuation or 

recurrence of these psychiatric conditions? 

 YES Can’t Tell NO 

4. If this is a study investigating the evidence concerning the efficacious use of omega-3 

fatty acids as a primary or supplemental treatment for psychiatric disorders or 

symptoms/behaviors, or a study investigating the association of the omega-3 or omega6/omega-3 fatty acid content of biomarkers with the onset, continuation or recurrence of 

psychiatric disorders or symptoms/behaviors, what type of research design was 

employed?* 

CONTROLLED (or addresses Question 2) Can’t Tell UNCONTROLLED 

b. Exclusion criterion: 

5. If this is a narrative or systematic review, opinion piece or editorial, letter, guideline or 

policy paper, etc., does it exclusively describe studies already reported elsewhere (i.e., it 

does not present any empirical evidence published for the first time)?

 YES Can’t Tell NO 

c. Context: 

6. The study appears to also or instead concern omega-3 fatty acids as an 

intervention/exposure associated with the following human health/disease domains 

(select at least one option; click on all that apply): 

C-1
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

 __transplantation __neurology 

__cancer __eye health 

__child/maternal health __none of the above 

7. Is this report written in English?

 YES NO 

8. Comments box 

*Question 4 alone was used at level 3 screening; screening levels 1 and 2 each employed 

questions 1-3 and 5-8.

C-2
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Data Abstraction Form 

Instructions: Please answer each question. Selecting response options means clicking on them. 

A text box (“BOX”) requires that you provide specific data, and allows you to provide 

clarification, as needed (e.g., when the available data are not straightforward). When data are not 

reported (= NR), the question does not apply (= N/A), you cannot tell what/where the data are in 

the report (= CT), the data are not broken down (= NBD) to permit the required abstraction (e.g., 

by study group), or you have no comment to make (= NC), type the code in the BOX. 

 ‘Participants’ refers to study participants. ‘Group’ refers to a study group, arm or cohort or, in 

a crossover design, a study phase. Often, you will be asked to abstract ‘full’ sample data as well 

as by group. If requested group data are not available, abstract full sample data and label it as 

such. 

 If more than one report describes this study, draw on each to abstract study data. This means 

that, for question 2, record all of the relevant report Refid#s, and for question 3, record all of the 

relevant reports’ data. When you are abstracting data from multiple reports for a given study, 

point out any inconsistencies. 

 If the research report describes more than one unique study, answer in this eForm all the 

questions for the first reported study while immediately notifying the review manager that 

another data abstraction form is required. 

BOX = single box at end of list 

All abstractors access each level, for verification possibilities. 

Each abstractor assigned level(s), and Refids

Initials of reviewer: BOX 

Reference identification #s (Refid#s) of all report(s) referring to this study, including duplicate 

reports, data-splitting reports, additional follow-ups, re-analyses, etc.: BOX 

First author’s last name, year of publication, country(s) in which study conducted (from each 

relevant report), [# study sites] (e.g., Smith, 1988, Canada [1 site]): BOX 

Number of unique, review-relevant studies that this report describes (if more than one, notify 

review manager): BOX 

Publication status, per report/Refid# referring to this study (e.g., Refid 3000=journal publication, 

Refid 6=conference abstract): 

Peer-reviewed journal publication

Journal publication 

 Conference abstract/poster 

Book 

 Book chapter 

 HTA/technical report 

 Thesis 

 Unpublished document 

Study sponsor’s internal report 

C-3
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Internet document/material 

Other 

BOX 

Identity of funding source(s), including category per source (e.g., government, industry, 

private/non-industry, hospital), and what each provided: BOX 

 

Question(s) addressed (select all that apply): 

a. Are omega-3 fatty acids efficacious as primary treatment for __________?

b. Are omega-3 fatty acids efficacious as supplemental treatment for __________?

c. Is omega-3 fatty acid intake, including diet and/or supplementation, associated with 

the onset of _________? 

d. Is omega-3 fatty acid intake, including diet and/or supplementation, associated with 

the continuation of _________?

e. Is omega-3 fatty acid intake, including diet and/or supplementation, associated with 

the recurrence of _________?

f. Is the onset of ________ associated with the omega-3 or omega-6/omega-3 fatty acid 

content of biomarkers?

g. Is the continuation of ________ associated with the omega-3 or omega-6/omega-3 

fatty acid content of biomarkers?

h. Is the recurrence of ________ associated with the omega-3 or omega-6/omega-3 fatty 

acid content of biomarkers? 

i. Are adverse events/side effects or contraindications associated with the intake of

specific sources (e.g., marine, plant), types (e.g., DHA, EPA, ALA) or doses of 

omega-3 fatty acids, including in specific subpopulations such as diabetics?

Psychiatric disorder(s)/symptom(s)/sign(s)/behavior(s) investigated as primary or exclusive 

focus of the study (select all that apply):

a. Anxiety 

 b. Depression/unipolar 

c. Bipolar/manic depression 

d. Eating 

e. ADHD or key symptoms/signs (e.g., impulsivity) 

f. Antisocial personality 

g. Aggression/violence 

h. Stress 

i. Alcoholism or other drug abuse 

j. Borderline personality

k. Schizophrenia/schizoaffective 

l. Autism

m. Suicide 

n. Other: BOX

 

Study design (select one): 

a. RCT parallel design

b. RCT crossover design 

C-4
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

c. RCT factorial design 

d. Controlled clinical trial (non-RCT) 

e. Multiple prospective cohorts 

f. At least one prospective cohort and one retrospective cohort 

g. Case-control 

h. Cross-sectional 

i. Before-after (pre-post) 

j. Single prospective cohort 

k. Single retrospective cohort 

l. Case series (noncomparative) 

m. Case study 

n. Sequential 

o. Other: BOX 

Any notable details (e.g., restricted randomization; blocking size) or problems (i.e., no or 

inappropriate run-in or washout procedures or durations; study stopped prematurely): BOX 

Full sample eligibility criteria (e.g., population [e.g., pediatric vs adult, required diagnosis, 

permitted or mandatory comorbid conditions], intervention(s)/medication(s) [mandated vs 

permitted], cointervention(s) [mandated vs permitted]) (complete both): 

Inclusion criteria: BOX

Exclusion criteria: BOX

Were the same eligibility criteria employed with reference to each study group? (select one) 

a. Yes 

b. No 

c. Unclear 

d. Not reported 

e. Not applicable (e.g., a single group study) 

Adequacy of reporting of eligibility criteria (select one): 

a. Likely adequate (= not inadequate) 

b. Likely inadequate (= missing, incomplete or conflicting data) 

Adequacy of eligibility criteria: 

a. Likely adequate (= not inadequate) 

b. Likely inadequate (e.g., the inclusion criteria will not lead to the study of the target 

population the investigators intend to study; populations with psychiatric diagnoses/conditions 

outside the investigators’ intended scope, yet who show the same symptoms/signs as the target 

population, have not been identified as requiring exclusion) 

Sample sizes (complete all):

 Total # individuals screened: BOX

 # selected/allocated participants (full [e.g., n=12]; by group [e.g., group 1 n=5; group 2 n=7]): 

BOX

C-5
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

 # completers (= final followup)/total (full; per group) (e.g., group 1: n=4/5; group 2: n=6/7): 

BOX 

 

Settings (complete both):

 Type(s) of setting (e.g., tertiary care hospital vs community facility) (full; by group): BOX

 Proportion of participants in relatively controlled (e.g., inpatients) settings during study (full; 

by group): BOX 

Study period (complete all):

 Intervention length (d, wk, mo, y) (by group only if it varies): BOX 

 Study duration, including units (h, d, wk, mo) (includes intervention length plus run-in period 

duration, washout duration[s], etc.): BOX 

 Run-in duration/protocol: BOX 

 Washout duration/protocol: BOX 

Did participants in each study group receive the intervention/exposure for the same length of 

time? (select one) 

a. Yes 

b. No 

c. Unclear 

d. Not reported 

 e. Not applicable (e.g., a cross-sectional survey)

Was the same study procedure employed with reference to each study group? (select one) 

a. Yes 

b. No 

c. Unclear 

d. Not reported 

e. Not applicable

Were participants in each study group assessed at the same number of followups, and with the 

same timing, during the study (select one)? 

a. Yes 

b. No 

c. Unclear 

d. Not reported 

e. Not applicable (e.g., a cross-sectional survey) 

Number and timing of followups (e.g., at 6 mo; at 6 y of age), and any definition of the ‘length of 

followup required to observe an/no impact of the exposure/intervention:’ BOX

Adverse events, and losses to followup (complete both):

 # withdrawals vs # dropouts, with reasons (full; by group): BOX 

 Adverse events/side effects and contraindications (full; by group): BOX 

Basic population characteristics (complete all):

C-6
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

 Mean age (mean (range) y) of all relevant participants at study onset (full; by group): BOX 

 Percentage of males (full; by group): BOX 

 Racial composition (proportions: full; by group) (e.g., Caucasian 50%, Asian 50% per group) 

BOX

Psychiatric status (complete all):

 At/by baseline, the ‘primary diagnosis/condition (with diagnostic subtype) and concurrent 

diagnosis/condition’ [i.e., condition = symptom(s)/signs(s), yet no formal diagnosis] 

(proportions/% in full; by group) (e.g., 100% major depressive disorder [recurrent], no 

concurrent conditions): BOX 

 Severity of key defining features/symptoms/signs (full; by group): BOX 

 Prominent features/symptoms/signs at study onset e.g., (e.g., bipolar patients in manic phase) 

(full; by group): BOX 

 Current episode duration (full; by group): BOX

 Age of onset (full; by group): BOX 

 Duration (i.e., time since diagnosis) (full; by group): BOX

 Number of previous episodes (full; by group): BOX

 Diagnostic method (e.g., interview), and classification system (e.g., DSM-IV): BOX 

 Method (e.g., scales) to determine severity: BOX 

 Pre-study medications, with daily dose (full; by group): BOX 

 Pre-study response to medications (e.g., symptoms well-controlled vs symptomatic) (full; by 

group): BOX 

 Pre-study psychologic interventions (full; by group): BOX 

 Likely etiology (full; by group): BOX

Pre-study/baseline comparability of groups regarding the definition of the primary 

diagnosis/subtype: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

Pre-study/baseline comparability of groups regarding the definition of the primary/concurrent

diagnosis/condition combinations: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

C-7
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline definition of the population 

(i.e., primary diagnosis/condition or primary/concurrent diagnosis/condition combinations) 

handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups regarding the severity of key 

features/symptoms/signs: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline severity of key defining 

features/symptoms/signs handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

C-8
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Comparability of groups regarding the prominent features/symptoms/signs at study onset (e.g., 

bipolar patients in manic phase): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences regarding the prominent features/symptoms/signs at 

study onset (e.g., bipolar patients in manic phase) handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Comparability of groups regarding the current episode duration: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences regarding the current episode duration handled in the 

study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

C-9
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups regarding the age of onset: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the age of onset handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX

Pre-study/baseline comparability of groups regarding duration (time since diagnosis): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in duration (time since diagnosis): handled in the 

study analysis? 

C-10
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Comparability of groups regarding the number of previous episodes: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences regarding the number of previous episodes handled in 

the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups regarding medication types/daily doses:

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

C-11
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

BOX

How were any between-group differences in the pre-study/baseline medication types/daily doses 

handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups regarding the response to medication (e.g., symptoms

well-controlled vs symptomatic):

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline response to medication (e.g., 

well-controlled vs symptomatic) handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX

Pre-study/baseline comparability of groups regarding psychologic interventions: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

C-12
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline psychologic interventions 

handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline total (daily, weekly or monthly) n-3 intake via diet, with amount per n-3 type 

(EPA, DHA, ALA), and source (e.g., fish servings; walnuts; flaxseed oil) (by group) (e.g., group 

1: NR [likely EPA &/or DHA], from 1-2 fish servings/wk; group 2: NR, 0 fish servings/wk): 

BOX 

Pre-study/baseline comparability of groups in the total amount of dietary n-3 intake: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline total (daily, weekly or monthly) n-3 dose via supplementation, with amount 

per n-3 type (EPA, DHA, ALA), and source (e.g., fish oil capsules) (by group) (e.g., group 1: 

1.8g/d EPA, 1.2g/d DHA, from 3 fish oil capsules/d; group 2: 0g/d EPA, 0g/d DHA, water 

placebo): BOX 

Pre-study/baseline comparability of groups in the total amount of n-3 intake from

supplementation: 

C-13
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

Pre-study/baseline (daily, weekly or monthly) total n-3 intake via all sources (diet 

+supplementation), per n-3 type (by group): BOX 

Pre-study/baseline comparability of groups in the total amount of n-3 intake from diet and 

supplementation: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

Pre-study/baseline total (daily, weekly or monthly) dietary n-6/n-3 intake (by group) (e.g., group 

1: 15/1; group 2: 10/1): BOX 

 

Pre-study/baseline comparability of groups in dietary n-6/n-3 intake: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

C-14
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

BOX

How were any between-group differences in the pre-study/baseline n-3 or n-6/n-3 intake handled 

in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX

Pre-study/baseline % (daily, weekly or monthly) caloric/energy intake from fat (by group): BOX 

 

Pre-study/baseline comparability of groups in % caloric/energy intake from fat: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline % caloric/energy intake from

fat handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Types of pre-study/baseline diet (proportion of participants on each diet: in full; by group): 

High fish diet 

Fish-vegetarian diet 

Low fish diet 

Low fat diet 

High fat diet 

C-15
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Mediterranean diet 

Other 

Unclear 

Not reported 

BOX

Absolute n-3 fatty acid content of the pre-study/baseline diet (full; by group): BOX

Relative n-3 fatty acid content of the pre-study/baseline diet (full; by group): BOX

How was the pre-study dietary intake of n-3, n-6 and n-6/n-3 evaluated/estimated (select all that

apply)? 

Nutritionist-administered quantitative food-frequency survey(s) 

Nutritionist-administered semi-quantitative food-frequency survey(s) 

Self-administered quantitative food-frequency survey(s) 

Self-administered semi-quantitative food-frequency survey(s) 

Parent-administered quantitative food-frequency survey(s) 

Parent-administered semi-quantitative food-frequency survey(s) 

Direct measurement(s) of food intake 

Survey(s) (e.g., 24-hour recall): BOX

Survey(s), yet no details provided 

Other: BOX

Unclear 

Not reported

Pre-study/baseline use of other licit (prescription and non-prescription) drugs (full; by group):

BOX 

Pre-study/baseline comparability of groups in use of other licit (prescription and nonprescription) drugs: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline use of other licit (prescription 

and non-prescription) drugs handled in the study analysis? 

Adequately = taken into consideration in the analysis 

C-16
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline use of other supplements (e.g., vitamins, minerals), including dose/frequency 

(full; by group): BOX 

Pre-study/baseline comparability of groups in use of other supplements (e.g., vitamins, minerals), 

including dose/frequency: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline use of other supplements 

(e.g., vitamins, minerals), including dose/frequency, handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline use of other complementary/alternative therapies, including dose/frequency 

(full; by group): BOX 

Pre-study/baseline comparability of groups in use of other complementary/alternative therapies, 

including dose/frequency: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

C-17
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline use of other 

complementary/alternative therapies, including dose/frequency, handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline (ab)use of alcohol (full; by group): BOX 

Pre-study/baseline comparability of groups in (ab)use of alcohol: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline (ab)use of alcohol handled in 

the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

C-18
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Pre-study/baseline use of illicit drugs (full; by group): BOX 

Pre-study/baseline comparability of groups in use of illicit drugs: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline use of illicit drugs handled in 

the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline use of smoking tobacco (full; by group): BOX 

Pre-study/baseline comparability of groups in use of smoking tobacco: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline use of smoking tobacco 

handled in the study analysis? 

C-19
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline general health status (full; by group): BOX 

Pre-study/baseline comparability of groups in general health status: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline general health status handled 

in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline status of other factors affecting (and affected by) mental health (e.g., 

stressors; exercise; quality of sleep; social support) (full; by group): BOX 

Pre-study/baseline comparability of groups regarding the status of other factors affecting (and 

affected by) mental health (e.g., stressors; exercise; quality of sleep; social support): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

C-20
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline status of other factors 

affecting (and affected by) mental health (e.g., stressors; exercise; quality of sleep; social 

support) handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline family history of psychiatric problems, including known diagnoses (full; by 

group): BOX 

Pre-study/baseline comparability of groups in terms of a family history of psychiatric problems, 

including known diagnoses: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline family history of psychiatric 

problems, including known diagnoses, handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

C-21
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline employment status (full; by group): BOX 

Pre-study/baseline comparability of groups in terms of employment status: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline employment status handled 

in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline income (full; by group): BOX 

Pre-study/baseline comparability of groups in terms of income: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

C-22
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

How were any between-group differences in the pre-study/baseline income handled in the study 

analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX

Pre-study/baseline education (full; by group): BOX 

Pre-study/baseline comparability of groups in terms of education: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline education handled in the 

study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline marital status (full; by group): BOX 

Pre-study/baseline comparability of groups in terms of marital status: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

C-23
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline marital status handled in the 

study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline biomarkers data (by biomarker: e.g., RBCs; for DHA, EPA, AA, AA/EPA, 

AA/DHA, AA/EPA+DHA levels, with units [e.g., % total fatty acids; absolute amount) (full; by 

group): BOX 

Pre-study/baseline comparability of groups in terms of DHA status (per biomarker): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups in terms of EPA status (per biomarker): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

C-24
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups in terms of EPA+DHA status (per biomarker): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups in terms of AA status (per biomarker): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups in terms of AA/DHA status (per biomarker): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

C-25
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

BOX 

Pre-study/baseline comparability of groups in terms of AA/EPA status (per biomarker): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX 

Pre-study/baseline comparability of groups in terms of AA/EPA+DHA status (per biomarker): 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., a single group study 

BOX

How were any between-group differences in the pre-study/baseline biomarker EFA status 

handled in the study analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for these in the 

analysis 

Not reported = no description of whether/how accounted for in the analysis 

Not applicable = e.g., a single group study 

BOX

ON-STUDY

Was the n-3 exposure provided/received as primary or supplemental intervention? BOX 

C-26
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

How was on-study dietary intake of n-3 or n-6/n-3 evaluated/estimated (select all that apply)? 

Nutritionist-administered quantitative food-frequency survey(s) 

Nutritionist-administered semi-quantitative food-frequency survey(s) 

Self-administered quantitative food-frequency survey(s) 

Self-administered semi-quantitative food-frequency survey(s) 

Parent-administered quantitative food-frequency survey(s) 

Parent-administered semi-quantitative food-frequency survey(s) 

Direct measurement(s) of food intake 

Survey(s) (e.g., 24-hour recall): BOX

Survey(s), yet no details provided 

Other: BOX

Unclear 

Not reported 

On-study GROUP 1 (highest dose n-3 [or lowest n-6/n-3 ratio if both n-3 and n-6 are modified] 

study first, active comparator next (e.g., n-6), placebo control last) (complete all):

 total (daily, weekly or monthly) n-3 dose via supplementation, with amount per n-3 type; 

source, frequency and timing of delivery; other active ingredients (e.g., 1.8g/d EPA, 1.2g/d 

DHA, from 3 [1g vegan outer] fish oil capsules/d, with breakfast, NR; e.g., 3g/d EPA+DHA 

[NBD], from 3 [1g gelcap] fish oil capsules/d, NR, 50mg Vitamin E per capsule; e.g., 0g/d, from

3 [1g gelcap] olive oil capsules/d, with breakfast, NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via diet, with amount per n-3 type, source, 

frequency and timing of delivery (e.g., NR, likely EPA or DHA, from 2 0.5oz oily fish 

servings/wk, as dinner; e.g., NR, likely ALA, from 8-10oz/wk flaxseed oil as salad dressing, 

NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via all sources (diet+supplementation), per n-3 

type (e.g., NR, at least 3g/d EPA+DHA): BOX 

 

 total (daily, weekly or monthly) n-6 intake from diet+supplementation: BOX

 total (daily, weekly or monthly) n-6/n-3 intake: BOX (e.g., 10:1 g/d): BOX 

 type, source and total (daily, weekly or monthly) intake of other mandated or permitted 

exposures, with dose/serving/frequency: BOX 

 n allocated-selected/ n completed (e.g., n=24/21): BOX 

 protocol (e.g., what is mandated vs permitted), with method and target values, to modify 

daily, weekly or monthly n-6 or n-6/n-3 intake (e.g., increase daily n-3 intake to Y% of total 

daily fat intake, decrease daily n-6 intake to X% of total daily fat intake; e.g., none, participants 

told to maintain background diet): BOX

C-27
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

On-study GROUP 2 (next highest dose n-3 [or lowest n-6/n-3 ratio if both n-3 and n-6 are 

modified] study first, active comparator next (e.g., n-6), placebo control last) (complete all; click 

here if there are no more study groups): 

 total (daily, weekly or monthly) n-3 dose via supplementation, with amount per n-3 type; 

source, frequency and timing of delivery; other active ingredients (e.g., 1.8g/d EPA, 1.2g/d 

DHA, from 3 [1g vegan outer] fish oil capsules/d, with breakfast, NR; e.g., 3g/d EPA+DHA 

[NBD], from 3 [1g gelcap] fish oil capsules/d, NR, 50mg Vitamin E per capsule; e.g., 0g/d, from

3 [1g gelcap] olive oil capsules/d, with breakfast, NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via diet, with amount per n-3 type, source, 

frequency and timing of delivery (e.g., NR, likely EPA or DHA, from 2 0.5oz oily fish 

servings/wk, as dinner; e.g., NR, likely ALA, from 8-10oz/wk flaxseed oil as salad dressing, 

NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via all sources (diet+supplementation), per n-3 

type (e.g., NR, at least 3g/d EPA+DHA): BOX 

 

 total (daily, weekly or monthly) n-6 intake from diet+supplementation: BOX

 total (daily, weekly or monthly) n-6/n-3 intake: BOX (e.g., 10:1 g/d): BOX 

 type, source and total (daily, weekly or monthly) intake of other mandated or permitted 

exposures, with dose/serving/frequency: BOX 

 n allocated-selected/ n completed (e.g., n=24/21): BOX 

 protocol (e.g., what is mandated vs permitted), with method and target values, to modify 

daily, weekly or monthly n-6 or n-6/n-3 intake (e.g., increase daily n-3 intake to Y% of total 

daily fat intake, decrease daily n-6 intake to X% of total daily fat intake; e.g., none, participants 

told to maintain background diet): BOX

 

On-study GROUP 3 (next highest dose n-3 [or lowest n-6/n-3 ratio if both n-3 and n-6 are 

modified] study first, active comparator next (e.g., n-6), placebo control last) (complete all; click 

here if there are no more study groups): 

 total (daily, weekly or monthly) n-3 dose via supplementation, with amount per n-3 type; 

source, frequency and timing of delivery; other active ingredients (e.g., 1.8g/d EPA, 1.2g/d 

DHA, from 3 [1g vegan outer] fish oil capsules/d, with breakfast, NR; e.g., 3g/d EPA+DHA 

[NBD], from 3 [1g gelcap] fish oil capsules/d, NR, 50mg Vitamin E per capsule; e.g., 0g/d, from

3 [1g gelcap] olive oil capsules/d, with breakfast, NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via diet, with amount per n-3 type, source, 

frequency and timing of delivery (e.g., NR, likely EPA or DHA, from 2 0.5oz oily fish 

C-28
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

servings/wk, as dinner; e.g., NR, likely ALA, from 8-10oz/wk flaxseed oil as salad dressing, 

NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via all sources (diet+supplementation), per n-3 

type (e.g., NR, at least 3g/d EPA+DHA): BOX 

 

 total (daily, weekly or monthly) n-6 intake from diet+supplementation: BOX

 total (daily, weekly or monthly) n-6/n-3 intake: BOX (e.g., 10:1 g/d): BOX 

 type, source and total (daily, weekly or monthly) intake of other mandated or permitted 

exposures, with dose/serving/frequency: BOX 

 n allocated-selected/ n completed (e.g., n=24/21): BOX 

 protocol (e.g., what is mandated vs permitted), with method and target values, to modify 

daily, weekly or monthly n-6 or n-6/n-3 intake (e.g., increase daily n-3 intake to Y% of total 

daily fat intake, decrease daily n-6 intake to X% of total daily fat intake; e.g., none, participants 

told to maintain background diet): BOX 

On-study GROUP 4 (next highest dose n-3 [or lowest n-6/n-3 ratio if both n-3 and n-6 are 

modified] study first, active comparator next (e.g., n-6), placebo control last) (complete all; click 

here if there are no more study groups): 

 total (daily, weekly or monthly) n-3 dose via supplementation, with amount per n-3 type; 

source, frequency and timing of delivery; other active ingredients (e.g., 1.8g/d EPA, 1.2g/d 

DHA, from 3 [1g vegan outer] fish oil capsules/d, with breakfast, NR; e.g., 3g/d EPA+DHA 

[NBD], from 3 [1g gelcap] fish oil capsules/d, NR, 50mg Vitamin E per capsule; e.g., 0g/d, from

3 [1g gelcap] olive oil capsules/d, with breakfast, NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via diet, with amount per n-3 type, source, 

frequency and timing of delivery (e.g., NR, likely EPA or DHA, from 2 0.5oz oily fish 

servings/wk, as dinner; e.g., NR, likely ALA, from 8-10oz/wk flaxseed oil as salad dressing, 

NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via all sources (diet+supplementation), per n-3 

type (e.g., NR, at least 3g/d EPA+DHA): BOX 

 

 total (daily, weekly or monthly) n-6 intake from diet+supplementation: BOX

 total (daily, weekly or monthly) n-6/n-3 intake: BOX (e.g., 10:1 g/d): BOX 

 type, source and total (daily, weekly or monthly) intake of other mandated or permitted 

exposures, with dose/serving/frequency: BOX 

C-29
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

 n allocated-selected/ n completed (e.g., n=24/21): BOX 

 protocol (e.g., what is mandated vs permitted), with method and target values, to modify 

daily, weekly or monthly n-6 or n-6/n-3 intake (e.g., increase daily n-3 intake to Y% of total 

daily fat intake, decrease daily n-6 intake to X% of total daily fat intake; e.g., none, participants 

told to maintain background diet): BOX 

On-study GROUP 5 (next highest dose n-3 [or lowest n-6/n-3 ratio if both n-3 and n-6 are 

modified] study first, active comparator next (e.g., n-6), placebo control last) (complete all; click 

here if there are no more study groups): 

 total (daily, weekly or monthly) n-3 dose via supplementation, with amount per n-3 type; 

source, frequency and timing of delivery; other active ingredients (e.g., 1.8g/d EPA, 1.2g/d 

DHA, from 3 [1g vegan outer] fish oil capsules/d, with breakfast, NR; e.g., 3g/d EPA+DHA 

[NBD], from 3 [1g gelcap] fish oil capsules/d, NR, 50mg Vitamin E per capsule; e.g., 0g/d, from

3 [1g gelcap] olive oil capsules/d, with breakfast, NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via diet, with amount per n-3 type, source, 

frequency and timing of delivery (e.g., NR, likely EPA or DHA, from 2 0.5oz oily fish 

servings/wk, as dinner; e.g., NR, likely ALA, from 8-10oz/wk flaxseed oil as salad dressing, 

NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via all sources (diet+supplementation), per n-3 

type (e.g., NR, at least 3g/d EPA+DHA): BOX 

 

 total (daily, weekly or monthly) n-6 intake from diet+supplementation: BOX

 total (daily, weekly or monthly) n-6/n-3 intake: BOX (e.g., 10:1 g/d): BOX 

 type, source and total (daily, weekly or monthly) intake of other mandated or permitted 

exposures, with dose/serving/frequency: BOX 

 n allocated-selected/ n completed (e.g., n=24/21): BOX 

 protocol (e.g., what is mandated vs permitted), with method and target values, to modify 

daily, weekly or monthly n-6 or n-6/n-3 intake (e.g., increase daily n-3 intake to Y% of total 

daily fat intake, decrease daily n-6 intake to X% of total daily fat intake; e.g., none, participants 

told to maintain background diet): BOX

On-study GROUP 6 (next highest dose n-3 [or lowest n-6/n-3 ratio if both n-3 and n-6 are 

modified] study first, active comparator next (e.g., n-6), placebo control last) (complete all; click 

here if there are no more study groups): 

C-30
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

 total (daily, weekly or monthly) n-3 dose via supplementation, with amount per n-3 type; 

source, frequency and timing of delivery; other active ingredients (e.g., 1.8g/d EPA, 1.2g/d 

DHA, from 3 [1g vegan outer] fish oil capsules/d, with breakfast, NR; e.g., 3g/d EPA+DHA 

[NBD], from 3 [1g gelcap] fish oil capsules/d, NR, 50mg Vitamin E per capsule; e.g., 0g/d, from

3 [1g gelcap] olive oil capsules/d, with breakfast, NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via diet, with amount per n-3 type, source, 

frequency and timing of delivery (e.g., NR, likely EPA or DHA, from 2 0.5oz oily fish 

servings/wk, as dinner; e.g., NR, likely ALA, from 8-10oz/wk flaxseed oil as salad dressing, 

NR): BOX 

 total (daily, weekly or monthly) n-3 exposure via all sources (diet+supplementation), per n-3 

type (e.g., NR, at least 3g/d EPA+DHA): BOX 

 

 total (daily, weekly or monthly) n-6 intake from diet+supplementation: BOX

 total (daily, weekly or monthly) n-6/n-3 intake: BOX (e.g., 10:1 g/d): BOX 

 type, source and total (daily, weekly or monthly) intake of other mandated or permitted 

exposures, with dose/serving/frequency: BOX 

 n allocated-selected/ n completed (e.g., n=24/21): BOX 

 protocol (e.g., what is mandated vs permitted), with method and target values, to modify 

daily, weekly or monthly n-6 or n-6/n-3 intake (e.g., increase daily n-3 intake to Y% of total 

daily fat intake, decrease daily n-6 intake to X% of total daily fat intake; e.g., none, participants 

told to maintain background diet): BOX 

Briefly describe whether there was a clearly planned and instituted difference, between study 

groups, in their (daily, weekly or monthly) total-gram n-3 and/or n-6/n-3 intake: BOX 

Briefly describe whether there was a clearly planned and instituted equivalence, across study 

groups, of (daily, weekly or monthly) caloric/energy intake from study-relevant 

exposures/interventions: BOX 

Briefly describe any problems with compliance whereby notable deviations (e.g., decreases) 

from the planned amounts of dietary or supplement intake (e.g., capsules or servings) in one or 

more of the study groups violated the difference(s) established a priori between study groups for 

n-3 and/or n-6/n-3 intake or the equivalence established a priori across study groups for 

caloric/energy intake (full; by group): BOX 

Briefly describe whether, and which, study groups/participants were asked to maintain their (prestudy/baseline) background diet while on-study (full; by group): BOX 

C-31
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Briefly describe whether, and how, without specific instruction to do so, or with specific 

instruction not to do so, participants’ (pre-study/baseline) background diet was altered while onstudy (full; by group): BOX 

Briefly describe whether, and which, study groups/participants were asked to maintain their (prestudy/baseline) therapies/medications while on-study (full; by group): BOX 

Briefly describe whether, and how, without specific instruction to do so, or with specific 

instruction not to do so, participants’ (pre-study/baseline) therapies/medication were altered 

while on-study (full; by group): BOX 

Briefly describe any evidence of selection bias: BOX 

Between-group comparability of within-group changes in the primary/concurrent 

diagnosis/condition combination[s] (i.e., population definition) from baseline, to the followup 

required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the primary/concurrent 

diagnosis/condition combination[s] (i.e., population definition) from baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

C-32
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the 

primary/concurrent diagnosis/condition combinations (i.e., population definition) from baseline, 

to each followup, handled in the study analysis? Or, if a single group study, how was any withingroup change in this variable from baseline, to each followup, handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the primary/concurrent diagnosis/condition 

combinations (i.e., population definition) from baseline, to each followup in each group: BOX

Between-group comparability of within-group changes in the severity of key defining 

features/symptoms/signs (e.g., leading to a change in medication type/dose) from baseline, to the 

followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

C-33
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the severity of key defining 

features/symptoms/signs (e.g., leading to a change in medication type/dose) from baseline, to 

final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the severity of key 

defining features/symptoms/signs (e.g., leading to a change in medication type/dose) from

baseline, to each followup, handled in the study analysis? Or, if a single group study, how was 

any within-group change in this variable from baseline, to each followup, handled in the study 

analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

C-34
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Briefly describe the nature of the change in the severity of key defining features/symptoms/signs 

(e.g., leading to a change in medication type/dose) from baseline, to each followup in each 

group: BOX

Between-group comparability of within-group changes in the prominent features/symptoms/signs 

observed at study onset/baseline (e.g., bipolar patients in manic phase), to the followup required 

to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significanceUnclear = no result of statistical test of 

significance reported, and, incomplete or conflicting data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the prominent features/symptoms/signs 

observed at study onset/baseline (e.g., bipolar patients in manic phase), to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

C-35
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the prominent 

features/symptoms/signs observed at study onset/baseline (e.g., bipolar patients in manic phase), 

to each followup, handled in the study analysis? Or, if a single group study, how was any withingroup change in this variable from baseline, to each followup, handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the prominent features/symptoms/signs observed at 

study onset/baseline (e.g., bipolar patients in manic phase), to each followup in each group: BOX

 

Between-group comparability of within-group changes in the medication types/daily doses from 

baseline, to the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the medication types/daily doses from 

baseline, to final followup: 

C-36
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the medication 

types/daily doses from baseline, to each followup, handled in the study analysis? Or, if a single 

group study, how was any within-group change in this variable from baseline, to each followup, 

handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the medication types/daily doses from baseline, to 

each followup in each group: BOX

Between-group comparability of within-group changes in the response to medication (symptoms 

well-controlled vs symptomatic) from baseline, to the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

C-37
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the response to medication (symptoms 

well-controlled vs symptomatic) from baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the response to 

medication (symptoms well-controlled vs symptomatic) from baseline, to each followup, handled 

in the study analysis? Or, if a single group study, how was any within-group change in this 

variable from baseline, to each followup, handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

C-38
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the response to medication (symptoms wellcontrolled vs symptomatic) from baseline, to each followup in each group: BOX

Between-group comparability of within-group changes in the psychologic interventions from

baseline, to the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the psychologic interventions from

baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

C-39
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the psychologic 

interventions from baseline, to each followup, handled in the study analysis? Or, if a single group 

study, how was any within-group change in this variable from baseline, to each followup, 

handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the psychologic interventions from baseline, to each 

followup in each group: BOX

Between-group comparability of within-group changes in the use of other licit (prescription and 

non-prescription) drugs from baseline, to the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

C-40
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

BOX 

Between-group comparability of within-group changes in the use of other licit (prescription and 

non-prescription) drugs from baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the use of other licit 

(prescription and non-prescription) drugs from baseline, to each followup, handled in the study 

analysis? Or, if a single group study, how was any within-group change in this variable from

baseline, to each followup, handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the use of other licit (prescription and nonprescription) drugs from baseline, to each followup in each group: BOX

Between-group comparability of within-group changes in other supplement use (vitamins; 

minerals), including dose/frequency, from baseline, to the followup required to observe an/no 

effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

C-41
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in other supplement use (vitamins; 

minerals), including dose/frequency, from baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance 

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in other supplement use 

(vitamins; minerals), including dose/frequency, from baseline, to each followup, handled in the 

study analysis? Or, if a single group study, how was any within-group change in this variable 

from baseline, to each followup, handled in the study analysis?

C-42
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in other supplement use (vitamins; minerals), including 

dose/frequency, from baseline, to each followup in each group: BOX

Between-group comparability of within-group changes in other complementary/alternative 

therapies from baseline, to the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance 

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in other complementary/alternative 

therapies from baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

C-43
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in other 

complementary/alternative therapies from baseline, to each followup, handled in the study 

analysis? Or, if a single group study, how was any within-group change in this variable from

baseline, to each followup, handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in other complementary/alternative therapies from

baseline, to each followup in each group: BOX

Between-group comparability of within-group changes in the (ab)use of alcohol from baseline, to 

the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

C-44
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the (ab)use of alcohol from baseline, to 

final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the (ab)use of alcohol 

from baseline, to each followup, handled in the study analysis? Or, if a single group study, how 

was any within-group change in this variable from baseline, to each followup, handled in the 

study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the (ab)use of alcohol from baseline, to each 

followup in each group: BOX 

C-45
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Between-group comparability of within-group changes in illicit drug use from baseline, to the 

followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance 

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in illicit drug use from baseline, to final 

followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

C-46
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

How were any between-group differences in the within-group change(s) in illicit drug use from

baseline, to each followup, handled in the study analysis? Or, if a single group study, how was 

any within-group change in this variable from baseline, to each followup, handled in the study 

analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in illicit drug use from baseline, to each followup in 

each group: BOX

Between-group comparability of within-group changes in smoking tobacco from baseline, to the 

followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in smoking tobacco from baseline, to 

final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

C-47
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in smoking tobacco 

from baseline, to each followup, handled in the study analysis? Or, if a single group study, how 

was any within-group change in this variable from baseline, to each followup, handled in the 

study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in smoking tobacco from baseline, to each followup in 

each group: BOX

Between-group comparability of within-group changes in general health status from baseline, to 

the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

C-48
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in general health status from baseline, to 

final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in general health status 

from baseline, to each followup, handled in the study analysis? Or, if a single group study, how 

was any within-group change in this variable from baseline, to each followup, handled in the 

study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

C-49
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Briefly describe the nature of the change in general health status from baseline, to each followup 

in each group: BOX

Between-group comparability of within-group changes in the other factors affecting (and 

affected by) mental health (e.g., stressors; exercise; quality of sleep; social support) from 

baseline, to the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in the other factors affecting (and 

affected by) mental health (e.g., stressors; exercise; quality of sleep; social support) from 

baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

C-50
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in other factors affecting 

(and affected by) mental health (e.g., stressors; exercise; quality of sleep; social support) from

baseline, to each followup, handled in the study analysis? Or, if a single group study, how was 

any within-group change in this variable from baseline, to each followup, handled in the study 

analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in other factors affecting (and affected by) mental 

health (e.g., stressors; exercise; quality of sleep; social support) from baseline, to each followup 

in each group: BOX

Between-group comparability of within-group changes in the family history of psychiatric 

problems, including known diagnoses, from baseline, to the followup required to observe an/no 

effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

C-51
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

BOX 

Between-group comparability of within-group changes in the family history of psychiatric 

problems, including known diagnoses, from baseline, to final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in the family history of 

psychiatric problems, including known diagnoses, from baseline, to each followup, handled in 

the study analysis? Or, if a single group study, how was any within-group change in this variable 

from baseline, to each followup, handled in the study analysis?

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in the family history of psychiatric problems, including 

known diagnoses, from baseline, to each followup in each group: BOX 

 

Between-group comparability of within-group changes in employment status from baseline, to 

the followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

C-52
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in employment status from baseline, to 

final followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in employment status 

from baseline, to each followup, handled in the study analysis? Or, if a single group study, how 

was any within-group change in this variable from baseline, to each followup, handled in the 

study analysis?

C-53
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in employment status from baseline, to each followup 

in each group: BOX

Between-group comparability of within-group changes in income from baseline, to the followup 

required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in income from baseline, to final 

followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

C-54
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in income from

baseline, to each followup, handled in the study analysis? Or, if a single group study, how was 

any within-group change in this variable from baseline, to each followup, handled in the study 

analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in income from baseline, to each followup in each 

group: BOX 

Between-group comparability of within-group changes in education from baseline, to the 

followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance 

C-55
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in education from baseline, to final 

followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

How were any between-group differences in the within-group change(s) in education from

baseline, to each followup, handled in the study analysis? Or, if a single group study, how was 

any within-group change in this variable from baseline, to each followup, handled in the study 

analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in education from baseline, to each followup in each 

group: BOX 

C-56
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Between-group comparability of within-group changes in marital status from baseline, to the 

followup required to observe an/no effect: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

Between-group comparability of within-group changes in marital status from baseline, to final 

followup: 

Adequate = statistically nonsignificant difference(s) reported (e.g., p-value; stated result of 

statistical test) 

Possibly adequate = no result of statistical test of significance reported, yet no notable 

difference(s) in reported data 

Inadequate = statistically significant difference(s) reported 

Possibly inadequate = no result of statistical test of significance reported, yet at least one 

notable difference in reported data 

Single group study, adequate = statistically nonsignificant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly adequate = no notable change in reported data in this group yet 

no reported result of statistical test of significance

Single group study, inadequate = statistically significant change in this group (e.g., p-value; 

stated result of statistical test) 

Single group study, possibly inadequate = notable change in reported data in this group yet 

no reported result of statistical test of significance 

Unclear = no result of statistical test of significance reported, and, incomplete or conflicting 

data reported 

Not reported = no reported data or result of a statistical test of significance 

Not applicable = e.g., no followup, as in a cross-sectional study 

BOX 

C-57
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

How were any between-group differences in the within-group change(s) in marital status from

baseline, to each followup, handled in the study analysis? Or, if a single group study, how was 

any within-group change in this variable from baseline, to each followup, handled in the study 

analysis? 

Adequately = taken into consideration in the analysis 

Inadequately = not taken into consideration in the analysis 

No differences = no differences reported 

Unclear = not enough information to rule out possibility that did not account for it in the 

analysis 

Not reported = no description of whether/how accounted for it in the analysis 

Not applicable = a single group study 

BOX 

Briefly describe the nature of the change in marital status from baseline, to each followup in each 

group: BOX

Name of n-3 product (e.g., Almarin, Coromega, Eiconol; Efamed, Epagis, MaxEPA, Menhaden 

oil, ResQ, Omacor, Ropufa): BOX

 Manufacturer: BOX

 Purity data: BOX

 Presence of other, potentially active agents in n-3 product: BOX

 n-3 composition (%) of the exposure (e.g., 18% EPA, 12% DHA in each fish oil capsule): 

BOX

Reported method(s) to maintain the freshness (i.e., preclude rancidity) of n-3 

exposures/interventions (e.g., added anti-oxidants to capsules, with fish oil exposure, to 

minimize oxidation): BOX

Reported method(s) to eliminate methylmercury from fish or its products/derivatives: BOX 

 

Note any descriptions of inappropriate methods of lipid extraction/preparation (e.g., failure to 

extract blood after a [overnight] fasting period; failure to collect blood in EDTA- or EGTAcontaining vials): BOX

Note any descriptions of inappropriate methods of lipid storage (e.g., failure to store samples at –

70 to –80 degrees C if not analyzed immediately): BOX 

Note any descriptions of inappropriate methods of lipid analysis (e.g., failure to conduct lab 

measurements on coded samples by technicians blinded to participants’ identity and allocation; 

failure to use a standard protocol [e.g., Bligh & Dyer] requiring, for example, purging samples 

with nitrogen, or using thin-layer chromatography or gas liquid chromatography): BOX

Adequacy of method to deodorize smell of especially fish oil exposure (select one):

Adequate = reported that study participants could not reliably guess which exposure they 

received 

Inadequate = reported that participants could reliably guess which exposure they received 

C-58
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Unclear = incomplete or conflicting data reported 

Not reported = no method reported, or method reported but no data reported 

Not applicable = did not use an exposure requiring or permitting such a method (e.g., 

flaxseed; full fish servings)

If this is a controlled study, briefly describe whether clinical outcome data from all study groups 

(e.g., active vs placebo) were simultaneously entered into data analysis: BOX

If this is a controlled study, briefly describe whether biomarker data from all study groups (e.g., 

active vs placebo) were simultaneously entered into data analysis: BOX

Data were analyzed according to which criterion (select one)? 

Intention-to-treat (all randomized/enrolled)

Those receiving at least one dose/serving 

Those completing the study (i.e., with final follow-up data) 

Unclear 

Other: BOX

Was the study adequately powered to detect a difference? BOX

Any further comments about the study: BOX 

C-59
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Quality Assessment Form—Randomized Controlled Trials 

1. Randomization: Was the study described as randomized (i.e. including words such as 

randomly, random, randomization)? Yes = 1 No = 0 =___ 

A trial reporting that it is ‘randomized’ is to receive one point. Trials describing an appropriate 

method of randomization (table of random numbers, computer generated) receive an additional 

point. Appropriate = 1 Not appropriate = 0 = ___ 

However, if the report describes the trial as randomized and uses an inappropriate method of 

randomization (e.g. date of birth, hospital numbers), a point is deducted. 

TOTAL POINTS: 0 1 2 SCORE = __

2. Double-blinding: Was the study described as double-blind? Yes = 1 No = 0 =___

A trial reporting that it is ‘double-blind’ is to receive one point. Trials that describe an 

appropriate method of double-blinding (identical placebo: color, shape, taste) are to receive an 

additional point. Yes = 1 No = 0 =___

However, if the report describes the trial as double-blind and uses an inappropriate method (e.g. 

comparison of tablets vs. injection with no dummy), a point is deducted. 

 TOTAL POINTS: 0 1 2 SCORE = ___

3. Withdrawals and dropouts: Was there a description of withdrawals and dropouts?

 Yes = 1 No = 0 SCORE = ___

A trial reporting the number of and reasons for withdrawals or dropouts is to receive one point. If 

there is no description, no point is given. 

 JADAD TOTAL SCORE = ___

4. Adequacy of Allocation Concealment: (select one):

-Central randomization; numbered or coded bottles or containers; drugs prepared by a pharmacy, 

serially numbered, opaque, sealed envelopes, 

etc..................................................................................... ADEQUATE

-Alternation; reference to case record # or date of birth, 

etc.................................................................................. INADEQUATE

-Allocation concealment is not reported, or, fits neither 

category..................................................... ........................... UNCLEAR

C-60
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Quality Assessment (Internal Validity) Forms—Designs Other 

than an RCT 

Controlled Study Designs 

DESIGN: COMPARATIVE BEFORE-AFTER STUDY 

1. Description of validated method(s) to identify the target population 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

2. Control for selection bias 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

3. Description of withdrawals/dropouts 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

4. Comparability of study groups on the basis of the design or analysis: age and sex 

a. Study controls for age and sex at baseline = 1 

b. Study fails to control for this confounding influence = 0 

c. Unable to determine = 0 

5. Comparability of study groups on the basis of the design or analysis: background diet 

a. Study controls for background diet (omega-6/omega-3 fatty acid intake) at baseline and in 

light of possible changes during intervention period = 1 

b. Study fails to control for this confounding influence = 0 

c. Unable to determine = 0 

6. Comparability of study groups on the basis of the design or analysis: caloric/energy intake 

a. Study controls for caloric/energy intake at baseline and in light of possible changes during 

intervention period = 1 

b. Study fails to control for this confounding influence = 0 

c. Unable to determine = 0 

C-61
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

7. Comparability of study groups on the basis of the design or analysis: the severity of the 

psychiatric disorder/condition 

a. Study controls for the severity of the psychiatric disorder/condition at baseline and in light of 

possible changes unrelated to the exposure during intervention period = 1 

b. Study fails to control for this confounding influence = 0 

c. Unable to determine = 0 

8. Comparability of study groups on the basis of the design or analysis: psychotropic medication 

a. Study controls for psychotropic medication at baseline and in light of possible changes 

unrelated to the exposure during intervention period = 1 

b. Study fails to control for this confounding influence = 0 

c. Unable to determine = 0 

9. Description of a validated primary clinical outcome measure(s)

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

10. Blind assessments of outcome

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

11. Description of type and amount of omega-3 fatty acid content in the intervention/exposure 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0

DESIGN: CASE-CONTROL STUDY (Newcastle-Ottawa, with assessment of an additional 

confounder) 

1. Is the case definition adequate? 

a. yes, with independent validation (e.g., clinical/research diagnostic criteria) (1 point) 

b. yes: e.g., record linkage or based on reports 

c. no description 

2. Representativeness of the cases 

a. consecutive or obviously representative series of cases (1 point) 

b. potential for selection biases, or not stated 

C-62
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

3. Selection of controls 

a. community controls (1 point) 

b. hospital controls 

c. no description 

4. Definition of controls 

a. no history of disease (requires clinical/research diagnostic criteria to determine this) (1 point) 

b. no description of source 

5. Comparability of cases and controls on the basis of the design or analysis: smoker status 

a. study controls for smoker status at baseline and in possible changes unrelated to the exposure 

during “intervening period” (1 point) 

b. study fails to control for this confounding influence 

6. Comparability of cases and controls on the basis of the design or analysis: type and dose of 

psychotropic medication 

a. study controls for type and dose of psychotropic medication at baseline and in possible 

changes unrelated to the exposure during “intervening period” (1 point) 

b. study fails to control for this confounding influence 

7. Comparability of cases and controls on the basis of the design or analysis: omega-6 fatty acid 

intake 

a. study controls for omega-6 fatty acid intake at baseline and in possible changes unrelated to 

the exposure during “intervening period” (1 point) 

b. study fails to control for this confounding influence 

8. Ascertainment of exposure 

a. validated dietary assessment questionnaire or structured interview where blind to case/control 

status (1 point) 

b. interview not blinded to case/control status 

c. written self-report or medical record only 

d. no description 

9. Same method of ascertainment for cases and controls 

a. yes (1 point) 

b. no 

10. Non-response rate 

a. same rate for both groups (1 point) 

b. non respondents described 

c. rate different and no designation 

C-63
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

DESIGN: (MULTIPLE-GROUP) CROSS-SECTIONAL STUDY 

1. Control for selection bias 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

2. Description of the same validated method to distinguish the study populations (i.e., to 

confirm/diagnose the presence and absence of psychiatric disorder/condition in the target and 

control population(s), respectively) 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

3. Homogeneity of the target psychiatric population: psychiatric diagnosis/condition 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

4. Homogeneity of the target psychiatric population: psychotropic medication(s) and dose(s) 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

5. Comparability of study groups on the basis of the design or analysis: age and sex 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

6. Comparability of study groups on the basis of the design or analysis: current amount of 

omega-3 fatty acid intake in background diet 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

7. Comparability of study groups on the basis of the design or analysis: current amount of 

omega-6 fatty acid intake, or omega-6/omega-3 fatty acid intake, in background diet 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

C-64
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

8. Comparability of study groups on the basis of the design or analysis: current smoker status 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

9. Description of a validated primary clinical outcome measure(s)

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

10. Description of the same appropriate methods used to extract, prepare, store and analyze lipid 

data from all study populations 

a. No inappropriate descriptions = 1 

b. At least one inappropriate description = 0 

c. Different methods used for different study groups = 0 

d. Unable to determine for one or more of the methods = 0 

Uncontrolled Study Designs 

DESIGN: SINGLE PROSPECTIVE COHORT STUDY (Modified Newcastle-Ottawa) 

1. Representativeness of the exposed cohort 

a. Truly or somewhat representative of the average individual at no (or elevated) risk for a 

psychiatric disorder/symptoms in the community = 1 

b. Selected group of users e.g., nurses, volunteers = 0 

c. No description of the derivation of the cohort = 0 

2. Ascertainment of exposure 

a. Validated dietary assessment questionnaire or structured interview = 1 

b. Written self-report = 0 

c. No description = 0 

3. Demonstration that outcome of interest was not present at start of study 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

4. Description of a validated method to quantify the amount, per type, of omega-3 fatty acids 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0

C-65
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

5. Assessment of outcome 

a. Independent blind assessment = 1 

b. Record linkage = 1 

c. Self-report = 0 

d. No description = 0 

6. Was followup long enough for outcomes to occur?

a. Yes (5 years) = 1 

b. No = 0 

c. Unable to determine = 0 

7. Adequacy of followup of cohort 

a. Complete followup, all subjects accounted for = 1 

b. Subjects lost to followup unlikely to introduce bias, small number lost, at least 90% followup, 

or description provided of those lost = 1 

c. Followup rate of less than 90% and no description of those lost = 0 

8. Analytic control for confounding: age and sex 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0

9. Analytic control for confounding: omega-6 fatty acid intake or omega-6/omega-3 fatty acid 

intake ratio 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0

10. Analytic control for confounding: smoking history 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0

DESIGN: CROSS-SECTIONAL SURVEY

1. Description of appropriate sampling technique(s) to identify the sample population 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

2. Description of a validated method to identify/diagnose the target psychiatric 

disorder/condition 

C-66
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

3. Description of a validated method to identify the current intake of (foods or supplements 

containing) omega-3 fatty acids 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

4. Description of a validated method to quantify the amount, per type, of omega-3 fatty acids 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

5. Analytic control for confounding: age and sex 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

6. Analytic control for confounding: smoking history/status 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

7. Analytic control for confounding: severity of psychiatric disorder/condition 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

8. Analytic control for confounding: current intake of (foods or supplements containing) omega6 fatty acids or omega-6/omega-3 fatty acids 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

9. Response rate (at least 75%): 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

C-67
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

DESIGN: CROSS-NATIONAL ECOLOGICAL ANALYSIS 

1. Description of the same validated method to identify all of the target study populations 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

2. Description of the same validated method to identify intake of omega-3 fatty acids (from foods 

known to contain them) from all of the target study populations 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

3. Description of appropriate sampling techniques to identify all of the target populations 

a. Yes = 1 (random sampling; stratified sampling to represent key population elements; large 

enough) 

b. No = 0 

c. Unable to determine = 0 

4. Description of sampling or analytic techniques to control for possible confounding (i.e., 

factors that can influence diet or mental health): age and sex 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

5. Description of sampling or analytic techniques to control for possible confounding (i.e., 

factors that can influence diet or mental health): other social factors (e.g., education) 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

6. Description of sampling or analytic techniques to control for possible confounding (i.e., 

factors that can influence diet or mental health): economic factors 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

7. Description of sampling or analytic techniques to control for possible confounding (i.e., 

factors that can influence diet or mental health): omega-6 fatty acid intake, or omega-6/omega-3 

fatty acid intake ratio 

C-68
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

8. Description of sampling or analytic techniques to control for possible confounding (i.e., 

factors that can influence diet or mental health): smoking history/status 

a. Yes = 1 

b. No = 0 

c. Unable to determine = 0 

9. Description of analytic techniques to control for possible confounding (i.e., factors that can 

influence diet or mental health): re-analysis excluding outlier data 

a. Yes = 1 

b. No outlier data identified = 1 

c. No = 0 

d. Unable to determine = 0 

C-69
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

Applicability Indices 

For studies involving at least one target population identified with a psychiatric disorder or 

condition (i.e., symptom/behavior):1 

Assign ‘I’ to a target study population of otherwise “healthy” North American (or similar) individuals 

identified with a psychiatric disorder or condition, diagnosed using a “typical” North American 

methodology/nomenclature (e.g., DSM-IV) or identified using at least one established psychiatric 

research instrument, with or without comorbid psychiatric conditions, potentially receiving “typical” 

North American types of treatment (e.g., medication types and doses) for the primary diagnosis, 

representing a somewhat broad socio-demographic spectrum (i.e., gender, race), and eating a diet 

“typical” of a broad spectrum North American population (e.g., with an estimated omega-6/omega-3 

intake ratio of at least 15). 

Assign ‘II’ to a target study population of otherwise ‘healthy’ North American (or similar) individuals 

identified with a psychiatric disorder or condition, likely diagnosed using a ‘typical’ North American 

methodology/nomenclature (e.g., DSM-IV) or identified using at least one established psychiatric 

research instrument, with or without comorbid psychiatric conditions, likely receiving ‘typical’ North

American types of treatment (e.g., medication types and doses) for the primary diagnosis, yet representing 

a more circumscribed socio-demographic picture (e.g., Asian-American/Canadian), and likely eating a 

diet “somewhat different” from that of a broad spectrum North American population (e.g., with an 

estimated omega-6/omega-3 intake ratio notably less than 15, yet likely not reaching a value of 4, such as 

observed in Japan). 

Assign ‘III’ to a target study population identified with a psychiatric disorder or condition, with or 

without comorbid psychiatric conditions, potentially diagnosed using a methodology/nomenclature or an 

established psychiatric research instrument other than a “typical” North American one, receiving 

treatment (e.g., medication types and doses) for the primary diagnosis that is potentially “atypical” of 

North America, representing a population whose socio-demographic characteristics are notably “atypical” 

of a broad spectrum North American population, and eating a diet that is “notably different” from that of 

a broad spectrum North American population (e.g., with an estimated omega-6/omega-3 intake ratio 

perhaps reaching a value of 4, such as observed in Japan, or 38-50, as observed in urban India). 

Assign ‘X’ when applicability cannot be ascertained due to incomplete or conflicting reporting of the 

details concerning the target study population, particularly relating to the primary diagnosis/condition 

and/or the background diet. 

1

Note that a control group (e.g., within a case-control design) might have been composed of 

individuals without an identified psychiatric diagnosis or condition. 

C-70
Appendix C. Data Assessment and Data Abstraction Forms (continued) 

For studies involving a target population with or without a known elevated risk for a psychiatric 

disorder or condition (i.e., symptom/behavior): 

Assign ‘I’ to a target study population of otherwise “healthy” North American (or similar) individuals, 

with or without a known elevated risk for onset of a psychiatric disorder or problems, representing a 

somewhat broad socio-demographic spectrum (i.e., gender, race), and eating a diet “typical” of a broad 

spectrum North American population (e.g., with an omega-6/omega-3 intake ratio of at least 15). 

Assign ‘II’ to a target study population of otherwise “healthy” North American (or similar) individuals, 

with or without a known elevated risk for onset of a psychiatric disorder or problems, yet representing a 

more circumscribed socio-demographic picture (e.g., Asian-American/Canadian), and likely eating a diet 

“somewhat different” from that of a broad spectrum North American population (e.g., with an omega6/omega-3 intake ratio notably less than 15, yet likely not reaching a value of 4, as observed in Japan). 

Assign ‘III’ to a target study population of otherwise “healthy” individuals, with or without a known 

elevated risk for onset of a psychiatric disorder or problems, yet representing a very circumscribed 

population whose socio-demographic characteristics are “notably atypical” of a broad spectrum North 

American population, and eating a diet that is “notably different” from that of a broad spectrum North 

American population (e.g., with an omega-6/omega-3 intake ratio perhaps reaching a value of 4, such as 

observed in Japan, or 38-50, as observed in urban India). 

Assign ‘X’ when applicability cannot be ascertained due to incomplete or conflicting reporting of the 

details concerning the target study population, particularly relating to the background diet.

C-71
Appendix D. Modified QUOROM Flow Chart 

Modified QUOROM Flow Chart 

Potentially relevant citations identified and screened for possible retrieval (n = 1212)

Citations excluded via screening of bibliographic records, with reasons (n = 955):

a. not a first publication of empirical evidence (e.g., review) (n = 500);

b. not involving human participants (n = 216);

c. no omega-3 fatty acid focus (intervention/exposure or biomarkers) (n = 167); &,

d. not related to predefined mental health outcomes (n = 72)

Reports retrieved for more detailed assessment of relevance (n = 257)

Reports excluded via Level 2 relevance assessment, with reasons (n = 137):

a. not a first publication of empirical evidence (e.g., review) (n = 91);

b. not involving human participants (n = 7);

c. no omega-3 fatty acid focus (intervention/exposure or biomarkers) (n = 23); &,

d. not related to predefined mental health outcomes (n = 16)

Reports excluded via Level 3 relevance assessment, with reasons (n = 27)

a. uncontrolled study (n = 27)

Other reports not proceeding, with reasons (n = 7)

a. never retrieved (n = 7)

Reports (n = 86) describing unique studies (n = 79) entered into qualitative synthesis

and, eligible for inclusion in meta-analysis (i.e., 6 studies were each described by > 2

reports)

Meta-analysis conducted for studies investigating the supplemental treatment of

schizophrenia (n = 4).

D-1
Appendix E. Evidence Tables 

E-1

Evidence Table 1: Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Akkerhuis, 

2003, 

NR 

[NR]: 

4 wk 

“Controlled 

Study” 

{15} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: 

n=NR/NR 

• Age (M & range): NR • % Male: NR

• Race: NR

• Disease: bipolar disorder • Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): NR 

• Maximum 6g/d EPA ethyl ester • n=NR/NR 

• placebo (undefined• n=NR/NR

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; NBD = not broken down; tx = treatment; meds = medication/medicated; SD = standard 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-2

Evidence Table 1 (continued): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Brue, 

2001, 

US 

[1]: 

12 wk 

parallel 

RCT 

{1785} 

• Inclusion: 

DSM-IV for AD/HD 

• Exclusion: 

serious & preexisting medical or psychological conditions, stimulant meds besides Ritalin 

• Enrolled/completed: 

n=60/51 

• Age (M & range): 8.4 (4-

12) y 

• % Male: 86% 

• Race: NR• Disease: AD/HD (DSMIV) 

• Duration: NR • Interventions: non-Ritalin 

pts n-3: ginkgo biloba, melissa officinalis, grapine, dimethyaminoethanol, Lglutamine; ritalin pts n-3: Ritalin + ginkgo biloba, melissa officinalis, grapine, dimethyaminoethanol, Lglutamine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Ritalin users: 1.0 g/d n-3, from 

NR (flaxseed) capsules 2/d, with breakfast & afternoon snack or dinner 

• Diet: NR • Cointerventions: NR • n=15/15 

• non-Ritalin users: 1.0 g/d n

from NR (flaxseed) capsule2/d, with breakfast & afternoon snack or dinner 

• Diet: NR • n=15/15 • non-Ritalin users: 0 g/d n-3

from NR (slippery elm) capsules 2/d, with breakfasafternoon snack or dinner 

• n=15/15 • Ritalin users: 0 g/d n-3, from 

NR (slippery elm) capsules 2x/d, with breakfast & afternoon snack or dinner 

• n=15/15 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; AD/HD = attention deficit/hype

3 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-3

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Emsley, 

2002, 

South 

Africa 

[1]: 

12 wk 

parallel 

RCT 

{89} 

• Inclusion: 18-55 

y, DSM-IV criteria for schizophrenia, received fixed doses of antipsychotics >6 mo, PANSS total score >50 

• Exclusion: 

substance abuse, significant medical conditions 

• Enrolled/completed: 

n=40/39 

• Age (M & SD): E-EPA: 

46.2 (10.6) y; pb: 43.6 (13.9) y

• % Male: NR• Race: NR• Disease: schizophrenia 

disorder (DSM-IV; antipsychotics >6 mo; PANSS score >50) 

• Duration: E-EPA: 23.1 

(8.5) y; pb: 22.2 (12.4) y 

• Interventions: 

chlorpromazine, clozapine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• 3 g/d E-EPA, from 3x2 [0.5 

g gelcap] capsules/d 

• Diet: unchanged; EPA: 0.56 

g/wk to 1.13g/wk 

• n=20/19 

• 3 g/d liquid paraffin oil, fro

3x2 [0.5 g gelcap] capsules/d 

• Diet: unchanged; EPA: 0.5

g/wk to 1.13 g/wk 

• n=20/20 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; EPA = eicosapentaenoic acid; 

Negative Syndrome Scale 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-4

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Fenton, 

2001, 

US 

[1]: 

16 wk 

parallel 

RCT 

{84} 

• Inclusion: 18-65 y, DSMIV criteria for 

schizophrenia/schizoaffective disorder, no change of meds in prior 30 d, pharmacological tx that conforms to schizophrenia pt outcome research team, residual symptoms defined as ≥ 1 

(+) &/or (-) symptom scores >4, total scores >45 with a score of >3 on ≥ 3 (+) or (-) items on the (+) & (-) PANSS scale 

• Exclusion: substance 

dependence/mental retardation, bleeding disorder, fish oil supplements, anticoagulants, cholestyramine, or clofibrate antilipemic agents 

• Enrolled/completed: 

n=90/75 

• Age (M & SD): 40 (10) y

• % Male: 61%

• Race: White 84%

• Disease: schizophrenia 

disorder, schizoaffective disorder (DSM-IV) 

• Duration: NR • Interventions: neuroleptic, 

risperidone, olanzapine, quetiapine, clozapine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): NS 

• 3 g/d EPA, from 6 

[gelcap] E-EPA capsules/d; 4mg vitamin E per capsule 

• Diet: maintain 

background diet; 0.367 (0.378) g/d, likely EPA or DHA, from fish in diet 

• n=45/37 

• 3 g/d mineral oil, from 

6 [gelcap] capsules/d; 4mg vitamin E per capsule 

• Diet: maintain 

background diet; 0.367 (0.378) g/d, likely EPA or DHA, from fish in diet 

• n=45/38 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; tx = treatment; meds = medication/medicated; SD = standard deviation; EPA = eicosap

docosahexaenoic acid; (+) = positive; (-) = negative; PANSS = Positive and Negative Syndrome Scale 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-5

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Fux, 

2004, 

Israel 

[1]: 

6 wk 

crossover 

RCT 

{3064} 

• Inclusion: current 

OCD according to DSM-IV, 18-75 y, currently on stable maximally tolerated dose of SSRI, response to tx but no further improvement over the last 2 mo 

• Exclusion: unstable 

medical disease, alcohol/drug abuse, comorbid Axis II psychiatric diagnosis 

• Enrolled/completed: 

n=11/10 

• Age (M & SD): 33.5 (5) y• % Male: 27%• Race: NR • Disease: OCD (DSM-IV; 

YBOCS: 26.0 (5); HDRS: 11.3 (7); HAM-A: 14.3 (8) 

• Duration: 14.1 ± 8 y • Interventions: paroxetine, 

fluvoxamine, fluoxetine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• 2 g/d E-EPA for 6 wk, from 

4 [0.5 g gelcap] fish oil capsules/d, 0.2% vitamin E 

• capsules: 96% pure semisynthetic ethyl-EPA, 4 % 

other fatty acids 

• Diet: NR • Cointerventions: NR • n=11/10 

• 2 g/d liquid paraffin oil 

6 wk 

• Capsules/d: NR • Diet: NR • n=11/10 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; SSRI = selective serotonin reuptake inhibitors; OCD = obsessive compulsive disorder; tx = treatment; meds = med

standard deviation; HAM-A = Hamilton Anxiety Rating Scale; HDRS = Hamilton Depression Rating Scale; YBOCS = Yale-Brown Obsess

eicosapentaenoic acid; OCD = Obsessive compulsive disorder 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-6

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Gesch, 

2002, 

UK 

[1]: 

~142-d 

(mean) 

parallel 

RCT 

{1772} 

• Inclusion: >18 

y 

• Exclusion: NR 

• Enrolled/completed: 

n=231/112 

• Age (M & range): NR

• % Male: NR• Race: NR • Disease: antisocial 

behaviour status 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• 0.08 g/d EPA, 0.044 g/d DHA, 

from 4 capsules/d 

• Diet: permitted: 1.26 g/d LA, 

0.16 g/d GLA 

• n=NR/57 

• NR, likely trace g/d EPA, 

trace g/d DHA, from 4 capsules/d (vegetable, oilbased) 

• Diet: NR • n=NR/55 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; meds = medication/medicated; SD = standard deviation; EPA = eicosapentaenoic acid; DHA = docosahexaenoic a
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-7

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hamazaki, 

2002, 

Thailand, 

[≥2]: 

2 mo 

parallel 

RCT 

{97} 

• Inclusion: elderly 

residents from farming village & employees of a university, no meds regularly 

• Exclusion: 

myocardial/cerebral infarction, cancer, other disease including alcoholism & severe hypertension 

• Enrolled/completed: 

n=41/40 

• Age (M & range): NR 

(50-60) y 

• % Male: 53.6% 

• Race: Thai 100%• Disease: healthy 

volunteers 

• Biomarkers (S 

between-grp differences): NS 

• 1.5 g/d DHA, 0.2 g/d EPA, 

from 10 fish oil capsules/d (3 g/d), after each meal or after two of the three meals/d 

• Diet: maintain background 

diet 

• n=20/19 

• 54.1% LA (n-6), 22.3% olei

acid (n-9), 10.8% palmitic a(n-7), 6.8% ALA (18:3n-3), 3.7% stearic acid, 0.5% (probably trace) DHA, from fish oil capsules/d (3 g/d mixed plant oil) after each meal or after 2 of 3 meals/d 

• Diet: maintain background 

diet 

• n=21/21 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; EPA = eicosapentaenoic acid; 

LA = linoleic acid; ALA = alpha linolenic acid 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-8

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hamazaki, 

1998, 

Japan 

[2]: 

3 mo 

parallel 

RCT 

{236} 

• Inclusion: 

nonsmoking students, good health determined by hx & physical exam, no chronic illness including alcoholism, no meds regularly 

• Exclusion: <70% 

capsule intake, > 3 kg changes in body weight, decrease in RBC DHA (DHA group only) 

• Enrolled/completed: 

n=59/46 

• Age (mean & range): 

Toyama: 22 (21-30) y; Kogakkan: NR (20-22) y

• % Male: 50.8% 

• Race: likely Asian• Disease: healthy volunteers • Biomarkers (S between-grp 

differences): NS 

• 1.5 g/d DHA, from 10 fish 

oil capsules/d, after each meal or after two of the three meals/d 

• Diet: maintain background 

diet 

• n=29/22 

• 54.1% linoleic acid, 22.3% 

oleic acid, 10.8% palmitic acid, 6.8% alpha linolenic acid, 3.7% stearic acid, 0.5% (probably trace) DHA, from fish oil capsules/d, after eacmeal or after two of the thremeals/d; 

• Diet: maintain background 

diet 

• n=30/24 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation;; RBC = red blood cells; DHA = 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-9

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hamazaki, 

1996, 

Japan 

[2]: 

3 mo 

parallel 

RCT 

{293} 

• Inclusion: 

healthy, nonsmoking, volunteers from 2 universities, no meds regularly 

• Exclusion: NR 

• Enrolled/completed: 

n=53/41 

• Age (median & range): 

Toyama: 22 (21-30) y; Yokkaichi: NR (19-20) y

• % Male: 35.8%• Race: Likely Asian• Disease: healthy 

volunteers 

• Biomarkers (S betweengrp differences): NS 

• 1.5 to 1.8 g/d DHA & some 

EPA, from 10 to 12 fish oil capsules/d (depending on pts weight), after each meal or after two of the three meals/d 

• Diet: maintain background diet • n=27/22 

• 54.1% LA (n-6), 22.3% olei

acid (n-9), 10.8% palmitic a(n-7), 6.8% alpha-linolenic acid (18:3n-3), 3.7% stearic acid, 0.5% (probably trace) DHA, from 10 to 12 (depending on pt’s weight) capsules/d, from 97% soybean oil + 3% fish oil afteach meal or after 2 of 3 meals/d 

• Diet: maintain background 

diet 

• n=26/20 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; DHA = docosahexaenoic acid
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-10

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design 

Eligibility 

Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Harding, 

2003, 

US 

[1]: 

4 wk 

comparative 

before-after 

study 

{1631} 

• Inclusion: 

age 7-12 y 

• Exclusion: 

pts with comorbid disorders, meds use, street drugs, other nutritional or botanical supplements 

• Enrolled/completed: 

20/20 

• Age (M & range): NR (7-

12) y

• % Male: NR • Race: NR• Disease: AD/HD (DSMIV) • Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• 0.18 g/d EPA, 0.12 g/d DHA, 

from NR capsules, vitamin E and other vitamins (B1, B2, B3, B5, B6, B12, C, A, D3, K) Folic acid, Biotin 

• n=10/10 

• Ritalin • n=10/10 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; AD/HD = attention deficit/hype

eicosapentaenoic acid 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-11

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hirayama, 

2004, 

Japan 

 [1]: 

2 mo 

parallel 

RCT 

{3041} 

• Inclusion: 

children 6-12 y, suspected or diagnosed AD/HD according to DSMIV & diagnostic interviews including behavioral observations by psychiatrists 

• Exclusion: NR 

• Enrolled/completed: n=40/40 • Age (M & range): n-3: 9 (6.8-

11.3) y; pb: 9 (7-10.3) y 

• % Male: n-3: 80%; pb: 80%

• Race: likely Asian • Disease: AD/HD (DSM-IV; N 

of symptoms, median scores – pts: 11 (7.5-4.5) 

• Duration: NR • Interventions: 

methylphenidate, risperidone, carbamazepine, fluvoxamine, sulpiride 

• Concurrent: Asperger's 

syndrome, conduct disorder, learning disorder, mood disorder 

• Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• 3.6g/wk DHA, 0.7g/wk EPA, 

from fish oil mixed with soybean milk, bread rolls & steamed bread 2/wk 

• n=20/20 

• olive oil placebo • n=20/20 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; DHA = docosahexaenoic acid

AD/HD = attention deficit/hyperactivity disorder 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-12

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Llorente, 

2003, 

US 

[1]: 

4 mo 

parallel 

RCT 

{26} 

• Inclusion: pregnant 

women, 18-42 y, planned to breastfeed their infants for ≥ 4 mo, not been 

pregnant >5 times 

• Exclusion: chronic 

medical conditions, taking dietary supplements other than vitamins, smoking 

• Enrolled/completed: 

n=138/89 

• Age (M & SD): DHA: 31.2 

(4.28) y; pb: 31.7 (4.86) y

• % Male: 0%• Race: White (82%), Black 

(NR), Hispanic (NR)

• Disease: N/A (BDI M & 

(SD): pb: 6.5 (4.2); DHA: 7.1 (4.7)) 

• Biomarkers (S between-grp 

differences): NS 

• 0.2 g/d DHA, from 1 

[algae-derived TG] capsule/d 

• n=NR/44 

• 0 g/d DHA, from 1 

[algae-derived TG] capsule/d 

• n=NR/45 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; DHA = docosahexaenoic acid 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-13

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Marangell, 

2003, 

US 

 [1]: 

6 wk 

parallel 

RCT 

{27} 

• Inclusion: 18-65 y, 

MADRS score >12, 

HDRS score >17, no psychotropic meds for at ≥ 2 wk, only 1 serving of fish/wk 

• Exclusion: comorbid 

psychiatric or medical illness, tx resistance (lifetime failure of >2 

antidepressant trials) 

• Enrolled/

completed: n=36/35 

• Age (M & SD): n-3: 46.9 

(11.6) y; pb: 47.9 (11.2) y

• % Male: n-3: 22.2%; pb: 

17.6%

• Race: NR

• Disease: major 

depressive disorder (DSM-IV) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): active 

= pb (no test reported) 

• 2 g/d DHA • Diet: NR • Cointerventions: NR • n=18/18 

• 0 g/d DHA (placebo: 

source undefined) 

• Capsules/d: NR • Diet: NR • n=18/17 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; MADRS = Montgomery Asberg Depression Rating Scale; HDRS = Hamilton Depressio

meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-14

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Nemets, 

2002, 

Israel 

[1]: 

4 wk 

parallel 

RCT 

{101} 

• Inclusion: major 

depressive disorder (DSM-IV); 18-75 y 

• Exclusion: alcohol/drug 

abuse, unstable medical disease, psychotic features, hypomania/mania, comorbid psychiatric diagnosis (except panic disorder, dysthymic disorder, OCD) 

• Enrolled/completed: 

n=20/19 

• Age (M & range): 53.4 

(28-73) y

• % Male: 15% • Race: Middle Eastern

• Disease: major 

depressive disorder (DSM-IV; HDRS >18) 

• Duration: EPA: 7.6 (7.6) 

y; pb: 8.0 (6.5) y 

• Interventions: fluoxetine, 

mirtazapine, paroxetine, fluvoxamine, citalopram, moclobernide 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• 2 g/d E-EPA from 2 

[unclear whether 0.5g or 1 g gelatin capsules] fish oil capsules/d 

• E-EPA (ethyl ester of 

EPA) derived from 96 % pure fish oil, amount probably of EPA & DHA (fish oil, 4% of total dose), vitamin E corresponding to 0.2% of total dose 

• Diet: NR • Cointerventions: NR • n=10/10 

• 0 g/d E-EPA, from 2g/d 

placebo, from 0.5g gelatin capsules 

• Capsules/d: NR • Diet: NR • n=10/9 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; HDRS = Hamilton Depression Rating Scale; OCD = Obsessive compulsive disorder; tx 

medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-15

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Ness, 

2003, 

Wales 

[1]: 

6 mo 

parallel 

RCT (one 

factor in 

factorial 

RCT) 

{1701} 

• Inclusion: 37-70 y, 

males, tx for angina 

• Exclusion: denying 

ever having stress related chest pain, awaiting coronary artery bypass surgery, eat oily fish 2/wk, can’t tolerate oily fish, serious illness, likelihood of moving from the area 

• Enrolled/completed: 

n=452/377 

• Age (M & SD): fish 

advice: 61.1 (6.7) y; no fish advice: 61.4 (6.2) y

• % Male: 100% • Race: NR• Disease: angina 

pectoris 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S 

between-grp differences): N/A 

• Diet: advice to eat more fatty 

fish (mackerel, herring, kipper, pilchard, sardine, salmon or trout), eat more fruit & vegetables, & stress management; 78% pts ate fatty fish wkly or took MaxEPA® capsules if could not tolerate taste of fish 

• Cointerventions: NR • n=229/226 

• NR (no fish advice) • Capsules/d: NR • Diet: no fish, fruit & 

vegetable, or stress management advice; 14% of pts had fish in tdiet 

• n=223/219 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; tx = treatment; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-16

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Peet, 

2002, 

England, 

Scotland 

[NR, likely 

2]: 

12 wk 

parallel 

RCT 

{87} 

• Inclusion: 18-70 y, 

>15 on HDRS, ongoing tx with 

antidepressants at adequate dose 

• Exclusion: NR 

• Enrolled/completed: 

n=70/60 

• Age (M & range): 44.8 y• % Male: 15.7%• Race: NR• Disease: depression 

(HRSD; score >15) 

• Duration: NR • Interventions: tricyclics, 

SSRIs, 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• 4.0 g/d E-EPA (E-EPA), from 

2x4 (500 mg gelcap) capsules/d, morning & evening 

• Diet: NR • Cointerventions: NR • n=17/15 

• 2.0 g/d E-EPA, from 2x2 

(500 mg gelcap) capsules/d, 0 g/d E-EPA from 2 x 2 (500 mg gelcaliquid paraffin capsules/dmorning & evening 

• Diet: NR • n=18/16 • 1.0 g/d E-EPA, from 2x1 

(500 mg gelcap) capsules/d, 0 g/d E-EPA from 2 x 3 (500 mg gelcaliquid paraffin capsules/dmorning & evening 

• n=17/15 • 0 g/d E-EPA, from 2x4 (5

mg gelcap) liquid paraffin capsules/d, morning & evening 

• n=18/14 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; SSRI = selective serotonin reuptake inhibitors; HDRS = Hamilton Depression Rating Sc

medication/medicated; SD = standard deviation; tx = treatment 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-17

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Peet, 

2002, 

England 

[9]: 

12 wk 

parallel 

RCT 

{104} 

• Inclusion: met 

DSM-IV criteria for schizophrenia, 18-70 y, time since 1st

diagnosis < 20 y, 

no important medical conditions 

• Exclusion: NR 

• Enrolled/completed: 

n=122/109 

• Age (M & range): pb: 39 (22-

61) y; EPA 1g: 38 (20-60) y; EPA 2g: 34 (20-62) y; EPA 4g: 37 (20-56) y

• % Male: pb: 65%: EPA 1g: 

66%: EPA 2g: 71%; EPA 4g: 63%

• Race: NR• Disease: schizophrenic 

disorder (DSM-IV; >50 on PANSS, >15 on Positive Symptoms subscale) 

• Duration: <20 y 

• Interventions: clozapine, 

olanzapine, risperidone, quetiapine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): NR 

• 4 g/d E-EPA, from 4x2 

[gelcap] E-EPA capsules/d, morning & evening 

• Diet: NR • Cointerventions: NR • n=27/25 

• 2 g/d E-EPA, from 4 [gelcap

E-EPA capsules/d; 2 g/d liquid paraffin, from 4 [gelcacapsules/d, morning & evening 

• Diet: NR • n=32/24 • 1 g/d E-EPA, from 2 [gelcap

E-EPA capsules/d; 3 g/d liquid paraffin, from 6 [gelcacapsules/d, morning & evening 

• Diet: NR • n=32/29 • 0 g/d E-EPA, from 4 g/d liqu

paraffin, from 4 x 2 [gelcap] capsules/d, morning & evening 

• Diet: NR • n=31/28 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; PANSS = Positive and Negati
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-18

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Peet, 

2001, 

India 

[1]: 

3 mo 

parallel 

RCT 

{140} 

• Inclusion: DSM-IV 

diagnosis of schizophrenia, symptomatic with PANSS score >40 

• Exclusion: significant 

physical illness or other psychiatric disorders, antipsychotic meds 

• Enrolled/completed: n=30/26 • Age (M & SD): EPA: 33.4 ± 8.5 

y; pb: 36.7 ± 8.1 y

• % Male: NR• Race: NR• Disease: schizophrenic disorder 

(DSM-IV; 100% symptomatic, PANSS score > 40) 

• Duration: EPA: 5.7 (3.9) y; pb: 

7.1 (4.1) y 

• Interventions: flupenthixol, 

haloperidol, clozapine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): EPA = ctrl (no test reported) 

• 2 g/d EPA, from EPA 

enriched oil 

• Diet: NR • Cointerventions: NR • n=15/14 

• 2 g/d corn oil (pb) • Diet: NR • n=15/12 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; tx = treatment; meds = medication/medicated; SD = standard deviation; PANSS = Posi

Scale 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-19

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Peet, 

2001, 

England 

[1]: 

3 mo 

parallel 

RCT 

{140} 

• Inclusion: DSMIV diagnosis of 

schizophrenia, symptomatic with a PANSS score > 40, on 

stable antipsychotic meds 

• Exclusion: 

physical illness/other psychiatric disorders 

• Enrolled/completed: 

n=55/45

• Age (M & range): EPA: 44.2 

(11.3) y; DHA: 42.0 (10.6) y; pb: 43.8 (10.8) y

• % Male: EPA: 67%; DHA: 

75%; pb: 57% 

• Race: NR• Disease: schizophrenic 

disorder (DSM-IV; PANSS 

>40) 

• Duration: NR • Interventions: 

antipsychotics, anticholinergic meds 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): EPA = DHA = ctrl (no test reported) 

• 2 g/d DHA, from DHA 

enriched oil 

• Diet: NR • Cointerventions: NR • n=NR/16 

• 2 g/d EPA, from EPA 

enriched fish oil 

• Capsules/d: NR • Diet: NR • n=NR/15 • 2 g/d corn oil (pb) • Capsules/d: NR • Diet: NR • n=NR/14 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; tx = treatment; meds = medication/medicated; SD = standard deviation; PANSS = Posi

Scale 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-20

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Richardson, 

2002, 

UK 

 [1]: 

12 wk 

parallel 

RCT 

{1819} 

• Inclusion: ability normal 

range on BAS, reading (BAS) >2 SD below expected level, English as 1st language, 

endorsement from family physician, above avg. scores for age on parent rating scales (AD/HD) 

• Exclusion: use of fatty 

acid supplements in last 6 mo, eat oily fish >2/wk, hx of neurological/major psychiatric disorder or medical problem, receiving tx for AD/HD 

• Enrolled/completed: 

n=41/29 

• Age (M & range): 10.25 

(8-12) y 

• % Male: HUFA: 82%; pb: 

89%

• Race: White 100% 

• Disease: learning 

difficulties, AD/HD (DSMIV) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• 0.186 g/d EPA, 0.48 g/d 

DHA, from 8 capsules/d; 0.096 g/d GLA (18:3n-3), 0.864 g/d cis-linoleic acid (n-6), 0.042 g/d AA, vitamin E & 8 mg/d thyme 

• Diet: NR • Cointerventions: NR • n=22/15 

• 0 g/d EPA, 0 g/d DH

from 8 capsules/d; olive oil (n-9) 

• Diet: NR • n=19/14 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; tx = treatment; meds = medication/medicated; SD = standard deviation; BAS = British A

attention deficit/hyperactivity disorder; ALA = alpha linolenic acid; AA = arachidonic acid 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-21

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Stevens, 

2003, 

US 

[1]: 

4 mo 

parallel 

RCT 

{3107} 

• Inclusion: 6-13 y, 

AD/HD diagnosed by clinical psychologist, psychiatrist or paediatrician, thirst/skin problems, with a thirst/skin score of >4 

• Exclusion: age, 

distance from test site, inability to swallow capsules, lack of interest, chronic illness 

• Enrolled/completed: 

n=50/33 

• Age (M & SD): n-3: 9.5 

(1.7) y; pb: 10.1 (2.0) y

• % Male: n-3: 88.9%; pb: 

86.7%

• Race: NR• Disease: ADHD • Duration: NR • Interventions: 

methylphenidate 

• Concurrent: thirst/skin 

symptoms 

• Cointerventions: NR • Biomarkers (S betweengrp differences): NS 

• 0.48 g/d DHA, 0.08 g/d EPA, 

0.04 g/d AA, 0.096 g/d GLA, 0.024 g/d vitamin E, from 8 [PUFA] capsules/d 

• Diet: NR • Cointerventions: NR • n=25/18 

• 6.4 g/d olive oil, from 8 

capsules/d 

• Diet: NR • n=25/15 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; AD/HD = attention deficit/hype
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-22

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Stoll, 

1999, 

US 

[2] 

4 mo 

parallel 

RCT 

{213} 

• Inclusion: male or 

female, 18-65 y, met DSM-IV criteria for bipolar disorder (types I or II), free medical & psychiatric comorbidity, ≥ 1 

manic or hypomanic episode within last y 

• Exclusion: no new 

psychotherapy tx 

• Enrolled/completed: n=44/30 • Age (M & SD): n-3: 14.4 (6.8) y; 

pb: 44.6 (10.4) y

• % Male: n-3: 35.7%; pb: 31.25%

• Race: NR • Disease: bipolar disorder (types I 

or II) (DSM-IV; ≥ 1 manic or 

hypomanic episode within past y, major depression, euthymic, mania phase) 

• Duration: NR • Interventions: carbamazepine, 

gabapentin, sertraline, lithium, bupropion, alprazolam, divalproex, sertraline, trazodone, lamotrigine, bupropion, paroxetine, clonazepam 

• Concurrent: NR • Cointerventions: psychiatrist or 

psychotherapist 

• Biomarkers (S between-grp 

differences): N/A 

• 6.2 g/d EPA, 3.4 g/d 

DHA, from 2x7 [1g gelatin outer] menhaden fish oil capsules/d; 0.2mg tbutylhydroquinone & 2mg tocopherols per capsule 

• Diet: NR • Cointerventions: NR • n=~22/14 

• 9.6 g/d olive oil ethyl 

ester, from 2x7 [1g gelatin outer] olive oil capsules/d; 0.2mg tbutylhydroquinone & 2tocopherols per capsul

• Diet: NR • n=~22/16 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; NARSAD = National Alliance and Depression 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-23

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Su, 

2003, 

China 

[1]: 

8 wk 

parallel 

RCT 

{5} 

• Inclusion: major 

depressive disorder pts (DSM-IV); no other comorbid Axis I or Axis II conditions, Rated >18 on HDRS, no change in meds or psychotherapy 4 wks prior to study, physically healthy, competent to understand study 

• Exclusion: NR 

• Enrolled/completed: 

n=28/22 

• Age (M & SD): n-3: 35.2 

(11.6) y; pb: 42.3 (10.7) y

• % Male: pb: 20%; n-3: 16%

• Race: likely Asian • Disease: major depressive 

disorder (DSM-IV; >18 HRSD) 

• Duration: NR • Interventions: fluoxetine 

equivalent 

• Concurrent: NR • Cointerventions: 

psychotherapy 

• Biomarkers (S between-grp 

differences): NR 

• 0.44 g/d EPA, 0.22 g/d DHA, 

from 2 x 5 (gelcap) fish oil (menhaden) capsules/d; 0.2mg/g t-butylhydroquinone & 0.2mg/g tocopherols (antioxidants); orange flavor 

• Diet: NR • Cointerventions: NR • n=14/12 

• NR, (probably trace) 

amount EPA & DHAfrom 2 x NR (gelcap) capsules/d, olive oil ester, same antioxidants as n-3 g

• Diet: NR • n=14/10 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; HDRS = Hamilton Depression Rating Scale; tx = treatment; meds = medication/medica
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-24

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Voigt, 

2001, 

US 

[1]: 

4 mo 

parallel 

RCT 

{132} 

• Inclusion: diagnosis of 

AD/HD by physician, met DSM-IV criteria for AD/HD, tx successfully with stimulant meds, clinical impairment in social/academic functioning 

• Exclusion: ineffective tx 

with stimulant meds, other psychotropics, other childhood psychiatric disorders, dietary supplements other than vitamins, significant life event in last 6 mo, hx of head injuries/seizures, mental retardation/ pervasive developmental disorder, premature birth, exposure to alcohol, tobacco/other drugs in utero, disorder of lipid metabolism/other chronic medical condition 

• Enrolled/completed: 

n=63/54 

• Age (M & SD): n-3: 9.1 

(2.1) y; pb: 9.5 (1.7) y

• % Male: n-3: 78%; pb: 

78%

• Race: n-3: 100% white; 

pb: 85%

• Disease: AD/HD 

(DSM-IV) 

• Duration: NR • Interventions: 

methylphenidate, dextroamphetamine, amphetamine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S 

between-grp differences): active = pb (no test reported) 

• 0.345 g/d DHA, from 1 

algae-derived triglyceride capsule/d 

• Diet: NR • Cointerventions: NR • n=32/27 

• NR • Capsules/d: NR • Diet: NR • n=31/27 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; AD/HD = attention deficit/hype
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-25

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Wardle, 

2000, 

England 

[1]: 

12 wk 

parallel 

RCT 

{1522} 

• Inclusion: serum 

cholesterol level >5.2 mM, no serious illness, no current/previous (within 3 mo) use of lipid-lowering meds, physician's permission to participate, signed informed consent 

• Exclusion: pregnancy, 

lactation, planning to become pregnant, serum cholesterol level >7.8 mM, use of lipid lowering meds in last 3 mo 

• Enrolled/completed: 

n=176/155 

• Age (M & SD): Low fat: 

52 (11) y; Mediterranean: 54 (11) y; ctrl: 53 (8) y

• % Male: Low fat: 58%; 

Mediterranean: 44%; ctrl: 43%

• Race: NR• Disease: 

hypercholesterolemia 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S 

between-grp differences): N/A 

• Mediterranean diet, rich in 

oily fish, monounsaturated fatty acid, fruit & vegetables 

• Diet: increase in fruit & 

vegetables & oily fish; reduction in fat to 30% of energy, with substitution of predominantly monounsaturated fats for saturated fats 

• Cointerventions: NR • n=61/53 

• Low fat diet, rich in 

polyunsaturated fats, low saturated fats 

• Capsules/d: NR • Diet: increase 

polyunsaturated fats & decrease saturated fats ithe diet 

• n=59/52 • controls not given specific 

advice in diet 

• Capsules/d: NR • Diet: maintain backgroun

diet 

• n=56/50 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; tx = treatment; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-26

Evidence Table 1 (cont’d): Experimental study evidence for the effects of omega-3 fatty acids on mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Zanarini, 

2003, 

US 

[1]: 

8 wk 

parallel 

RCT 

{64} 

• Inclusion: women, age 18-

40 y, met DSM-IV criteria for borderline personality disorder 

• Exclusion: medically ill, 

currently on psychotropic drugs, taking E-EPA supplements or had >1-2 servings of fatty fish/wk, abusing alcohol/actively suicidal, met criteria for schizophrenia, schizoaffective disorder, bipolar I or II disorder, currently in a major depressive episode 

• Enrolled/completed: 

n=30/27 

• Age (M & SD): 26.3 (6.2) 

y

• % Male: 0%• Race: White 76.7% 

• Disease: borderline 

personality disorder (DSM-IV) 

• Duration: NR • Interventions: 

psychotropic medications 

• Concurrent: NR • Cointerventions: 

psychotherapy 

• Biomarkers (S betweengrp differences): N/A 

• 1.0 g/d E-EPA, from 2 

[0.5 g] capsules/d 

• Diet: NR • Cointerventions: NR • n=20/18 

• 0 g/d E-EPA, from 2 

(mineral oil) capsules/d 

• Diet: NR • n=10/9 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; tx = treatment; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-27

Evidence Table 2: Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

 N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Alling, 

1984, 

Sweden 

[1]: 

N/A (i.e., no 

followup in 

crosssectional 

studies), 

Multiplegroup 

crosssectional 

study 

 {429} 

• Inclusion: pts: 

chronic alcoholics; ctrl: meds free, no somatic or mental illness 

• Exclusion: NR 

• Enrolled/completed: 

n=34/34 

• Age (M & range): pts: 54 

(41-68) y; ctrl: 39 (22-58) y

• % Male: 100%• Race: NR• Disease: chronic 

alcoholism 

• Duration: 19 (10-37) y • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A (i.e., 

no followup in crosssectional designs) 

• Chronic alcoholics • n=13 

• Healthy controls • n=21 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicable; NR = not reported; ctrl = control(s); M 

medication/medicated 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-28

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Amore, 

2003, 

Italy 

[2]: 

N/A, 

Casecontrol 

study 

{7} 

• Inclusion: 

schizophrenic pts, living mother 

• Exclusion: 

refusal either by pt or mother to participate 

• Enrolled/completed: 

n=366

• Age (M & range): 

schizophrenic pts: 28 (20-62) y, siblings: 37 (10-67) y, ctrl: 36 (21-60) y

• % Male: schizophrenic 

pts: 67.3%, siblings: 46.4%, ctrl: 67.3%

• Race: NR • Disease: schizophrenia 

disorder (DSM-IV; Axis I disorders SCID-P) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Medicated schizophrenic pts • n=113 

• Siblings • n=140 • Healthy controls • n=113 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicable; NR = not reported; ctrl = control(s); M 

medication/medicated 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-29

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Arvindakshan, 

2003, 

India 

[1]: 

N/A, 

Multiple-group 

crosssectional 

study at 

baseline of 

before-after 

study 

{1657} 

• Inclusion: NR • Exclusion: pts: WAIS-R 

full-scale IQ <80, high levels of dietary supplements, severe malnourishment, seizure disorder, head injury with loss of consciousness, alcohol & substance abuse & dependence, excessive smoking, type II diabetes, lipid disorders, cardiovascular disease, hypertension, obesity; ctrl: psychosis & major mood disorder, use of meds 

• Enrolled/completed: 

n=73 

• Age (mean & SD): 

schizophrenics: 29.57 (7.03) y; ctrl: 31.29 (9.86) y 

• % Male: schizophrenic 

pts: 64.3%; ctrl: 66.7% 

• Race: NR • Disease: schizophrenic 

disorder (DSM-IV) 

• Duration: 10.14 (6.04) 

y 

• Interventions: 

haloperidol, risperidone, olanzapine, clozapine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S 

between-grp differences): N/A 

• Schizophrenic pts • n=28 

• Healthy controls • n=45 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicable; NR = not reported; ctrl = control(s); M 

treatment; meds = medication/medicated; SD = standard deviation; WAIS-R = Wechsler Adult Intelligence Scale-Revised; IQ = Intelligen

Institutes of Health; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-30

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source

Delivery) & 

N Enrolled/Complete

Arvindakshan, 

2003, 

 India, 

[2]: 

N/A, 

Multiple-group 

crosssectional 

study 

{47} 

• Inclusion: 18-45 y, 

drug-free FEP pts with schizophrenia or schizoaffective or schizophreniform disorder, chronic schizophrenics 

• Exclusion: full 

scale IQ, dietary supplements, malnourishment, seizure disorder, head injury with loss of consciousness, alcohol/substance abuse/dependence, type II diabetes, lipid disorders, CV disease, hypertension, obesity; ctrl: psychosis or major mood disorder; use of meds 

• Enrolled/completed: n=97/97 • Age (M & SD): ctrl: 29.24 (8.87) y; 

never-med schizophrenic pts: 29.40 (9.73) y; med schizophrenic pts: 31.31 (SD 10.31) y

• % Male: ctrl: 55.6%; never-med 

pts: 60%; med pts: 65.6% 

• Race: NR• Disease: schizophrenia, 

schizoaffective or schizophreniform disorder (DSMIV) 

• Duration: non-medicated 

schizophrenic/schizoaffective/ schizophreniform: 2.47 (4.89) y; medicated schizophrenics: 10.12 (6.92) y 

• Interventions: risperidone, 

clozapine, olanzapine, typical antipsychotics 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Non-medicated 

schizophrenic pts 

• n=20 

• Medicated 

schizophrenic pts 

• n=32 • Healthy controls 

• n=45 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; FEP = first episode psychosis; tx = treatment; meds = medication/medicated; SD = standard deviation

Intelligence Quotient; NIH = National Institutes of Health 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-31

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Assies, 

2001, 

Holland 

 [1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{149} 

• Inclusion: NR • Exclusion: 

major medical illness, mental retardation, endocrine disorders, & cholesterollowering diet or meds 

• Enrolled/completed: n=33/33 • Age (M & SD): pts: 21.2 (2.39) y; ctrl: 

20.9 (2.23) y

• % Male: pts: 89.5%; ctrl: 85.7%• Race: NR• Disease: schizophrenia disorder 

(paranoid, disorganized, undifferentiated), schizoaffective disorder, bipolar disorder, psychotic disorder (DSM-IV) 

• Duration: schizophrenia pts: 11.2 

(10.4) mo 

• Interventions: olanzapine, pimozide, 

risperidone, clozapine, paroxetine, fluvoxamine, oxazepam, temazepam, alprazolam, biperideen, trihexyfenidyl, dexetimide, lithium carbonate 

• Concurrent: cannabis abuse • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts & other 

diagnoses 

• n=19 

• Matched controls • n=14 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicable; NR = not reported; ctrl = control(s); M 

medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-32

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

BuydensBranchey, 

2003, 

US 

 [1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{3018} 

• Inclusion: 

DSM-IV criteria cocaine dependence 

• Exclusion: 

intravenous substance use, used opiates during y before study, used >0.8g/kg of pure ethanol during y before study 

• Enrolled/completed: 

n=24/24 

• Age (M & SD): 39.0 (6.1) 

y (aggressive: 38 y; nonaggressive: 39.6 y)

• % Male: 100%• Race: NR• Disease: cocaine addicts 

(DSM-IV) 

• Duration: NR • Interventions: NR • Concurrent: aggression • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Aggressive cocaine addicts • Diet: standard diet • n=6 

• Non-aggressive cocaine 

addicts 

• Diet: standard diet • n=18 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; FEP = first episode psychotic; meds = medication/medicated; SD = standard deviation; NIDA = Nation

NIAAA = National Institute of Alcohol Abuse and Alcoholism 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-33

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Chiu, 

2003, 

Taiwan 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{39} 

• Inclusion: pts: no 

medical illness, 18-65 y; ctrl: hx of mental disorder & use of psychotropic agents 

• Exclusion: bipolar 

pts with mixed episode of mood symptoms or other comorbid Axis I disorders, low fat diet or vegetarian 

• Enrolled/completed: 

n=40/40 

• Age (M & SD): pts: 39 

(10.5) y; ctrl: 38.7 (12.8) y 

• % Male: pts: 50%; ctrl: 45% • Race: 100% Han

• Disease: bipolar I disorder 

(DSM-IV; manic phase) 

• Duration: 11.1 (9.6) y • Interventions: 

benzodiazepine, lithium, valproate, carbamazepine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Bipolar disorder pts, 

acute manic phase 

• n=20 

• Healthy volunteers • n=20 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-34

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Edwards, 

1998, 

UK 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{249} 

• Inclusion: NR • Exclusion: 

physical illness of a nature/ severity suggestive of low omega-3 fatty acid levels 

• Enrolled/completed: 

n=24/24 

• Age (M & SD): pts: 38.7 

(10.2) y; ctrl: 39.4 (10.9) y

• % Male: pts: 20%; ctrl: 

14.3%

• Race: NR• Disease: major 

depressive episode (DSM-IV; BDI: 26.9 [4.7]) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: 

antidepressants 

• Biomarkers (S betweengrp differences): N/A 

• Major depressive episode pts • n=10 

• Matched healthy controls • n=14 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-35

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Ellis, 

1977, 

UK 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{1590} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: 

n=16/16 

• Age (M & range): NR

• % Male: NR• Race: NR• Disease: endogenous 

depression, nondepressive psychiatric disorders 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Depressive disorder pts • n=6 

• Non-depressive psychiatric 

disorder pts

• n=4

• Age- & sex-matched health

controls

• n=6

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-36

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Evans, 

2003, 

US 

 [2]: 

Multiplegroup 

crosssectional 

study at 

baseline of 

single 

prospective 

cohort 

study 

{3101} 

• Inclusion: DSM-IV 

diagnosis of schizophrenia > 6 mo followup; medically healthy 

• Exclusion: 

seizures or severe head injury with loss of consciousness, hx of substance abuse < 6 mo 

• Enrolled/completed: 

n=41/41 

• Age (M & SD): FEP: 

19.28 (5.1) y; ctrl: 25 (4.2) y

• % Male: FEP: 87.5% • Race: NR• Disease: FEP & 

schizophreniform disorder (DSM-IV) 

• Duration: < 1 mo • Interventions: 

risperidone, olanzepine, 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• FEP pts • n=16 

• Healthy controls • n=25 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation; NIH = National Institutes of Health; FEP = fir
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-37

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Fehily, 

1981, 

 UK 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{2241} 

• Inclusion: NR • Exclusion: 

NR 

• Enrolled/completed: 

n=NR/60 

• Age (M & range): 

endogenous depression: 52 (21-74) y, reactive depression: 38 (22-65) y, other psychiatric disorders: 35 (19-59) y

• % Male: NR• Race: NR• Disease: endogenous 

depression, reactive depression, schizophrenia, personality disorders 

• Duration: NR • Interventions: hypnotic, 

tranquilliser, neuroleptic 

• Concurrent: bipolar 

disorder 

• Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Endogenous depression pts • n=26 

• Reactive depression pts • n=23 • Other psychiatric disorder p• n=11 • Controls • n=NR 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-38

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Fischer, 

1992, 

Germany 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{346} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: n=24/24 • Age (range): high dose: NR 

(24-42) y; low dose: NR (35-53) y; untreated: NR (24-33) y; ctrl: NR (21-41) y

• % Male: high dose: 78%; low 

dose: 29%; untreated: 50%; ctrl: 100%

• Race: NR• Disease: schizophrenic 

disorder (high dose & low dose monotherapy (phenothiazine or thioxanthene) 

• Duration: NR • Interventions: perazine, 

flupentixol, levome-promazine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts, high 

dose 

• n=9 

• Schizophrenic pts, low dose • n=7 • Schizophrenic pts, untreate• n=2 • Controls • n=6 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-39

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design 

Eligibility 

Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hakkarainen, 

2004, 

Finland 

[1]: 

9 y 

single 

prospective 

cohort study 

from RCT 

{3001} 

• Inclusion: 

males, 50-69 y, residing in southwestern Finland 1985 

• Exclusion: 

NR 

• Enrolled/completed: 

n=29,133/27,111 

• Age (M & range): NR • % Male: NR • Race: NR • Disease: 

depression/suicide 

• Duration: 5-8 y 

(median=6) 

• Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A

• n=29,133/27,111 • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-40

mpleted 

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Co

Hibbeln, 

1998, 

US 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{232} 

• episodes 

of violent physical aggression, absence of major medical problems, completion of the DSM-III SCID, abstinent from alcohol, meds free 

• Exclusion: violent pts: major 

psychotic or a major affective disorder, head trauma resulting in loss of consciousness for >1h, amphetamine, hallucinogen, or opiate dependence, & current dependence on cocaine/ other illicit drugs; ctrl: 1 episode of violent physical aggression 

• Enroll

n=58/58 

• Age (M & SD): pts: 38.5 

(6.4) y; ctrl: 39.9 (8.0) y

• % Male: pts: 78%; ctrl: 

71%

• Race: NR 

• Disease: violent (DSM-IIIR & RDC; >5 episodes of 

violent, physical aggression) 

• Duration: NR • Interventions: NR • Concurrent: alcohol 

dependent 

• Cointerventions: no pts 

on MAOI’s or SSRI’s in < 3 mo 

• Biomarkers (S betweengrp differences): N/A 

•• n=27 

• Non-violent controls • n=31 

Inclusion: hx of >5 ed/completed: Violent pts 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; MAO = monoamine oxidase; SSRI = selective serotonin reuptake inhibitors; tx = treatment; meds = mstandard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-41

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hibbeln, 

1998, 

US 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{233} 

• Inclusion: ctrl: 

negative alcohol breath tests & urine drug testing, no major medical disorders, did not meet criteria for current or lifetime psychiatric or substance use disorder; pts: abstinent for 21-63 d at time of study 

• Exclusion: lifetime hx 

of major psychotic illness or bipolar affective disorder 

• Enrolled/completed: n=176/176 • Age (M & SD): late-onset 

alcoholics: 45.5 (8.8) y; earlyonset alcoholics: 36.5 (8.7) y; ctrl: 37 (15.7) y

• % Male: late-onset: 85%; earlyonset: 96%; ctrl: 77.5%• Race: White, Black • Disease: alcoholics (DSM-III-R; 

early onset: excessive alcohol use < 25 y age) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Early onset alcoholic pts • n=88 

• Late onset alcoholic 

pts 

• n=39 • Healthy controls • n=49 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-42

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Holman, 

1995, 

US 

 [1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{314} 

• Inclusion: pts: 

females, diagnosed as anorexia nervosa by staff psychiatrist; ctrl: healthy females <19 y 

• Exclusion: NR 

• Enrolled/completed: 

n=27/27 

• Age (M & range): pts: 

18.4 (15-24) y, ctrl: 23.5 (1.7) y

• % Male: 0%• Race: NR• Disease: anorexia 

nervosa 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Anorexic pts • n=8 

• Healthy controls • n=19 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation; NIH = National Institutes of He
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-43

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Horrobin, 

1989, 

England, 

Scotland, 

Ireland 

 [3]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{389} 

• Inclusion: 

schizophrenia disorder according to DSM-III criteria 

• Exclusion: NR 

• Enrolled/completed: 

n=203/203 

• Age (M & range): pts: 40.8 

(20-71) y; ctrl: 35.7 (19-66) y

• % Male: pts: 72.6%, ctrl: 

51.3%

• Race: NR

• Disease: schizophrenic 

disorder (DSM-III-R & Research Diagnostic Criteria) 

• Duration: NR • Interventions: neuroleptic 

drugs 

• Concurrent: tardive 

dyskinesia (AIMS score > 2) 

• Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts • n=84 

• Controls • n=119 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; TD = tardive dyskinesia; NBD = not broken down; tx = treatment; AIMS = Abnormal Inv
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-44

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Iribarren, 

2004, 

US 

 [3]: 

N/A, 

Single 

population 

crosssectional 

survey 

{3076} 

• Inclusion: 

Black or White, males or females, age 18-30 y 

• Exclusion: NR 

• Enrolled/completed: 

n=5,115/3,581 

• Age (M & SD): Black men 

29.4 (3.7) y; White men 30.5 (3.3) y; Black women 29.6 (3.8) y; White women 30.6 (3.4) y

• % Male: 44.5%• Race: Black: 45.7%, 

White: 54.2%

• Disease: Hostility • Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• n=5,115/3,581 • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-45

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Kaiya, 

1991, 

Japan 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{363} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: 

n=107/107 

• Age (M & SD): ctrl: 36.3 

(12.6) y; schizophrenia: 35.7 (9.9) y; other disorders: 36.3 (12.6) y

• % Male: ctrl: 37.5%; 

schizophrenia: 61%; other disorders: 37.5%

• Race: NR• Disease: schizophrenia, 

affective, & paranoid disorder (DSM-III, DSM-III-R; platelets hyposensitive to prostaglandin) 

• Duration: NR • Interventions: neuroleptics, 

haloperidol equivalents, antidepressants 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts • Diet: maintain Japanese 

diet rich in rice & seafood 

• n=59 

• Other psychiatric disorder p• Diet: maintain Japanese die

rich in rice & seafood 

• n=24 • Controls • Diet: maintain Japanese die

rich in rice & seafood 

• n=24 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-46

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Khan, 

 2002, 

US, 

 [3]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{71} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: n=68/68 • Age (M & SD): FEP: 22.40 

(4.08) y; chronic medicatedschizophrenics: 45.89 (6.32) y; ctrl: 24 (5.6) y

• % Male: FEP: 81.8%; chronic 

med-schizophrenics: 100%; ctrl: 87.5%

• Race: NR• Disease: schizophrenia or 

schizophreniform disorder (DSM-IV) 

• Duration: FEP: ± 4.5 d; chronic 

med schizophrenics: 23.55 (7.38) y 

• Interventions: clozapine, 

haloperidol, olanzapine, risperidone 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Medicated schizophrenic pts • n=30 

• Non-medicated FEP pt• n=22 • Healthy controls • n=16 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; FEP = first episode psychosis; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-47

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Langan, 

1985, 

US 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{419} 

• Inclusion: admission to 

the young adult psychosomatic ward (University of Wisconsin Clinical Sciences Center for anorexia nervosa), availability of plasma leftover after laboratory studies upon admission 

• Exclusion: NR 

• Enrolled/completed: 

n=28/26 

• Age (M & SD): pts: 16.8 

(2.3) y; ctrl: 20.7 (1.0) y

• % Male: pts: 6% ctrl: 0%

• Race: NR• Disease: anorexia 

nervosa 

• Duration: 17.2 (1-39) mo • Interventions: NR • Concurrent: 10/15 pts 

secondary amenorrhea 

• Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Anorexic pts • n=17 

• Healthy controls • n=11 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation; NIH = National Institutes of Health 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-48

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Leask, 

2000, 

UK 

[2]: 

N/A, 

Casecontrol 

study 

 {3142} 

• Inclusion: national 

birth cohort 1946; national birth cohort 1958 

• Exclusion: NR 

• Enrolled/completed: 

n=24,218 

• Age (M & range): 1946: pts: 

43 (NR) y; ctrl: 43 (NR) y; 1958: 16-28 y 

• % Male: 1946: 52%; 1958: 

51% 

• Race: NR • Disease: 1946: 

schizophrenia (DSM-III-R); 1958: schizophrenia (CATEGO) 

• Duration: N/A • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

diff): N/A 

• National birth cohort, 1946 • n=5,362 

• National birth cohort, 

1958 

• n=18,856 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-49

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Maes, 

1999, 

Belgium 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{209} 

• Inclusion: NR • Exclusion: pts: Axis I dx, 

unipolar major depression, Axis II, borderline & antisocial personality disorder, abnormal heart & lungs XR tx fluoxetine, trazodone, MAOIs, antipsychotic drugs, anticonvulsants, lithium, ECT 1 y before study; ctrl: abnormal lab tests, acute or chronic medical illness, acute infectious/allergic reactions < 2 study, low fat diet/cholesterol lowering drugs, meds affecting fatty acid metabolism/endocrine/ immune functions, BMI >normal, smokers, not on normal Belgium diet 

• Enrolled/completed: 

n=48/48 

• Age (M & SD): pts: 52.2 

(13.6) y; ctrl: 48.3 (15.2) y

• % Male: pts: 53%; ctrl: 64% • Race: White 100% 

• Disease: major depression 

(DSM-III-R) 

• Duration: NR • Interventions: 

antidepressants 

• Concurrent: NR • Cointerventions: 

benzodiazepines permitted 

• Biomarkers (S between-grp 

differences): N/A 

• Major depression pts • n=34 

• Controls • n=14 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; MAO = monoamine oxidase; tx = treatment; meds = medication/medicated; SD = stand
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-50

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Maes, 

1996, 

Belgium 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{285} 

• Inclusion: no medical 

illness 

• Exclusion: ethnic 

minority, mental disorders, low fat diet, Axis I diagnosis beside unipolar depression, substance use/abuse disorder, borderline or antisocial personality disorder, MAOIs, anticonvulsants, lithium or ECT 1 y prior to study, abnormal heart & lungs XR 

• Enrolled/completed: 

n=74/74 

• Age (M & SD): ctrl: 42.0 

(13.6) y; minor depression: 44.5 (14.3) y; major depression: 47.4 (17.0) y

• % Male: ctrl: 50%; minor: 

36%; major: 31%

• Race: 100% Flemish• Disease: major & minor 

depression (DSM-III-R) 

• Duration: NR • Interventions: 

antidepressants, benzodiazepines, haloperidol, chlorazepate 

• Concurrent: melancholia, 

adjustment disorder, depressed mood, dysthymia 

• Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Major depression pts • n=36 

• Minor depression pts • n=14 • Healthy volunteers • n=24 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; MAO = monoamine oxidase; meds = medication/medicated; SD = standard deviation; E

EKG = electrocardiogram; XR = radiograph 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-51

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Mahadik, 

1996, 

US 

[2]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{278} 

• Inclusion: DSM-III-R 

diagnosis of schizophrenia, BMD, monitoring of FEP pts for 1st 6 mo of illness, 

healthy; ctrl: no hx of psychosis, major mood disorder, type II diabetes 

• Exclusion: substance 

abuse/dependence, seizure disorder, head injury/loss of consciousness, family hx Huntington's disease, dementia, mental retardation 

• Enrolled/completed: 

n=26/26 

• Age (M & SD): 

schizophrenic: 26.75 (10) y; BMD: 33.00 (6.8) y; ctrl: 33.63 (5.5) y

• % Male: schizophrenic: 

100%; BMD: 91.7%; ctrl: 75%

• Race: NR• Disease: schizophrenia, 

bipolar mood disorder (DSM-III-R) 

• Duration: FEP pts: 4.6 (2.8) 

d 

• Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts • n=12 

• Bipolar disorder pts • n=6 • Controls • n=8 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab= placebo; MAO = monoamine oxidase; SSRI = selective serotonin reuptake inhibitors; FEP = first episode psychosis; BMD = bipolar dismedication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-52

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

McCreadie, 

1997, 

UK 

[1]: 

N/A, 

Casecontrol 

study 

 {3143} 

• Inclusion: 

schizophrenic pts 

• Exclusion: NR 

• Enrolled/completed: 

n=137/137 

• Age (M & range): NR • % Male: pts: 64%; ctrl: NR • Race: NR • Disease: schizophrenia 

(ICD-9) 

• Duration: N/A • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

diff): N/A 

• Schizophrenic pts • n=45 

• Siblings • n=92 • National surveys: • Great Britain 1946, n=13,68• Scotland 1958, n=1,648 • Scotland 1980, n=1,718 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-53

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Mellor, 1996, 

England 

[1]: 

1 wk 

single 

prospective 

cohort study at 

baseline of a 

noncomparative 

before-after 

study 

{2101} 

• Inclusion: 

currently longterm inpatients, receiving neuroleptic meds 

• Exclusion: NR 

• Enrolled/completed: 

n=20/20 

• Age (M & range): 56.1 (NR) 

y 

• % Male: 65% • Race: NR • Disease: chronic 

schizophrenia (DSM-III-R) 

• Duration: NR • Interventions: N/A • Concurrent: NR • Cointerventions: N/A • Biomarkers (S between-grp 

diff): N/A 

• Chronic schizophrenia pts • n=20 

• N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-54

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Mitchell, 

1987, 

New 

Zealand 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{401} 

• Inclusion: diagnosed with 

AD/HD by parents on RBPC & by teachers on CTQ; ctrl: score < P 65 on 4 subscales of hyperactivity 

• Exclusion: NR 

• Enrolled/completed: 

n=97/97 

• Age (M & SD): hyperactive: 

9.1 (2.3) y; ctrl: 8.7 (2.3) y

• % Male: hyperactive: 

85.5%; ctrl: 81.8%

• Race: European: 

hyperactive: 92%; ctrl: 92%

• Disease: hyperactive 

(DSM-III, RBPC, CTQ; >P 90 on subscales of RBPC) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Hyperactive children • n=48 

• Controls • n=49 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; RBPC = Revised Behavior Problem Checklist; CTQ = Conners Teacher Questionnaire; meds = medic

standard deviation; P = percentile 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-55

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Mitchell, 

1983, 

New 

Zealand 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{439} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: 

n=43/43 

• Age (M & range): 

maladjusted: (7.5-13) y; ctrl: (10-13) y

• % Male: maladjusted: 

91%; ctrl: 50%

• Race: NR

• Disease: maladjusted 

children (Handicapped Pupils & School Health Service Regulations) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Maladjusted (hyperactive) 

children 

• n=23 

• Normal children• n=20

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-56

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Obi, 

1979, 

Nigeria 

 [1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{458} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: 

n=12/12 

• Age (M & range): 

schizophrenia: NR (30-50) y; ctrl: NR (22-45) y

• % Male: NR

• Race: NR• Disease: schizophrenic 

disorder 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Schizophrenic pts • n=6 

• Healthy controls • n=6 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-57

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Peet, 

1998, 

England 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{251} 

• Inclusion: suffering 

from a major depressive episode, unipolar illness, 18-65 y 

• Exclusion: NR 

• Enrolled/completed: 

n=30/30 

• Age (M & SD): pts: 47.4 

(11.0) y; ctrl: 47.0 (10.3) y

• % Male: pts: 53%; ctrl: 53%• Race: NR• Disease: major depressive 

episode, unipolar illness (DSM-IV) 

• Duration: NR • Interventions: dothiepin, 

paroxetine, fluoxetine, trazodone, lofepramine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Major depressed pts, unipolar • n=15 

• Healthy controls • n=15 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-58

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Peet, 

1997, 

UK 

[1]: 

N/A, 

Casecontrol 

study 

{3145} 

• Inclusion: 

schizophrenic pts; ctrl: nonpsychiatric pts 

• Exclusion: NR 

• Enrolled/completed: n=110/110 • Age (M & range): pts: 34 (NR) y; 

ctrl: NR

• % Male: pts: 85% ctrl: (NR)

• Race: NR• Disease: schizophrenia (DSMIV) • Duration: NR • Interventions: N/A • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts • n=55 

• Non-psychiatric contro• n=55 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-59

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source

Delivery) & 

N Enrolled/Complete

Peet, 

1995, 

 UK 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{303} 

• Inclusion: pts: 

neuroleptic-treated, physically healthy, schizophrenia (DSM-III criteria); ctrl: hospital staff, no hx of mental disorder, on no meds 

• Exclusion: NR 

• Enrolled/completed: 

n=39/39 

• Age (M & range): pts: 55 

(28-75) y

• % Male: pts: 69.5%

• Race: NR• Disease: schizophrenia 

disorder (DSM-III-R) 

• Duration: >5 y • Interventions: 

chlorpromazine 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts with tardive 

dyskinesia 

• n=23 

• Healthy controls • n=16 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-60

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Ranjekar, 

2003, 

India 

 [2]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{3094} 

• Inclusion: schizophrenics or 

BMD 

• Exclusion: WAIS-R full 

scale IQ<80, high use of diet supplements, undernourishment or malnourishment, seizure disorder, head injury, substance abuse/dependence, type II diabetes, lipid disorders, CV disease, hypertension, family hx of same, obesity; ctrl: medications/substance abuse 

• Enrolled/completed: 

n=72/72

• Age (M & SD): ctrl: 39.72 

(8.87) y; schizophrenics: 37.32 (7.18) y; BMD: 40.8 (8.29) y

• % Male: 100%• Race: NR• Disease: schizophrenic 

disorder & BMD (DSMIV) 

• Duration: NR • Interventions: atypical 

antipsychotics, antidepressants 

• Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Schizophrenic pts • n=31 

• Bipolar disorder pts

• n=10 • Healthy controls • n=31 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; tx = treatment; meds = medication/medicated; SD = standard deviation; WAIS-R = Wechsler Adult Int

cardiovascular 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-61

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Sasaki, 

2000, 

Japan 

[2]: 

N/A, 

Casecontrol 

study 

 {3144} 

• Inclusion: 

schizophrenic pts 

• Exclusion: NR 

• Enrolled/completed: n=337/337 • Age (M & range): pts: 32 ± 9 y; 

healthy siblings: 34.6 ± 8.4; ctrl: 31 ± 10 y 

• % Male: pts: 60%; healthy siblings: 

59.5%; ctrl: 46% 

• Race: Asian • Disease: schizophrenia (DSM-IV) • Duration: N/A • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp diff): N/A 

• Schizophrenic pts • n=100 

• Healthy siblings • n=37 • Healthy controls • n=200 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; pb = placebo; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-62

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Silvers, 2002, 

New Zealand 

[122 

geographic 

areas; 11,921 

households]: 

N/A, 

Single 

population 

crosssectional 

survey 

{1483} 

• Inclusion: 

resident of New Zealand in 1996 & 1997 

• Exclusion: NR 

• Enrolled/completed: 

n=12,506/4,644 

• Age (M & range): grp 1: NR 

(15-24) y; grp 2: NR (25-44) y; grp 3: NR (45-64) y; grp 4: >65 y

• % Male: NR• Race: NR• Disease: adults age >15 y • Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• n=12,506/4,644 (adults age > 

15 y) 

• N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-63

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Stevens, 

1995, 

US 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{301} 

• Inclusion: 

males, 6-12 y, healthy with diagnosis of or suspected AD/HD, PTCRS score >15; ctrl: PTCRS <15 

• Exclusion: NR 

• Enrolled/completed: n=96/96 • Age (M & SD): AD/HD: 9.1 (2.0) y; 

ctrl: 9.1 (2.3) y

• % Male: 100%

• Race: NR• Disease: AD/HD (>15 PTCRS) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Hyperactive (AD/HD) 

boys 

• n=53 

• Normal boys • n=43 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; PTCRS = Parent/Teacher Conners Rating Scale; meds = medication/medicated; SD = standard devia

deficit/hyperactivity disorder 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-64

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Suzuki, 

2004, 

Japan 

[1]: 

N/A, 

Single 

population 

crosssectional 

survey 

{3038} 

• Inclusion: lung cancer, 

diagnosis confirmed by histological examination, physically capable of completing questionnaires, no cognitive impairment, ability to provide written consent, problem with pts participation judged by physician 

• Exclusion: NR 

• Enrolled/completed: 

n=902/771 

• Age (M & SD): HADS-D 

<4: 64.0 (9.5) y; HADS-D 

>5: 64.3 (9.1) y

• % Male: HADS-D <4: 

72.2%; HADS-D >5: 72% 

• Race: likely Asian

• Disease: lung cancer • Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• n=902/771 • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-65

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention* 

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)* 

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Tanskanen, 

2001, 

Finland 

[1]: 

N/A, 

Single 

population 

crosssectional 

survey 

{142} 

• Inclusion: 25-64 y • Exclusion: NR 

• Enrolled/completed: 

n=3,004/1,767 

• Age (M & range): 25-64 y• % Male: NR 

• Race: NR• Disease: N/A • Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• n=3,004/1,767 • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-66

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Tanskanen, 

2001, 

Finland 

[1]: 

N/A, 

Single 

population 

crosssectional 

survey 

{1874} 

• Inclusion: 25-

64 y, Finnish adults 

• Exclusion: NR 

• Enrolled/completed: 

n=5,105/3,204 

• Age (M & range): 48.8 

(NR) y 

• % Male: NR • Race: NR • Disease: N/A (20% mild 

depressive symptoms, 6.3% moderate, 1.5% severe) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• n=5,105/3,204 • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-67

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Tiemeier, 

2003, 

Holland 

 [1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{1457} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: 

n=682/682 

• Age (M & range): 

subthreshold depressive pts: 73.9 (61-93) y; depressive disorder pts: 73.7 (61-97) y; ctrl: 72.5 (61-101) y

• % Male: subthreshold 

depressive pts: 22.7%; depressive disorder pts: 27.4%; ctrl: 41.4%

• Race: NR• Disease: depressive 

disorders (major depression, dysthymia, minor depression) (DSM-IV; >16 on CES-D) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Depressive disorders • n=106 

• Depressive symptoms • n=115 • Controls • n=461 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-68

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Vaddadi, 

1996, 

Australia 

[3]: 

N/A, 

Multiplegroup 

crosssectional 

study at 

baseline of 

multiple 

prospective 

cohort 

study 

 {282} 

• Inclusion: NR • Exclusion: hx of 

established neurological illness, developmental handicap or currently receiving nonsteroidal antiinflammatory drugs 

• Enrolled/completed: n=114/52 • Age (M & range): pts: 35.4 

(18-64) y

• % Male: pts: 75%

• Race: NR• Disease: schizophrenia & 

schizoaffective disorder (DSM-III-R) 

• Duration: 12.3 (8.9) y • Interventions: neuroleptics • Concurrent: tardive 

dyskinesia (TD) 

• Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Schizophrenic pts 

without TD 

• n=40 

• Schizophrenic pts with TD • n=32 • Normal controls • n=39

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; TD = tardive dyskinesia; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-69

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Vancassel, 

2001, 

France 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{131} 

• Inclusion: no hx of 

endocrine or systemic disease 

• Exclusion: NR 

• Enrolled/completed: n=33/33 • Age (M & range): autism: 8.3 

(3-17) y; mentally retarded: 8.7 (1-19) y

• % Male: autism: 73.3%; 

mentally retarded: 72.2%

• Race: NR• Disease: autism, mentally 

retarded (DSM-III-R & DSMIV) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Autistic children • n=15 

• Mentally retarded 

children 

• n=18 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-70

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Virkkunen, 

1987, 

Finland 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{397} 

• Inclusion: committed 

>1 violent crime, >2 

episodes of loss of control of aggressive impulses resulting in serious assault/bodily harm, DSM-III criteria for antisocial personality/intermittent explosive disorder/ alcohol abuse 

• Exclusion: mentally 

retarded (IQ < 68), chromosome abnormality, antisocial personality, no violent tendency, schizophrenia 

• Enrolled/completed: 

n=50/50 

• Age (M & range): antisocial: 

28.5 (12.9) y; explosive: 36.8 (16.4) y; ctrl: 33 (11.1) y

• % Male: 100%

• Race: NR• Disease: violent, alcohol 

abuse, epilepsy, borderline personality disorder, paranoid personality disorder, antisocial personality disorder (DSMIII; committed >1 violent 

crime, >2 episodes of loss 

of control) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• Violent antisocial 

personality disorder pts 

• n=15 

• Intermittent explosive 

disorder pts 

• n=19 • Healthy controls • n=16 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-71

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Woo, 

2002, 

 China 

[NR]: 

36 mo 

single 

prospective 

cohort 

study 

{1777} 

• Inclusion: age 

>70 y 

• Exclusion: NR 

• Enrolled/completed: 

n=2,032/1,171 

• Age (M & SD): 80 (7.1) y• % Male: 49.2% 

• Race: Asian 100%

• Disease: N/A • Duration: N/A • Interventions: N/A • Concurrent: N/A • Cointerventions: N/A • Biomarkers (S between-grp 

differences): N/A 

• n=2,032/1,171 • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-72

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Yang, 

1999, 

Taiwan 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{1962} 

• Inclusion: pts: met 

DSM-IV AD/HD diagnosis, >80% on standard, Child Activity Level Form ctrl: 4-8 y, verified in good health 

• Exclusion: ctrl: 

children with suspected case of AD/HD 

• Enrolled/completed: 

n=52/52 

• Age (M & SD): ctrl: 5.2 

(1.1) y; pts: 5.7 (0.9) y

• % Male: ctrl: 91%; pts: 

90%

• Race: likely Asian 

• Disease: AD/HD (DSMIV; >80% on Standard, 

Child Activity Level Form) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• AD/HD children • n=20 

• Healthy control 

children 

• n=32 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation; AD/HD = attention deficit/hyperactivity disord
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-73

Evidence Table 2 (cont’d): Observational study evidence for the association between omega-3 fatty acids and mental health 

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Yao, 

2002, 

US 

[1]: 

N/A, 

Multiplegroup 

crosssectional 

study 

{1459} 

• Inclusion: pts: IQ >75, 

12-45 y, no hx of neuroleptic tx, DSM-IV criteria for schizophrenia, schizophreniform, schizoaffective disorder; ctrl: 12-45 y, no hx or current psychiatric/neurologic disorder 

• Exclusion: pts: 

substance use within 4 wk of study, medical illness, hyperlipidemia, starvation < 2 wk, neurologic disorders, head injury with loss of consciousness, psychosis >2 y, comorbidity for DSM-IV Axis I diagnosis; ctrl: hx of psychosis or major mood disorder, family hx of psychosis/major mood disorder 

• Enrolled/completed: 

n=22/22 

• Age (M & range): pts: 26 

(17-44) y; ctrl: 26 (19-39) y

• % Male: pts: 54.5%; ctrl: 

54.5%

• Race: NR

• Disease: schizophrenia, 

schizophreniform, schizoaffective disorder (DSM-IV) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Drug-naïve, FEP 

schizophrenic pts 

• n=11 

• Normal controls • n=11 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation; tx = treatment; FEP first episode psychosis 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-74

Evidence Table 3: Cross-national ecological analytic evidence for the association between omega-3 fatty acids and mental hea

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Christensen 

1988, 

 [8 

countries]: 

N/A, 

Crossnational 

ecological 

analysis 

{3125} 

• Inclusion: NR • Exclusion: NR 

• Enrolled/completed: NR • Age (M & range): NR • % Male: NR • Race: NR • Disease: schizophrenia • Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• Diet: saturated fatty acids, n-3 

and n-6 fatty acids: fat from land animals & birds; 1.7 - 32.1% of energy derived from fat from land animals & birds; EPA, DHA & ALA: fat from vegetables, fish & seafood; 7.5 - 14.5% of 

energy derived from fat from vegetables, fish & seafood 

• n=8 countries 

• N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = historymeds = medication/medicated; SD = standard deviation; EPA = eicosapentaenoic acid; DHA = docosa

linolenic acid 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-75

Evidence Table 3 (cont’d): Cross-national ecological analytic evidence for the association between omega-3 fatty acids and me

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hibbeln, 

2002, 

US 

 [23 

countries]: 

N/A, 

Crossnational 

ecological 

analysis 

{59} 

• Inclusion: 

major postpartum depressive symptoms 

• Exclusion: NR 

• Enrolled/completed: 

n=14,532/14,532 

• Age (M & SD): 28.4 (1.3) 

y

• % Male: 0%• Race: NR• Disease: major 

postpartum depressive symptoms (EPDS; EPDS score >12/13) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• n=23 countries (total) • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; EPDS= Edinburgh Postpartum Depression Scale; meds = medication/medicated; SD = standard devi
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-76

Evidence Table 3 (cont’d): Cross-national ecological analytic evidence for the association between omega-3 fatty acids and me

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hibbeln, 

2001, 

 [26 

countries]: 

N/A, 

Crossnational 

ecological 

analysis 

{1503} 

• Inclusion: 

countries with data on seafood consumption & deaths due to homicide (WHO) 

• Exclusion: US 

(rate of death due to homicide too high) 

• Enrolled/completed: NR • Age (M & range): NR

• % Male: NR

• Race: NR• Disease: homicide 

deaths 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• n=26 countries (total) • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; WHO = World Health Organization 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-77

Evidence Table 3 (cont’d): Cross-national ecological analytic evidence for the association between omega-3 fatty acids and me

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

 (Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Hibbeln, 

1998, 

 US 

[9 

countries]: 

N/A, 

Crossnational 

ecological 

analysis 

{239} 

• Inclusion: ≥ 1 

depressive episode, including grief lasting > 1 y 

• Exclusion: criteria 

for a manic episode 

• Enrolled/completed: NR • Age (M & range): NR (18-

65) y

• % Male: US: 41%, 

Alberta: 41%, Puerto Rico: 43%, France: 38%, Germany: 48%, Italy: 47%, Lebanon: 43%, Taiwan: 52%, Korea: 48%, New Zealand: 34%

• Race: NR• Disease: major 

depression (DSM-III) 

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S betweengrp differences): N/A 

• n=9 countries • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicable; NR = not reported; ctrl = control(s); M 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-78

Evidence Table 3 (cont’d): Cross-national ecological analytic evidence for the association between omega-3 fatty acids and me

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Noaghiul, 

2003, 

[11 

countries 

(bipolar 

disorder), 

14 

countries 

(schizophrenia 

disorder]: 

N/A, 

Crossnational 

ecological 

analysis 

{3020} 

• Inclusion: community 

samples with clearly defined sample population, large sample size, age 18-64 y, appropriate sampling methods, structured diagnostic instruments 

• Exclusion: NR 

• Enrolled/completed: NR • Age (M & range): NR (18-

64) y

• % Male: NR

• Race: NR• Disease: Bipolar 

Disorder/Schizophrenia

• Duration: NR • Interventions: NR • Concurrent: NR • Cointerventions: NR • Biomarkers (S between-grp 

differences): N/A 

• n=11 countries (bipolar 

disorder), 14 countries (schizophrenia) 

• N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n completing the st

controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = not applicab

control(s); M = mean; hx = history; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

E-79

Evidence Table 3 (cont’d): Cross-national ecological analytic evidence for the association between omega-3 fatty acids and me

Author, 

Year, 

Location 

[N sites]: 

Length & 

Design Eligibility Criteria 

Prestudy/ 

Baseline Population 

Characteristics 

Intervention

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Comparator(s)

(Dose/Type/Source/ 

Delivery) & 

N Enrolled/Completed 

Peet, 

2004, 

 UK 

[8 

countries] 

N/A, 

Crossnational 

ecological 

analysis 

{3128} 

• Inclusion: data 

in data-bases on international variations in outcome of schizophrenia, prevalence of depression, patterns of food usage 

• Exclusion: NR 

• Enrolled/completed: 8/8 

(countries) 

• Age (M & range): NR 

• % Male: NR• Race: NR• Disease: 

Schizophrenia/Depression 

• Duration: NR • Biomarkers (S between-grp 

differences): N/A 

• n=8 countries • N/A 

length = intervention/exposure length; design = research design; intervention = intervention/exposure; disease = diagnosis & severity; du

diagnosis; concurrent = concurrent conditions; pts = participants; n = number of participants; enrolled = n qualified; completed = n compl

randomized controlled trial; wk = week; y = year; g = gram; mo = month; d = day; grp = group; S = significant; NS = nonsignificant; N/A = 

reported; ctrl = control(s); M = mean; meds = medication/medicated; SD = standard deviation 
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

Listing of Reports of Included Studies 

Akkerhuis GW, Nolen WA. Lithium-associated psoriasis 

and omega-3 fatty acids. Am J Psychiatry 2003; 

160(7):1355. 

Alling C, Gustavsson L, Kristensson-Aas A, Wallerstedt S.

Changes in fatty acid composition of major

glycerophospholipids in erythrocyte membranes from 

chronic alcoholics during withdrawal. Scand J Clin Lab 

Invest 1984; 44(4):283-289. 

Amore M, Balista C, McCreadie RG, Cimmino C, Pisani F, 

Bevilacqua G et al. Can breast-feeding protect against 

schizophrenia? Case-control Study. Biol Neonate 2003; 

83(2):97-101. 

Arvindakshan M, Sitasawad S, Debsikdar V, Ghate M, 

Evans D, Horrobin DF et al. Essential polyunsaturated fatty

acid and lipid peroxide levels in never-medicated and 

medicated schizophrenia patients. Biol Psychiatry 2003; 

53(1):56-64. 

Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, 

Mahadik SP. Supplementation with a combination of 

omega-3 fatty acids and antioxidants (vitamins E and C) 

improves the outcome of schizophrenia. Schizophr Res 

2003; 62(3):195-204. 

Assies J, Lieverse R, Vreken P, Wanders RJ, Dingemans

PM, Linszen DH. Significantly reduced docosahexaenoic 

and docosapentaenoic acid concentrations in erythrocyte 

membranes from schizophrenic patients compared with a 

carefully matched control group. Biol Psychiatry 2001; 

49(6):510-522. 

Brue AW, Oakland TD, Evans RA. The use of a dietary

supplement combination and an essential fatty acid as an 

alternative and complementary treatment for children with

attention-deficit/hyperactivity disorder. Sci Rev Altern Med 

2001; 5(4):187-194. 

Buydens-Branchley L, Branchey M, McMakin DL, 

Hibbeln JR. Polyunsaturated fatty acid status and

aggression in cocaine addicts. Drug Alcohol Depend 2003; 

71(3):319-323. 

Chiu CC, Huang SY, Su KP, Lu ML, Huang MC, Chen CC

et al. Polyunsaturated fatty acid deficit in patients with 

bipolar mania. Eur Neuropsychopharmacol 2003; 13(2):99-

103. 

Christensen O, Christensen E. Fat consumption and 

schizophrenia. Acta Psychiatr Scand 1988; 78(5):587-591. 

Dickerson FB, Boronow JJ, Stallings CR, Lee BA, Agarwal 

R, Fenton WS et al. Placebo response in a double-blind 

therapeutic supplementation trial in stabilized outpatients 

with schizophrenia. Schizophr Res 2003; 59(1):97-98. 

Edwards R, Peet M, Shay J, Horrobin D. Depletion of 

docosahexaenoic acid in red blood cell membranes of 

depressive patients. Biochem Soc Trans 1998; 26(2):S142. 

Edwards R, Peet M, Shay J, Horrobin D. Omega-3 

polyunsaturated fatty acid levels in the diet and in red blood 

cell membranes of depressed patients. J Affect Disord 

1998; 48(2-3):149-155. 

Ellis FR, Sanders TAB. Long chain polyunsaturated fatty

acids in endogenous depression. J Neurol Neurosurg 

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Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ. 

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schizophrenia. Am J Psychiatry 2002; 159(9):1596-1598. 

Evans DR, Parikh VV, Khan MM, Coussons C, Buckley

PF, Mahadik SP. Red blood cell membrane essential fatty

acid metabolism in early psychotic patients following 

antipsychotic drug treatment. Prostaglandins Leukot Essent 

Fatty Acids 2003; 69(6):393-399. 

Fehily AMA, Bowey OAM, Ellis FR, Meade BW. Plasma

and erythrocyte membrane long chain polyunsaturated fatty

acids in endogenous depression. Neurochem Int 1981; 

3(1):37-42. 

Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable 

M. A placebo-controlled trial of omega-3 fatty acid (ethyl

eicosapentaenoic acid) supplementation for residual 

symptoms and cognitive impairment in 

schizophrenia.[comment]. Am J Psychiatry 2001; 

158(12):2071-2074. 

Fischer S, Kissling W, Kuss HJ. Schizophrenic patients 

treated with high dose phenothiazine or thioxanthene 

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thrombocytes. Biochem Pharmacol 1992; 44(2):317-323. 

Fux M, Benjamin J, Nemets B. A placebo-controlled crossover trial of adjunctive EPA in OCD. J Psychiatr Res 2004; 

38(3):323-325. 

Gesch CB, Hammond SM, Hampson SE, Eves A, Crowder

MJ. Influence of supplementary vitamins, minerals and 

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D, Lonnqvist J. Is low dietary intake of omega-3 fatty acids 

associated with depression? Am J Psychiatry 2004; 

161(3):567-569.

E-80
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

Hamazaki T, Sawazaki S, Itomura M, Asaoka E, Nagao Y,

Nishimura N et al. The effect of docosahexaenoic acid on 

aggression in young adults. A placebo-controlled doubleblind study. J Clin Invest 1996; 97(4):1129-1133. 

Hamazaki T, Sawazaki S, Nagao Y, Kuwamori T, Yazawa

K, Mizushima Y et al. Docosahexaenoic acid does not 

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study. Lipids 1998; 33(7):663-667. 

Hamazaki T, Thienprasert A, Kheovichai K,

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Harding KL, Judah RD, Gant CE. Outcome-based

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330. 

Hibbeln JR, Linnoila M, Umhau JC, Rawlings R, George 

DT, Salem N, Jr. Essential fatty acids predict metabolites of 

serotonin and dopamine in cerebrospinal fluid among 

healthy control subjects, and early- and late-onset 

alcoholics. Biol Psychiatry 1998; 44(4):235-242. 

Hibbeln JR, Umhau JC, Linnoila M, George DT, Ragan 

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Hibbeln JR. Fish consumption and major 

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Holman RT, Adams CE, Nelson RA, Grater SJ, Jaskiewicz

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Horrobin DF, Manku MS, Morse-Fisher N, Vaddadi KS, 

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phospholipids in schizophrenics. Biol Psychiatry 1989; 

25(5):562-568. 

Iribarren C, Markovitz JH, Jacobs Jr DR, Schreiner PJ, 

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acids and fish: Relationship with hostility in young adults - 

The CARDIA study. Eur J Clin Nutr 2004; 58(1):24-31. 

Kaiya H, Horrobin DF, Manku MS, Fisher NM. Essential

and other fatty acids in plasma in schizophrenics and 

normal individuals from Japan. Biol Psychiatry 1991; 

30(4):357-362. 

Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, 

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never-medicated first-episode of psychosis and after years 

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MC, Heird WC. Effect of maternal docosahexaenoic acid

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Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, 

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E-81
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

in serum phospholipids and cholesteryl esters of depressed 

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Mahadik SP, Mukherjee S, Horrobin DF, Jenkins K, 

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E-82
Appendix E. Evidence Tables and Listing of Included Studies (continued) 

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E-83
Appendix F. Additional Acknowledgements 

Additional Acknowledgements 

The UO-EPC gratefully acknowledges the following individuals who served on our Technical 

Expert Panel (TEP). Acknowledgement does not reflect endorsement of this report. 

Mimi Butterfield MD MPH 

Research Associate 

Staff Physician, Women Veterans Comprehensive Health Center 

Clinical Associate, Department of Psychiatry, 

Duke University

Durham, NC

(Past American Psychiatric Association representative) 

Kathryn M. Connor MD 

Assistant Professor 

Department of Psychiatry and Behavioral Sciences 

Research Director 

Anxiety and Traumatic Stress Program

Duke University Medical Center 

Durham, NC

Jonathan Davidson MD 

Director, Anxiety & Traumatic Stress Program

Professor, Dept. of Psychiatry and Behavioral Sciences 

Duke University Medical Center 

Durham, NC

James Friel PhD 

Professor, 

Department of Human Nutritional Sciences 

Faculty of Human Ecology 

University of Manitoba 

Winnipeg, MB

Paul Grof MD PhD 

Director, Affective Disorders Services, 

Director, Research, Mood Disorders Program 

University of Ottawa Institute of Mental Health Research 

Royal Ottawa Hospital 

Ottawa, ON 

Bill Harris PhD 

Co-director, 

Lipid and Diabetes Research Center 

Saint Luke’s 

Kansas City, MO 

Bruce Holub PhD 

Professor, 

Department of Human Biology and Nutritional

F-1
Appendix F. Additional Acknowledgements (continued) 

Sciences 

University of Guelph 

Guelph, ON 

(Industry representative) 

Matthew Rudorfer MD 

Scientist, 

National Institute of Mental Health 

Bethesda, MD

Richard Shader MD 

Professor, 

Program Director, Pharmacology and Experimental 

Therapeutics Program

Dept. of Pharmacology & Experimental Therapeutics 

Tufts University School of Medicine 

Boston, MA 

F-2
Appendix F. Additional Acknowledgements (continued) 

The UO-EPC gratefully acknowledges the following individuals who reviewed the initial draft 

of this evidence report, and provided constructive feedback. Acknowledgement does not reflect 

endorsement of this report. 

David Atkins MD 

Chief Medical Officer, AHRQ 

Rockville, MD 

Robin Emsley MD 

Head, Department of Psychiatry

University of Stellenbosch 

Cape Town, South Africa 

James Friel Phd 

Department of Human Nutritional Sciences 

University of Manitoba 

Winnipeg, Manitoba 

Reeta Hakkarainen MB 

National Public Health Institute 

Department of Mental Health and Alcohol 

Research 

Helsinki, Finland 

Mary V Seeman MD 

Centre for Addiction and Mental Health 

Toronto, Ontario 

Anne Thurn PhD 

Director, 

Evidence-Based Review Program

Office of Dietary Supplements 

Bethesda, MD

F-3
U.S. Department of Health and Human Services 

Mike Leavitt, Secretary 

Office of Public Health and Science 

Richard H. Carmona, M.D., M.P.H., F.A.C.S., Surgeon General of the United States

Agency for Healthcare Research and Quality

Carolyn M. Clancy, M.D., Director