Clinical trial NCT01399827
Conditions: Attention Deficit Hyperactivity Disorder (ADHD) Deficient Emotional Self-Regulation (DESR)
Sponsor: Massachusetts General Hospital
Start date: 2012-02-01; Completion date: 2017-11-01
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to a) assess the efficacy of omega-3 fatty acids in the treatment of Deficient Emotional Self-Regulation (DESR) among stimulant treated Attention Deficit Hyperactivity Disorder (ADHD) adults, b) assess the side effect profile of omega-3 fatty acids in the treatment of DESR among stimulant treated ADHD adults, c) assess effects of omega-3 fatty acid supplementation on ADHD symptoms and associated features in stimulant treated ADHD adults, and d) predict value of fatty acids present in red blood cell membranes. This study will be a 12-week trial with adults 18-55 years of age with ADHD and symptoms of DESR.

Detailed description:

Arms: arm 1: 1060 mg EPA Omega-3 Fatty Acids arm 2: None
Interventions: intervention 1: ADHD Medication intervention 2: Omega-3 Fatty Acids
Intervention descriptions: intervention 1: For those subjects not on stable ADHD treatment (defined as a stable, effective dose for at least one month, determined by the study clinician, of a medication that is FDA approved to treat ADHD), OROS-Methylphenidate will be openly prescribed. Subjects on a stable dose of medication for ADHD will be instructed to continue on their current dose of medication. intervention 2: Omega-3 Fatty Acids prescribed to participants randomized to active medication. They may be randomized to receive 1060mg of EPA (2 capsules containing 530mg EPA and 137mg DHA). Dosage will remain constant throughout study.

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol: 
Omega-3 Fatty Acid Supplementation to ADHD Pharmacotherapy in ADHD Adults with DESR Traits: A 
Double-Blind, Placebo-Controlled, Randomized Clinical Trial 
 
 
 
 
Craig B.H. Surman, MD 
Joseph Biederman, MD 
Massachusetts General Hospital 
Clinical and Research Program in Pediatric Psychopharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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I. 
BACKGROUND AND SIGNIFICANCE 
Deficient Emotional Self Regulation (DESR) in ADHD Population 
Recent work has demonstrated that adults with attention deficit hyperactivity disorder (ADHD) are at elevated 
risk for deficient emotional self regulation (DESR) 1-6.  DESR refers to 1) deficits in self-regulating the 
physiological arousal caused by strong emotions; 2) difficulties inhibiting inappropriate behavior in response to 
either positive or negative emotions; 3) problems refocusing attention from strong emotions and 4) difficulty 
executing an organized response, mental or behavioral, to emotionally activating situations4.  DESR traits include 
low frustration tolerance, impatience, quickness to anger, and being easily excited to emotional reactions. In 
adults, these difficulties have been associated with significant impairments, including occupational impairment, 
educational failure, criminal history, adverse driving outcomes, marital satisfaction, and parenting stress.  
Although they have been shown to be elevated among ADHD patients 4, 7-9, in DSM-IV, DESR traits are not 
considered to be diagnostic of the disorder.  Importantly, although DESR is also associated with anxiety and 
mood disorders 6, it differs from the core emotional features of these disorders because the cardinal feature of 
these disorders is the experience of strong emotions, not their self-regulation 10. Because DESR is not a 
diagnostically specific domain, it has not previously been specifically targeted in treatment trials of ADHD.   
Barkley 5 found that 60% of adults with ADHD in a clinical sample reported traits of DESR, in contrast to 15% of 
controls. We found a similar prevalence of DESR in our family study of ADHD adults 6 and studies of the broader 
concept of emotional dysregulation have found strong associations in ADHD adults participating in the 
registration trials for atomoxetine 11, and in a clinical trial of OROS methylphenidate 2.  However, although 
ADHD adults are at high risk for DESR, among ADHD patients, we found only a modest correlation between the 
sum of ADHD symptoms and the sum of items indexing DESR (0.49, unpublished data) among 206 ADHD 
adults enrolled in a family study and a lower correlation among 114 ADHD adults enrolled in a treatment trial 
(r=0.16, unpublished data).  This suggests that changes in DESR will not routinely follow changes in ADHD 
symptoms during treatment trials.   
Our prior work has shown that the high rates of DESR among ADHD patients cannot be accounted for by the 
known comorbidity of ADHD with mood and anxiety disorders 6.  In that study, although DESR was significantly 
associated with mood and anxiety disorders, it was significantly elevated among ADHD patients even after 
statistically adjusting for the presence of both lifetime history and current status of these disorders. In fact, mood, 
anxiety and ADHD made independent contributions to DESR. These findings underscore the point that DESR is 
not simply the experience of the strong emotions that are cardinal symptoms of mood and anxiety disorders.  
Instead, DESR indexes the ability to self-regulate such emotions 4, 10. 
Barkley et al. 5 examined the frequency and severity of problems with DESR in three groups:  Adults with ADHD 
(N=146), Clinical control adults not diagnosed with ADHD (N=97), and a Community control group (N=109).  
Adults with ADHD had significantly more DESR than either Clinical or Community adults.  DESR uniquely 
contributed to 6 of 10 domains and overall impairment.  We then evaluated this issue using more detailed 
measures of occupational impairment, educational history, criminal history, adverse driving outcomes, marital 
satisfaction, parenting stress, and offspring severity of ADHD, ODD, & CD.    Severity of DESR independently 
contributed to most measures of impairment beyond severity of the two ADHD symptom dimensions, and in 
many cases was the only predictor of some impairments.  They concluded that DESR severity is not merely 
redundant with ADHD symptom dimensions but adds additional explanatory and predictive power to 
understanding various forms of adult impairment. 
Another study by the same group evaluated DESR in hyperactive (N = 135) and control (N = 75) children 
followed to adulthood (mean age 27 years) 12. They examined the additional contribution of DESR apart from 
ADHD symptoms to global ratings of impairment in 10 major life activities, adverse occupational and educational 
outcomes, criminal and driving outcomes, and money management difficulties at ages 21 and 27. DESR was 
associated with impairments beyond those contributed by the two traditional dimensions.  Similar findings were 
identified by our group.  We evaluated DESR and functional impairments among 206 adults with ADHD and 123 
adults without ADHD 6. We used the Quality of Life, Enjoyment and Satisfaction Scale-Short Form (QLES-Q-


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SF) and Social Adjustment Scale Self Report (SAS-SR) to assess quality of life and psychosocial functioning. 
Among the ADHD subjects, individuals with extreme DESR symptoms had lower quality of life reports on all 16 
individual items from the QLES-Q-SF. Adults with ADHD with extreme DESR also reported significantly worse 
social adjustment in all individual SAS-SR functional domains, except for Parenting.  ADHD subjects with 
extreme DESR were more likely to have never been married or to be divorced than ADHD subjects without 
extreme DESR.   ADHD subjects with extreme DESR had a higher risk for traffic accidents and being arrested.   
The impact of DESR on driving may have a substantial public health impact given that we and others have 
consistently found driving deficits among ADHD adults 13-17 and elevated rates of driving anger, hostility, and 
road rage, which is a major contributor to driving impairments. 
Treatment Studies of DESR in ADHD 
The few extant treatment studies of DESR in ADHD suggest that current treatments are, at best, only partially 
effective.  Reimherr et al. 2 reported a double-blind, placebo-controlled, crossover trial of OROS-methylphenidate 
(MPH) of 41 ADHD adults. Although OROS-MPH treatment led to significant improvements in symptoms of 
emotional regulation as measured by the WRAADDS, the improvements in emotional regulation were modest, 
leading to residual disability.  For example, ADHD patients without emotional regulation deficits showed a 49% 
improvement in ADHD symptoms compared with only 29% for ADHD patients with emotional regulation 
deficits 2.   In an open label study of Lisdexamfetamine Dimesylate (LDX) for ADHD adults, In work with Adler 
et al. (under review), we assessed the effects of immediate release mixed amphetamine salts (MAS IR) and 
extended release MAS (MAS XR) on ADHD symptoms and on emotional dysregulation as measured by the 
WRAADDS.  Although both medications led to robust statistically significant improvements in DSM-IV ADHD 
symptoms both during the day and in the evening, neither medication led to significant improvements in 
emotional dysregulation. 
Treatment of DESR in ADHD with OROS-MPH 
We recently completed a 6-week, parallel design, randomized, placebo controlled study of OROS-MPH treatment 
in ADHD adults (OROS-MPH N=40; Placebo N=47). We assessed behaviors reflective of DESR with the 
Emotional Control subscale of the Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A).  
In this sample, we had previously shown robust efficacy for OROS-MPH in the treatment of DSM-IV ADHD 
symptoms 18.  In contrast, OROS-MPH did not separate from placebo in the treatment on the Emotional Control 
subscale of the BRIEF-A.  The subgroup of subjects demonstrating good response of their ADHD symptoms 
(Clinical Global Impressions-Improvement ≤2 and ADHD rating scale decrease>30%) still showed poor 
emotional control at the end of the study. 
Omega-3 Fatty Acids 
One possible therapeutic approach suitable for the treatment of DESR is omega-3 fatty acids.  This is for several 
reasons: 1) omega-3 fatty acids have been shown to have some benefits in the management of severe mood 
dyregulation in the context of bipolar disorder in children, a condition that is also frequently associated with 
ADHD; 2) across several studies, ADHD patients have been shown to have lower blood levels of essential fatty 
acids 19, 3) omega-3 fatty acids have been shown to improve some cases of depression, which is also associated 
with DESR; and 4) omega-3 fatty acids are a nutritional supplement known to have positive effects on non-
psychiatric health and to have a benign adverse effect profile. 
Physiological Role of Omega-3 Fatty Acids 
Omega-3 fatty acids are present in the phospholipid layer of cell membranes in humans.  They are a typical 
component of the human diet when fish is consumed.  Omega-3 fatty acids and other polyunsaturated fatty acids 
act as precursors for prostaglandins and eicosanoids (second messengers) in normal cell physiology.  
Eicosapentaeonic acid is a metabolite of alpha-linolenic acid, an essential fatty acid (i.e., which must be ingested 
for survival).  EPA in turn is metabolized to form docosahexaenoic acid (DHA).  Essential fatty acids, in large 
part EPA and DHA, make up 20% of the brain’s dry weight.  Various studies show that omega-3 fatty acids may 
have beneficial effects on health by lowering serum lipids, decreasing platelet aggregation, preventing diabetes 


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and maintaining arterial elasticity 20-27.  Decrease in platelet aggregation, while beneficial in the prevention of 
atherosclerotic plaques, can lead to increase in bleeding time, but no study has suggested that this is a clinically 
significant adverse effect.  As omega-3 fatty acids are part of normal metabolism, the likelihood of unwanted side 
effects is low.  Thus far the only adverse effects reported with omega-3 fatty acids are mild gastrointestinal 
disturbance (loose stool), minimized by taking them with food.  
It has been postulated that phospholipid abnormalities in cell membranes may be implicated in psychiatric 
disorders in general and in bipolar disorder in particular 28-31.  This is the so-called “phospholipid theory of 
psychopathology”, which proposes that neurotransmitter receptor functioning is affected by the fatty acid 
composition of the phospholipids of the cell membrane 29, 30, 32, 33.  With reduced omega-3 fatty acids, the fatty 
acid composition of the cell membrane phospholipids would be altered, less fluid and less efficient, possibly 
leading to altered neurotransmitter binding and psychopathology.  Several studies have shown reduced levels of 
omega-3 fatty acids in the red blood cell membranes 34, fibroblasts 35 and even in the post-mortem brain tissue of 
schizophrenic patients 36.  Other studies demonstrate increased uptake of omega-3 fatty acids into the red blood 
cell membranes of treated subjects, raising the question as to whether subjects have a dietary deficiency in omega-
3 fatty acids which can be corrected by supplementation 37.  Another possibility is that some affected individuals 
are unable to take up omega-3 adequately into cell membranes.  No clear guidelines exist on normal blood levels 
of omega-3 fatty acids, but the increase in blood levels and RBC cell membranes with supplementation argues for 
the idea that individuals are depleted and can benefit from supplementation.  
Omega-3 Fatty Acids in ADHD 
Colquhoun and Bunday 38 were the first to propose that a deficiency of essential fatty acids caused ADHD.  They 
based this hypothesis on several sources of evidence: 1) Boys are more likely than girls to have ADHD and males 
are known to have much higher fatty acid requirements than females;  2) many of the ADHD children they 
studied had abnormal thirst, a cardinal sign of EFA deficiency; 3) Many of the ADHD children they studied 
showed eczema, allergies and asthma which had been associated with fatty acid deficiencies; and 4) zinc 
deficiency has been reported in ADHD 39 and zinc is required for fatty acid metabolism. 
Several studies have implicated omega-3 fatty acids in ADHD.  In a review of eight studies 19, two found no 
differences between ADHD patients and controls but six found ADHD to be associated with low omega-3 fatty 
acid levels and/or higher omega-6 to omega-3 ratios.  The negative studies were small, and one did not make a 
formal ADHD diagnosis but instead assessed “maladaptive hyperactive” children.  Because it is not possible to 
obtain brain levels of fatty acids from ADHD patients, we cannot determine the degree to which these peripheral 
findings implicate fatty acid associated brain dysfunction.  The fatty acid differences between ADHD and control 
youth do not appear to be due to dietary differences 19 and may reflect genetic differences in fatty acid metabolism 
40.   
Omega-3 Fatty Acids and Mental Health 
Recent studies have proposed that dietary supplements with fish oil (a concentrated source of EPA and DHA) 
have been useful in the treatment in adults of schizophrenia 34, 41, 42, subthreshold psychosis 43 and depression 44-46.   
Peet et al. 44 added EPA in a range of doses to usual treatment in 70 depressed adult patients in a placebo 
controlled double blind study.  They found that those receiving the lowest dose (1 gram) showed a significantly 
better outcome than the placebo group on three depression rating scales.  Nemets et al 46 supplemented 20 
depressed patients in a double blind placebo controlled study and also found highly significant improvement in 
depression in the omega-3 group by the third week of treatment.   
The small literature regarding the use of EPA in treating bipolar disorder is particularly relevant given the extreme 
emotional dysregulation associated with that disorder.   The first study of omega-3 fatty acids for bipolar disorder, 
was a 4-month double blind placebo controlled study in which the authors added EPA+DHA, a total of 9.6g (6.2g 
and 3.4 g respectively) to ongoing treatment in 30 adults with bipolar disorder 47. These authors reported a 
significantly longer period of remission for those supplemented with omega-3s.  Furthermore, these omega-3 
supplemented subjects performed better on measures of depression and functioning than the placebo group.   On 


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the other hand, a discouraging outcome was reported by authors associated with The Stanley Foundation Bipolar 
Network which conducted a 4 month double-blind randomized controlled study of EPA monotherapy in 116 
bipolar adults.  This long term monotherapy large scale study failed to show efficacy.  Six g of EPA daily used as 
monotherapy was compared with placebo for 4 months in the treatment of either acute depression or rapid cycling 
illness 48.   
In parallel open label pilot studies of omega-3 fatty acids and atypical antipsychotic medications 49, we found that 
children with bipolar disorder taking omega-3 fatty acids experienced a significant decrease in manic symptoms, 
although the effect was modest compared to that for risperidone.  Subjects had blood tests measuring omega-3 
and omega-6 fatty acid levels at baseline, week 8 and monthly for 3 more months after the end of the acute study 
period.  Fourteen subjects had blood analyzed for omega-3 fatty acids at baseline, eleven at week 8, and only 4 
subjects during the subsequent follow-up visits.  Changes in blood levels did not reach statistical significance due 
to small sample size. Nonetheless, certain trends were evident.  Plasma and RBC levels of DHA+EPA increased 
steadily from baseline to endpoint, with the majority increase by week 8. In both plasma and RBCs, the ratio of 
omega-6 fatty acids to omega-3 fatty acids in omega-3 fatty acid supplemented subjects dropped from baseline to 
endpoint, the majority of the decrease occurring by week 8. 
Although the small literature on omega-3 supplementation is difficult to interpret, it suggests that omega-3 
supplementation can have a modest impact in the management of the severe mood dysregulation associated with 
bipolar disorder. This suggests that it may be efficacious for a less severe form of emotional self regulation such 
as expressed in DESR, Given the evidence for the deleterious impact of DESR on daily functioning, along with 
the known healthful effects of omega-3 and its benign side effects profile, studying this agent for the treatment of 
DESR in ADHD is an important next step. If Omega 3 is efficacious in ameliorating DESR, it would represent a 
safe, acceptable, and widely available treatment alternative to a persistent, common, and broadly impairing set of 
symptoms. 
II. 
SPECIFIC AIMS 
Primary Aims 
Aim 1:  Assess the efficacy of omega-3 fatty acids in the treatment of DESR among ADHD adults treated 
with traditional ADHD pharmacotherapy. Hypothesis 1: omega-3 fatty acids will be safe and effective for the 
treatment of DESR when used in combination with traditional medication (FDA approved medication to treat 
ADHD) for treating adults with ADHD. 
Aim 2:  Assess the side effect profile of omega-3 fatty acids in the treatment of DESR among ADHD adults 
treated with traditional ADHD pharmacotherapy.  Hypothesis 2: The combined use of omega-3 fatty acids 
plus traditional ADHD medication (FDA approved for treatment of ADHD) will be well tolerated in adults with 
ADHD.  
Exploratory Aims 
Aim 3: Assess effects of omega-3 fatty acid supplementation on ADHD symptoms and associated features in 
ADHD adults treated with traditional ADHD pharmacotherapy. Hypothesis 3: predicts that compared to 
ADHD treatment alone, omega-3 fatty acid treatment as a supplement to ADHD treatment will yield a greater 
reduction of ADHD symptoms (as measured by the AISRS and CGI), symptoms of executive dysfunction (as 
measured by BRIEF-A subscales) and functioning (as measured by the GAF). This is a reasonable hypothesis 
given that stimulants and other ADHD treatments are not fully effective in treating ADHD symptoms 50. 
III. SUBJECT SELECTION 
We plan to enroll 60 subjects to the study. We will recruit subjects from the pool of existing subjects and new 
referrals to the Pediatric Psychopharmacology Program at the MGH.  If a potential subject's clinician ascertains 
that the patient has an interest in study participation, the clinician will offer contact information for the study to 
him or her.  The patient can then contact the study coordinator for more information on the actual study. All 
subjects that enter the study will undergo standard screening and diagnostic procedures. Clinical records are not 


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scanned in order to recruit subjects. Subjects who have completed a previous medication trial in our program may 
be eligible to participate in this study. Other medical records on a subject will not be used at any point. 
The majority of subjects referred to our program first participate in our general screening protocol entitled, 
“Screening Protocol for Adults with Attention Deficit Hyperactivity Disorder” (Protocol # 2002-P-001856). After 
participating in this screening protocol, subjects are assigned to specific studies based upon eligibility 
requirements (i.e. age, prior medication efficacy or tolerability).  For the current study, we will screen for traits of 
DESR using 10 questions from the BRIEF-A Emotional Control scale.  These items will be asked as an addition 
to the standard phone screen administered to potential participants in studies of adult ADHD at our program.  
Individual’s scoring >65 by T-score on the Emotional Control scale, or those with sufficient symptoms for further 
evaluation by clinician judgment, will be screened in person for the study. We will also screen subjects using the 
36-item DERS, which measures emotional control. Potentially eligible subjects (as per the results of screening 
protocol) will receive a link to complete this screen via email. Subjects who score >99 (representing more than 1 
SD above the mean) will be eligible. Subjects who meet criteria based on either the BRIEF-A Emotional Control 
scale or the DERS will be eligible to participate. 
Study Entry Criteria 
Inclusion 
1. Male or female adults ages 18-55 years. 
2. A diagnosis of childhood onset ADHD, according to the Diagnostic and Statistical Manual of Mental 
Disorders, Fourth Edition 51 (DSM-IV) based on clinical assessment. Childhood onset will be defined 
according to established research criteria, requiring onset of two symptoms of inattentive or of 
impulsive/hyperactive traits by the age of 12. 
3. A score of 24 or more on the Adult ADHD Investigator Symptom Report Scale (AISRS), or, for those 
individuals stably treated with a medication approved by the FDA for ADHD, a CGI-ADHD severity score of 
no greater than 4 (“moderately ill”).  
a. Those subjects treated with traditional ADHD pharmacotherapy must be on a stable, 
effective dose (per clinician evaluation) of an FDA-approved treatment for ADHD for at 
least one month at the time of enrollment. 
4. A DESR T-score on the BRIEF-A Emotional Control Scale of at least 65 and/or a score of 99 or more on the 
DERS. 
Exclusion 
1. For those subjects not treated for their ADHD at the time of enrollment, a history of non-response or 
intolerance to methylphenidate at adequate doses as determined by the clinician.  
2. A history of intolerance to omega-3 fatty acids as determined by the clinician.  
3. Pregnant or nursing females. 
4. Serious, unstable medical illness including hepatic, renal, gastroenterological, respiratory, cardiovascular, 
endocrinologic (thyroid), neurologic (seizure), immunologic, or hematologic disease.  
5. Glaucoma. 
6. Clinically unstable psychiatric conditions including suicidality, homicidality, bipolar disorder, psychosis, or 
lifetime history of a clinically serious condition potentially exacerbated by a stimulant such as mania, or 
psychosis. 
7. Tics or a family history or diagnosis of Tourette’s syndrome. 
8. Current (within 3 months) DSM-IV criteria for abuse or dependence with any psychoactive substance other 
than nicotine. 


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9. Allergies to fish or shellfish; multiple adverse drug reactions. 
10. Any other concomitant medication with primarily central nervous system activity other than specified in 
Concomitant Medication portion of the protocol. 
11. Current use of MAO Inhibitor or use within the past two weeks. 
12. Investigator and his/her immediate family; defined as the investigator’s spouse, parent, child, grandparent, or 
grandchild. 
 
While stably treated or remitted hypertension (defined by a stable current blood pressure of no more than 120/80) 
is not exclusionary, any subject with a history of high blood pressure not treated for ADHD at study entry will be 
asked to obtain approval from their primary care physician certifying that their hypertension is stable and that they 
may safely begin stimulant therapy. Subjects not treated for ADHD upon entry into the study will be informed of 
the cardiovascular risks of OROS-MPH, and any subject with a history of hypertension who is unwilling to 
consult with their current treater prior to beginning treatment with OROS-MPH—or to grant study staff 
permission to consult with the subject’s current treater—will be excluded because of the potential risks to subject 
safety. Per the FDA approved OROS-MPH package insert, high blood pressure is not a contraindication of 
OROS-MPH therapy; however, due to the cardiovascular side effects, it is recommended that subjects with a 
history of high blood pressure be monitored carefully. Cardiovascular risk factors are carefully monitored 
throughout the study for all subjects by way of screening electrocardiograms and pulse/blood pressure readings at 
every office visit. Patients with current hypertension are not eligible.  
 
IV. SUBJECT ENROLLMENT 
Informed consent will be obtained prior to the performance of any protocol procedures and prior to administration 
of study drug. The informed consent and assent documents will be used to explain in simple terms the risks and 
benefits of study participation to the subject. The nature of the study will be fully explained to the subject by a 
board-certified physician who is either the primary investigator or co-investigator. The subject will be encouraged 
to ask questions pertaining to their participation in the study and the subject may take as much time as they feel 
necessary to consider his/her participation in the study as well as consult with family members or their physician.  
Participation in this study is voluntary and the subjects may withdraw from the study at any time. The IRB-
approved informed consent documents will be signed and dated by the subject and the physician obtaining 
consent.  
V. STUDY PROCEDURES 
We will conduct a 12-week, double blind, placebo-controlled, randomized clinical trial to compare efficacy and 
tolerability of Omega-3 fatty acids for DESR as a supplement to FDA approved treatment for ADHD (“traditional 
ADHD treatment”) in ADHD adults. We will randomize 30 subjects to Omega-3 fatty acids plus traditional 
ADHD treatment and 30 to placebo plus traditional ADHD treatment. OROS-methylphenidate (OROS-MPH) will 
be prescribed openly to all subjects not receiving treatment for ADHD at trial entry. This is ecologically valid 
because long-acting stimulants are first line treatments for ADHD. For subjects taking a stable dose of medication 
for ADHD (as defined by a stable, effective dose for at least one month) prior to study entry, Omega-3 (or 
placebo) will be administered as a supplement to their treatment regimen as usual, which will be monitored by the 
study clinician in collaboration with the subject’s current prescriber.  
After providing study information and obtaining IRB approved informed consent, participants will complete a 
brief interview to obtain demographic background information. They will then undergo a comprehensive 
assessment including a psychiatric assessment reviewing current and lifetime DSM-IV Axis I conditions, medical 
history, physical assessment (vitals, EKG, and urine screening tests) and a neuropsychological evaluation to 
confirm and IQ>80, which can be completed at evaluation or baseline. The information obtained at this visit will 
be reviewed to assure that all inclusion and exclusion criteria are met prior to receiving study medication at the 


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baseline visit. Subjects who do not meet all the criteria for enrollment after these assessments will be 
discontinued. 
We anticipate that subjects may enter this trial following completion of/withdrawal from other protocols in our 
office, and that there may be procedural overlap. So as to not burden subjects with redundant time commitments, 
we will use the following diagnostic data previously collected:  If a subject has completed an evaluation with one 
of the study clinicians within the previous year prior to entrance into this study, they will not be asked to repeat 
any overlapping diagnostic procedures. With subjects’ permission, we will use the diagnostic data that had been 
previously collected. However, the study clinician will review the interval time period to assess for clinically 
significant medical or psychiatric history, to ensure that the subject meets appropriate study entrance criteria.   
Any subjects taking medication exclusionary to the study must be tapered off this medication prior to baseline 
visit.  Only subjects not responding to current treatment will be tapered from medication. Subjects will not be 
asked to taper a medication that is optimally and comfortably managing clinical concerns for entry into this study.  
Medication tapers will be monitored by the study clinician in agreement with the research subject. 
Participants who fulfill the inclusion and exclusion criteria will be randomized to placebo or Omega-3 fatty acids 
treatment for the period of 12 weeks. The MGH Clinical Trials pharmacy will be responsible for creating and 
maintaining the study medication randomization schema. 
Vital signs (blood pressure, pulse, weight) will be measured at every visit. Height will be measured at baseline 
and at the end of the study. Electrocardiograms will be performed at evaluation and again at the end of the study. 
In addition, a urine drug screen will be performed at evaluation, week 6, and week 12. If the participant is found 
to have taken an illicit drug, he/she will have a discussion with the doctor to determine if he/she can be in the 
study; subjects will be discontinued if there is evidence of ongoing substance use. Females who are able to have 
children will also have a urine pregnancy test at evaluation, week 6, and week 12. If a participant has a positive 
pregnancy test she will not be able to take part in the study. Those subjects who terminate study participation 
before the completion of the study will be asked to complete all tasks scheduled to take place on the final study 
visit at the time of study discontinuation. 
Subjects will be evaluated at weeks 1- 6, 9 and 12 in the office, with optional phone contact between these visits. 
The need for phone contact between visits will be established by the clinician at office visits, or by needs of the 
subjects as they arise. At each office visit assessment of safety and efficacy will be obtained by administering 
measures of efficacy (CGI, GAF, AISRS, BRIEF-A), tolerability (adverse events), and safety (vital signs). 
Neuropsychological assessments will be repeated at study endpoint.   
Although every effort will be made to encourage subjects to keep regularly scheduled appointments, in the event 
that a subject is unable to come into the office within a reasonable timeframe of a scheduled visit, and the treating 
research clinician feels that subject safety will not be jeopardized by doing so, the clinician can conduct the visit 
with the subject over the telephone. However, study evaluation visit, baseline visit, mid-point visit (week 6) or the 
final study visit may not be conducted over the phone. Additionally, phone visits may not replace scheduled office 
visits for two consecutive visits. This interval of office visits with phone contact as needed has proven utility in 
both clinical care and in a recent methylphenidate trial conducted in adults at our research unit. 
During the study, the following, assessments and instruments will be used: 
Background Information: 
 
Subjects will complete a brief interview after the informed consent process to obtain demographic 
information including: socioeconomic status, educational history, occupation, marital status, history of 
head injuries, and history of trauma. 
Neuropsychological battery: 
 
Wechsler Abbreviated Scale of Intelligence (WASI) Vocabulary and Matrix: to calculate verbal, 
performance, and full-scale IQ. 


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Cambridge Neuropsychological Test Automated Battery (CANTAB):  
CANTAB is designed to look at frontal lobe (executive functioning). Select subtests will include the following:  
 
Spatial Working Memory (SWM), tests comprehension, learning and reversal.  
 
Stockings of Cambridge (SOC), assesses spatial planning and motor control.  
 
Intra-Extra Dimensional Set Shifting (IED), tests rule acquisition and attentional set shifting.  
 
Reaction Time (RTI), measures speed of response. 
 
Rapid Visual Information Processing (RVP), tests sustained visual attention.  
 
Affective Go/No-go (AGN), assesses information processing biases for positive and negative stimuli.  
 
Verbal Recognition Memory (VRM), assesses immediate free recall, and immediate and delayed 
recognition memory 
Clinician rated assessments: 
 DSM-IV Global Assessment of Functioning (GAF) scale. The GAF will assess global functioning using a 
scale from 1 (worst) to 100 (best). 
 Clinical Global Impressions (CGI) scale for ADHD as well as for Mood and Anxiety and DESR. The 
CGI is a measure of illness severity, improvement, and efficacy of treatment; CGI’s for mood and anxiety 
will capture emergent comorbid psychiatric symptoms.  
 DSM-IV based Adult ADHD Investigator Symptom Rating Scale (AISRS). Each of the individual 
symptoms of ADHD is rated 0 to 3 on a scale of severity. 
 Hamilton Depression (HAM-D) and Anxiety52 (HAM-A) Scales to evaluate depression/anxiety 
symptoms. 
 Columbia-Suicide Severity Rating Scale (C-SSRS) to evaluate any suicidal behavior. 
 Adverse Experiences and Concomitant Medications. 
Subject rated scales: 
 The 18-item ADHD Rating Scale to evaluate frequency of ADHD symptoms on a scale of 0 to 4.  
 The 75-item Behavior Rating Inventory of Executive Function – Adult Form (BRIEF-A) to assess levels 
of executive function deficits. 
 The 36-item Difficulties in Emotion Regulation Scale53 (DERS) to provide an overall emotional 
regulation score, as well as scores measuring the following sub-domains: (1) awareness and 
understanding of emotion; (2) acceptance of emotion; (3) ability to stay on task during negative emotion 
(e.g., refrain from impulsive behaviors); and (4) access to effective emotional regulation strategies. 
 The 20-item Positive and Negative Affect Schedule54 (PANAS) to measure experience of positive and 
negative emotions. 
 The 32-item Acceptance and Action Questionnaire55 (AAQ) to measure the use of experiential avoidance 
as an emotion regulation strategy. 
 The 10-item Emotion Regulation Questionnaire56 (ERQ) to measure the use of two emotion regulation 
strategies: reappraisal and suppression. 
 The Adult Self-Report Form57 (ASR) to measure a wide range of psychiatric syndromes (i.e., depressive 
problems, anxiety problems, antisocial personality problems) in adults. The ASR provides dimensional 
scale scores for each syndrome that are age- and gender-normed. 


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 The 34-item Aggression Questionnaire58 (AQ) to assess components of aggression and hostility. 
 The Social Adjustment Self Report Questionnaire (SAS) to measure overall social adjustment and 
satisfaction. 
 The 16-item Quality of Life Enjoyment & Satisfaction Questionnaire (Q-LES-Q) to measure overall 
satisfaction across different aspects of daily life. 
 The 8-item Emotional dysregulation subscale of the Barkley Current Behavior Scale—Self-Report (CBS 
DESR) to measure emotional reactivity. 
 The 25-item Endicott Work Productivity Scale (EWPS) to measure behaviors and feelings likely to 
reduce productivity and efficiency in work activities. 
 
Self-report and clinician-rated measures will be collected using DatStat IllumeTM, a platform for electronic data 
capture that streamlines data collection and management, and ensures data integrity, resulting in improved data 
quality. The DatStat software allows researchers to design and implement study surveys for collecting, storing, 
retrieving, and manipulating data electronically. Participants and/or research staff enter survey responses into 
electronic assessment forms, and the responses are then transmitted securely via encrypted connection and stored 
in a secured database. This electronic data capture obviates the need for subsequent data entry by staff, thus 
minimizing human error. 
 
These surveys are completed securely via the internet by using any device with standard web access and browsers. 
For this study, participants and staff will complete the electronic assessments on computer terminals at the 
research site under the supervision of study staff. 
In the event that the electronic data capture system is unavailable during a study visit (due to technical issues), 
rating scales will be collected in paper and then entered into the program manually once the system becomes 
available.  
For quality control purposes, clinician-administered measures completed during the visits may be audiotaped, 
with subjects’ permission. These recordings will be used to monitor quality control and inter-rater reliability in 
this study by the PI. Each recording will be coded with subject initials and number to maintain confidentiality. 
These recordings will be de-identified and stored on a password protected computer accessible only to the 
appropriate study staff. 
Upon completion of the study, participants can choose to pursue follow-up care, as possible, at our MGH practice 
or continue treatment with their primary care physician. Study clinicians may also offer psychiatric referrals to 
treaters in their communities.  
Study Medication 
At the baseline visit, subjects will receive a prescription for OROS-MPH, or instructions to continue with their 
current ADHD treatment regimen, and will be randomized to receive either Omega-3 fatty acids or placebo (under 
double blind conditions).  
For those subjects not on stable ADHD treatment (defined as a stable, effective dose for at least one month, 
determined by the study clinician, of a medication that is FDA approved to treat ADHD), OROS-MPH will be 
openly prescribed. OROS-MPH and Omega-3 treatment will be concurrently titrated. OROS-MPH will be openly 
prescribed, starting with an initial dose of 36 mg/day. OROS-MPH will be titrated to optimal response (not 
exceeding a maximum daily dose of 1.3 mg/kg or 108 mg/day, whichever is lower), according to clinician 
judgment, during the first six weeks of the trial.  During this titration period, dose will be increased on a weekly 
basis in 18-36 mg/day increments, according to clinician judgment, with the goal of obtaining a well-tolerated and 
effective dose, according to a priori definitions of efficacy as at least a CGI-Improvement of 1 or 2. At any time, 


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11
the dose may be reduced if adverse effects present or if the subject discontinues treatment. At subsequent visits, a 
higher dose may be resumed if tolerated. 
Those individuals on an effective, stable dose of traditional ADHD treatment (as defined by a stable, effective 
dose for at least one month, as determined by the study clinician, of a medication that is FDA approved for the 
treatment of ADHD), will continue with this treatment as usual. Currently-treated subjects must have a CGI-
ADHD severity rating of no greater than 4 (“moderately ill”), because a score greater than 4 indicates that their 
ADHD symptoms, independent of DESR, are not effectively treated by their current medication regimen. 
Omega-3 fatty acids dosing will start and remain at 1060mg of EPA or two capsules for the duration of the study 
in the form of Nordic Natural ProEPA Xtra brand which contains 530mg EPA and 137mg DHA. Nordic Naturals 
is also able to make a matched placebo product and will provide us with a detailed Certificate of Analysis 
attesting to the contents of the capsules. Our proposed dosing is well within the FDA approval for EPA. The 
MGH Clinical Trials pharmacy will fill Omega-3/placebo prescriptions labeled with subject study ID number and 
randomization number, but all study-staff will remain blind to the subject’s assignment. The study clinician will 
be responsible for dispensing Omega-3/placebo.   
At each visit, measures of safety and effectiveness will be administered and subjects will be evaluated for 
response and side effects to the treatment. To assess and ensure drug accountability and compliance, study 
medication will be returned and counted at study visits.  
Information regarding subjects' status of assignment to medication or placebo will be available at all times 
through the MGH Clinical Trials Pharmacy. In addition, the randomization list will be available to the 
investigator at all times, in case of emergency.  
Concomitant Medications / Treatments 
A detailed past and present treatment history will be taken as part of initial evaluation. Patients who are currently 
stably treated with an SSRI, SNRI, or Wellbutrin will be permitted to continue on their current regimen, provided 
the patient’s regimen remains the same throughout the study. Subjects treated with these medications must be on a 
stable dose for at least one month prior to study entry. No new SSRI medications, SNRI medications, Wellbutrin, 
or alterations to the current regimen may be initiated throughout the duration of study participation. Other than 
SSRIs, SNRIs, or Wellbutrin, concomitant medications with primarily central nervous system activity are not 
allowed in this study.  No subject will be tapered from medication that is useful to him or her.  Non-
pharmacological treatments such as individual, family or group therapy will be allowed if they were in place 
before the patient joined the study.  The patient’s therapy regimen must remain the same throughout the study.  
 
Study Discontinuation Criteria 
Subjects who 1) develop intolerable AE(s) despite dose adjustments; 2) have (a) clinically relevant serious AE(s) 
as determined by the investigator including changes in vital signs; 3) have worsening ADHD symptoms (much 
worse or very much worse as rated on CGI-Improvement at two consecutive visits); or 4) have emergent 
psychosis, suicidality, substance use, or worsening mood and/or anxiety (much worse or very much worse as rated 
on CGI-Improvement); 5) subject non-compliance or withdrawal; 6) pregnancy will no longer continue in the 
study. If study participation is discontinued due to safety reasons, participants will receive two follow-up visits, 
giving adequate time for appropriate psychiatric referrals to treaters in their communities. 
VI. 
BIOSTATISTICAL ANALYSIS 
 
Data processing and management will follow procedures developed by the investigators and used in ongoing 
studies.  60 subjects will be randomized (1:1) into one of two treatment groups: omega-3 fatty acids plus  ADHD 
medication, or placebo plus ADHD medication. The MGH Clinical Trials pharmacy will be responsible for 
creating and maintaining the study medication randomization schema. Because this is a randomized trial 
following subjects over a short period of time missing data are not expected to impact our analyses such that 
standard statistical analyses will be employed. Changes in outcome ratings within and between study groups over 


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12
time will be tested with longitudinal generalized estimating equation (GEE) regression models estimated using 
STATA within the framework of the general linear model (GLM).  Each model will predict outcome scores from 
treatment group (binary predictor), study visit (ordinal predictor) and the group by visit interaction.  All analyses 
will be intention to treat (ITT). 
Our primary test of Hypothesis 1 examines the change in DESR symptoms (as measured by the BRIEF-A 
Emotional Control scale) over 12 weeks. This hypothesis predicts a significant group by visit interaction in the 
GEE model of emotional control. Hypothesis 2 examines side effects associated with the combined use of omega-
3 fatty acids plus ADHD medication.  The prevalence of binary side effects reported over the course of the trial 
(i.e. for each side effect, the cumulative sum from the first assessment to endpoint) will be compared between 
groups using Poisson regression at study endpoint.  We will compare continuous measures with longitudinal GEE 
models as for Aim 1. Hypothesis 3 predicts that compared to ADHD treatment alone, omega-3 fatty acid 
treatment as a supplement to ADHD treatment will yield a greater reduction of ADHD symptoms (as measured by 
the AISRS and CGI), symptoms of executive dysfunction (as measured by BRIEF-A subscales) and functioning 
(as measured by the GAF).  These analyses will use the GEE framework as used for Hypothesis 1. For 
Hypotheses 1, the power to detect a 0.5 standard deviation difference between groups is 0.96 with alpha set at 
0.05 as we require only one statistical test.  Lacking preliminary data on the expected effect size, we chose an 
effect size of 0.5 because we are looking for a clinically significant effect.  Although less than the effect size for 
treatments of ADHD symptoms by non-stimulants (~0.7) or stimulants (~0.9) [93], an effect size of 0.5 is similar 
to what is seen for the effects of antidepressants for depression [94] and thus would be considered clinically 
significant. For our analyses of cumulative binary adverse events at endpoint, although there are many statistical 
tests, we will use an alpha level of 0.05 to err on the side of safety.  For low counts of AEs in the ADHD 
treatment only group (e.g., 2) we will have 86% power to detect a 1.7-fold increase or more in the ADHD 
treatment plus omega-3 group. For higher counts in the ADHD treatment group only (e.g., 10) power will be 
higher; we will have 91% power to detect a 1.3-fold increase or more in the ADHD treatment plus omega-3 
group.  For longitudinal continuous measures, power will be the same as for Hypothesis 1. 
 
 
Because this is a pilot, proof of concept study designed to identify the feasibility of a larger, higher-
powered study, we are not providing a power analysis calculation.   
VII. 
RISKS AND DISCOMFORTS 
All efforts are made to minimize risks to subjects. Consistent with good clinical practice, safety will be monitored 
by the Principal Investigator, and will reflect the oversight of study clinicians, as identified in the key personnel. 
Adverse events will be recorded and reported according to institutional policies. Risks of study medication have 
been incorporated into the exclusionary criteria for this proposal. 
Study clinician evaluation and subject questionnaires: Some questions may make subjects feel uncomfortable. 
Subjects may refuse to answer any question. In the event that a participant reports risk of harm to himself or 
herself, or to another person, study clinicians will assess the level of risk, and take appropriate actions, including 
disposition of an immediate referral to a local Psychiatric Emergency Room.  
Study Medication – Omega-3 Fatty Acids: In prior Omega-3 studies of ADHD the most common side effects 
reported were diarrhea, nausea, fishy aftertaste, belching, irritable bowel, indigestion, and other symptoms of 
digestive upsets. These events were mild, transient, and infrequent.  In the prescribing information for Lovaza (an 
FDA approved Omega-3 formulation), the most common adverse events (incidence >3% and greater than 
placebo) were belching, infection, flu syndrome, and dyspepsia. 
Study Medication – OROS-MPH (for subjects not treated for ADHD at trial entry): The medication used in this 
study for subjects who are not treated for ADHD at trial entry will be one of the most commonly prescribed 
stimulant class of medication; the extended duration methylphenidate, OROS-MPH (Concerta®). OROS MPH is 
currently FDA-approved for ADHD in children, adolescents and adults. Commonly-observed side effects 
associated with the use of OROS MPH include difficulty falling asleep, low appetite, headaches, stomachaches, 
nervousness, and dizziness. Side effects tend to be mild. Rare, but serious side effects of OROS MPH include 


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13
seizures, eyesight changes, and blockage of esophagus, stomach or intestine. There are also reports of changes in 
behavior or cognition, including psychotic symptoms, and aggression/hostility. Persons with a history of tics may 
experience return of symptoms. OROS MPH is a federally controlled substance which can be abused or lead to 
dependence. Heart-related problems including sudden death, stroke and heart attack, have been reported with use 
of methylphenidate and other stimulant medicines. Recently published controlled data from our group has 
demonstrated efficacy and tolerability of OROS MPH in a large sample of healthy adults with ADHD (Biederman 
et al, 2006). Dosing for this protocol is consistent with our clinical experience with this medication. 
Study Medication—ADHD Medications: Stimulants are considered a first line of treatment for ADHD. 
Commonly prescribed stimulant medications include Methylphenidate (Ritalin, Metadate, Daytrana); 
Dexmethylphenidate (Focalin); Amphetamine-Dextroamphetamine (Adderall); Dextroamphetamine (Dexedrine, 
Dextrostat); and Lisdexamfetamine (Vyvanse). 
Commonly observed side effects associated with the use of these FDA-Approved stimulants include insomnia, 
decreased appetite, weight loss, headache, increased pulse, and shifting moods.  Other less common side effects 
include irritability, stomach pain, headache, depression, hair loss, and lack of spontaneity. Stimulants have also 
been associated with more rare, but serious, side effects such as sudden death, stroke, and heart attack in adults 
with a history of heart disease.  
In addition to stimulants, Atomoxetine (Strattera) is approved for the treatment of ADHD in adults. Commonly 
observed side affects associated with the use of this medication include constipation, nausea, dry mouth, 
decreased appetite, dizziness, erectile dysfunction, and urinary hesitation. Other less common side effects include 
abdominal discomfort, fatigue, irritability, and drowsiness. 
Subjects receiving ADHD pharmacotherapy prior to trial entry will continue their regimen as usual. While the 
study clinician will not be prescribing ADHD treatment to those subjects being stably treated prior to study entry, 
s/he will monitor subjects closely in collaboration with their primary prescriber.  
 
Confidentiality 
All research-related records, initiated as a result of a subject’s participation in this study that reveal the subject’s 
identity, will remain confidential except as may be required by law. Results of urine drug or pregnancy testing 
will not become part of the subject’s medical record. Data obtained from this study will not identify the subjects 
individually. Subjects will be assigned code-names and ID numbers.  Data obtained from our studies may be 
published. Original research-related records may be reviewed by the Partners Human Research Committee, and 
regulatory authorities, for the purpose of verifying clinical trial procedures and/or data. Information may be held 
and processed on a computer.  Access to these computerized records will be password protected and restricted to 
study staff. Subjects will only be contacted regarding future studies if they indicate that they are interested in 
being contacted by initialing in the specific section of the consent form. 
VIII. 
POTENTIAL BENEFITS 
There may be no direct benefit to subjects participating in this study. Potential benefits to the participants include 
education about ADHD, a trial of medication that could be continued after the study, and the opportunity to 
contribute 
to 
medical 
science 
and 
thus 
help 
others 
with 
similar 
disorder. 


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14
SUMMARY 
  
Eval Baseline   
(Visit 0) 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
9 
Week 12 (Or 
Drop) 
  
  
  
  
  
  
  
  
  
  
  
Consent 
X 
 
 
 
 
 
 
 
 
 
Procedures 
ECG 
X 
 
 
 
 
 
 
 
 
X 
Vital Signs 
(weight, BP, 
pulse) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
X 
Urine Drug 
Screen 
X 
 
 
 
 
 
 
X 
 
X 
Urine 
Pregnancy 
(females only) 
X 
 
 
 
 
 
 
X 
 
X 
Assessments 
Background 
Interview 
X 
 
 
 
 
 
 
 
 
 
WASI 
X 
 
 
 
 
 
 
 
 
 
CANTAB 
X* 
X* 
 
 
 
 
 
X 
 
X 
Clinician 
Interview 
X 
 
 
 
 
 
 
 
 
 
Clinician Rated Scales 
AISRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D; 
HAM-A 
 
X 
 
 
 
 
 
X 
 
X 
C-SSRS 
 
X 
 
 
 
 
 
X 
 
X 
GAF 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Rated Scales 
BRIEF-A 
X 
X 
 
 
 
 
 
X 
 
X 
ADHD RS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DERS 
X  
X 
  
  
  
  
  
X 
  
X 
PANAS 
  
X 
  
  
  
  
  
X 
  
X 
AAQ 
  
X 
  
  
  
  
  
X 
  
X 
ERQ 
  
X 
  
  
  
  
  
X 
  
X 
ASR 
  
X 
  
  
  
  
  
X 
  
X 
AQ 
  
X 
  
  
  
  
  
X 
  
X 
SAS 
  
X 
  
  
  
  
  
X 
  
X 
Q-LES-Q 
  
X 
  
  
  
  
  
X 
  
X 


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15
CBS- DESR 
Subscale 
  
X 
  
  
  
  
  
X 
  
X 
EWPS 
  
X 
  
  
  
  
  
X 
  
X 
* Can be completed at evaluation or /baseline 
 


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16
 
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