4

Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program

Mapping the Evidence: Sex 

Effects in High-impact 

Conditions for Women Veterans 

– Depression, Diabetes, and

Chronic Pain

September 2015

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Durham Veterans Affairs Healthcare System

Durham, NC

John W. Williams, Jr. MD, MHSc, Director 

Investigators:

Principal Investigators: 

Wei Duan-Porter, MD, PhD

John W. Williams, Jr., MD, MHSc

Co-investigators: 

Karen Goldstein, MD, MPH

Jennifer McDuffie, PhD, MPH

Jaime M. Hughes, MPH, MSW

Megan Clowse, MD

Ruth Klap, PhD

Varsha Masilamani, MBBS

Nancy M. Allen LaPointe, PharmD, MHS

Research Associate:

Avishek Nagi, MS
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and 

policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding 

for four ESP Centers, and each Center has an active University affiliation. Center Directors are 

recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based 

Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA 

Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as 

designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help: 

Develop clinical policies informed by evidence;

Implement effective services to improve patient outcomes and to support VA clinical practice

guidelines and performance measures; and

Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence 

syntheses have informed the clinical guidelines of large professional organizations. 

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the 

capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program 

development and evaluation, and dissemination efforts. The ESP CC establishes standard operating 

procedures for the production of evidence synthesis reports; facilitates a national topic nomination, 

prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial 

review processes; ensures methodological consistency and quality of products; produces “rapid response 

evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for 

Information Dissemination and Education Resources (CIDER) to develop a national dissemination 

strategy for all ESP products; and interfaces with stakeholders to effectively engage the program. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program 

Manager, at Nicole.Floyd@va.gov. 

Recommended citation: Duan-Porter W, Goldstein K, McDuffie J, Clowse M, Hughes J, Klap R, 

Masilamani V, Allen LaPointe NM, Williams JW Jr. Mapping the Evidence: Sex Effects in Highimpact Conditions for Women Veterans. VA ESP Project #09-010; 2015.

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Center located at 

the Durham VA Medical Center, Durham, NC, funded by the Department of Veterans Affairs, Veterans Health 

Administration, Office of Research and Development, Quality Enhancement Research Initiative. The findings and 

conclusions in this document are those of the author(s) who are responsible for its contents; the findings and 

conclusions do not necessarily represent the views of the Department of Veterans Affairs or the United States 

government. Therefore, no statement in this article should be construed as an official position of the Department 

of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, consultancies, 

honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties) that 

conflict with material presented in the report. 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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STRUCTURED ABSTRACT

Background: Women are entering the military at unprecedented rates and comprise a rapidly 

increasing segment of Veterans Health Administration (VHA) enrollees. In response, the VHA 

Women’s Health Service requested an evidence map to (1) identify effective interventions in 

women, (2) better understand sex differences in intervention effects for high-impact medical 

conditions, and (3) identify gaps in evidence about the efficacy of interventions in women. 

Methods: We used a stakeholder-driven approach to identify high-priority conditions and 

interventions. From an initial list of 36 conditions, we used a forced-rank methodology to 

identify 3 conditions for evaluation: depressive disorders, type 2 diabetes mellitus, and chronic 

pain conditions (chronic low back pain [CLBP], chronic knee osteoarthritis [OA], and 

fibromyalgia [FM]). We evaluated treatments in broad categories, including medications, 

behavioral interventions, supervised exercise, and quality improvement interventions, along with 

certain condition-specific interventions. For each condition, we searched MEDLINE and the 

Cochrane Database of Systematic Reviews (CDSR) to identify relevant systematic reviews 

published from January 1, 2009, through October 31, 2014. Data abstracted from eligible 

systematic reviews included study design, outcomes, the number and design of primary studies, 

proportion of men and women in included studies, and whether sex effects were part of study 

aims, analysis plan, or results. For studies containing sex-specific results, we also abstracted the 

method used for evaluating sex effects (eg, meta-regression) and the outcomes that differed due 

to sex effects.

When information on sex effects was absent from eligible reviews, we selected high-priority

interventions for further evaluation. For these interventions, we examined the largest recent 

systematic review to identify primary randomized controlled trials (RCTs) as candidates for 

review. We examined RCTs that randomized at least 75 patients per treatment arm to determine

whether they reported sex effects. We chose this sample size criterion in order to limit evaluation 

to RCTs that had the potential for adequate statistical power to detect interaction effects 

(intervention * sex). 

Results: A combined search of PubMed and CDSR yielded 2531 unique citations, of which 582 

full-text articles were retrieved; 313 systematic reviews were eligible, and 268 were fully 

abstracted. Of these, 86 addressed interventions for depression, 114 addressed interventions for 

diabetes, and 68 addressed interventions for 3 types of chronic pain: CLBP (n=26), FM (n=34), 

and knee OA (n=8). Most reviews limited eligibility to RCTs, and the number of primary studies 

included in the systematic reviews ranged from 0 to 347. Only half (48%) of the reviews 

summarized the gender distribution of the populations of the included studies, but when 

summarized, women were well represented. Sex effects were reported in only 30 of the 313 

(10%) eligible reviews: 14 (16%) for depressive disorders, 13 (8%) for diabetes, and 3 (4%) for 

chronic pain. Individual patient data (IPD) meta-analysis—the analysis method best suited to 

evaluating sex effects—was rarely used (n=16 of 268 abstracted reviews, 6%).
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Overall, we found only a minority of RCTs had sample sizes large enough to examine moderator 

effects, and only 14% of these (9 of 66) examined interactions between sex and the main 

comparison, intervention type versus control group. When sex effects analyses were identified, 

most commonly no effect was found. Those with evidence of a sex effect often showed greater 

benefit in women (Table), but differential effects were typically small. There were important 

gaps in evidence on sex effects for multiple interventions in all conditions examined, either 

because no reviews evaluating sex effects were identified or because no IPD meta-analyses were 

identified. 

Table. Summary of sex effects identified in systematic reviews

Condition Possible differences in treatment 

effects between men and women

Possible lack of differences in 

treatment effects between men and

women 

Depressive disorders Greater improvement in depressive 

symptoms

CBT, duloxetinea

SSRIs in older adults

More adverse effects on sexual 

dysfunction

Paroxetine

Depressive symptoms

Antidepressants overall, quality 

improvement, self-helpa

Combined antidepressant and 

psychotherapy for dysthymia

Adverse effects overall

Antidepressants

Diabetes Fracture risk

Lower for sulfonylureas (compared 

with thiazolidinediones)

Glycemic control

Linagliptina, vildagliptina

Weight loss

Bariatric surgery

Chronic painb Greater improvement in CLBP

Quality improvement 

CLBP

Antidepressants a Findings are from IPD meta-analysis. b Fibromyalgia is not listed because studies predominantly enrolled women. Knee osteoarthritis is not listed because 

no reviews were identified.

Abbreviations: CBT=cognitive behavioral therapy; CLBP=chronic low back pain; OA=osteoarthritis; 

SSRI=selective serotonin reuptake inhibitor

Conclusions: There is a large body of evidence for many of the examined interventions, 

particularly medications, psychotherapy, and exercise. However, systematic reviews and primary 

RCTs examined sex effects infrequently. When examined, sex effects generally favored greater 

benefits in women, but the differential effects were small and the analysis approaches were often 

suboptimal. All RCTs and systematic reviews should report the proportion of men and women 

enrolled, and sex effects should be examined in adequately powered RCTs or IPD meta-analyses. 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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ABBREVIATIONS TABLE

AHRQ Agency for Healthcare Research and Quality

CI Confidence interval

CLBP Chronic low back pain

ES Effect size

ESP Evidence-based Synthesis Program

FM Fibromyalgia

HSR&D Health Services Research & Development

IPD Individual-patient data

MD Mean difference

MeSH Medical Subject Heading

OA Osteoarthritis

QUERI Quality Enhancement Research Initiative

QI Quality improvement

RCT Randomized controlled trial

SMD Standardized mean difference

SOE Strength of evidence

VA Veterans Affairs

VHA Veterans Health Administration

WMD Weighted mean difference
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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TABLE OF CONTENTS

TABLES

INTRODUCTION......................................................................................................................... 1

METHODS .................................................................................................................................... 2

Topic Prioritization ..................................................................................................................... 2

Search Strategy ............................................................................................................................ 3

Study Selection ............................................................................................................................ 3

Data Abstraction .......................................................................................................................... 5

Quality Assessment ..................................................................................................................... 5

Data Synthesis ............................................................................................................................. 5

Peer Review ................................................................................................................................. 6

RESULTS ...................................................................................................................................... 7

Literature Flow ............................................................................................................................ 7

Depressive Disorders ................................................................................................................... 9

Overview ................................................................................................................................. 9

Systematic Reviews: Reporting of Sex Effects for Depression Interventions ...................... 10

Primary Studies: Reporting of Sex Effects for Depression Interventions ............................. 12

Diabetes ..................................................................................................................................... 13

Overview ............................................................................................................................... 13

Systematic Reviews: Reporting of Sex Effects for Diabetes Interventions .......................... 14

Primary Studies: Reporting of Sex Effects for Diabetes Interventions ................................. 16

Chronic Pain .............................................................................................................................. 17

Overview ............................................................................................................................... 17

Systematic Reviews: Reporting of Sex Effects for Chronic Pain Interventions ................... 18

Primary Studies: Reporting of Sex Effects for Chronic Pain Interventions .......................... 19

Summary: Reporting of Sex Effects Across All Conditions ..................................................... 19

DISCUSSION .............................................................................................................................. 20

Achieving Adequate Representation of Women in Clinical Studies ........................................ 21

Prioritizing Areas for Evaluation of Sex Effects ....................................................................... 21

Study Limitations ...................................................................................................................... 23

Conclusion ................................................................................................................................. 23

REFERENCES ............................................................................................................................ 24

Table 1. Eligible interventions and outcomes for medical conditions of interest ........................... 3

Table 2. Definitions of statistical approaches used in the included systematic reviews ................. 6

Table 3. Summary of sex effects identified in systematic reviews ............................................... 19

Table 4. Gaps in evidence on sex effects ...................................................................................... 20

FIGURES

Figure 1. Literature flow diagram ................................................................................................... 8

Figure 2. Number of primary studies included in largest review for each condition–intervention 

dyad ............................................................................................................................................... 10

Figure 3. Number of reviews reporting sex effects for depression interventions ......................... 11

Figure 4. Number of primary studies included in largest reviews of diabetes interventions ........ 13

Figure 5. Number of reviews reporting sex effects for diabetes interventions ............................. 14
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Figure 6. Number of primary studies included in largest review for each condition–intervention 

dyad ............................................................................................................................................... 17

APPENDICES

Appendix A. Condition Prioritization Instructions ........................................................................44 

Appendix B. Search Strategies ......................................................................................................45 

Appendix C. Eligibility Criteria for Systematic Reviews ..............................................................49 

Appendix D. Responses to Reviewer Comments ..........................................................................53 

Appendix E. Overall Effects of Selected Interventions: Depression .............................................63 

Appendix F. Overall Effects of Selected Interventions: Diabetes .................................................66 

Appendix G. Overall Effects of Selected Interventions: Chronic Pain .........................................69 

Appendix H. Systematic Review References by Condition ..........................................................73
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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EVIDENCE MAP

INTRODUCTION 

The Veterans Health Administration (VHA) has prioritized systematic, evidence-based 

improvements in the delivery of healthcare to women Veterans. Women are entering the military 

at unprecedented rates. Women currently represent more than 20% of recruits, and women 

Veterans now number more than 2 million, accounting for nearly 8% of the U.S. Veteran 

population.1,2

 The number of women Veterans using VHA services has doubled in the past 

decade,3

 in part as a result of higher enrollment among Veterans returning from Iraq and 

Afghanistan.2 During the 2012 fiscal year, 362,014 women Veterans sought medical care at 

VHA facilities, and compared with their male counterparts, they were younger, more ethnically 

diverse, and more likely to reside in urban areas.3 

Women Veterans have distinct health problems and healthcare priorities compared with male 

Veterans. The burden of mental health disorders, such as depression, is higher for women 

Veterans compared with male Veterans.4-6 More than one-fifth of women Veterans have been 

exposed to military sexual trauma,7 and such exposures are associated with higher rates of 

posttraumatic stress disorder8 and other chronic medical illnesses.9

 Musculoskeletal conditions 

are also highly prevalent, affecting 55.9% of women Veterans.

3

 

While there has been increasing awareness of sex and gender differences in health and 

healthcare, particularly since national initiatives in the early 1990s to improve participation by 

women in clinical research,10 there are still significant challenges in applying the clinical 

evidence base to women. For example, there was only 30% overall participation by women in 

clinical trials used to support the 2007 American Heart Association guidelines for cardiovascular 

health in women.11 Additionally, published studies infrequently report or discuss the 

appropriateness of analyses for sex or gender effects.12,13 This may be due in part to hesitation 

about discussing subgroup analyses from clinical trials that were underpowered to detect sex 

differences.14,15 Also, when patients are randomized to treatment groups and subsequently 

divided according to sex, the latter division is not random.16 The presence of such deficits in our 

clinical knowledge base is especially concerning given well-documented sex differences in 

effectiveness and adverse effects for some treatments, including certain medications.17-19 Thus, 

systematic evaluation of current clinical evidence for sex differences in treatment effectiveness, 

along with identification of key gaps in our knowledge of these differences, is a critical next step 

for improving health outcomes for women Veterans. 

The VHA’s Women’s Health Service (WHS) oversees national policy, clinical operations, and 

research programs that address the healthcare needs of women Veterans. The WHS requested an 

evidence map to aid prioritization and development of implementation projects and research 

initiatives. Evidence mapping is an emerging approach that describes key characteristics of 

existing studies for a broad area of medicine.20-22 In this project, we used evidence mapping to 

(1) better understand sex differences in intervention outcomes for high-impact medical 

conditions, (2) identify effective interventions for women, and (3) identify gaps in evidence 

about the efficacy and effectiveness of interventions in women. 
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METHODS 

Our aim was to deliver an evidence map that provides (1) an overview of the volume of studies 

evaluating interventions for selected high-impact conditions in women Veterans and (2) a set of 

executive summaries that describe the effects of these interventions and whether there has been 

evaluation of differential effectiveness in women compared with men (hereafter referred to 

collectively as “sex effects”).

Consistent with the general principles of evidence mapping, our goal was to provide high-level 

information about broad questions rather than detailed information on a narrow set of questions. 

We used a stakeholder-driven approach to identify high-priority conditions and interventions. 

Given the diversity of interventions and range of prioritized conditions, we focused on 

systematic reviews in order to best estimate the volume of research and treatment effects. 

Systematic reviews follow a structured approach to identifying relevant studies and summarize 

the results, often using quantitative estimates (ie, meta-analyses) to generate pooled effect 

estimates. For treatment efficacy, we prioritized results from systematic reviews that exclusively 

used randomized trials for effect estimates. However, we did not conduct a quality assessment of 

these studies, and estimates of treatment effect should be interpreted cautiously. For adverse 

effects, we also closely examined systematic reviews that included observational studies. We 

piloted our methodology in an evidence map of a set of diverse interventions for depressive 

disorders and presented these results to key stakeholders. We then refined our methods and 

applied the updated protocols to the remaining conditions of interest. 

TOPIC PRIORITIZATION

We used a forced-rank methodology that included presentation of initial rankings to 

stakeholders, followed by discussion and reranking to identify conditions for inclusion in the 

mapping project.23 Stakeholders included representatives from HSR&D Center for the Study of 

Healthcare Innovation, Health Services Research and Development Service, Office of Research 

and Development, the Women’s Health Research Network, Women’s Health Services, and 

Mental Health Services, Department of Veterans Affairs. We initially selected 34 conditions 

based on (1) disease prevalence among U.S. women and women Veterans, (2) the burden of 

disease, (3) the availability and breadth of effective treatments, and (4) women Veterans’ 

priorities for gender-specific care (Appendix A).3,24-28 Given resource capacity, it was agreed 

with stakeholders that we would address a limited set of these conditions. We used multiple 

rounds of iterative prioritization to select the final conditions of interest. After the first round, 

depression and chronic pain were ranked highest, but 4 conditions (obesity, type 2 diabetes, 

posttraumatic stress disorder, and alcohol use disorder) had very similar prioritization scores. 

Thus, we submitted these 4 conditions to a second round of priority rating, and diabetes was

rated highest priority in this group. We also focused the chronic pain topic to more specific 

diagnoses in order to better determine eligible interventions and improve interpretation of our 

results. Our final conditions of interest were the following: (1) depressive disorders, (2) type 2 

diabetes, and (3) chronic pain (consisting of 3 diagnoses: chronic low back pain [CLBP], 

fibromyalgia [FM], and chronic knee pain due to osteoarthritis [knee OA]). For each condition, 

we selected treatments in broad categories, including medications, behavioral interventions, 

supervised exercise, and quality improvement interventions. We also included certain condition-
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specific interventions, such as bariatric surgery for diabetes, and joint injections, acupuncture, 

and spinal manipulation for chronic back and knee pain (Table 1).

Table 1. Eligible interventions and outcomes for medical conditions of interest

Depressive disorders Type 2 diabetes Chronic pain conditions

Interventions Antidepressants

Psychotherapy

Guided self-help

Exercise

Quality improvementa

Insulin, oral medications 

Psychoeducation, 

weight management

Exercise 

Quality improvementa

Bariatric surgery

Antidepressants, muscle 

relaxants, 

anticonvulsants

Psychotherapy, 

biofeedback, 

mindfulness-based 

practices

Guided self-help

Exercise

Acupuncture, spinal 

manipulation

Joint injections

Quality improvementa

Outcomes Symptom severity

Clinical response and 

remission

Functional status, quality 

of life

Adverse effects

Glycemic control 

Weight/body mass index

Microvascular and 

macrovascular events

Mortality

Adverse effects

Pain severity 

Fatigueb

Functional status, quality 

of life

Mortality

Adverse effects a Quality improvement interventions included collaborative care, multidisciplinary care, and technology-enhanced 

interventions.

b Fatigue was an outcome only for fibromyalgia.

SEARCH STRATEGY

In collaboration with an expert reference librarian, we searched MEDLINE and the Cochrane 

Database of Systematic Reviews to identify eligible systematic reviews published from January 

1, 2009, through October 31, 2014. Search strategies (Appendix B) used Medical Subject 

Headings (MeSH) and free-text terms for the conditions of interest, eligible interventions, and 

systematic reviews. We restricted the search to the past 6 years because systematic reviews are 

typically outdated within 5 years of publication and because of the likely high volume of relevant 

reviews.29 In addition to electronic searching, we screened published reviews of reviews for 

eligible studies. 

STUDY SELECTION

To be included in the evidence map, systematic reviews had to meet the following criteria:

Design: Systematic reviews must describe a search strategy, eligibility criteria, and an 

analysis plan. We excluded clinical guidelines, systematic review protocols, and reviews 

focusing on a single drug unless the drug uniquely represented a class of medications (eg, 

metformin) or the review used individual patient data (IPD) meta-analysis. We prioritized 

IPD meta-analysis because these studies are well suited to evaluating moderator effects.

30

Participants: Systematic reviews must focus on adults with one of the eligible conditions 

(depressive disorders, diabetes, or chronic pain conditions). Reviews that evaluated 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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mixed conditions were included if they reported results separately for an eligible 

condition. 

Interventions: For each condition, we included interventions in several broad categories, 

including medications, behavioral interventions (eg, psychotherapy, psychoeducation), 

exercise performed in organized groups (eg, tai chi, pool therapy) or with behavioral 

support, self-management strategies, and quality improvement interventions (eg, 

multidisciplinary care, technology-enhanced interventions). Table 1 summarizes the 

eligible interventions, including some condition-specific ones. Detailed eligibility criteria 

are provided in Appendix C. 

Outcomes: For each condition, we focused on outcomes that would be the most relevant 

for clinical providers and patients, including patient-centered outcomes such as 

symptoms and health-related quality of life. Refer to Table 1 for a summary and 

Appendix C for details.

Timing: Any intervention duration and length of follow-up were eligible.

Setting: Studies conducted in outpatient settings were preferred, but we accepted those 

that were in mixed or unclear settings.

Other criteria: Only English-language systematic reviews published since January 2009 

were included. For reviews with multiple publications (eg, technical monograph and 

journal article) or updated reviews (eg, 2 Cochrane publications by the same group on the 

same topic), we included only the most recent report, prioritizing the journal article over 

the monograph. 

Two reviewers screened citations for eligibility, and citations deemed potentially relevant by 

either reviewer were retained for full-text review. Full-text publications were evaluated for 

eligibility by 2 reviewers; disagreements were resolved through discussion or by a third 

reviewer.

We anticipated that some interventions for each condition would have few or no systematic 

reviews that addressed sex effects. To determine the feasibility of a systematic review evaluating 

sex effects, we selected certain high-interest interventions for further evaluation. For each 

intervention, we selected the largest recent systematic review and used the list of included 

primary trials as candidates for review. We then examined those primary trials that randomized 

at least 75 patients per treatment arm and determined whether they reported sex effects. We 

chose this sample size criterion in order to limit our evaluation to trials that had the potential to 

be adequately powered to detect interaction effects (intervention * sex).31 For depressive 

disorders, we looked at quality improvement interventions or psychotherapy, whereas for 

diabetes, we focused on diet, physical activity, and culturally tailored psychoeducation. For 

CLBP, we selected behavioral interventions, and for chronic knee OA, exercise interventions. 
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DATA ABSTRACTION

For depressive disorders and chronic pain conditions, we evaluated all eligible systematic 

reviews. For diabetes, we evaluated all reviews of nonpharmacological interventions and applied 

an additional procedure to prioritize among the large number of eligible systematic reviews 

addressing medications (n=120). 

To prioritize the diabetes medication articles for abstraction, we first selected all reviews that 

examined multiple classes of medications and reviews of single-drug classes when there were 6 

or fewer reviews per class. For medication classes with more than 6 eligible reviews (ie, 

metformin, incretin mimetics, insulin, and thiazolidinediones), we selected reviews using the 

following criteria: evaluated an entire drug class (vs single drug studies), published most 

recently, published in a top-tier journal (eg, Journal of the American Medical Association, 

Annals of Internal Medicine, British Medical Journal), conducted by an organization known for 

high-quality reviews (eg, Cochrane Collaboration), or evaluated outcomes such as glycemic 

control, cardiovascular events, mortality, or adverse events. The remaining unselected but 

eligible reviews (n=58) underwent a text search for sex effects and were fully abstracted only if 

the text search was positive (n=13). 

Data were abstracted into a customized DistillerSR database (Evidence Partners Inc., Manotick, 

ON, Canada) by one reviewer and over-read by a second reviewer. Disagreements were resolved 

by discussion or by obtaining a third reviewer’s opinion when consensus could not be reached. 

Abstracted data included study design (eg, systematic review with or without meta-analysis, 

network meta-analysis, or IPD meta-analysis), conditions, interventions, outcomes, the number 

and design of primary studies, proportion of men and women in included studies, and whether 

sex effects were part of study aims, analysis plan, and/or results. For studies containing sexspecific results, we also abstracted the number of studies included in the sex analyses, method 

used for evaluating sex effects (eg, meta-regression, subgroup analyses by study design 

characteristics), and sex effects of the intervention. 

QUALITY ASSESSMENT

A formal assessment of systematic review methodological rigor was beyond the scope of this 

project. However, to indicate reviews of higher quality, we recorded whether the review was 

conducted by the Cochrane Collaboration, the Agency for Healthcare Research and Quality’s 

Evidence-based Practice Centers, or the VA Evidence-based Synthesis Program. These 

organizations are known for their expertise and high-quality systematic reviews. Further, to help 

readers interpret estimates of treatment effect, we included review authors’ comments on study 

quality or the overall quality of the evidence, when this was available. 

DATA SYNTHESIS

We used descriptive statistics for the amount and types of evidence for included interventions per

condition of interest (Table 2). We generated heat maps and barplots to graphically portray the 

number of studies (using the review with the largest number of included studies) and number of 

reviews reporting sex effects for each condition–intervention dyad. We report intervention sex 

effects in detail, giving priority to reviews using IPD meta-analyses and those originating from 

organizations known for high-quality reviews. 
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The primary goals of this synthesis were to describe the volume of recent systematic reviews, 

including the number of studies contributing to these reviews, and the number of reviews 

reporting sex effects. A secondary goal was to give general estimates of treatment effect. For 

these overall treatment effects, we prioritized higher quality, more recent, and more inclusive 

systematic reviews. Because there were often multiple reviews addressing the same intervention, 

we examined reviews for consistency of findings. However, we remind readers that the reviews 

have not been assessed for quality, and so in some cases the estimates of intervention effect may 

be incorrect.

Table 2. Definitions of statistical approaches used in the included systematic reviews

Term Definition

Cohen’s d An appropriate measure of effect size for the comparison between 2 means. 

Cohen’s d may be interpreted as the following: small effect=0.2 to <0.5; 

medium effect=0.5 to <0.8; large effect=0.8 or above.

Effect estimate or

effect size (ES)

Refers collectively or generally to different versions of the SMD.

Hazard ratio (HR) The ratio of the hazards, or chance of events occurring in 2 groups, such as 

the intervention arm compared with the control arm.

Hedges' g A variation of Cohen's d that corrects for biases due to small sample sizes.

Individual patient 

data meta-analysis 

(IPD)

A specific type of systematic review. Rather than extracting summary 

(aggregate) data from study publications or from investigators, the original 

research data are sought directly from the researchers responsible for each 

study. These data can then be reanalyzed centrally and combined in metaanalyses, if appropriate.

Mean difference 

(MD)

A summary statistic used in meta-analyses of continuous data when 

outcomes are measured using the same scale (eg, blood pressure in mmHg).

In some cases, an MD will be “weighted” wherein the “weight” given to each 

study reflects how much influence each study has on the overall results of the 

meta-analysis, determined by the precision of its estimate of effect. 

Odds ratio (OR) A summary statistic used in meta-analyses for dichotomous outcomes, it is 

the ratio of the odds of an outcome in 2 groups (eg, the odds of the outcome 

in intervention patients compared with the odds of the outcome in control 

patients).

Risk ratio (RR) A summary statistic used in meta-analyses for dichotomous outcomes. Also 

called “relative risk,” it is the ratio of the risk of an outcome in 2 groups (eg, 

the risk of the outcome in intervention patients compared with the risk of the 

outcome in control patients).

Standardized mean 

difference (SMD)

A summary statistic used in meta-analyses when the studies all assess the 

same outcome but measure it in a variety of ways (eg, all studies measure 

depression but they use different psychometric scales). SMD is the mean 

difference in outcomes between groups, divided by the standard deviation of 

the outcome among participants.

PEER REVIEW

A draft of this report was reviewed by technical experts and clinical leadership. A transcript of 

their comments and our responses are provided in Appendix D. 
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RESULTS

We organize the results into an overview describing the literature flow and key characteristics of 

the included systematic reviews, followed by brief executive summaries for each condition. In 

each summary, we describe the reviews, general applicability of results to women, and reporting 

of sex effects. Descriptions of overall treatment effects reported by reviews that did not conduct 

sex-specific analyses are summarized in Appendix E (depressive disorders), Appendix F 

(diabetes), and Appendix G (chronic pain). 

LITERATURE FLOW

The literature search identified 2531 unique citations from a combined search of MEDLINE, the 

Cochrane Database of Systematic Reviews, and the bibliographies of umbrella reviews. After 

applying inclusion/exclusion criteria at the title-and-abstract screening level, 582 were retrieved 

for full-text review. Of these, 269 did not meet eligibility criteria. Of the 313 remaining eligible 

reviews, 45 diabetes reviews were examined for sex and gender terms and found to be negative; 

these 45 were not abstracted further. The remaining 268 systematic reviews were retained for full 

data abstraction (Figure 1). 

Unless otherwise indicated by the specific term “study” or “RCT,” all results apply to these 268 

systematic reviews, to which we refer to hereafter as “reviews.” Appendix B contains details of 

the search strategies, and Appendix H provides a full alphabetical bibliography of the reviews 

included for each condition. 
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Figure 1. Literature flow diagram 

*We performed a keyword search for sex and gender terms on 45 of the 159 eligible diabetes reviews. The search 

was negative, which indicated sex or gender was not addressed in these articles. These 45 were thus not abstracted 

further, leaving 114 diabetes reviews for full data abstraction.

Of the 268 reviews that were fully abstracted, 86 addressed interventions for depression, 114 

addressed interventions for type 2 diabetes, and 68 addressed interventions for the 3 types of 

chronic pain: CLBP (n=26), FM (n=34), and knee OA (n=8). Thirty-seven abstracted reviews 

(14%) originated from an organization known for high-quality reviews. There were more chronic 

pain reviews (25%) from these organizations than depression or diabetes reviews (11% each). 

The majority of abstracted reviews – 86% for depression, 61% for diabetes, and 84% for chronic 

pain – were restricted to RCTs. 

Among fully abstracted reviews for all conditions other than fibromyalgia, only half (48%) 

summarized the gender distribution of the populations of the included studies. Sex effects were 

reported in only 30 of the 313 eligible reviews (10%) for all conditions. IPD meta-analysis—the 

method best suited to evaluating moderating variables such as gender—was rarely used (n=16 of 

268 abstracted reviews, 6%)
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DEPRESSIVE DISORDERS

Overview

The 86 reviews most frequently evaluated interventions for a range of depressive disorders 

(n=43) or major depressive disorder alone (n=29). Reviews evaluating treatments for relapse 

prevention, treatment-resistant depression, persistent depressive disorder (dysthymia), and 

subsyndromal depression were much less frequent (n≤7 for each). The most frequently evaluated 

interventions were psychotherapy (n=44) and antidepressant medications (n=24). Four of the 

psychotherapy reviews evaluated internet-delivered therapy. Eight reviews evaluated the effects 

of combined psychotherapy and antidepressant medication, and 7 reviews evaluated exercise, 

including one focused on yoga. Quality improvement interventions and guided self-help were 

reviewed infrequently. 

The eligible reviews included from 3 to 243 primary studies, and all but 13 reviews restricted 

inclusion to randomized controlled trials (RCTs). Nine reviews originated from an organization 

known for high-quality systematic reviews.32-40 Fifty-two of 86 reviews (60%) reported the sex 

distribution of patients enrolled in the primary studies. When reported, women constituted the 

majority of participants for all of the interventions examined. However, relatively few of the 

recent, large systematic reviews evaluating psychotherapy or the combination of psychotherapy 

and antidepressants reported the sex distribution of the primary studies. Similarly, the minority 

of reviews addressing subsyndromal depression or relapse prevention reported the sex 

distribution of the primary studies. 

Figure 2 shows a heat map of the number of primary studies evaluated in the largest review for 

each depressive condition–intervention dyad. Darker red indicates more primary studies and 

lighter red indicates fewer studies. Most reviews used quantitative analyses (ie, meta-analyses) to 

evaluate intervention effects. Ten reviews used IPD meta-analyses,41-50 a statistical method that 

is particularly well-suited to evaluating moderator effects such as sex. 
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Figure 2. Number of primary studies included in largest review for each condition–

intervention dyad 

Note: Combined refers to medication plus psychotherapy.

Systematic Reviews: Reporting of Sex Effects for Depression Interventions

Of the 86 reviews, 14 (16%) reported results about sex effects (Figure 3). Sex effects were 

evaluated most frequently in reviews of antidepressant medications. One review focused on 

persistent depressive disorder,51 and the remainder included a broad range of depressive 

disorders or major depressive disorder. Sex effects were explored using meta-regression and less 

frequently using qualitative analyses. Only 3 reviews41,48,50 used IPD meta-analyses to explore 

sex effects. Next, we describe key findings from these reviews by depression intervention. 
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Figure 3. Number of reviews reporting sex effects for depression interventions

Note: Combined refers to medication plus psychotherapy.

Psychotherapy. Four reviews used meta-regression to evaluate sex effects.37,52-54 In a review of 

53 trials, cognitive behavioral therapy (CBT) was found to be more effective as the proportion of 

women enrolled in the trial increased, but the effect was small.52 This finding was supported by 

another review,54 but no differential sex effect was found when CBT was compared with 

pharmacotherapy.37 Sex was not associated with treatment effects for short-term psychodynamic 

therapy.53 A fifth review evaluated sex effects qualitatively.55 This review identified a single 

study supporting greater efficacy for pharmacotherapy than psychotherapy for infertile women 

with depression (Hedges’ g -0.94, CI -1.47 to -0.41). 

Antidepressants. Six reviews reported sex effects.

34,48,50,56-58 In an IPD meta-analysis, women 

treated with duloxetine showed small additional benefit compared with men on the Sheehan 

Disability Scale (n=6; -0.99, CI -1.91 to -0.07).48 Another IPD meta-analysis of desvenlafaxine 

trials reported that sex and baseline social impairment predicted some outcomes, but detailed 

results were not given.50 A comprehensive review conducted by an EPC that used multiple 

treatment comparison meta-analyses did not show differences in antidepressant treatment effects 

as a class by age, sex, ethnicity, or comorbid conditions.34 However, the authors noted that most 

studies did not address differences in efficacy or effectiveness between men and women. Limited 

data on adverse effects suggested that men treated with paroxetine were at higher risk for sexual 

dysfunction than women were, and that women receiving paroxetine compared with sertraline 

may be at higher risk for sexual dysfunction. Overall, adverse effects of antidepressants for men 

and women were similar. 
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Other reviews evaluated single drugs or antidepressants in older adults. A review restricted to 

sertraline and venlafaxine found that women showed small additional benefit compared with 

men when treated with venlafaxine.58 One review used meta-regression to evaluate the 

association between the proportion of men enrolled and treatment effects.56 In older adults with a 

depressive disorder, selective serotonin reuptake inhibitors (SSRIs) were somewhat less effective 

in men than in women at 3 of the 5 short-term follow-ups assessed.

Combined antidepressants and psychotherapy. A single review used meta-regression to 

evaluate the association between the proportion of women enrolled and the effects of combined 

treatments.51 In patients with dysthymia, sex did not moderate the effect of psychotherapy plus 

antidepressants compared with antidepressants alone. 

Quality improvement. One review using meta-regression analysis found no important 

difference between studies that enrolled a majority of females compared with a majority of 

males.59

Self-help. A single review used IPD meta-analysis to evaluate sex effects in primary care 

patients with a diagnosis of depression or elevated symptoms on a self-report scale.41

Intervention effects did not vary by sex. 

Other interventions. Sex effects were not examined in reviews of exercise or interventions for 

subsyndromal depression, interventions to prevent relapse, or interventions for treatmentresistant depression. 

In summary, sex effects were examined infrequently, and the methodology most often employed 

(meta-regression) was suboptimal for drawing valid conclusions. Small sex effects were found 

for some antidepressants and psychotherapy, generally favoring better outcomes in women. 

Primary Studies: Reporting of Sex Effects for Depression Interventions

We selected a sample of primary studies included in the eligible systematic reviews that 

randomized at least 75 patients per treatment arm to determine if these studies evaluated and 

reported treatment effects by sex. Reviews of quality improvement interventions40 and 

psychotherapy60 were used for this analysis because we did not identify any IPD meta-analyses 

for these high-priority interventions. 

We examined 21 clinical trials evaluating collaborative care interventions (an approach to quality 

improvement) for depressive disorders. The number of patients randomized ranged from 153 to 

1801. One trial enrolled only women,61 and 5 enrolled Veterans.62-66 Of the 21 trials, only 2 

evaluated subgroup effects by sex and found no effect on outcomes.67,68 

Ten of the 92 studies (11%) included in the review60 randomized at least 75 patients to 

psychotherapy and to a comparator arm. Sample sizes in these studies ranged from 177 to 903. 

Two trials enrolled only women,69,70 and none enrolled Veterans. Only one trial potentially 

evaluated sex as a moderator, stating “no demographic characteristic ... moderated time to 

remission.”71
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DIABETES

Overview

We conducted full data abstraction for 114 reviews evaluating diabetes. Of 159 eligible reviews, 

we examined all medication studies and prioritized for full abstraction those that were most 

likely pertinent and/or were positive by text searching for keywords related to sex effects. We 

fully abstracted reviews for all other interventions. Among all eligible reviews, the most 

frequently evaluated interventions were medications (n=120), while fewer examined exercise 

(n=14) and mixed psychoeducation and behavioral interventions (n=6). Twelve reviews 

examined the effects of bariatric surgery. Dietary (n=4) and quality improvement interventions 

(n=3) were reviewed less frequently. 

Abstracted reviews included from 0 to 347 primary studies, and 70 (61%) were restricted to 

RCTs. Twelve reviews (10%) originated from an organization known for high-quality systematic 

reviews.72-83 Figure 4 shows the number of primary studies evaluated in the largest systematic 

review for each intervention category. Most reviews (n=101; 89%) used quantitative analyses (ie, 

meta-analyses) to evaluate intervention effects. Only 5 reviews used IPD meta-analyses, and all 

of these evaluated medications. 

Overall, 48 reviews (42%) reported the proportion of women included in primary studies, but 

this varied widely by intervention. Most reviews on bariatric surgery (n=9, 75%) provided 

information on inclusion of women, while about half of reviews on exercise (n=6, 43%) and 

mixed behavioral interventions (n=3, 50%) did so. Somewhat fewer medication reviews (n=30, 

40%) reported on inclusion of women, and none did so for diet or quality improvement 

interventions. 

Figure 4. Number of primary studies included in largest reviews of diabetes interventions
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Systematic Reviews: Reporting of Sex Effects for Diabetes Interventions

Of the 159 eligible reviews, 13 (8%) reported results on sex effects (Figure 5). Additionally, 6 

reviews examined the risk for various types of cancer associated with different diabetes 

medications (eg, metformin and insulin), and included estimates for breast cancer risk.84-89

Finally, one review proposed to evaluate oral medications for women with preexisting diabetes 

or impaired glucose tolerance, but despite an adequate search strategy, found no eligible 

articles.82

Sex effects were reported most frequently in reviews of medications (n=10).90-99 Two reviews 

examined sex effects on diabetic remission after bariatric surgery.100,101 One review evaluated a 

range of psychoeducation interventions for minority women with diabetes and provided 

qualitative syntheses for various outcomes.102 Sex effects were most often explored using metaregression (n=8). Only 3 reviews91,96,97 applied IPD meta-analyses to explore sex effects; all 

evaluated dipeptidyl peptidase-4 (DPP-4) inhibitors and included data only from industrysponsored studies. Sex effects were not examined in reviews of supervised exercise, diet, or 

quality improvement. Next, we describe key findings from reviews reporting sex effects by 

diabetes intervention. 

Figure 5. Number of reviews reporting sex effects for diabetes interventions
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Psychoeducation and mixed behavioral interventions. Of 6 eligible reviews, one examined 

the effects of diabetes self-management education in black and Hispanic women, focusing on 

specific intervention features associated with positive results.102 This review included 10 RCTs 

and 3 cohort studies with comparators. Qualitative syntheses were reported for multiple 

outcomes, including HbA1c (3 of 10 applicable studies showed positive effects). Intervention 

features were organized into 9 categories (eg, intervention setting, frequency of sessions, and 

mode of delivery). Multiple features in each category were associated with improvements in 

various outcomes. 

Medications. Of 120 eligible reviews addressing medications, 10 reported sex effects.

90-99 Two

focused exclusively on adverse effects, with one evaluating risk for bladder cancer associated 

with pioglitazone92 and one evaluated fracture risk associated with sulfonylureas.95 The review 

examining the risk of bladder cancer associated with pioglitazone found similar estimates of 

increased risk in men (HR 1.64, CI 1.01 to 2.67) and women (HR 1.69, CI 0.64 to 4.47), 

although only the results for men reached statistical significance.92 The review on fracture risk 

associated with sulfonylureas included 21 eligible studies and reported results from a single RCT 

showing that there was decreased fracture risk for sulfonylureas compared with 

thiazolidinediones in women (RR 0.37, CI 0.23 to 0.61) but not in men (RR 0.85, CI 0.52-

1.40).95

The remaining 8 reviews investigated various outcomes, including glycemic control, 

cardiovascular events and/or mortality, and risk for hypoglycemia.90,91,93,94,96-99 Single reviews 

evaluated multiple classes of medications,90 insulin therapy,93 and metformin,94 while 5 reviews 

addressed incretin mimetics.

91,96-99 The review on 8 medication classes included 218 RCTs; sex 

was evaluated as a source of heterogeneity and no association was found.90 One review evaluated 

the effect of short-term intensive insulin therapy on b-cell function, insulin resistance, and longterm remission, and identified 7 eligible studies; the proportion of men was associated with study 

heterogeneity, and improvement in insulin resistance decreased with increasing male 

representation.93 The review addressing the efficacy of metformin for preventing cardiovascular 

events and mortality included 35 RCTs and found no significant effect for cardiovascular events 

or survival.94 However, when limiting the analysis to trials that evaluated metformin 

monotherapy (n=4), there was significantly decreased risk for all-cause mortality with metformin 

use (Mantel-Henzel OR 0.55, CI 0.36 to 0.89) and significantly increased benefit in trials with 

more women (slope -0.039, CI -0.076 to -0.003).94 

Among 5 reviews examining incretin mimetics, one evaluated both glucagon-like peptide 1 

receptor agonists and DPP-4 inhibitors, and included 38 RCTs.99 This review examined 

hemoglobin A1c (HbA1c), weight, and hypoglycemia for exenatide, liraglutide, vildagliptin, and 

sitagliptin; adjusted analyses with key study information (eg, age, sex and study duration) did not 

change the results, and most covariates were not associated with significant effects.99 One review 

of DPP-4 inhibitors included 43 RCTs and also evaluated glycemic control, weight, and 

hypoglycemia; multiple covariates (eg, sex and study duration) were employed in metaregression and none had a significant effect.98 Lastly, 3 reviews of DPP-4 inhibitors applied IPD 

meta-analyses to data from industry studies.91,96,97 Using data from 8 RCTs, one review reported 

subgroup analyses showing different point estimates for risk of death from cardiovascular 

disease for men (HR 0.25, CI 0.10 to 0.60) and women (HR 0.96, CI 0.21 to 4.37) when 

comparing linagliptin with placebo, glimepiride, or voglibose.97 Another review evaluated 
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linagliptin among participants with and without renal dysfunction and included data from 3 

RCTs; both men and women had improved glycemic control with linagliptin, with no evidence 

of interaction effect for sex and treatment efficacy.91 The third review examined risk of 

cardiovascular events with vildagliptin, utilizing data from 25 RCTs; overall, no significant 

associations were found between vildagliptin and risk for cardiovascular events among both men 

and women.96

Bariatric surgery. Of 12 reviews on bariatric surgery, 2 examined sex effects on diabetes 

remission after bariatric surgery; both found no significant associations.100,101 Both reviews 

evaluated multiple types of bariatric surgery, included prospective and retrospective studies, and 

noted the generally low quality of included primary studies. One review included 39 studies, 

only 3 of which were RCTs; overall, diabetes remission rates varied significantly with the type of 

procedure (range 32.7% to 80.5% at 12 months) but not with age, sex, preoperative body mass 

index, or HbA1c.100 This review also examined adverse events and complications following 

bariatric surgery but did not report sex-specific analyses for these outcomes.100 The other review 

found 15 eligible studies and included data from 13 in meta-analyses evaluating the likelihood of 

diabetes remission; results showed decreased likelihood of remission with increasing age and 

diabetes duration but no significant associations with sex.101

In summary, sex effects were rarely examined, and reviews reporting sex results most often used 

meta-regression, a technique that is poorly suited to evaluating sex differences.103,104 All IPD 

meta-analyses examining sex effects were on incretin mimetics and there were no significant sex 

effects for any outcome. Using meta-regression, one review found greater improvement of 

insulin resistance following short-term intensive insulin therapy in trials with more women; 

however, this physiologic outcome is of unclear clinical significance. No sex effects were found 

for diabetes remission after bariatric surgery. Multiple features of diabetes self-management 

education may be associated with positive effects in minority women. 

Primary Studies: Reporting of Sex Effects for Diabetes Interventions

Reviews of dietary interventions,105 mixed behavioral interventions,106 and culturally tailored 

psychoeducation83 were selected for further analysis of a sample of primary studies (see 

Methods) because we did not identify any IPD meta-analyses for these high-priority 

interventions. 

Six of the 20 primary studies (30%) evaluating dietary interventions randomized at least 75 

patients to each treatment arm.107-112 Sample sizes in these studies ranged from 162 to 1224. One 

trial enrolled only women,109 and none enrolled Veterans. Two RCTs evaluated sex as a 

moderator, and neither found a differential response for effects on weight110 or HbA1c.108

Only 2 of 17 studies (12%) evaluating mixed behavioral interventions met the sample size 

requirement (n=182113 and n=606114). These studies enrolled mixed samples of men and women, 

and did not describe Veteran enrollment. One study evaluated sex effects and found a greater 

effect of physical activity on glycemic control in men.113

Thirty-three clinical RCTs evaluated culturally tailored psychoeducation, and of these, 11 (33%) 

met the sample size requirement.115-125 The number of patients randomized ranged from 201 to 

567. Two RCTs enrolled only women,116,117 and none enrolled Veterans. One study evaluated 
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sex effects and found no differential effect for HbA1c, fasting blood glucose, or diabetes 

knowledge.115

CHRONIC PAIN

Overview

Three pain conditions were prioritized for review: chronic low back pain (CLBP), fibromyalgia 

(FM), and chronic knee pain due to osteoarthritis (knee OA). CLBP was limited to 

musculoskeletal or mechanical low back pain to differentiate it from inflammatory conditions for 

which specific treatments would be indicated. 

Sixty-eight systematic reviews evaluated interventions specifically for CLBP (n=26), FM 

(n=34), and knee OA (n=8); one review evaluated acupuncture for both CLBP and knee OA. The 

most frequently evaluated interventions were exercise (n=21), medications (antidepressant, n=9; 

anticonvulsant, n=6; joint injection, n=5; and topical nonsteroidal anti-inflammatory drug, n=3), 

acupuncture and chiropractic manipulation (n=12), behavioral treatment (n=8), and combination 

interventions (n=4). One review on CLBP evaluated quality improvement interventions. 

The eligible reviews included from 2 to 102 primary studies, and all but 11 reviews restricted 

inclusion to RCTs. Sixteen reviews originated from an organization known for high-quality 

systematic reviews. Figure 6 shows a heat map of the number of primary studies evaluated in the 

largest review for each chronic pain condition–intervention dyad. Most reviews used quantitative 

meta-analyses to evaluate intervention effects. One review used IPD meta-analyses. 

The percentage of women included in the primary studies was reported in 8 of 26 reviews on 

CLBP and ranged from 45% to 100%.126-133 For FM, the percentage of women included in the 

primary studies was reported in 23 of the 34 reviews on FM and ranged from 50% to 100% 

(median 95.5%). Five of 8 reviews of OA reported on the percentage of women, with the range 

being 50% to 100%. 

Figure 6. Number of primary studies included in largest review for each condition–

intervention dyad 
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Systematic Reviews: Reporting of Sex Effects for Chronic Pain Interventions

Of the 68 systematic reviews, only 3 (4%) reported results about sex effects. Sex effects were 

discussed in 2 reviews of CLBP126,132 and one review of FM.

134 All of these reviews explored sex 

effects using meta-regression. We describe below key findings from reviews reporting sex 

effects for CLBP interventions, as well as some general findings from FM reviews. 

Chronic low back pain. No review examined sex effects as a primary aim in CLBP; however, 2 

evaluated sex effects using meta-regression. In a review evaluating the effectiveness of 

antidepressants and other medications for pain, sex was not associated with differences in

treatment effect.

126 In a review examining quality improvement interventions, increasing 

proportion of women in the primary studies was associated with greater intervention 

effectiveness (beta=0.002; SE 0.001).132 

Fibromyalgia. Only one review proposed to evaluate differential effects in men and women, but 

individual patient-level data were not available.134 Also, we anticipated that analyses for sex 

effects would be difficult and require very large sample sizes, given that generally, more than 

90% of the study participants were women. However, since women were the overwhelming 

majority of participants in trials for FM, reviews without sex specific analyses remain highly 

applicable to women. For this reason, we briefly outline results from FM reviews below, with 

more detailed results provided in Appendix G. 

Of 34 eligible reviews, 14 examined medications (n=7 for antidepressants,

134-140 n=5 for 

anticonvulsant agents,137,141-144 and n=2 for both classes145,146). The largest review of 

antidepressants addressed the effectiveness of duloxetine and milnacipran, and included 10 

studies; there were small improvements in pain (SMD -0.23, CI -0.29 to -0.18), and quality of 

life (SMD -0.20, CI of -0.25 to -0.14).134 Additional reviews that also evaluated these 

medications136,137 found similar results. Reviews on anticonvulsants (ie, gabapentin and 

pregabalin) also showed improvement in pain.137,141-144

Six reviews evaluated various forms of exercise,

147-152 and while most of these showed some 

effectiveness for pain, there did not appear to be differences between different types of exercise 

(eg, aquatic vs land-based). Six reviews examined different types of psychotherapy or behavioral 

interventions.153-158 A recent large review of CBT found low-quality evidence to support a small 

improvement in pain symptoms with CBT.153 Five reviews examined acupoint 

stimulation/acupuncture159-163 and found varying results depending on the type of comparator; 

compared with sham acupuncture, acupuncture did not significantly reduce FM-related pain. 

Two reviews on meditative movement therapies (ie, yoga, tai chi, and qigong) produced 

conflicting results, and it remains unclear if these therapies are beneficial.149,151 One review 

examined chiropractic care and concluded that there was no significant difference between 

intervention and control groups.164

Knee OA. None of the 8 reviews for knee OA included plans for an analysis of sex effects either 

as a primary aim or as a subgroup analysis.

165-172 
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Primary Studies: Reporting of Sex Effects for Chronic Pain Interventions

Reviews of knee OA167 and behavioral interventions for CLBP173 were selected for further

analysis of a sample of primary studies (see Methods) because we did not identify any IPD metaanalyses for these high-priority interventions. 

Thirty RCTs evaluated behavioral interventions for CLBP, and of these, 7 (23%) met the sample 

size requirement.174-180 The number of patients randomized ranged from 161 to 409. No trials 

were limited to enrolling women and none reported on Veteran enrollment. None of the trials 

evaluated sex effects.

Eight of the 54 studies (15%) included in the review of exercise interventions for knee OA met 

the sample size requirement.

181-188 Sample sizes in these studies ranged from 182 to 439. No 

trials enrolled only women and none enrolled Veterans. Only one trial evaluated sex as a 

moderator, stating that “both sexes ... showed similar improvement in self-reported disability, 

pain and 6-minute walk distance.”182

SUMMARY: REPORTING OF SEX EFFECTS ACROSS ALL 

CONDITIONS

In Table 3, we summarize the key findings, across all conditions evaluated, of systematic 

reviews that address differential treatment effects between men and women. Overall, sex effects 

were evaluated more frequently in systematic reviews for depressive disorders. When differential 

treatment effects were identified, the differences between men and women were typically small. 

Table 3. Summary of sex effects identified in systematic reviews

Condition Possible differences in treatment 

effects between men and women

Possible lack of differences in 

treatment effects between men and

women 

Depressive disorders

(Page 9) 

Greater improvement in depressive 

symptoms

CBT, duloxetinea

SSRIs in older adults

More adverse effects on sexual 

dysfunction

Paroxetine

Depressive symptoms

Antidepressants overall, quality 

improvement, self-helpa

Combined antidepressant and 

psychotherapy for dysthymia

Adverse effects overall

Antidepressants

Diabetes

(Page 12) 

Fracture risk

Lower for sulfonylureas (compared 

with thiazolidinediones)

Glycemic control

Linagliptina, vildagliptina

Weight loss

Bariatric surgery

Chronic painb

(Page 17)

Greater improvement in CLBP

Quality improvement 

CLBP

Antidepressants a Findings are from individual patient data meta-analysis. b Fibromyalgia is not listed because studies predominantly enrolled women. Knee osteoarthritis is not listed because 

no reviews were identified.

Abbreviations: CBT=cognitive behavioral therapy; CLBP=chronic low back pain; SSRI=selective serotonin 

reuptake inhibitor
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DISCUSSION 

We identified 313 recently published systematic reviews evaluating eligible interventions for our 

3 prioritized conditions. The most frequently evaluated interventions varied by condition: 

medications and psychotherapy for depression, medications for diabetes, and multiple 

interventions (eg, exercise, acupuncture or chiropractic manipulation, antidepressants) for the 

selected chronic pain conditions. For some eligible interventions in each condition, we were 

unable to find current reviews. Most reviews limited eligibility to RCTs, and the number of 

primary studies included ranged from 0 to 347. Systematic reviews varied in their reporting of 

the proportion of men and women enrolled in primary studies, ranging from a low of 31% of 

reviews for CLBP to a high of 60% of reviews for depressive disorders. When reported, women 

were well represented in primary studies for depression, and women predominated in the FM 

studies; representation in diabetes, CLBP, and knee OA studies was more variable. 

Although systematic reviews were numerous, few evaluated sex as a moderator of treatment 

effects (16% for depressive disorders, 8% for diabetes, and 4% for chronic pain). Additionally, 

most reviews examining sex effects used meta-regression, a statistical technique that is subject to 

ecological fallacy and recommended only for moderators that are study design 

characteristics.103,104 IPD meta-analysis is a more robust approach for evaluating sex effects, but 

it requires greater resources.

30 IPD meta-analysis was used by only a small fraction (n =16) of all

included reviews. Table 4 summarizes the gaps in evidence on sex effects.

Table 4. Gaps in evidence on sex effects

Condition Sex effects not examined No IPD meta-analysis on sex 

effects

Depressive disorders All interventions for relapse 

prevention, treatment-resistant 

depression and subsyndromal 

depression; exercise for any 

depressive disorder

Psychotherapy, combined 

antidepressants and psychotherapy, 

quality improvement

Diabetes All nonpharmacologic interventions 

except bariatric surgery

All medications except DPP-4 

inhibitors; all nonpharmacologic 

interventions

Chronic pain CLBP

All interventions except 

antidepressants and quality 

improvement

Knee OA

All interventions

CLBP

All interventions

Knee OA

All interventions

Abbreviations: CLBP=chronic low back pain; DPP-4=dipeptidyl peptidase-4; OA=osteoarthritis

To better understand the feasibility of conducting new reviews comparing treatment effect 

estimates separately for men and women, we evaluated reports of primary RCTs for 7 different 

condition–intervention dyads. Overall, we found that a minority of RCTs had sample sizes large

enough to examine moderator effects and that only 14% of these (9 of 66) examined interactions 

between sex and intervention groups. The paucity of RCTs examining sex effects is 

disappointing but is consistent with previous studies.189,190 
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To our knowledge, this is the first study to examine the evaluation of sex effects in systematic 

reviews. Our major finding is that, despite efforts to increase participation of women in trials and 

a greater focus on possible treatment differences between women and men, the sex distribution 

of included populations is summarized inconsistently, and evaluations for sex effects are rarely 

conducted. Thus, we urgently need to address the large gaps in our knowledge of sex differences 

in treatment effectiveness and adverse effects.

ACHIEVING ADEQUATE REPRESENTATION OF WOMEN IN CLINICAL 

STUDIES

In response to underrepresentation of women and minorities, the NIH Revitalization Act of 1993 

established guidelines for the inclusion of women in all clinical research studies.191 NIH and 

other research organizations have called for evaluation of sex effects at all stages of research, 

from the cellular level to human studies.192 Increased understanding of sex effects can lead to 

improvements in clinical practice by informing whether sex and gender differences require 

tailoring of clinical interventions for optimal benefit among women. In a recent example, the 

U.S. Food and Drug Administration issued sex-specific dosage recommendations for zolpidem in 

2013, in response to data about higher adverse effects in women using standard dosing.193 When 

interventions are found to be differentially effective in men and women, it also provides impetus 

and rationale for research into more effective treatments for both sexes.

In order for the VA to ensure equitable benefit of VA research, it is important to evaluate sex 

effects and advance the scientific knowledge of evidence-based approaches to improving care for 

women Veterans. However, inclusion of women in VA research is particularly challenging 

because women remain a minority within the Veteran population, and the enrollment of women 

Veterans in VHA, while growing, remains a relatively low proportion (6.5% in 2012).3

Additionally, multiple barriers exist to the recruitment and retention of women and minorities in 

clinical trials,194 including fear and distrust of the research enterprise, lack of transportation, 

interference with work and/or family responsibilities, financial costs, and other burdens as a 

result of participation. Investing in methods to overcome these barriers will be important for VA. 

Recognizing the needs and challenges associated with enrolling women, the VA established the 

Women’s Health Research Network to facilitate research participation by women Veterans and 

encourage investigation of topics important for women Veterans’ health.195,196 This network is 

working to increase research capacity in VA by (1) informing VA investigators about issues 

important for women Veterans’ health and health care, (2) providing training in oversampling 

techniques and subgroup analyses, and (3) developing a national practice-based research network 

to facilitate enrollment.195,196

PRIORITIZING AREAS FOR EVALUATION OF SEX EFFECTS

While evaluating sex effects is important, it can be costly. Examining moderator effects requires 

larger sample sizes, and the current lack of reporting on sex effects by clinical studies may be 

due in part to hesitance around identification of spurious subgroup effects in underpowered 

studies.15 IPD meta-analysis could overcome small sample sizes in primary studies, but this 

requires cooperation and willingness to share data among investigators, more resources for data 

repositories, and adequate protections for patient privacy.197 Therefore, the research community 

needs guiding principles for when information on sex effects is likely to be worth the additional 
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resources needed. We suggest several sources for consideration that could prompt designing new 

clinical studies to evaluate sex or gender effects:

Basic science and early-phase clinical studies that suggest differential sex effects (eg, 

animal models, genomic evidence, pharmacokinetics); 

Observational studies or small RCTs that indicate differential effects; however, 

limitations in study design or statistical power decrease confidence in such findings; 

Effects of unique biological events, such as menopause, that may alter the risk of disease 

or response to therapies; 

Conceptual or theoretical models where knowledge of behavioral effects and other social 

science constructs strongly suggest a sex effect. 

The following examples illustrate the application of these criteria. First, antidepressants are used

for a wide range of conditions including depressive disorders and chronic pain syndromes. 

Pharmacokinetic evidence198 supports different antidepressant doses for men and women. In the 

systematic reviews we evaluated, limited data suggested that adverse effects may differ for men 

and women with some antidepressants. Since adverse effects are a major cause of poor 

medication adherence, a better understanding of sex effects in adverse effects for different 

antidepressants could help clinicians tailor treatment. 

Second, for diabetes interventions, multiple medications (eg, insulin and sulfonylureas) were 

associated with weight gain, but there was no evaluation of sex effects for this adverse outcome. 

There are many reasons why the effects of weight gain may be different between men and 

women, including physiologic, behavioral, and social factors.199,200 Further, women may 

prioritize this outcome more than men, making knowledge of sex effects for weight gain 

particularly relevant for women.

Third, in examining the treatment of chronic pain, we found one review showing that 

multicomponent interventions for CLBP may be more effective in women. There are multiple 

reasons why these multifaceted interventions may have different efficacy in women when 

compared with men. One possibility is that such interventions lead to better incorporation and 

coordination of behavioral components, which may be more acceptable to women and even 

preferable over medications. For example, similar preferences for behavioral interventions have 

been found in the context of insomnia treatment for women Veterans.201 Additionally, 

multicomponent interventions could more robustly manage comorbidities, such as sleep 

disorders and mental health diagnoses, which are more common among women and highly 

prevalent among women Veterans.

3,202 Thus, it would be valuable to confirm the presence of sex 

effects using IPD meta-analyses, as well as further evaluate the possibly differential role of key 

intervention components. 

Additionally, it would be worthwhile to systematically evaluate how sex differences in 

preference for treatment type, including complementary and alternative treatments, would affect 

acceptability, adherence, and efficacy. Some work has shown that women Veterans may be more 

likely to prefer these treatments for pain,

202 but we are lacking information on how these 

preferences impact actual use and efficacy. 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

Conditions for Women Veterans

23

STUDY LIMITATIONS

Evidence maps are designed to give a broad overview of the evidence base. Our results are best 

used to describe areas where research has been conducted and where sex effects have been 

evaluated. However, we evaluated only systematic reviews published since 2009, so we may 

have missed older reviews of interventions. Also, we did not formally evaluate the quality of 

included reviews, and so our estimates of intervention effects should be considered preliminary. 

Reviews that found no evidence of differential intervention effects for men and women may have 

simply been underpowered to detect a clinically important difference. For IPD meta-analyses, we 

used an inclusive definition and allowed reviews that simply used available datasets, often from 

industry-sponsored trials, instead of requiring that such analyses systematically identify all 

eligible trials. When studies included in IPD meta-analyses are selected for convenience rather 

than systematically, selection bias can compromise the findings.

CONCLUSION

There is a large body of evidence for many of the examined interventions, particularly 

medications, psychotherapy, and exercise. However, systematic reviews and RCTs examined sex 

effects infrequently. When examined, sex effects generally favored greater benefits in women, 

but the differential effects were small and the analysis approaches were suboptimal. All RCTs 

and systematic reviews should report the proportion of men and women enrolled, and sex effects 

should be examined in adequately powered RCTs or IPD meta-analyses. 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

Conditions for Women Veterans

24

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235. Cuijpers P, van Straten A, Hollon SD, Andersson G. The contribution of active 

medication to combined treatments of psychotherapy and pharmacotherapy for adult 

depression: a meta-analysis. Acta Psychiatr Scand. 2010;121(6):415-423. 

236. Cuijpers P, Andersson G, Donker T, van Straten A. Psychological treatment of 

depression: results of a series of meta-analyses. Nord J Psychiatry. 2011;65(6):354-364. 
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237. Cuijpers P, Sijbrandij M, Koole SL, Andersson G, Beekman AT, Reynolds CF, 3rd. 

Adding psychotherapy to antidepressant medication in depression and anxiety disorders: 

a meta-analysis. World Psychiatry. 2014;13(1):56-67. 

238. Cuijpers P, Dekker J, Hollon SD, Andersson G. Adding psychotherapy to 

pharmacotherapy in the treatment of depressive disorders in adults: a meta-analysis 

(Structured abstract). J Clin Psychiatry. 2009;70(9):1219-1229. 

http://onlinelibrary.wiley.com/o/cochrane/cldare/articles/DARE12009109415/frame.html. 

239. Spijker J, van Straten A, Bockting CL, Meeuwissen JA, van Balkom AJ. Psychotherapy, 

antidepressants, and their combination for chronic major depressive disorder: a 

systematic review. Can J Psychiatry. 2013;58(7):386-392. 

240. Danielsson L, Noras AM, Waern M, Carlsson J. Exercise in the treatment of major 

depression: a systematic review grading the quality of evidence. Physiother Theory 

Pract. 2013;29(8):573-585. 

241. Mura G, Moro MF, Patten SB, Carta MG. Exercise as an add-on strategy for the 

treatment of major depressive disorder: a systematic review. CNS Spectr. 

2014;19(6):496-508. 

242. Cramer H, Lauche R, Langhorst J, Dobos G. Yoga for depression: a systematic review 

and meta-analysis. Depress Anxiety. 2013;30(11):1068-1083. 

243. Josefsson T, Lindwall M, Archer T. Physical exercise intervention in depressive 

disorders: meta-analysis and systematic review. Scand J Med Sci Sports. 2014;24(2):259-

272. 

244. Silveira H, Moraes H, Oliveira N, Coutinho ES, Laks J, Deslandes A. Physical exercise 

and clinically depressed patients: a systematic review and meta-analysis. 

Neuropsychobiology. 2013;67(2):61-68. 

245. Bridle C, Spanjers K, Patel S, Atherton NM, Lamb SE. Effect of exercise on depression 

severity in older people: systematic review and meta-analysis of randomised controlled 

trials. Br J Psychiatry. 2012;201(3):180-185. 

246. Krogh J, Nordentoft M, Sterne JA, Lawlor DA. The effect of exercise in clinically 

depressed adults: systematic review and meta-analysis of randomized controlled trials. J 

Clin Psychiatry. 2011;72(4):529-538. 

247. Woltmann E, Grogan-Kaylor A, Perron B, Georges H, Kilbourne AM, Bauer MS. 

Comparative effectiveness of collaborative chronic care models for mental health 

conditions across primary, specialty, and behavioral health care settings: systematic 

review and meta-analysis. Am J Psychiatry. 2012;169(8):790-804. 

248. Cuijpers P, van Straten A, Schuurmans J, van Oppen P, Hollon SD, Andersson G. 

Psychotherapy for chronic major depression and dysthymia: a meta-analysis. Clin 

Psychol Rev. 2010;30(1):51-62. 

249. Kriston L, von Wolff A, Westphal A, Holzel LP, Harter M. Efficacy and acceptability of 

acute treatments for persistent depressive disorder: a network meta-analysis. Depress 

Anxiety. 2014;31(8):621-630. 

250. von Wolff A, Holzel LP, Westphal A, Harter M, Kriston L. Selective serotonin reuptake 

inhibitors and tricyclic antidepressants in the acute treatment of chronic depression and 

dysthymia: a systematic review and meta-analysis. J Affect Disord. 2013;144(1-2):7-15. 

251. Krishna M, Honagodu A, Rajendra R, Sundarachar R, Lane S, Lepping P. A systematic 

review and meta-analysis of group psychotherapy for sub-clinical depression in older 

adults. Int J Geriatr Psychiatry. 2013;28(9):881-888. 
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252. Lee SY, Franchetti MK, Imanbayev A, Gallo JJ, Spira AP, Lee HB. Nonpharmacological prevention of major depression among community-dwelling older 

adults: a systematic review of the efficacy of psychotherapy interventions. Arch Gerontol 

Geriatr. 2012;55(3):522-529. 

253. Cameron IM, Reid IC, MacGillivray SA. Efficacy and tolerability of antidepressants for 

sub-threshold depression and for mild major depressive disorder. J Affect Disord. 

2014;166:48-58. 

254. Chiesa A, Serretti A. Mindfulness based cognitive therapy for psychiatric disorders: a 

systematic review and meta-analysis. Psychiatry Res. 2011;187(3):441-453. 

255. Lopes Rocha F, Fuzikawa C, Riera R, Ramos MG, Hara C. Antidepressant combination 

for major depression in incomplete responders--a systematic review. J Affect Disord. 

2013;144(1-2):1-6. 

256. Feng CY, Chu H, Chen CH, et al. The effect of cognitive behavioral group therapy for 

depression: a meta-analysis 2000-2010. Worldviews Evid Based Nurs. 2012;9(1):2-17. 

257. Glue P, Donovan MR, Kolluri S, Emir B. Meta-analysis of relapse prevention 

antidepressant trials in depressive disorders. Aust N Z J Psychiatry. 2010;44(8):697-705. 

258. Guidi J, Fava GA, Fava M, Papakostas GI. Efficacy of the sequential integration of 

psychotherapy and pharmacotherapy in major depressive disorder: a preliminary metaanalysis. Psychol Med. 2011;41(2):321-331. 

259. Piet J, Hougaard E. The effect of mindfulness-based cognitive therapy for prevention of 

relapse in recurrent major depressive disorder: a systematic review and meta-analysis. 

Clin Psychol Rev. 2011;31(6):1032-1040. 

260. Zintzaras E, Miligkos M, Ziakas P, et al. Assessment of the relative effectiveness and 

tolerability of treatments of type 2 diabetes mellitus: a network meta-analysis. Clin Ther. 

2014;36(10):1443-1453.e1449. 

261. Guo X, Liu X, Wang M, Wei F, Zhang Y, Zhang Y. The effects of bariatric procedures 

versus medical therapy for obese patients with type 2 diabetes: meta-analysis of 

randomized controlled trials. Biomed Res Int. 2013;2013:410609. 

262. Li JF, Lai DD, Ni B, Sun KX. Comparison of laparoscopic Roux-en-Y gastric bypass 

with laparoscopic sleeve gastrectomy for morbid obesity or type 2 diabetes mellitus: a 

meta-analysis of randomized controlled trials. Can J Surg. 2013;56(6):E158-164. 

263. Picot J, Jones J, Colquitt JL, Loveman E, Clegg AJ. Weight loss surgery for mild to 

moderate obesity: a systematic review and economic evaluation. Obes Surg. 

2012;22(9):1496-1506. 

264. Dixon JB, Murphy DK, Segel JE, Finkelstein EA. Impact of laparoscopic adjustable 

gastric banding on type 2 diabetes. Obes Rev. 2012;13(1):57-67. 

265. Yip S, Plank LD, Murphy R. Gastric bypass and sleeve gastrectomy for type 2 diabetes: a 

systematic review and meta-analysis of outcomes. Obes Surg. 2013;23(12):1994-2003. 

266. van Vugt M, de Wit M, Cleijne WH, Snoek FJ. Use of behavioral change techniques in 

web-based self-management programs for type 2 diabetes patients: systematic review. J 

Med Internet Res. 2013;15(12):e279. 

267. Liang X, Wang Q, Yang X, et al. Effect of mobile phone intervention for diabetes on 

glycaemic control: a meta-analysis. Diabet Med. 2011;28(4):455-463. 

268. Chudyk A, Petrella RJ. Effects of exercise on cardiovascular risk factors in type 2 

diabetes: a meta-analysis. Diabetes Care. 2011;34(5):1228-1237. 
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269. Schwingshackl L, Missbach B, Dias S, Konig J, Hoffmann G. Impact of different training 

modalities on glycaemic control and blood lipids in patients with type 2 diabetes: a 

systematic review and network meta-analysis. Diabetologia. 2014;57(9):1789-1797. 

270. Vaes AW, Cheung A, Atakhorrami M, et al. Effect of 'activity monitor-based' counseling 

on physical activity and health-related outcomes in patients with chronic diseases: A 

systematic review and meta-analysis. Ann Med. 2013;45(5-6):397-412. 

271. Hovanec N, Sawant A, Overend TJ, Petrella RJ, Vandervoort AA. Resistance training 

and older adults with type 2 diabetes mellitus: strength of the evidence. J Aging Res. 

2012;2012:284635. 

272. Lee MS, Jun JH, Lim HJ, Lim HS. A systematic review and meta-analysis of tai chi for 

treating type 2 diabetes. Maturitas. 2015;80(1):14-23. 

273. MacLeod SF, Terada T, Chahal BS, Boule NG. Exercise lowers postprandial glucose but 

not fasting glucose in type 2 diabetes: a meta-analysis of studies using continuous 

glucose monitoring. Diabetes Metab Res Rev. 2013;29(8):593-603. 

274. McGinley SK, Armstrong MJ, Boule NG, Sigal RJ. Effects of exercise training using 

resistance bands on glycaemic control and strength in type 2 diabetes mellitus: a metaanalysis of randomised controlled trials. Acta Diabetol. 2014. 

275. Oliveira C, Simoes M, Carvalho J, Ribeiro J. Combined exercise for people with type 2 

diabetes mellitus: a systematic review. Diabetes Res Clin Pract. 2012;98(2):187-198. 

276. Umpierre D, Ribeiro PA, Schaan BD, Ribeiro JP. Volume of supervised exercise training 

impacts glycaemic control in patients with type 2 diabetes: a systematic review with 

meta-regression analysis. Diabetologia. 2013;56(2):242-251. 

277. Yang Z, Scott CA, Mao C, Tang J, Farmer AJ. Resistance exercise versus aerobic 

exercise for type 2 diabetes: a systematic review and meta-analysis. Sports Med. 

2014;44(4):487-499. 

278. Strasser B, Siebert U, Schobersberger W. Resistance training in the treatment of the 

metabolic syndrome: a systematic review and meta-analysis of the effect of resistance 

training on metabolic clustering in patients with abnormal glucose metabolism. Sports 

Med. 2010;40(5):397-415. 

279. Yan JH, Gu WJ, Pan L. Lack of evidence on Tai Chi-related effects in patients with type 

2 diabetes mellitus: a meta-analysis. Exp Clin Endocrinol Diabetes. 2013;121(5):266-

271. 

280. Zhou J, Zhang L, Liu H, Mallampati T, Xu M, Yang J. Tai Chi for type 2 diabetes 

mellitus. Cochrane Database of Systematic Reviews. 2012(3). 

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009717/abstract. 

281. Castaneda-Gonzalez LM, Bacardi Gascon M, Jimenez Cruz A. Effects of low 

carbohydrate diets on weight and glycemic control among type 2 diabetes individuals: a 

systemic review of RCT greater than 12 weeks. Nutr Hosp. 2011;26(6):1270-1276. 

282. Dong JY, Zhang ZL, Wang PY, Qin LQ. Effects of high-protein diets on body weight, 

glycaemic control, blood lipids and blood pressure in type 2 diabetes: meta-analysis of 

randomised controlled trials. Br J Nutr. 2013;110(5):781-789. 

283. Schwingshackl L, Hoffmann G. Comparison of the long-term effects of high-fat v. lowfat diet consumption on cardiometabolic risk factors in subjects with abnormal glucose 

metabolism: a systematic review and meta-analysis. Br J Nutr. 2014;111(12):2047-2058. 

284. Ricci-Cabello I, Ruiz-Perez I, Rojas-Garcia A, Pastor G, Goncalves DC. Improving 

diabetes care in rural areas: a systematic review and meta-analysis of quality 

improvement interventions in OECD countries. PLoS One. 2013;8(12):e84464. 
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285. Searle A, Spink M, Ho A, Chuter V. Exercise interventions for the treatment of chronic 

low back pain: A systematic review and meta-analysis of randomised controlled trials. 

Clin Rehabil. 2015. 

286. Wang XQ, Zheng JJ, Yu ZW, et al. A meta-analysis of core stability exercise versus 

general exercise for chronic low back pain. PLoS One. 2012;7(12):e52082. 

287. Schaafsma FG, Whelan K, van der Beek AJ, van der Es-Lambeek LC, Ojajarvi A, 

Verbeek JH. Physical conditioning as part of a return to work strategy to reduce sickness 

absence for workers with back pain. Cochrane Database Syst Rev. 2013;8:Cd001822. 

288. Ferreira ML, Smeets RJ, Kamper SJ, Ferreira PH, Machado LA. Can we explain 

heterogeneity among randomized clinical trials of exercise for chronic back pain? A 

meta-regression analysis of randomized controlled trials. Phys Ther. 2010;90(10):1383-

1403. 

289. Fersum KV, Dankaerts W, O'Sullivan PB, et al. Integration of subclassification strategies 

in randomised controlled clinical trials evaluating manual therapy treatment and exercise 

therapy for non-specific chronic low back pain: a systematic review. Br J Sports Med. 

2010;44(14):1054-1062. 

290. Miyamoto GC, Costa LO, Cabral CM. Efficacy of the Pilates method for pain and 

disability in patients with chronic nonspecific low back pain: a systematic review with 

meta-analysis. Braz J Phys Ther. 2013;17(6):517-532. 

291. Pereira LM, Obara K, Dias JM, et al. Comparing the Pilates method with no exercise or 

lumbar stabilization for pain and functionality in patients with chronic low back pain: 

systematic review and meta-analysis. Clin Rehabil. 2012;26(1):10-20. 

292. Standaert CJ, Friedly J, Erwin MW, et al. Comparative effectiveness of exercise, 

acupuncture, and spinal manipulation for low back pain. Spine (Phila Pa 1976). 

2011;36(21 Suppl):S120-130. 

293. Orrock PJ, Myers SP. Osteopathic intervention in chronic non-specific low back pain: a 

systematic review. BMC Musculoskelet Disord. 2013;14:129. 

294. Rubinstein SM, van Middelkoop M, Assendelft WJ, de Boer MR, van Tulder MW. 

Spinal manipulative therapy for chronic low-back pain. Cochrane Database Syst Rev. 

2011(2):Cd008112. 

295. Rubinstein SM, van Middelkoop M, Kuijpers T, et al. A systematic review on the 

effectiveness of complementary and alternative medicine for chronic non-specific lowback pain. Eur Spine J. 2010;19(8):1213-1228. 

296. Xu M, Yan S, Yin X, et al. Acupuncture for chronic low back pain in long-term followup: a meta-analysis of 13 randomized controlled trials. Am J Chin Med. 2013;41(1):1-19. 

297. Falco FJ, Manchikanti L, Datta S, et al. An update of the effectiveness of therapeutic 

lumbar facet joint interventions. Pain Physician. 2012;15(6):E909-953. 

298. Parr AT, Manchikanti L, Hameed H, et al. Caudal epidural injections in the management 

of chronic low back pain: a systematic appraisal of the literature. Pain Physician. 

2012;15(3):E159-198. 

299. Chou R, Baisden J, Carragee EJ, Resnick DK, Shaffer WO, Loeser JD. Surgery for low 

back pain: a review of the evidence for an American Pain Society Clinical Practice 

Guideline. Spine (Phila Pa 1976). 2009;34(10):1094-1109. 

300. van Middelkoop M, Rubinstein SM, Kuijpers T, et al. A systematic review on the 

effectiveness of physical and rehabilitation interventions for chronic non-specific low 

back pain. Eur Spine J. 2011;20(1):19-39. 
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301. Clarke CL, Ryan CG, Martin DJ. Pain neurophysiology education for the management of 

individuals with chronic low back pain: systematic review and meta-analysis. Man Ther. 

2011;16(6):544-549. 

302. Moore RA, Wiffen PJ, Derry S, Toelle T, Rice AS. Gabapentin for chronic neuropathic 

pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;4:Cd007938. 

303. Boyers D, McNamee P, Clarke A, et al. Cost-effectiveness of self-management methods 

for the treatment of chronic pain in an aging adult population: a systematic review of the 

literature. Clin J Pain. 2013;29(4):366-375. 

304. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Available 

at: http://www.rheumatology.org/I-Am-A/Rheumatologist/Research/ClinicianResearchers/Western-Ontario-McMaster-Universities-Osteoarthritis-Index-WOMAC. 

Accessed September 16, 2015. 
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APPENDIX A. CONDITION PRIORITIZATION INSTRUCTIONS 

Please prioritize the list of health conditions by assigning 0 to 3 stars to items listed below. When 

prioritizing, consider the following: (1) prevalence of the condition in Veterans, (2) the burden of 

the illness, (3) priorities for gender-specific care for women Veterans (not Active Duty), and (4) 

conditions with known disparities between women Veterans and non-Veterans. Items are 

categorized by conditions affecting men and women compared with gender-specific conditions.

You are given a total of 11 stars to allocate to any of the 34 items listed in the 2 categories. You 

may use up to 3 stars per item. To add stars to a selection, position your mouse over the dots in 

the right hand column. More stars equal higher priority. 

Alzheimer’s disease

Anxiety (ie, GAD, panic disorder) 

Osteoporosis 

Coronary artery disease (ie, chronic angina)

Coronary artery disease (ie, acute coronary syndrome/myocardial infarction) 

Chronic obstructive pulmonary disease 

Cerebrovascular disease (ie, ischemic stroke)

Depression (ie, MDD & dysthymia) 

Diabetes mellitus-type2

Eating disorders 

Connective tissue disease (ie, fibromyalgia) 

Headache (ie, migraine) 

Hepatitis-C 

HIV

Hyperlipidemia

Hypertension 

Irritable bowel syndrome 

Incontinence 

Insomnia 

Joint disorders (ie, osteoarthritis: hip and knee) 

Joint disorders (ie, rheumatoid arthritis)

Obesity/overweight

Chronic pain 

Posttraumatic stress disorder

Spine disorders (ie, chronic low back pain) 

Substance use disorder

Traumatic brain injury

Thyroid disorders 

Tobacco use disorder

SEPARATOR BETWEEN SEX-SPECIFIC ITEMS

Contraceptive care

Infertility

Menstrual disorders (ie, abnormal uterine bleeding) 

Menopausal disorders

Depressive disorders (ie, postpartum depression) 

Depressive disorders (ie, premenstrual dysphoric disorder) 

Prenatal care
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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APPENDIX B. SEARCH STRATEGIES

CONDITION: MAJOR DEPRESSIVE DISORDER

PubMed: Searched October 31, 2014

Search Query Items found

#1 Search "Depressive Disorder"[Mesh:NoExp] OR "Depressive Disorder, 

Major"[MeSH] OR "major depressive disorder"[tiab] OR "major depressive 

disorders"[tiab] OR "major depression"[tiab] OR “Involutional Psychoses”[tiab] OR 

“Involutional Psychosis”[tiab] OR “Involutional Depression”[tiab] OR “Involutional 

Melancholia”[tiab] OR "Dysthymic Disorder"[Mesh] OR "Dysthymic Disorder"[tiab] 

OR "Dysthymic Disorders"[tiab] OR “dysthymia”[tiab]

87024

#2 Search “Psychotherapy”[Mesh] OR “Behavior Therapy”[Mesh] OR acceptance 

therap*[tiab] OR commitment therap*[tiab] OR cognitive therap*[tiab] OR behavioral 

therap*[tiab] OR behavior therap*[tiab] OR behaviour therap*[tiab] OR behavioural 

therap*[tiab]OR interpersonal therap*[tiab] OR acceptance therap*[tiab] OR 

commitment therap*[tiab] OR mindfulness therap*[tiab] OR problem-solving 

therap*[tiab] OR problem solving therap*[tiab] OR psychodynamic therap*[tiab] OR 

psychotherap*[tiab]

172225

#3 Search "antidepressive agents"[Pharmacological Action] OR "antidepressive 

agents"[MeSH Terms] OR "antidepressive"[tiab] OR antidepressant*[tiab]

141775

#4 Search “Delivery of Health Care, Integrated”[Mesh] OR “Patient Care Team”[Mesh] 

OR “Patient Care Planning”[Mesh] OR “Disease Management”[Mesh] OR 

“Comprehensive Health Care” [Mesh:noexp] OR “Patient Care 

Management”[Mesh:noexp] OR “coordinated care”[tiab] OR coordinated 

program*[tiab] OR “team care”[tiab] OR “team treatment”[tiab] OR “team 

assessment”[tiab] OR “team consultation”[tiab] OR (collaborat*[ti] AND care [ti]) OR 

“shared care”[tiab] OR (collaborat*[ti] AND manage*[ti]) OR “Quality 

Improvement”[Mesh]

154585

#5 ("Exercise"[Mesh:NoExp] OR "Exercise"[Majr] OR "Circuit-Based Exercise"[Mesh] 

OR "Muscle Stretching Exercises"[Mesh] OR "Physical Conditioning, 

Human"[Mesh] OR "Resistance Training"[Mesh] OR "Resistance Training"[tiab] OR 

"Exercise"[tiab] OR "Exercises"[tiab] OR "physical activity"[tiab] OR "aerobic 

activity"[tiab] OR "Exercise Movement Techniques"[Mesh] OR "Sports"[Mesh] OR 

"yoga"[tiab] OR "Exercise Therapy"[Mesh]

#5 Search #1 AND (#2 OR #3 OR #4 OR #5) 32393

#6 Search #5 AND (systematic[sb] OR "Systematic Review"[tiab] OR metaanalysis[tiab] OR "meta analysis"[tiab])1792

#7 Search #6 NOT (("Adolescent"[Mesh] OR "Child"[Mesh] OR "Adolescent"[Mesh]) 

NOT "Adult"[Mesh])

1677

#8 Search #7 NOT ("Animals"[Mesh] NOT "Humans"[Mesh]) 1677

#9 Search #7 NOT ("Animals"[Mesh] NOT "Humans"[Mesh]) Filters: published in the 

last 5 years

631

#10 Search #7 NOT ("Animals"[Mesh] NOT "Humans"[Mesh]) Sort by: Author Filters: 

published in the last 5 years; English

581

Cochrane Library: Searched October 31, 2014

ID Search Results

#1 major depressive disorder:ti,ab,kw (Word variations have been searched) 2783
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ID Search Results

#2 major depression:ti,ab,kw (Word variations have been searched) 3691

#3 major depression disorder:ti,ab,kw (Word variations have been searched) 24

#4 dysthymic disorder:ti,ab,kw (Word variations have been searched) 241

#5 dysthymia:ti,ab,kw (Word variations have been searched) 379

#6 involutional depression:ti,ab,kw (Word variations have been searched) 12

#7 involutional melancholia:ti,ab,kw (Word variations have been searched) 0

#8 involutional psychosis:ti,ab,kw (Word variations have been searched) 0

#9 involutional psychoses:ti,ab,kw (Word variations have been searched) 0

#10 (or #1-#9) 6077

#11 #10 Publication Year from 2009 to 2014, in Cochrane Reviews (Reviews only) 

and Other Reviews 117

CONDITION: TYPE 2 DIABETES 

PubMed: Searched February 6, 2015

Search Query Items found

#1 Search "Diabetes Mellitus, Type 2"[Mesh] OR "Type 2 Diabetes Mellitus"[tiab] OR 

"Type II Diabetes Mellitus"[tiab] OR "Adult-Onset Diabetes Mellitus"[tiab] OR "Adult 

Onset Diabetes Mellitus"[tiab] OR "Maturity-Onset Diabetes Mellitus"[tiab] OR 

"Maturity Onset Diabetes Mellitus"[tiab] OR "Non-Insulin-Dependent Diabetes 

Mellitus"[tiab] OR "Non-Insulin Dependent Diabetes Mellitus"[tiab] OR "Noninsulin 

Dependent Diabetes Mellitus"[tiab] OR "Ketosis-Resistant Diabetes Mellitus"[tiab] 

OR "Ketosis Resistant Diabetes Mellitus"[tiab] OR "Stable Diabetes Mellitus"[tiab]

97698

#2 Search "Hypoglycemic Agents"[Mesh] OR "Hypoglycemic Agents"[Pharmacological 

Action] OR "Metformin"[Mesh] OR "Metformin"[tiab] OR "Glyburide"[Mesh] OR 

"Glyburide"[tiab] OR "Glipizide"[Mesh] OR "Glipizide"[tiab] OR "glibenclamide 

receptor"[Supplementary Concept] OR "glibenclamide"[tiab] OR "Gliclazide"[Mesh] 

OR "Gliclazide"[tiab] OR "glimepiride"[Supplementary Concept] OR 

"glimepiride"[tiab] OR "repaglinide"[Supplementary Concept] OR "repaglinide"[tiab] 

OR "nateglinide"[Supplementary Concept] OR "nateglinide"[tiab] OR 

"pioglitazone"[Supplementary Concept] OR "pioglitazone"[tiab] OR 

"rosiglitazone"[Supplementary Concept] OR "rosiglitazone"[tiab] OR 

"Acarbose"[Mesh] OR "Acarbose"[tiab] OR "miglitol" [Supplementary Concept] OR 

"miglitol"[tiab] OR "sitagliptin"[Supplementary Concept] OR "sitagliptin"[tiab] OR 

"vildagliptin"[Supplementary Concept] OR "vildagliptin"[tiab] OR 

"saxagliptin"[Supplementary Concept] OR "saxagliptin"[tiab] OR 

"Linagliptin"[Supplementary Concept] OR "Linagliptin"[tiab] OR 

"alogliptin"[Supplementary Concept] OR "alogliptin"[tiab] OR 

"colesevelam"[Supplementary Concept] OR "colesevelam"[tiab] OR 

"Bromocriptine"[Mesh] OR "Bromocriptine"[tiab] OR "canagliflozin"[Supplementary 

Concept] OR "canagliflozin"[tiab] OR "2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-

hydroxymethyltetrahydro-2H-pyran-3,4,5-triol"[Supplementary Concept] OR 

"dapagliflozin"[tiab] OR "empagliflozin"[Supplementary Concept] OR 

"empagliflozin"[tiab] OR "exenatide"[Supplementary Concept] OR "exenatide"[tiab] 

OR "liraglutide"[Supplementary Concept] OR "liraglutide"[tiab] OR 

"albiglutide"[Supplementary Concept] OR "albiglutide"[tiab] OR "ZP10A 

peptide"[Supplementary Concept] OR "Lixisenatide"[tiab] OR 

"dulaglutide"[Supplementary Concept] OR "dulaglutide"[tiab] OR 

"pramlintide"[Supplementary Concept] OR "pramlintide"[tiab]

220517
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Search Query Items found

#3 Search #1 AND #2 31000

#4 Search "Insulins"[Mesh] OR "Lispro"[tiab] OR "Aspart"[tiab] OR "insulin 

glulisine"[Supplementary Concept] OR "glulisine"[tiab] OR "isophane insulin, 

human"[Supplementary Concept] OR "glargine"[Supplementary Concept] OR 

"glargine"[tiab] OR "insulin detemir"[Supplementary Concept] OR "detemir"[tiab] OR 

"insulin degludec"[Supplementary Concept] OR "degludec"[tiab]

162510

#5 Search #1 AND #4 18805

#6 Search "Exercise"[Mesh] OR "Exercise"[tiab] OR "Exercise Therapy"[Mesh] OR 

"physical activity"[tiab]

296513

#7 Search #1 AND #6 6871

#8 Search "Weight Reduction Programs"[Mesh] OR "Weight Reduction Program"[tiab] 

OR "Weight control Program"[tiab] OR "Nutrition Therapy"[Mesh] OR "weight 

management"[tiab]

83630

#9 Search #1 AND #8 2694

#10 Search "Bariatric Surgery"[Mesh] OR "Bariatric Surgery"[tiab] 17552

#11 Search #1 AND #10 1329

#12 Search "Patient Care Management"[Mesh] OR "multidisciplinary care"[tiab] OR 

"shared medical appointments"[tiab] OR "chronic disease management"[tiab] OR 

"stepped-care models"[tiab] OR "stepped-care model"[tiab] OR "stepped care 

models"[tiab] OR "stepped care model"[tiab] OR (nurse managed clinic[tiab] OR 

nurse managed clinics[tiab]) OR (nurse managed clinic[tiab] OR nurse managed 

clinics[tiab]) OR "Cell Phones"[Mesh] OR "smartphone applications"[tiab] OR 

"Quality Improvement"[Mesh]

554128

#13 Search #1 AND #12 3965

#14 Search #3 OR #5 OR #7 OR #9 OR #11 OR #13 41293

#15 Search #14 NOT (("Adolescent"[Mesh] OR "Child"[Mesh] OR "Infant"[Mesh]) NOT 

"Adult"[Mesh])

40423

#16 Search #15 NOT ("Animals"[Mesh] NOT "Humans"[Mesh]) 37107

#17 Search #16 AND (systematic[sb] OR "Systematic Review"[tiab] OR "Umbrella 

Review"[tiab] OR meta-analysis[tiab] OR "meta analysis"[tiab]) AND "English"[lang]

1442

CONDITION: CHRONIC PAIN 

PubMed: Searched February 27, 2015

Search Query Items found

#1 Search "chronic pain"[MeSH Terms] OR "chronic pain"[tiab] OR "chronic 

pains"[tiab] OR "Fibromyalgia"[Mesh] OR "Fibromyalgia"[tiab] OR 

"Fibromyalgias"[tiab] OR "Muscular Rheumatism"[tiab] OR "Fibrositis"[tiab] OR 

"Pain Syndrome"[tiab] OR "chronic low back pain"[tiab] OR "chronic knee pain"[tiab]

OR “knee osteoarthritis”[MeSH Terms] OR “knee osteoarthritis”[tiab]

41472

#2 Search #1 AND (systematic[sb] OR "Systematic Review"[tiab] OR "Umbrella 

Review"[tiab] OR meta-analysis[tiab] OR "meta analysis"[tiab]) AND "English"[lang]

2031

#3 Search #2 NOT ("Animals"[Mesh] NOT "Humans"[Mesh]) 2025

#4 Search #3 NOT (("Adolescent"[Mesh] OR "Child"[Mesh] OR "Infant"[Mesh]) NOT 

"Adult"[Mesh])

1985

#5 Search (("2009/10/01"[Date - Publication] : "3000"[Date - Publication])) AND #4 1145

#6 Search #5 AND ("Behavior Therapy"[Mesh] OR "psychoeducation"[tiab] OR 

"CBT"[tiab] OR "biofeedback"[tiab] OR (("therapy"[tiab]) AND ("mindfulness"[tiab] 

92
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Search Query Items found

OR "cognitive"[tiab] OR "behavior"[tiab] OR "behavioral"[tiab] OR "relaxation"[tiab] 

OR "acceptance"[tiab])))

#7 Search #5 AND ("Exercise"[Mesh:NoExp] OR "Exercise"[Majr] OR "Circuit-Based 

Exercise"[Mesh] OR "Muscle Stretching Exercises"[Mesh] OR "Physical 

Conditioning, Human"[Mesh] OR "Resistance Training"[Mesh] OR "Resistance 

Training"[tiab] OR "Running"[Mesh] OR "Running"[tiab] OR "Jogging"[Mesh] OR 

"Jogging"[tiab] OR "Swimming"[Mesh] OR "Swimming"[tiab] OR "Walking"[Mesh] 

OR "Walking"[tiab] OR "Exercise"[tiab] OR "Exercises"[tiab] OR "physical 

activity"[tiab] OR "aerobic activity"[tiab] OR "Exercise Movement 

Techniques"[Mesh] OR "Sports"[Mesh] OR "yoga"[tiab] OR "Physical Therapy 

Modalities"[Mesh:NoExp] OR "Physical Therapy"[tiab] OR "Exercise 

Therapy"[Mesh] OR "Hydrotherapy"[Mesh] OR "Hydrotherapy"[tiab])

196

#8 Search #5 AND ("Muscle Relaxants, Central"[Mesh] OR "Baclofen"[Mesh] OR 

"Baclofen"[tiab] OR "Carisoprodol"[Mesh] OR "Carisoprodol"[tiab] OR 

"cyclobenzaprine" [Supplementary Concept] OR "cyclobenzaprine"[tiab] OR 

"Methocarbamol"[Mesh] OR "Methocarbamol"[tiab] OR "tizanidine"[Supplementary 

Concept] OR "tizanidine"[tiab])

2

#9 Search #5 AND ("Anti-Inflammatory Agents, Non-Steroidal" [Pharmacological 

Action] OR "Anti-Inflammatory Agents, Non-Steroidal"[Mesh] OR "NSAIDs"[tiab] OR 

"Nonsteroidal Anti Inflammatory Agents"[tiab] OR "Nonsteroidal Anti Inflammatory 

Agent"[tiab])

41

#10 Search #5 AND ("Capsaicin"[Mesh] OR "Capsaicin"[tiab]) 10

#11 Search #5 AND (("Lidocaine"[MeSH Terms] OR "lidocaine"[tiab]) AND 

("transdermal patch"[MeSH Terms] OR "transdermal"[tiab] OR "patch"[tiab]))

1

#12 Search #5 AND ("Antidepressive Agents"[Mesh] OR "Antidepressive Agents" 

[Pharmacological Action] OR "Duloxetine"[tiab] OR "Venlafaxine"[tiab])

60

#13 Search #5 AND ("pregabalin" [Supplementary Concept] OR "pregabalin" [tiab]) 38

#14 Search #5 AND ("gabapentin" [Supplementary Concept] OR "gabapentin" [tiab]) 23

#15 Search #5 AND ("Hyaluronic Acid"[Mesh] OR "Hyaluronic Acid"[tiab]) 4

#16 Search #5 AND ("Steroids"[Mesh] OR "steroid"[tiab] OR "steroids"[tiab]) 28

#17 Search #5 AND ("Acupuncture Therapy"[Mesh] OR "Acupuncture"[Mesh] OR 

"Acupuncture"[tiab] OR "Chiropractic"[Mesh] OR "Manipulation, Chiropractic"[Mesh] 

OR "Chiropractic"[tiab] OR "Chiropractor"[tiab])

58

#18 Search #5 AND ("Patient Care Management"[Mesh] OR "multidisciplinary 

care"[tiab] OR "colocated care"[tiab] OR "shared medical appointments"[tiab] OR 

"pain clinic"[tiab] OR "Telephone"[MAJR] OR "Cell Phones"[Mesh] OR "smartphone 

applications"[tiab] OR "telephone-based care"[tiab] OR "telephone care"[tiab] OR 

"Quality Improvement"[Mesh] OR "Continuity of Patient Care"[Mesh] OR "PatientCentered Care"[Mesh] OR "chronic disease management"[tiab])

196

#19 Search #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 

OR #16 OR #17 OR #18

538

Cochrane Library: Searched February 27, 2015

ID Search Results

#1 "chronic pain":ti,ab,kw (Word variations have been searched) 2689

#2 "fibromyalgia":ti,ab,kw (Word variations have been searched) 1249

#3 #1 or #2 Publication Year from 2009 to 2015, in Cochrane Reviews (Reviews and 

Protocols) 88
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APPENDIX C. ELIGIBILITY CRITERIA FOR SYSTEMATIC REVIEWS

PICOTS 

Element Inclusion Criteria Exclusion Criteria

Populations Depressive disorders: Adults with major depressive 

disorder, persistent depressive disorder (dysthymia), or 

subsyndromal depression/minor depression/depression-NOS; 

also included are reviews broadly addressing effects of 

treatment in patients with co-occurring chronic medial illness

Diabetes: Adults with type 2 diabetes mellitusa

Chronic pain: Adults with musculoskeletal causes of chronic 

low back pain, fibromyalgia, or chronic knee pain due to 

osteoarthritis

Depressive disorders: Reviews focused on bipolar disorder, 

grief, premenstrual dysphoric disorder, psychotic depression, 

depression subtypes (eg, atypical depression; melancholic 

depression); also excluded are reviews focused on subsets of 

depressed patients who have a specific comorbid medical 

condition (eg, diabetes, heart disease) or psychiatric illness (eg, 

alcohol misuse)

Diabetes: None

Chronic pain: Reviews focused only on acute back or knee 

pain, other pain syndromes (eg, patellofemoral)

Interventions Depressive disordersb

: 

Antidepressants (SSRI, SNRI, TCA)

Therapy: CBT, CT, IPT, MBCT, PST, ST, 

psychodynamic, reminiscence therapy delivered in 

person, in groups, or by internet

Supervised exercise

Guided self-help based on principles of CBT

QI strategies: collaborative care, co-located care, 

women-only clinic

Diabetes: 

Oral hypoglycemics: metformin, DPP-4 inhibitors (eg, 

saxagliptin), sulfonylureas (eg, glipizide, glyburide), 

GLP-1 inhibitors (eg, exanatide, liraglutide), 

thiazolidenediones (eg pioglitazone)

Insulin

Exercise programs: aerobic or strengthening performed 

in organized groups or with support from behavioristc

Behavioral: psychoeducation, weight control programd

Bariatric surgery

QI strategies: multidisciplinary care (eg, co-located 

behaviorist, registered dietician, or diabetic educator), 

Depressive disorders:

Alternative: dietary supplements (eg, fish oil; vitamin D), 

yoga, acupuncture, St. John’s wort, SAM-e 

Medications: atypical antipsychotics, ketamine, adjunctive 

medications used for augmentation (eg, psychostimulants, 

thyroid hormone, lithium) that have not been specified as 

eligible medications; reviews of single medications, rather 

than a drug class, unless review is an individual patient 

data meta-analysis

Somatic: electroconvulsive therapy, light therapy, 

transcranial magnetic stimulation, vagal nerve stimulation, 

deep brain stimulation

Psychotherapies: dialectical behavioral therapy, music 

therapy, traditional long-term psychodynamic therapy, pet 

therapy

Treatment sequencing (eg, switching antidepressants)

Interventions to prevent depressive disorder (eg, interferon 

therapy for hepatitis C) 

Diabetes:

Interventions to prevent diabetes

Alternative: dietary supplements, acupuncture, meditationbased interventions (eg, transcendental meditation)
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PICOTS 

Element Inclusion Criteria Exclusion Criteria

shared medical appointments, chronic disease 

management (eg, telephone and internet-based 

interventions), stepped-care models, nurse-managed 

clinics, women-only clinic, smartphone applications

Chronic pain: 

Antidepressants: SNRIs (duloxetine, venlafaxine, 

milnacipran), TCA, SSRI

Calcium channel 2 delta ligandse

: pregabalin, 

gabapentin

Muscle relaxantse

Topical treatments: NSAIDs, capsaicin, lidocaine patch

Joint injection: steroid (if back, must be lumbar region)f

, 

hyaluronic acidg

Behavioral treatments focused on pain management: 

psychoeducation, CBT, mindfulness-based and 

acceptance-based therapy, relaxation therapy, 

biofeedback in groups or by internet

Exercise: aerobic, strengthening, or stretching 

performed with supervision (eg, physical therapist, pool 

therapy), as part of a class (eg, yoga class, tai chi), or 

as medically directed self-care

Integrative and complementary medicinee

: acupuncture; 

spinal manipulation (chiropractic care)

QI strategies: multidisciplinary care (eg, 

multidisciplinary pain clinic), co-located care (eg, 

behaviorist in primary care), women-only clinic; 

telephone-based care 

Self-management strategies used to decrease pain 

symptoms

Medications: any medication or class of medication not 

listed in the included section, insulin pump regimens, 

types or intensity of insulin regimens, colesevalam, alphaglucosidase inhibitors, bromocriptine, miglitol; reviews of 

single medications unless the medication is insulin, 

metformin, repaglinide, nateglinide, pioglitazone, 

rosiglitazone, or pramlintide, or review is an individual 

patient data meta-analysis

Somatic: type or intensity of glucose monitoring

Surgical interventions other than bariatric surgery

QI: endocrinology clinics, QI interventions with clinician as 

intervention target (eg, decision support via computer 

reminders)

Chronic pain:

Complementary and integrative medicine: massage, 

dietary supplements 

Medications: acetaminophen, oral NSAIDs, antiepileptics 

(except for gabapentin, pregabalin); antispasmodics; 

antipsychotics, clozapine, benzodiazepine and opioids; 

reviews of single medications except: amitriptyline, 

pregabalin, gabapentin, duloxetine, milnacipran, 

capsaicin, lidocaine, or review is an individual patient 

data meta-analysis

Marijuana/cannabinoids

Injections/physical: nerve blocks, therapeutic ultrasound, 

traction, back braces, knee braces, TENS unit, trigger 

point injections

Surgical interventions (eg, spinal fusion; total hip or total 

knee arthroplasty, spinal cord stimulator)

Therapies: dialectical behavioral therapy, music therapy, 

traditional long-term psychodynamic therapy, pet therapy

Treatment sequencing (eg, acetaminophen then NSAID)

Interventions to prevent chronic pain

Comparators All conditions: Any active or inactive comparators None
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PICOTS 

Element Inclusion Criteria Exclusion Criteria

Outcomes All conditions: Patient health outcomes and adverse effects

Depressive disorders: Depressive symptoms, 

functional status

Diabetes: Glycemic control, weight, mortality, 

microvascular and macrovascular eventsh

, adverse 

effectsi

Chronic pain: Pain severity, functional status

Depressive disorders: Provider outcomes, acceptance of 

intervention, prevalence of intervention, cost of intervention 

without reporting patient health outcomes

Diabetes: Provider outcomes, adherence to and/or acceptance 

of intervention, blood pressure, lipids, prevalence of intervention, 

cost of intervention

Chronic pain: Provider outcomes, adherence to and/or 

acceptance of intervention, prevalence of intervention; cost of 

intervention without reporting patient health outcomes

Timing Any duration of follow-up None

Settings Depressive disorders: Any setting

Diabetes: Outpatient settings

Chronic pain: Outpatient settings

Depressive disorders: None

Diabetes: In-hospital setting, or focused on effects in lowincome countries

Chronic pain: Focused on work-based programs

Design All conditions: Systematic reviews or individual patient level 

meta-analyses; must have search strategy, eligibility criteria, 

and analysis/synthesis plan 

Depressive disorders: May include RCTs 

(antidepressants, therapy, exercise), or quasiexperimental studies (QI interventions), or observational 

studies (if focused on adverse effects)

Diabetes: May include RCTs (medications, behavioral 

interventions), or quasi-experimental studies (QI 

interventions), or observational studies (if focused on 

adverse effects)

Chronic pain: May include RCTs (medications, 

behavioral, exercise), or quasi-experimental studies (QI 

strategies), or observational studies (if focused on 

adverse effects)

Nonsystematic reviews

Publications English-language only Non-English publications
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PICOTS 

Element Inclusion Criteria Exclusion Criteria

Published October 2009 to present Publications before October 2009 a Mixed diabetes populations were included if patients with type 2 diabetes were analyzed separately.

b Interventions may be for acute-phase treatment, treatment-resistant depression, or maintenance. c Includes tai chi, Pilates, yoga, and related forms of exercise.

d Includes supervised programs that use changes in physical activity, diet, or a combination of these approaches to achieve weight change or improved glycemic 

control. e For chronic low back pain and fibromyalgia only.

f For chronic low back pain and chronic knee pain only.

g For chronic knee pain only.

h Includes stroke, cardiac event (eg, myocardial infarction), nephropathy, neuropathy (including diabetic foot ulcer), and changes in cognition. I Includes cancer, osteoporosis, hypoglycemia, changes in cognition, lactic acidosis, adverse gastrointestinal effects, and cardiovascular and serious adverse 

events.

Abbreviations: CBT=cognitive behavioral therapy; CT=cognitive therapy; DPP-4=dipeptidyl peptidase 4; GLP-1=glucagon-like peptide-1; IPT=interpersonal 

therapy; MBCT=mindfulness-based cognitive therapy; NOS=not otherwise specified; NSAID=nonsteroidal anti-inflammatory drug; PICOTS=population, 

intervention, comparator, outcome, timing, setting; PST=problem-solving therapy; QI=quality improvement; RCT=randomized controlled trial; SAM-e=Sadenosylmethionine; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; ST psychodynamic=short-term 

psychodynamic; TCA=tricyclic antidepressant; TENS= transcutaneous electrical nerve stimulation
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APPENDIX D. RESPONSES TO REVIEWER COMMENTS

Mapping the Evidence: Sex Effects in High-impact Conditions for Women Veterans – Depression, Diabetes, and 

Chronic Pain

Question 

Text

Reviewer 

Number Comment Response

Are the 

objectives, 

scope, and 

methods for

this review 

clearly 

described?

1 Yes Acknowledged

3 Yes Acknowledged

4 Yes Acknowledged

5 Yes Acknowledged

7 Yes Acknowledged

8 Yes Acknowledged

Is there any 

indication of 

bias in our 

synthesis of 

the 

evidence?

1 No Acknowledged

3 No Acknowledged

4 No Acknowledged

5 No Acknowledged

7 No Acknowledged

8 No Acknowledged

Are there 

any 

published or 

unpublished

studies that 

we may 

have 

overlooked?

1 No Acknowledged

3 No Acknowledged

4 Yes - It is difficult to know whether studies were 

overlooked, give the way results are reported in broad 

categories, but the evidence reviewed does not appear to 

be comprehensive or include the most high impact/high 

quality reviews available. For example, only one review of 

medications for low back pain is discussed (on page 22, 

citation 193). Other reviews of medications for back pain 

are available and seemingly should be included, but I can't 

tell if they were because the number of reviews of 

medications is presented for all chronic pain conditions 

combined. For LBP injections, 2 reviews from low tier 

journals are highlighted, but the high quality American Pain 

Society sponsored reviews of interventional therapies by 

Roger Chou et al (published in Journal of Pain in 2009) are 

not included.

We identified 3 Chou citations in the Journal of Pain during 

2009. These were examined and found not eligible. 

However, we identified another review from this author in 

Spine (2009), which has been included in the final report. 

We also conducted a supplemental search for studies that 

addressed eligible interventions for chronic knee pain due 

to osteoarthritis. Additional eligible reviews were identified 

and are included in the final report.

We think the relatively low number of eligible articles for 

chronic pain conditions is in part due to the interventions 

chosen for evaluation.
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

5 No Acknowledged

7 No Acknowledged

8 No Acknowledged

Additional 

suggestions 

or 

comments 

can be 

provided 

below. If 

applicable, 

please 

indicate the 

page and 

line 

numbers 

from the 

draft 

1 Methodology seems very sound - further examination of 

primary trials is valuable and a good plan.

Thank you.

3 Overall feedback: 

This review seeks to create “...an evidence map to aid 

prioritization and development of implementation projects 

and research initiatives” in order to address the emerging 

healthcare needs of women Veterans, which has the 

potential to be of great benefit to policy makers and 

researchers alike. Overall the manuscript flows 

exceedingly well and the authors present the information in 

a balanced, logical, thoughtful, and succinct manner. 

Particular strengths are the inclusiveness of the treatments 

types that were reviewed and the consistent organization 

and framing that facilitates readership from section to 

section. 

Overall this reviewer found that the manuscript may be 

enhanced by some minor adjustments or additions in the 

following specific areas: 

1. The title, “Women’s Health Evidence Map”, is rather 

broadly worded given that the paper focuses on three 

health conditions (depression, DM, and chronic pain). This 

reviewer recommends re-working the title or adding a 

subtitle that speaks to the content area covered in the 

report. A subtitle may be particularly suitable if subsequent 

papers may expand the health evidence map by reviewing 

additional health conditions. 

2. In various locations the studies contained within 

are referred to descriptively as “low grade”, “low quality”, 

“high quality”, “good quality” and so forth. There is a 

paragraph within the paper that indicates that a formal 

Thank you.

We agree that the title was incomplete. It has been revised 

to “Mapping the Evidence: Sex Effects in High-impact 

Conditions for Women Veterans—Depression, Diabetes, 

and Chronic Pain.”

We’ve standardized the descriptors and clarified when we 

are referring to a high-quality review (as defined by a 

Cochrane, ESP, or EPC review) versus a summary 

statement about the quality of the evidence made by the 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

assessment of methodological rigor is “beyond the scope 

of the project” (see Quality Assessment page 5) however 

subsequent use of these descriptors suggests at least 

informal evaluation of the papers. This reviewer suggests 

including a description (perhaps in the Quality Assessment 

section) that at least informally anchors these descriptors. 

In addition, would recommend standardizing the 

descriptors—eg, using low quality or low grade unless 

these two descriptors differ from one another.

3. The description of the iterative process and use of 

stakeholders to determine the health conditions chosen left 

this reviewer looking for additional information. For 

example, what was the composition of the stakeholder 

group? Why only three conditions versus some other 

number? Did the iterative process yield agreement/ranking 

that only suggested review of 3 health conditions with a 

fourth (or fifth, etc.,) not reaching a reasonable consensus 

or convergence of opinion? 

4. Diabetes Section: page 16 the follow sentence may be 

improved by revising “last” to “lastly”: “Last, all 3 reviews of 

DPP-4 inhibitors applied IPD meta-analyses to data from 

industry studies.137,142,143. “

5. Evidence Gaps for Sex Effects Subsection: The 

paragraph that starts “In response to underrepresentation 

of women and minorities...” while containing important 

information, seems out of place in a summary of the 

evidence gaps for sex effects and more suited to the 

subsequent section entitled “Achieving Adequate 

Representation of Women in Clinical Studies”. The 

paragraph on “evidence gaps” may be enhanced by further 

description of where sex effects lead to reasonably sound 

information (information of use clinically) or to highlight 

what guidance is lacking with regard to clinical care given 

the very limited information regarding sex effects.

review authors.

We’ve added additional detail to the methods to describe 

the stakeholders and the process for prioritizing the 

included conditions.

 

Edit made.

We have moved this paragraph to the recommended 

section.

We considered the suggestion to add recommendations 

for clinical care. First, our goal was more descriptive. We 

also did not conduct a quality assessment of the 

systematic reviews. Furthermore, the sex results were 

generally small and arrived at by poorly suited analytic 

techniques. Thus, we do not feel confident in making 

specific clinical treatment recommendations. However, in 

order to address the clinical implications of our results, we 

have identified promising areas that could, with further 

research, lead to sex-specific clinical recommendations. In 

addition, we offer some discussion of how these proposed 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

6. Achieving Adequate Representation of Women in 

Clinical Studies Subsection: It seems implicit in this 

paragraph that inclusion of women Veterans in research 

studies is somehow only available for women Veterans 

who are enrolled in VA care (i.e, the sentence on page 27 

reads: “Inclusion of women in VA research is particularly 

challenging because the enrollment of women Veterans in 

VHA, while growing, remains a relatively low proportion 

(6.5% in 2012).”. One could argue that adequate 

representation is also hampered by only enrolling women 

in VA care (into studies) rather that expanding recruitment 

to women Veterans more broadly. In addition, adequate 

representation of the needs of women Veterans more 

broadly is also affected by only studying only/primarily 

women enrolled in VA care. This portion of the paper may 

be improved by acknowledgement of these limitations and 

how these limitations may affect or influence the 

knowledge base.

7. Prioritizing Areas for Evaluation of Sex Effects 

Subsection: most of this paragraph appears to speak to 

the prior sub-section content, which is Achieving Adequate 

Representation of Women in Clinical Studies. This 

reviewer suggests relocating this information to the above 

section and adding additional text in the Prioritizing Areas 

for Evaluation of Sex Effects that that includes suggestions 

that speak to the three content areas (depression, 

diabetes, chronic pain) that were so thoroughly reviewed in 

earlier portions of the paper.

8. The paper would benefit from additional discussion 

points that address or highlight:

a. Key points for care based on what is known now—as 

limited as that may be (perhaps in the Discussion or even 

more suited for the Evidence Gaps subsection on page 26) 

areas of research would impact clinical care for women. 

We addressed this suggestion by broadening our 

discussion regarding barriers to recruitment, so that we 

noted (1) the small proportion of total veteran population 

who are women and (2) general barriers found for study 

participation by minorities and women. Thus, while we 

agree that expanding to women Veterans not enrolled in 

VA may increase the participant pool somewhat, we think 

this would ultimately not make a substantial difference. 

Additionally, recruiting these women poses significant 

complications for VA-based research, given that such 

projects often utilize VHA resources (eg, EHR). 

Thank you for this comment. We’ve revised and expanded 

this section to include examples specific to conditions 

evaluated in the report. 

We appreciate this suggestion but have intentionally 

avoided statements on clinical implications. The primary

goal was to describe the volume of studies and whether 

sex effects have been examined. Without a careful quality 

assessment, we are hesitant to suggest clinical actions 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

as a result of the health evidence map. Suggesting content 

along the lines of clinical implications.

b. Future directions/research gaps. This could be a 

separate section or become part of a slightly re-worked 

section that is currently titled: Prioritizing Areas for 

Evaluation of Sex Effects. The content of that “prioritizing 

areas” is broad and speaks to the pressing need for 

researchers to incorporate adequate methodology to 

address sex effect questions within their projects. The 

content I would recommend adding (here or elsewhere) 

are gaps within the content areas of depression, DM, and 

chronic pain that would provide recommendations for the 

scientific community on possible future directions.

based on the estimates of intervention effects that we 

report.

Thank you for this suggestion. We’ve added example of 

gaps and types of studies that could be conducted to 

address these gaps for the conditions reviewed. We’ve 

also discussed the potential clinical implications of results 

from these proposed studies.

4 In general, I found this evidence map to be difficult to 

follow and to review. I believe this is attributable primarily 

to the enormous scope of the review. Attempting to provide 

brief overviews of the evidence for all of the interventions 

in all three huge clinical areas has resulted in extremely 

superficial and potentially misleading summaries of 

evidence for the individual interventions and conditions. 

The overview approach also obscures and detracts from 

the findings on sex effects, which is the main focus and 

strength of the report. (For example, the evidence for 

medications in chronic LBP, see specific comment below.) 

I think these problems could be substantially addressed by 

focusing just on evidence (and lack thereof) regarding sex 

differences. 

Specific comments: 

1. The definition and merits of individual patient data (IPD) 

meta-analysis should be briefly described (and citations 

provided) in the methods section. Also, as IPD is an 

unfamiliar abbreviation, it should be included in the 

abbreviation list and spelled out in the table footnotes. 

Thank you for this comment. We agree that the scope is 

large and the key messages could be difficult to identify 

with the current report structure. Therefore, we’ve 

substantially reorganized the report to consolidate the 

findings on sex effects across the three conditions. We’ve 

moved the information on intervention effects in general to 

an Appendices (by condition), as these were not the 

primary focus of our evidence map. 

We’ve added a definition for IPD meta-analysis to Table 2 

(Definitions of statistical approaches) and added a brief 

rationale for the merits of this approach to the methods 

section. We’ve been careful to define this abbreviation 

when used in tables.
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

2. The choice to limit reviews to the past 5 years may 

create an unintended bias for lower quality reviews in fields 

with few large funded RCTs (such as chronic low back 

pain). If a definitive high quality review has been published 

and no new trials are available, subsequent reviews are 

unlikely to be higher quality. 

3. Brief presentation of review findings without any details 

or quality assessment is potentially misleading. In the pain 

section in particular, included reviews have limitations that 

are not acknowledged and some of the best quality 

reviews seem to be absent. 

4. Page 22, line 41-42: The two reviews were not of “joint 

injections.” One reviewed facet joint injections and the 

other reviewed epidural injections. Also, I believe the 

authors meant to say “reduction in pain” or “improvement 

in pain relief”, rather than “reduction in pain relief.” Without 

information about the quality of the reviews, the 

comparisons, the specific pain indication, or the time frame 

of the outcomes, the summary statement about 

improvement may be misleading. (In general, very short 

term improvement in pain is not considered clinically 

important in the setting of chronic pain.)

5. Page 22, lines 54-59: The description of this metaanalysis is confusing. It was an indirect (no direct 

comparisons) meta-analysis of 15 placebo-controlled trials 

that was sponsored by Eli Lilly with the purpose of 

comparing duloxetine to other analgesics. It included trials 

of several typical opioids (“narcotics” “scheduled opioids”), 

tramadol (“non-scheduled opioids”), duloxetine, paroxetine 

Limiting reviews to the past 5 years was based on the 

rationale that reviews older than this are often out of date. 

Although we agree this decision could lead to missing 

reviews on some interventions (eg, no recent published 

review), we disagree that it would introduce a bias toward 

selecting low-quality reviews. 

We agree that brief presentations of intervention effects 

without quality assessment could be misleading. We’ve 

addressed this in several ways. First, we reorganized the 

report to emphasize sex effects, where we offer more 

information on review author’s comments on the quality of 

the evidence, and provide discussion of the limits of 

certain analytic techniques (ie, meta-regression vs IPD 

meta-analyses). We have also added statements in the 

Methods and Results sections cautioning readers that the 

reviews have not been assessed for quality and thus 

estimates of effect may be wrong.

We had defined the term “joint injections” loosely and have 

now specified these injections as facet and epidural. We 

have made the edit to “reduction in pain.”

We agree that without information about quality, etc., 

summary statements may be misleading. Therefore, 

throughout the report, information on general (ie, non-sexspecific) effects of interventions has been moved to 

Appendices, partially due to several reviewers’ correct 

observation that it had not been collected as rigorously.

This information has been moved to an appendix and 

therefore gets less emphasis. We added the modifier that 

this was an industry-sponsored study. We did not add an 

extensive discussion of the strengths and weaknesses of 

the review, since we did not quality-rate the studies or 

include this type of discussion for other reviews.
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

(“SSRIs”), and etoricoxib (“NSAIDS”). For a variety of 

reasons (controversial methods, differences in trial designs 

between drugs), their findings require additional discussion 

and context. Also, this should not be the only systematic 

review of medications for LBP.

5 page 7: I had some trouble following the literature flow 

chart (Figure 1). I wonder if it would be better to break 

down the figure into 3 smaller figures for depression, 

diabetes and chronic pain.

Page 10: did any of the depression studies report on 

menopausal status?

page 25: the second paragraph notes the percentage of 

studies evaluating sex as a moderator (19%; 9%; 5%). I 

think this information should be added to the abstract.

We considered this suggestion but decided a single figure 

was preferable. However, we revised the figure for clarity.

This is an interesting question but we did not abstract data 

on menopausal status.

We have added this information to the Abstract.

7 Thank you for this very thorough review. I can only say that 

I am disappointed in the findings (that very few studies 

addressed gender differences) not in the quality of the 

report which was very complete.

They only thing I might have considered is including a 

longer time frame since the last 5 years seemed very 

short, especially for pain and depression related findings.

We agree it is disappointing that so few studies address 

sex effects. Limiting the review to the past 5 years was 

based on the rationale that reviews older than this are 

often out of date. At this time, we are not able to extend 

the timeframe for included systematic reviews. 

8 This report is very clearly written and laid out and tackles 

an important issue within and outside the VA, which is the 

extent to which sex/gender differences are examined 

systematically as well as the potential for the larger nonVA literature to help identify opportunities for leveraging 

national investments in research for use in improving 

women Veterans' care in the VA health care setting. The 

review also focuses on top priority conditions of high 

prevalence and quality of life impact for men and women, 

offering opportunities to consider differences and potential 

disparities in a broad way even though this is focused and 

Thank you for these comments. 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

framed as a Women's Health Evidence Map. Given 

women's numerical minority in VA, this framing is 

appropriate.

The writing and methods are clear and easy to read and 

follow. The material provided is solid and usefully 

displayed. Modest issues arise in use of abbreviations 

throughout the tables and figures, which warrant attention. 

For example, Figures 4 and 5 on pages 14 and 15 have 

"psyched" as an abbreviation and while this is likely for 

psychoeducation, the "psyched" abbreviation has other 

meanings in our vernacular so some other abbreviation 

without alternative interpretation would be helpful. 

The Discussion (and thus Abstract in part) would benefit 

from clearer presentation of the main takeaway messages. 

Emphasis appears, perhaps unintentionally, to be on 

studies often showing greater benefit in women. However, 

the first takeaway point would seem to take precedence, 

ie, that a remarkably small fraction of the investment in 

these trials has been on examining sex/gender differences. 

The policy implications, however, of readers focusing on 

the positive findings in that small fraction that examined 

these issues are potentially very significant and may suffer 

from publication bias and other issues. In other words, the 

efforts to require inclusion of women in trial enrollment, 

analysis and reporting has been underway for decades, 

with substantial evidence that women's response to 

pharmaceutical agents, for example, can be meaningfully 

clinically different than men's. So your primary takeaway 

message appears to be that this emphasis has failed 

despite regulatory requirements. Very little time is spent on 

this failure in the Discussion so the findings lack 

contextualization. Instead, much more time is spent on the 

summary of sex effects in the very small fraction of studies 

that bothered to report on sex/gender differences, and 

given publication biases toward positive results, we lack 

adequate knowledge of what might have been found in the 

We were able to spell out terms within the figures, and 

included abbreviation callouts where needed.

We’ve revised the discussion to address the issues you 

raise. These changes include moving the summary of sex 

effects to the results section, moving the table of gaps in 

evidence to an earlier section of the discussion, and giving 

more emphasis in the text to the general paucity of studies 

evaluating sex-specific effects. 
Mapping the Evidence: Sex Effects in High-Impact Evidence-based Synthesis Program

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Question 

Text

Reviewer 

Number Comment Response

large majority that failed to examine these issues. The 

findings that were gleaned from the review are 

nonetheless of value, but they are not the whole story --

the concern is that they will become the whole story for 

those looking to avoid the methodological investment of 

time and resources needed to more definitively 

characterize intervention effects by subgroup. 

Page 27: Very little information is included with respect to 

what VA has done to increase inclusion of women 

Veterans in VA research through the Women's Health 

Research Network, which includes consortium 

development (ie, training of VA investigators on issues 

around women Veterans' health and health care; training 

in oversampling techniques and subgroup analysis 

approaches) and development of a national practice based 

research network that facilitates inclusion of women by 

developing local VA facility capacity to identify, recruit and 

retain women in VA research. This network is probably 

worth mentioning/citing, as it is also now responsible for 

increasing inclusion on women in the VA Cooperative 

Studies Program. Suggest you consider the following 

references to support building up this particular and brief 

paragraph:

Frayne SM, Carney DV, Bastian L, Bean-Mayberry B, 

Sadler AN, Klap R, Phibbs CS, Kimerling R, Vogt D, Yee 

E, Lin J, Yano EM. The VA women’s health practice-based 

research network: Amplifying women veterans’ voices in 

VA research. J Gen Intern Med. 2013;28(Suppl 2):S504-

S509. 

Bielawski MP, Goldstein K, Mattocks KM, Bean-Mayberry 

B, Yano EM, Bastian LA. Improving care of chronic 

conditions for women veterans: What we have learned 

from comparative effectiveness research. J Comparative 

Effectiveness, 2014 Mar;3(2):155-166. 

Thank you for your comment and suggestions. We have 

expanded our discussion of VA initiatives to encourage 

research on women’s health topics and improve inclusion 

of women Veterans in VA research.
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Question 

Text

Reviewer 

Number Comment Response

Yano EM. A partnered research initiative to accelerate 

implementation of comprehensive care for women 

Veterans: The VA Women’s Health CREATE. Med Care. 

2015 Apr;53(4 Suppl 1):S10-14. 

I think this report is going to have substantial impacts 

within and outside the VA both for advancing the tenets of 

equitable benefits of our research investment by gender 

and for informing ongoing opportunities for reducing 

gender disparities and also for targeting scarce resources 

more efficiently when differences do not indeed exist.
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APPENDIX E. OVERALL EFFECTS OF SELECTED 

INTERVENTIONS: DEPRESSION

The information provided in this appendix reflects what was reported by the authors of the 

original, primary publication. We have not separately assessed the article for quality or accuracy.

Effects by Diagnostic Group for Depressive Disorders

Major depressive disorder or depressive disorder. Antidepressants were evaluated using IPD 

meta-analysis,42-50 multiple treatment comparison meta-analysis,34,203 conventional metaanalysis,56,58,204-207 qualitatively,57 and using mixed approaches.208 A review of 165 

antidepressant trials in patients with major depressive disorder found clinical response rates of 

54.3% for antidepressants and 37.9% for placebo.204 The most comprehensive comparative 

effectiveness review (n=234 studies) used a multiple treatment comparison analysis to compare 

different antidepressants.34 This study, conducted by an EPC, found that antidepressants were 

effective and that there were no clinically important differences in efficacy or effectiveness 

between antidepressants for acute- or continuation-phase treatment. Subgroup analyses did not 

show differences in treatment effects by age, sex, ethnicity, or comorbid condition. 

Five reviews evaluated antidepressants for late-life depression.34,44,45,56,208 Results were 

inconsistent with some reviews finding antidepressants less effective for older adults (>65 years 

of age) than for younger adults.44,208 Other reviews found no moderating effect of older age.34

Antidepressants were associated with decreased suicidal risk in older (≥65 years of age) and 

younger adults.45 

Psychotherapy for depressive disorders was examined in 35 reviews.32,33,35-38,52-54,60,209-233

Reviews evaluating multiple therapies (n=92-132 included trials) found psychotherapy compared 

with inactive control more effective for reducing depressive symptoms (n=117; SMD 0.67, CI 

0.60 to 0.75), and psychotherapy increased the proportion of patients with a clinical response or 

clinical remission.60,211 Therapies examined included cognitive behavioral therapy (CBT), 

problem-solving therapy (PST), short-term psychodynamic therapy, interpersonal therapy, 

behavioral activation, and nondirective counseling. However, when accounting for publication 

bias (SMD 0.42) or when restricting analyses to the highest quality studies (Cohen’s d 0.22), 

effects were diminished.33,210 Effects did not differ significantly for different types of 

psychotherapy. Therapy was more effective than control for improving hopelessness but not 

suicidality.210 For major depressive disorder and subsyndromal depression, psychotherapy did 

not differ from antidepressant medication but was less effective than antidepressants in patients 

with dysthymia.37,215,228 Four reviews evaluated psychotherapy in older adults, finding the 

strongest evidence of efficacy for CBT (n=14; Hedges’ g -0.57, CI -0.80 to -0.34).216,223,224,227

Reviews concluded that CBT is effective in individual and group formats.224,226 Four reviews 

evaluated computerized therapy (predominately based on CBT) compared with inactive control 

or treatment as usual for patients with depressive disorders.230-233 Consistent with the other 

reviews, the largest identified 19 RCTs and found computerized therapy effective for depressive 

disorders (n=19; Cohen’s d -0.56, CI -0.71 to -0.41).232 An ESP review found that 6 to 8 sessions 

of CBT or PST improved depressive symptoms more than control (n=7; SMD -0.42, CI -0.74 

to -0.10) for patients recruited from primary care settings.36 Cochrane reviews concluded that 
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low-quality evidence suggested that third-wave therapy (eg, behavioral activation, acceptance 

and commitment therapy) may be effective and similar to other psychotherapies.32,35 

Seven reviews evaluated a combination of antidepressants plus psychotherapy compared with 

one of these treatments alone for acute-phase treatment of depressive disorders.55,234-239 The 

largest review found greater reduction in depressive symptoms for combined treatment than for 

antidepressants alone (n=23; Hedges’ g 0.43, CI 0.29 to 0.57).237 Another review found a small 

benefit from combined treatment compared with psychotherapy plus placebo pill (n=16; Cohen’s 

d 0.25, CI 0.03 to 0.46).235 

Seven reviews evaluated aerobic exercise compared with other physical activity, antidepressants, 

or treatment as usual.240-246 Exercise was more effective than control with effect sizes ranging 

from small to moderate. 243-246 Aerobic exercise was not more effective than other physical 

activity (n=8; SMD 0.01, CI -0.23 to 0.24) or antidepressants. 240 However, aerobic exercise 

improved depressive symptoms when used to augment treatment as usual (n=4; SMD -0.44, CI -

0.79 to -0.09).240,241 A single review of yoga242 found evidence that yoga was more effective than 

usual care. These reviews did not examine sex effects. 

A single IPD meta-analysis evaluated low-intensity self-help interventions for depressive 

disorders or mixed depression and anxiety.41 Self-help interventions were more effective than 

treatment as usual for reducing depressive symptoms (n=16 comparisons; SMD -0.42, CI -0.55 

to -0.29). An analysis of potential moderators of intervention effects suggested that intervention 

effects did not vary by sex but were greater as baseline severity increased.

Three reviews evaluated quality improvement interventions that were predominately a form of 

collaborative care.40,59,247 The largest review247 identified 40 trials, finding moderate benefit on 

depressive symptoms for collaborative care compared with treatment as usual or other enhanced 

care (Cohen’s d 0.31, CI 0.16 to 0.47). 

Dysthymia/persistent depressive disorder. Six reviews evaluated interventions for 

dysthymia.51,55,204,248-250 A multiple treatment comparison meta-analysis found antidepressants 

more effective than placebo (n=45; OR for response 2.35 to 6.98 for various antidepressants).249

A conventional meta-analysis also found antidepressants more effective than placebo (n=9; RR 

for response 1.75, CI 1.49 to 2.04).204 There were no differences in treatment response between 

SSRIs and tricyclic antidepressants, but dropouts were fewer with SSRIs (n=7, RR=0.41; CI 

0.19, 0.86).250 Psychotherapy was more effective than control for reducing depressive symptoms 

(n=8; Cohen’s d 0.23, CI 0.06 to 0.41) but less effective than antidepressants (n=10, Cohen’s d 

-0.31, CI -0.53 to -0.09).55,248 In one review, interpersonal psychotherapy plus antidepressants 

was more effective than antidepressants alone (OR 1.83),249 but in another review, combined 

treatment was not more effective than antidepressants alone for patients with chronic major 

depressive disorder, dysthymia, double depression, or recurrent depression (n=8; RR for 

response 1.20, CI 0.98 to 1.48).51 No other interventions were evaluated. 

Subyndromal/minor depressive disorder. Two reviews evaluated psychotherapy in older 

adults with subsyndromal depression.251,252 In the larger review,252 psychotherapy, including 

CBT, PST, and behavioral activation, was more effective than wait-list, placebo pill, or treatment 

as usual controls (n=5; 701 patients; no effect estimate). A single review253 identified 8 trials 

evaluating antidepressants for subsyndromal depression or mild major depressive disorder. 

Antidepressants showed small improvements for depressive symptoms compared with placebo 
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(n=2; MD Hamilton Depression Rating Scale -1.39, CI -2.41 to -0.36). None of these reviews 

evaluated sex effects, and no other interventions were evaluated.

Treatment-resistant depression. Three reviews evaluated interventions for treatment-resistant 

depression and found the evidence sparse.39,254,255 Mindfulness-based cognitive therapy plus 

treatment as usual was more effective than treatment as usual in 2 trials (MD on Beck 

Depression Inventory -10.28, CI -17.18 to -3.38).254 Compared with active management, an ESP 

review identified 2 good-quality trials that showed similar benefit from augmenting 

antidepressant treatment with other antidepressants or psychotherapy, or switching 

antidepressants.39 None of these reviews evaluated sex effects, and no other interventions were 

evaluated.

Relapse prevention. Seven reviews evaluated interventions for treatment-resistant 

depression.34,214,254,256-259 Psychotherapy alone or in combination with an antidepressant 

decreased the risk of relapse (n=8; RR=0.79, CI 0.66 to 0.96).258 Specific therapies that were 

found effective were group or individual CBT,256,258 interpersonal therapy,214 and mindfulnessbased cognitive therapy.254,258,259 Antidepressants (primarily SSRIs and SNRIs) were effective in 

preventing relapse (n=54; OR for relapse 0.35, CI 0.32 to 0.39) in patients who had responded to 

an antidepressant.257 An EPC-conducted multiple treatment comparison meta-analysis found no 

clinically important differences in efficacy between different antidepressant medications.34 None 

of these reviews evaluated sex effects, and no other interventions were evaluated.
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APPENDIX F. OVERALL EFFECTS OF SELECTED 

INTERVENTIONS: TYPE 2 DIABETES

The information provided in this appendix reflects what was reported by the authors of the 

original, primary publication. We have not separately assessed the article for quality or accuracy. 

Effects by Interventions for Diabetes

Medications. Of 120 eligible reviews on medications, we performed full data extraction on 75, 

prioritizing those that evaluated multiple drug classes or addressed less frequently examined 

categories (eg, meglitinides), among other criteria (see Methods). Glycemic control (n=38; 

reviews) and weight (n=25) were the most frequently included outcomes. Cardiovascular events 

(n=12) and mortality (n=16) were evaluated less often. Among adverse events, hypoglycemia 

was the most frequently discussed (n=29). The largest review, originating from an organization 

known for high-quality reviews, focused on risk for lactic acidosis associated with metformin 

therapy and included 347 studies.78 This study evaluated 70,490 patient-years of metformin use 

compared with 55,451 patient-years among nonusers, with 39% of women among both users and 

nonusers, and found no reported cases of lactic acidosis. The upper bound for the true incidence 

was estimated to be 4.3 cases per 100,000 patient-years among metformin users compared with 

5.4 cases for nonusers.78 

The next largest review included 277 RCTs, with 46% women overall, and examined 

effectiveness (dichotomously defined as reaching hemoglobin A1c target or not) and risk for 

adverse events for multiple drug classes compared with metformin.260 This review used network 

meta-analysis, conducting 173 direct and 180 indirect comparisons. Most drug classes were 

found to improve the likelihood of achieving glycemic targets when added to existing metformin 

therapy, ranging from the lowest benefit for rosiglitazone (OR 1.2, CI 1.1 to 1.3) to the highest 

for glucagon-like peptide 1 agonists (OR 11.1, CI 3.4 to 35.9). Sulfonylureas (OR 3.95, CI 1.82 

to 8.55), -glycosidase inhibitors (OR 3.24, CI 1.69 to 6.24), and meglitinides (OR 3.25, CI 1.83 

to 5.75) were all associated with increased risk for hypoglycemia when added to metformin.260

Bariatric surgery. Of 12 reviews on bariatric surgery, only 3 were restricted to RCTs.261-263

Weight loss and diabetes remission were evaluated by nearly all reviews. The 3 largest and most 

recent reviews included 39 studies,100 35 studies,264 and 33 studies.265 One of these reviews 

examined multiple surgical procedures and reported sex effects on diabetes remission (key 

results reported above).100 The other reviews evaluated gastric banding versus multiple 

comparators,264 and gastric bypass versus sleeve gastrectomy.265 Gastric banding was associated 

with average 47% excess weight loss over 2 years.264 There were no differences in rates of 

diabetes remission (67% and 81% at 3 and 36 months for gastric bypass, compared with 56% 

and 80% for sleeve gastrectomy) or in excess weight loss between the 2 procedures.265 

Psychoeducation and mixed behavioral interventions. Six reviews investigated the effect of 

psychoeducation and/or mixed behavioral interventions on glycemic control (n=6 reviews) 

and/or weight (n=3 reviews). Included studies ranged from 13 to 33, and 4 reviews were 

restricted to RCTs.79,83,106,266 Three reviews reported proportion of women included in primary 

studies (range 45% to 70%),102,266,267 and one specifically evaluated treatment effects in minority 

women.102
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Four reviews evaluated mixed interventions consisting of psychoeducation and exercise with or 

without dietary advice.79,83,102,106 The other 2 mixed interventions included mobile phone 

applications267 and internet-based self-management strategies.266 The largest review (n=33 

studies) was conducted by the Cochrane collaboration, and examined culturally appropriate 

health education and exercise in ethnic minority groups in middle- and upper-income countries.83 

There was high-quality evidence to support that these interventions reduced HbA1c at 6 months 

(n=14; MD -0.53%, CI -0.72% to -0.35%), with some sustained effect at 12 months (-0.2%) and 

24 months (-0.3%). There were no statistically significant effects on body mass index. Subgroup 

analyses were not performed. Another review, based on a 2011 AHRQ report, inspected the 

progression of diabetes-related complications and found significantly decreased risks of 

peripheral neuropathy, nonfatal myocardial infarction, and death with lifestyle interventions at 

13.3 years of follow-up.79 There were no significant differences in risk for retinopathy or 

nephropathy between the intervention and control groups. 

One review of internet-based self-management provided qualitative results showing that 

psychoeducation and behavioral techniques via mobile phone applications were associated with 

improved HbA1c (n=10; WMD -0.81, CI -1.11% to -0.50%).267 

Supervised exercise. Of 14 reviews on supervised exercise, 10 were restricted to RCTs, and the 

number of included studies ranged from 2 to 34. Six systematic reviews reported proportions of 

women in primary studies (median 53%, range 3% to 88% female), but none reported sex 

effects. Nearly all reviews (n=13) reported results for glycemic control, while 4 reported on 

weight loss,74,268-270 and 6 reported other outcomes.74,269,271-274 None reported adverse events. 

Five reviews compared the effects of aerobic exercise, resistance exercise, and combinations of 

the 2 on HbA1c.268,269,275-277 The largest and most recent review restricted to RCTs included 26 

primary studies with a minimum intervention duration of 12 weeks.276 This review found that all 

forms of exercise reduced HbA1c (aerobic MD -0.70%, CI -1.02% to -0.38%; resistance 

MD -0.62%, CI -1.14% to -0.11%; combined MD -0.47%, CI -0.64% to -0.31%) and that 

exercise volume (ie, frequency and duration) is a main determinant of the effect on glycemic 

control. However, a slightly older review that included 34 RCTs with a minimum treatment 

duration of 8 weeks reported that combined aerobic and resistance exercise improved glycemic 

control more than aerobic exercise alone (MD -0.67%, CI -0.93% to -0.40%; MD -0.60%, 

CI -0.98% to -0.27%, respectively).268

Five reviews investigated only resistance exercise271,274,278 or aerobic exercise alone.270,273 All 

reported improved HbA1c for intervention groups compared with control. Four reviews 

examined other specific types of exercise. Of these, 3 reviews examined tai chi,272,279,280 and one 

investigated yoga74; none found a statistically significant effect on glycemic index, weight, or 

cardiovascular risk.

Dietary interventions. Four eligible reviews on dietary interventions were restricted to RCTs 

and reported on both HbA1c and weight/BMI.105,281-283 Adverse events were not reported, and 

none reported gender distribution or sex effects. None originated from an organization known for 

high-quality systematic reviews. The number of trials ranged from 8 to 20. 

The largest review (n=20 studies)105 examined 6-month outcomes after various dietary 

interventions (ie, high fiber, high protein, low carbohydrate, low glycemic index, Mediterranean, 
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vegan, or vegetarian) compared with one of multiple control diets (ie, ADA, high glycemic 

index, low fat, or low protein). This review concluded that the Mediterranean diet was the most 

effective at decreasing HbA1c (n=3; MD -0.41%, CI -0.58% to -0.24%) while low-carbohydrate 

(n=7; MD -0.12%), low glycemic index (n=3; MD -0.14%), and high protein (n=2; MD -0.28%) 

were all more effective than diets with higher carbohydrate content. Both the Mediterranean and 

low carbohydrate diets produced weight loss (MD -1.84 and -0.69 kg, respectively), but the 

difference was statistically significant only for the Mediterranean diet. 

Quality improvement. Three reviews evaluated different quality improvement strategies. None 

provided the gender distribution of included studies and none reported sex effects. The largest 

review (n=52 studies) examined the effect of care management on glycemic control.75 

Statistically significant reductions in HbA1c were found (WMD -0.22%, CI -0.40% to -0.04%), 

but given high heterogeneity, the authors suggested these results were unlikely to be important. 

The second eligible review included 26 studies, which investigated 9 quality improvement 

strategies applied to rural settings.284 Quality improvement was more effective than control for 

reducing HbA1c (MD -0.41%, CI -0.75% to -0.07%), and subgroup analyses showed that using 

multiple strategies and a community setting for interventions were more effective compared with 

fewer strategies or a clinical setting, respectively. The third review (n=20 studies) was restricted 

to RCTs that evaluated computerized decision support systems (CDSS) in primary care.73 This 

qualitative synthesis reported that CDSS alone or with reminders improved process of care but 

did not affect health outcomes, whereas when CDSS was combined with feedback on selfmanagement performance or case management, HbA1c improved. 
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APPENDIX G. OVERALL EFFECTS OF SELECTED 

INTERVENTIONS: CHRONIC PAIN 

The information provided in this appendix reflects what was reported by the authors of the 

original, primary publication. We have not separately assessed the article for quality or accuracy. 

Effects by Chronic Pain Condition

Chronic low back pain. Twelve reviews evaluated exercise for CLBP.127,128,130,131,133,285-291 One 

additional review compared acupuncture, spinal manipulation, and exercise.292 Exercise 

interventions included yoga and Pilates (n=6 studies),127,128,131,133,290,291 core stability, aerobic or 

general exercise,

130,286 mixed programs,285,287-289 and nonspecific programs.292 The largest review 

(n=40) found that all types of exercise compared with minimal care improved pain (MD -4.83 

[100-point scale], CI -9.36 to -0.30) and disability (MD -6.41, CI -9.76 to -3.05). The number of 

exercise sessions was significantly associated with increasing effect sizes on pain, suggesting 

that for each additional session, the effect size would increase by 0.13 (CI 0.02 to 0.24).288

Another review of similar size (n=39 studies) found that strength/resistance (n=11; ES: -0.50, CI 

-0.77 to -0.24) as well as coordination/stabilization-focused exercise programs are effective in 

reducing pain (n=12, ES -0.47, CI -0.77 to -0.18).285 Four reviews found moderate evidence of 

yoga or Pilates reducing pain over short-term, but not long-term, follow-up (largest review n=4; 

SMD -0.61, CI -0.97 to 0.26),127,128,131,133 while 2 reviews found no significant effect on pain or 

functionality (n=4) when comparing Pilates with no treatment or lumbar stabilization.

290,291

Adverse events were rarely reported for exercise interventions.

Five reviews

129,293-296 and one IPD meta-analysis168 evaluated either acupuncture or chiropractic 

manipulation compared with usual care, no treatment, or sham intervention. One additional 

review compared acupuncture, spinal manipulation, and exercise.

292 The largest review of 

acupuncture (n=32 studies) reported significant reductions in self-reported pain (n=3-4; 

SMD -16.76 to -0.72; CI -33.33 to -0.19) and overall function (n=3-4; SMD -0.94 to -0.36; 

CI -1.61 to -0.04).129 However, significant, unexplained variation in treatment effects limit these 

findings. Another review found acupuncture to be more effective in reducing pain compared with

sham acupuncture (n=5; SMD 0.20; CI 0.09 to 0.32) or no intervention (n=5; SMD 0.49; CI 0.33 

to 0.64).168 The most recent large review of chiropractic manipulation (n=26 studies) reported 

significant but not clinically relevant effects on short-term pain relief (SMD -4.16; CI -6.97 

to -1.36) and functional status (SMD -0.22; CI -0.36 to -0.07).294 Manual therapy was no more 

effective than sham intervention or exercise.

293

Two reviews evaluated injections (one on facet joint and the other on epidural), and using 

qualitative synthesis, found fair evidence for reduction in pain.297,298 Complications were rare.

One additional large qualitative review examined multiple nonsurgical interventional therapies 

for low back pain, finding that epidural steroid injections were moderately effective for shortterm but not long-term symptom relief. There was insufficient evidence for other interventional 

therapies for chronic low back pain, including facet joint injection and intradiscal steroid 

injection.

299 Sex effects were not examined in any review.

One Cochrane review evaluated 30 trials of behavioral therapy compared with waitlist or usual 

care controls for CLBP.173 Operant behavior therapy was more effective than waitlist control 

(n=3; SMD -0.43, CI -0.75 to -0.11), and behavioral treatment was more effective than usual care 
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for short-term pain relief (n=2; MD -5.18, CI -9.79 to -0.57). This review did not examine sex 

effects. Another review300 that evaluated many types of interventions (n=70) examined 21 

behavioral studies and agreed with the conclusions of the Cochrane review. One review tested 

neurophysiological education only, but did not find clinically significant changes.301 

One industry-sponsored review of medications, using indirect meta-analysis, evaluated serotonin 

norepinephrine reuptake inhibitors (SNRIs) and SSRIs compared with NSAIDs, tramadol, and 

narcotics and found that, compared with placebo, scheduled opioids were most effective in 

reducing pain (n=8; SMD -0.39, CI -0.47 to -0.31), followed by nonscheduled opioids, Cox II 

inhibitors, and duloxetine.126 

One review of QI interventions evaluated pain rehabilitation programs compared with

controls.132 This review identified 18 trials, finding a moderate effect of pain rehabilitation 

programs on improving disability (beta=0.429, SE=0.160, p=0.0009) and quality of life 

(beta=0.417, SE=0.033, p<.001). 

Fibromyalgia. Of the 34 reviews of FM interventions, 11 were conducted by an organization 

known for high-quality reviews.134-137,141,144,147,150,153,161,302 Fourteen examined medication 

treatment for FM: 7 for antidepressants134-140 5 for anticonvulsant agents,137,141-144 and 2 for both 

classes of drugs.145,146 Of the reviews of different antidepressant drug classes, one examined a 

tricyclic agent,135 and 3 focused on SNRIs.

134,136,137 A review that included 7 studies focusing 

specifically on FM found that amitriptyline reduced pain more than placebo with an RR of 2.9 

(CI 1.7 to 4.9) based on 4 studies with second-tier data.135 Another review that included 10 

studies focused on FM found that SNRIs, specifically duloxetine and milnacipran, had small 

beneficial effects on both pain with a SMD -0.23 (95% CI -0.29 to -0.18), and quality of life with 

a SMD of -0.20 (95% CI of -0.25 to -0.14).134 For this review of SNRIs, the intended subgroup 

sex effects analyses for outcome of pain were not conducted due to lack of available individual 

patient-level data. This same review noted no difference between placebo and SNRI with respect 

to serious adverse effects, though more patients withdrew for adverse events in the SNRIs arms 

than in the placebo arm with an RR of 1.83 (CI 1.53 to 2.18). Additional reviews that focused 

solely on milnacipran,137 duloxetine,136 or a mixture of SNRIs, milnacipran, SSRIs, and tricyclic 

antidepressants supported the above findings related to pain relief.

The anticonvulsant agents gabapentin and pregabalin were found to improve pain in 5 

reviews.

141-144,302 In one trial of 150 patients included in the most recent of these reviews,302

gabapentin was noted to decrease pain more than 30% from baseline at 2400mg daily versus 

placebo with an RR of 1.6 (CI 1.07 to 2.42). Similarly, pregabalin reduced fibromyalgia pain 

50% compared with placebo (RR 1.59, CI 1.33 to 1.90) based on high-quality evidence from 5 

studies including 3256 patients,141 and an RR of 1.5 to 1.7 in a second review at doses 300mg to 

600mg per day.142 A dose-response relationship with pregabalin was also noted for both pain 

control and adverse events,

142,143 which were most frequently dizziness and somnolence.142,302

Serious adverse events were not higher with anticonvulsant treatment. 

We identified 6 reviews with meta-analyses that included trials of various forms of exercise as 

treatment for pain associated with FM.147-152 Four of 5 types of exercise were found to decrease 

pain when compared with placebo, but it is less clear if any types of exercise are superior 

compared with other forms of exercise. Specifically, low- to moderate-quality evidence from 7 

studies suggests that supervised aquatic exercise training causes moderate decreases in pain with 
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an MD of -6.59 (CI -10.71 to -2.48) on a 100-point scale; but this review did not find a 

significant improvement in pain compared with land-based exercise.

147 Another review152 also 

found improvement with aquatic therapy, especially if the duration was at least 20 weeks. 

Aerobic exercise was also found to lead to significant reductions in pain with an SMD of -0.31 

(CI -0.46 to -0.17).148 In a multiple treatment comparison analysis, low-quality evidence suggests 

that moderate to high-intensity resistance exercise training reduces pain in FM.150 Adverse 

effects related to aerobic exercise were infrequent.

148 

Results for meditative movement therapies (MMT) such as yoga, tai chi, and qigong were 

conflicting. One review evaluating 7 studies found that these therapies did not reduce pain but 

may improve health-related quality of life.

149 Another review found a medium-to-high effect size 

for MMT based on weak data.151 In both reviews, MMT was found to be safe with a low rate of 

dropout due to adverse events in one review149 and no serious adverse events in the second.151

Six reviews examined different types of behavioral interventions.

153-158 One review of 21 studies 

conducted in adults with FM found low-quality evidence that CBT compared with control 

produced an end-of-treatment benefit of 0.5 points on a scale from 0 to 10 with respect to pain 

(SMD -0.27, CI -0.47 to -0.07) and a benefit of 0.7 points for reducing disability (SMD -0.30, CI 

-0.51 to -0.08).153 Another review of 23 studies found that CBT produced a moderate positive 

effect on pain (n=8; Hedge’s g 0.60, CI +0.43 to +0.76). Psychological treatments other than 

CBT had a smaller effect size (n=18; Hedge’s g 0.27, CI +0.17 to +0.37)158 Mindfulness-based 

stress reduction also led to a small beneficial effect on FM-related pain155,156 and quality of 

life,

155 based on generally low-quality evidence. The same was true of electromyogram-based 

biofeedback, but not electroencephalogram-based biofeedback.

157 No specific information was 

noted about adverse events. 

Five reviews examined acupoint stimulation/acupuncture for FM159-163 and came to similar 

conclusions. These reviews included from 9 to 16 RCTs. Compared with sham acupuncture, 

acupuncture did not significantly reduce FM-related pain. Based on one RCT with 16 

participants, acupuncture did appear to be more effective than no treatment with an RR 

of -30.19% (CI -55.23% to -5.15%) and more effective as an adjunct to standard therapy based 

on one RCT with 58 patients with an RR of -37.50% (CI -48.75% to -26.25%).161 There was 

some low-quality evidence that acupuncture is more effective at reducing pain than 

medications.

159-161 Electro-acupuncture may be better than manual acupuncture at pain 

reduction.161 That review concluded there is insufficient information about adverse events to 

draw definitive conclusions; however, another review162 reported adverse effects from 8 of 25 

studies as bruising, nausea, fainting, discomfort with needles, and temporary edema of the hand. 

One trial reported that a patient had mild scalding on the skin after being included in a cupping 

group. One review examined 4 studies of chiropractic care for FM and concluded that there was 

no significant difference between intervention and control groups.164

Knee OA. We identified 8 reviews that examined intervention effects on pain due to knee 

OA.

165-172 One large review evaluating 54 trials found high-quality evidence that land-based 

therapeutic exercise significantly reduced pain compared with control (nonexercise or 

nontreatment) with an SMD -0.49 (CI -0.39 to -0.59).167 Eight studies included measurement of 

serious adverse events, and none were reported. Similar, a review of pre-operative interventions 

included 4 trials which found that exercise programs significantly decreased pain from knee OA 
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with a SMD -0.43 (CI -0.13 to 0.73).170 One review of 7 trials of proprioceptive-based exercise 

found no improvement in pain and a small improvement in function.303

One review of medications used a multiple treatment comparison meta-analysis to examine the 

effects of topical NSAIDs for pain in patients with chronic musculoskeletal pain.166 The review 

included 34 studies, 16 of which focused on knee OA. Topical NSAIDs were more effective than 

placebo (RR 1.29 for 50% pain reduction or equivalent measure; CI 1.21 to 1.38) but not more 

effective than oral NSAIDs for pain in the context of osteoarthritis (RR 1.02, CI 0.94 to 1.11). 

Topical NSAIDs led to fewer gastrointestinal side effects than oral NSAIDs but led to an 

increase in local adverse events (mostly skin-related). This review did not evaluate sex effects.

Three reviews examined injections for knee OA. One review165 examined the trajectory of intraarticular hyaluronic acid therapeutic effects on knee OA and found a beneficial effect on pain 

that peaked at 8 weeks post-injection (n=54; ES 0.46, CI 0.28 to 0.65), diminishing to a small 

effect at 24 weeks (ES 0.21, CI 0.10 to 0.31).One review 172 considered 4 RCTs and 2 studies 

that compared platelet-rich plasma (PRP) injections as compared with intra-articular normal 

saline or hyaluronic acid. Based on 4 studies, this review found that PRP led to greater 

improvements in the WOMAC, a composite score304 of pain, stiffness and function with an MD 

of -18.0 (-28.8 to -8.3). Of note, they report that there was an increase in nonspecific adverse 

events among those who received PRP versus control (8.4% vs 3.8%). A third review of 6 RCTs 

found no benefit of joint lavage on pain due to knee OA.169 None of these reviews evaluated sex 

effects.

One review using IPD meta-analysis of 31 studies examined acupuncture for chronic pain 

including 9 studies of knee OA.168 Acupuncture decreased pain of knee OA compared with both 

no acupuncture (SMD 0.57, CI 0.29 to 0.85) and sham acupuncture (SMD 0.37, CI 0.03 to 0.72). 

This review did not evaluate sex effects.
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APPENDIX H. SYSTEMATIC REVIEW REFERENCES BY 

CONDITION 

This appendix lists full citations for included systematic reviews in alphabetical order by 

condition. The asterisk beside a reference indicates the review reported sex effects.

Depressive Disorders (86) 

Andrews G, Cuijpers P, Craske MG, et al. Computer 

therapy for the anxiety and depressive disorders is 

effective, acceptable and practical health care: a 

meta-analysis. PLoS One 2010;5(10):e13196. PMID: 

20967242.

Baardseth TP, Goldberg SB, Pace BT, et al. 

Cognitive-behavioral therapy versus other therapies: 

redux. Clin Psychol Rev 2013;33(3):395-405. PMID: 

23416876.

*Bower P, Kontopantelis E, Sutton A, et al. Influence 

of initial severity of depression on effectiveness of 

low intensity interventions: meta-analysis of 

individual patient data. BMJ 2013;346:f540. PMID: 

23444423.

*Braun SR, Gregor B, Tran US. Comparing bona fide 

psychotherapies of depression in adults with two 

meta-analytical approaches. PLoS One 

2013;8(6):e68135. PMID: 23840824.

Bridle C, Spanjers K, Patel S, Atherton NM, Lamb 

SE. Effect of exercise on depression severity in older 

people: systematic review and meta-analysis of 

randomised controlled trials. Br J Psychiatry. 

2012;201(3):180-185. PMID: 22945926.

*Calati R, Salvina Signorelli M, Balestri M, et al. 

Antidepressants in elderly: metaregression of doubleblind, randomized clinical trials. J Affect Disord 

2013;147(1-3):1-8. PMID: 23245467.

Cameron IM, Reid IC, MacGillivray SA. Efficacy 

and tolerability of antidepressants for sub-threshold 

depression and for mild major depressive disorder. J 

Affect Disord 2014;166:48-58. PMID: 25012410.

Carpenter DJ, Fong R, Kraus JE, et al. Meta-analysis 

of efficacy and treatment-emergent suicidality in 

adults by psychiatric indication and age subgroup 

following initiation of paroxetine therapy: a complete 

set of randomized placebo-controlled trials. J Clin 

Psychiatry 2011;72(11):1503-14. PMID: 21367354.

*Carter GC, Cantrell RA, Victoria Z, et al. 

Comprehensive review of factors implicated in the 

heterogeneity of response in depression. Depress 

Anxiety 2012;29(4):340-54. PMID: 22511365.

Chiesa A, Serretti A. Mindfulness based cognitive 

therapy for psychiatric disorders: a systematic review 

and meta-analysis. Psychiatry Res 2011;187(3):441-

53. PMID: 20846726.

Churchill R, Moore TH, Furukawa TA, et al. "Third 

wave" cognitive and behavioural therapies versus

treatment as usual for depression. Cochrane Database 

Syst Rev 2013;10:Cd008705. PMID: 24142810.

Cramer H, Lauche R, Langhorst J, Dobos G. Yoga 

for depression: a systematic review and metaanalysis. Depress Anxiety. 2013;30(11):1068-1083. 

PMID: 23922209.

Cuijpers P, Andersson G, Donker T, et al. 

Psychological treatment of depression: results of a 

series of meta-analyses. Nord J Psychiatry 

2011;65(6):354-64. PMID: 21770842.

Cuijpers P, de Beurs DP, van Spijker BA, et al. The 

effects of psychotherapy for adult depression on 

suicidality and hopelessness: a systematic review and 

meta-analysis. J Affect Disord 2013;144(3):183-90. 

PMID: 22832172.

Cuijpers P, Dekker J, Hollon SD, et al. Adding 

psychotherapy to pharmacotherapy in the treatment 

of depressive disorders in adults: a meta-analysis 

(Structured abstract). J Clin Psychiatry. Vol. 70; 

2009:1219-1229.

Cuijpers P, Geraedts AS, van Oppen P, et al. 

Interpersonal psychotherapy for depression: a metaanalysis. Am J Psychiatry 2011;168(6):581-92. 

PMID: 21362740.

Cuijpers P, Karyotaki E, Weitz E, et al. The effects of 

psychotherapies for major depression in adults on 

remission, recovery and improvement: a metaanalysis. J Affect Disord 2014;159:118-26. PMID: 

24679399.

Cuijpers P, Koole SL, van Dijke A, et al. 

Psychotherapy for subclinical depression: metaanalysis. Br J Psychiatry 2014;205(4):268-274. 

PMID: 25274315.
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*Cuijpers P, Reynolds CF, 3rd, Donker T, et al. 

Personalized treatment of adult depression: 

medication, psychotherapy, or both? A systematic 

review. Depress Anxiety 2012;29(10):855-64. PMID: 

22815247.

Cuijpers P, Sijbrandij M, Koole SL, et al. The 

efficacy of psychotherapy and pharmacotherapy in 

treating depressive and anxiety disorders: a metaanalysis of direct comparisons. World Psychiatry 

2013;12(2):137-48. PMID: 23737423.

Cuijpers P, Sijbrandij M, Koole SL, et al. Adding 

psychotherapy to antidepressant medication in 

depression and anxiety disorders: a meta-analysis. 

World Psychiatry 2014;13(1):56-67. PMID: 

24497254.

Cuijpers P, Smit F, Bohlmeijer E, et al. Efficacy of 

cognitive-behavioural therapy and other 

psychological treatments for adult depression: metaanalytic study of publication bias. Br J Psychiatry 

2010;196(3):173-8. PMID: 20194536.

Cuijpers P, Turner EH, Mohr DC, et al. Comparison 

of psychotherapies for adult depression to pill 

placebo control groups: a meta-analysis. Psychol 

Med 2014;44(4):685-95. PMID: 23552610.

Cuijpers P, van Straten A, Bohlmeijer E, et al. The 

effects of psychotherapy for adult depression are 

overestimated: a meta-analysis of study quality and 

effect size. Psychol Med 2010;40(2):211-23. PMID: 

19490745.

Cuijpers P, van Straten A, Hollon SD, et al. The 

contribution of active medication to combined 

treatments of psychotherapy and pharmacotherapy 

for adult depression: a meta-analysis. Acta Psychiatr 

Scand 2010;121(6):415-23. PMID: 19922522.

Cuijpers P, van Straten A, Schuurmans J, et al. 

Psychotherapy for chronic major depression and 

dysthymia: a meta-analysis. Clin Psychol Rev 

2010;30(1):51-62. PMID: 19781837.

Danielsson L, Noras AM, Waern M, et al. Exercise in 

the treatment of major depression: a systematic 

review grading the quality of evidence. Physiother 

Theory Pract 2013;29(8):573-85. PMID: 23521569.

*Driessen E, Cuijpers P, de Maat SC, et al. The 

efficacy of short-term psychodynamic psychotherapy 

for depression: a meta-analysis. Clin Psychol Rev 

2010;30(1):25-36. PMID: 19766369.

*Driessen E, Cuijpers P, Hollon SD, et al. Does 

pretreatment severity moderate the efficacy of 

psychological treatment of adult outpatient 

depression? A meta-analysis. J Consult Clin Psychol 

2010;78(5):668-80. PMID: 20873902.

Feng CY, Chu H, Chen CH, et al. The effect of 

cognitive behavioral group therapy for depression: a 

meta-analysis 2000-2010. Worldviews Evid Based 

Nurs 2012;9(1):2-17. PMID: 22221447.

Fournier JC, DeRubeis RJ, Hollon SD, et al. 

Antidepressant drug effects and depression severity: 

a patient-level meta-analysis. JAMA 2010;303(1):47-

53. PMID: 20051569.

*Gartlehner G, Hansen RA, Morgan LC, et al. 

Comparative benefits and harms of secondgeneration antidepressants for treating major 

depressive disorder: an updated meta-analysis. Ann 

Intern Med 2011;155(11):772-85. PMID: 22147715.

Gibbons RD, Brown CH, Hur K, et al. Suicidal 

thoughts and behavior with antidepressant treatment: 

reanalysis of the randomized placebo-controlled 

studies of fluoxetine and venlafaxine. Arch Gen 

Psychiatry 2012;69(6):580-7. PMID: 22309973.

Gibbons RD, Hur K, Brown CH, et al. Benefits from 

antidepressants: synthesis of 6-week patient-level 

outcomes from double-blind placebo-controlled 

randomized trials of fluoxetine and venlafaxine. Arch 

Gen Psychiatry 2012;69(6):572-9. PMID: 22393205.

*Gibiino S, Marsano A, Serretti A. Specificity profile 

of venlafaxine and sertraline in major depression: 

metaregression of double-blind, randomized clinical 

trials (Provisional abstract). International Journal of 

Neuropsychopharmacology. Vol. 17; 2014:1-8.

Glue P, Donovan MR, Kolluri S, et al. Meta-analysis 

of relapse prevention antidepressant trials in 

depressive disorders. Aust N Z J Psychiatry 

2010;44(8):697-705. PMID: 20636190.

Gould RL, Coulson MC, Howard RJ. Cognitive 

behavioral therapy for depression in older people: a 

meta-analysis and meta-regression of randomized 

controlled trials. J Am Geriatr Soc 2012;60(10):1817-

30. PMID: 23003115.

Griffiths KM, Farrer L, Christensen H. The efficacy 

of internet interventions for depression and anxiety 

disorders: a review of randomised controlled trials. 

Med J Aust 2010;192(11 Suppl):S4-11. PMID: 

20528707.

Guidi J, Fava GA, Fava M, et al. Efficacy of the 

sequential integration of psychotherapy and 

pharmacotherapy in major depressive disorder: a 

preliminary meta-analysis. Psychol Med 

2011;41(2):321-31. PMID: 20444307.

Hofmann SG, Sawyer AT, Witt AA, et al. The effect 

of mindfulness-based therapy on anxiety and 

depression: A meta-analytic review. J Consult Clin 

Psychol 2010;78(2):169-83. PMID: 20350028.
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Hunot V, Moore TH, Caldwell DM, et al. "Third 

wave" cognitive and behavioural therapies versus 

other psychological therapies for depression. 

Cochrane Database Syst Rev 2013;10:Cd008704. 

PMID: 24142844.

Jakobsen JC, Hansen JL, Simonsen E, et al. The 

effect of interpersonal psychotherapy and other 

psychodynamic therapies versus 'treatment as usual' 

in patients with major depressive disorder. PLoS One 

2011;6(4):e19044. PMID: 21556370.

Jakobsen JC, Hansen JL, Simonsen E, et al. The 

effect of adding psychodynamic therapy to 

antidepressants in patients with major depressive 

disorder. A systematic review of randomized clinical 

trials with meta-analyses and trial sequential 

analyses. J Affect Disord 2012;137(1-3):4-14. PMID: 

21501877.

Jakobsen JC, Hansen JL, Simonsen S, et al. Effects of 

cognitive therapy versus interpersonal psychotherapy 

in patients with major depressive disorder: a 

systematic review of randomized clinical trials with 

meta-analyses and trial sequential analyses. Psychol 

Med 2012;42(7):1343-57. PMID: 22051174.

Jakobsen JC, Hansen JL, Storebo OJ, et al. The 

effects of cognitive therapy versus 'no intervention' 

for major depressive disorder. PLoS One 

2011;6(12):e28299. PMID: 22174786.

Jakobsen JC, Lindschou Hansen J, Storebo OJ, et al. 

The effects of cognitive therapy versus 'treatment as 

usual' in patients with major depressive disorder. 

PLoS One 2011;6(8):e22890. PMID: 21829664.

Josefsson T, Lindwall M, Archer T. Physical exercise 

intervention in depressive disorders: meta-analysis 

and systematic review. Scand J Med Sci Sports. 

2014;24(2):259-272. PMID: 23362828.

Kasper S, Corruble E, Hale A, et al. Antidepressant 

efficacy of agomelatine versus SSRI/SNRI: results 

from a pooled analysis of head-to-head studies 

without a placebo control. Int Clin Psychopharmacol 

2013;28(1):12-9. PMID: 23023074.

Kennedy SH, Andersen HF, Thase ME. Escitalopram 

in the treatment of major depressive disorder: a metaanalysis (Structured abstract). Current Medical 

Research and Opinion. Vol. 25; 2009:161-175.

Khoury B, Lecomte T, Fortin G, et al. Mindfulnessbased therapy: a comprehensive meta-analysis. Clin 

Psychol Rev 2013;33(6):763-71. PMID: 23796855.

Kiosses DN, Leon AC, Arean PA. Psychosocial 

interventions for late-life major depression: evidencebased treatments, predictors of treatment outcomes, 

and moderators of treatment effects. Psychiatr Clin 

North Am 2011;34(2):377-401, viii. PMID: 

21536164.

Krishna M, Honagodu A, Rajendra R, et al. A 

systematic review and meta-analysis of group 

psychotherapy for sub-clinical depression in older 

adults. Int J Geriatr Psychiatry 2013;28(9):881-8. 

PMID: 23147496.

Krishna M, Jauhari A, Lepping P, et al. Is group

psychotherapy effective in older adults with 

depression? A systematic review. Int J Geriatr 

Psychiatry 2011;26(4):331-40. PMID: 20973096.

Kriston L, von Wolff A, Westphal A, et al. Efficacy 

and acceptability of acute treatments for persistent 

depressive disorder: a network meta-analysis. 

Depress Anxiety 2014;31(8):621-30. PMID: 

24448972.

Krogh J, Nordentoft M, Sterne JA, Lawlor DA. The 

effect of exercise in clinically depressed adults: 

systematic review and meta-analysis of randomized 

controlled trials. J Clin Psychiatry. 2011;72(4):529-

538. PMID: 21034688.

Lee SY, Franchetti MK, Imanbayev A, et al. Nonpharmacological prevention of major depression 

among community-dwelling older adults: a 

systematic review of the efficacy of psychotherapy 

interventions. Arch Gerontol Geriatr 2012;55(3):522-

9. PMID: 22483200.

Levkovitz Y, Tedeschini E, Papakostas GI. Efficacy 

of antidepressants for dysthymia: a meta-analysis of 

placebo-controlled randomized trials. J Clin 

Psychiatry 2011;72(4):509-14. PMID: 21527126.

Lopes Rocha F, Fuzikawa C, Riera R, et al. 

Antidepressant combination for major depression in 

incomplete responders--a systematic review. J Affect 

Disord 2013;144(1-2):1-6. PMID: 22835845.

Lynch D, Laws KR, McKenna PJ. Cognitive 

behavioural therapy for major psychiatric disorder: 

does it really work? A meta-analytical review of 

well-controlled trials. Psychol Med 2010;40(1):9-24. 

PMID: 19476688.

Machado M, Einarson TR. Comparison of SSRIs and 

SNRIs in major depressive disorder: a meta-analysis 

of head-to-head randomized clinical trials (Structured 

abstract). Journal of Clinical Pharmacy and 

Therapeutics. Vol. 35; 2010:177-188.
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*Mancini M, Sheehan DV, Demyttenaere K, et al. 

Evaluation of the effect of duloxetine treatment on 

functioning as measured by the Sheehan disability 

scale: pooled analysis of data from six randomized, 

double-blind, placebo-controlled clinical studies. Int 

Clin Psychopharmacol 2012;27(6):298-309. PMID: 

22954893.

Mura G, Moro MF, Patten SB, Carta MG. Exercise as 

an add-on strategy for the treatment of major 

depressive disorder: a systematic review. CNS 

Spectr. 2014;19(6):496-508. PMID: 24589012.

Nieuwsma JA, Trivedi RB, McDuffie J, et al. Brief 

psychotherapy for depression: a systematic review 

and meta-analysis. Int J Psychiatry Med 

2012;43(2):129-51. PMID: 22849036.

Okumura Y, Ichikura K. Efficacy and acceptability of 

group cognitive behavioral therapy for depression: a 

systematic review and meta-analysis. J Affect Disord 

2014;164:155-64. PMID: 24856569.

Papakostas GI, Culpepper L, Fayyad RS, et al. 

Efficacy of desvenlafaxine 50 mg compared with 

placebo in patients with moderate or severe major 

depressive disorder: a pooled analysis of six 

randomized, double-blind, placebo-controlled studies 

(Provisional abstract). Database of Abstracts of 

Reviews of Effects; 2013:312-321.

Piet J, Hougaard E. The effect of mindfulness-based 

cognitive therapy for prevention of relapse in 

recurrent major depressive disorder: a systematic 

review and meta-analysis. Clin Psychol Rev 

2011;31(6):1032-40. PMID: 21802618.

Ramsberg J, Asseburg C, Henriksson M. 

Effectiveness and cost-effectiveness of 

antidepressants in primary care: a multiple treatment 

comparison meta-analysis and cost-effectiveness 

model. PLoS One 2012;7(8):e42003. PMID: 

22876296.

Richards D, Richardson T. Computer-based 

psychological treatments for depression: a systematic 

review and meta-analysis. Clin Psychol Rev 

2012;32(4):329-42. PMID: 22466510.

Rocha FL, Fuzikawa C, Riera R, et al. Combination

of antidepressants in the treatment of major 

depressive disorder: a systematic review and metaanalysis. J Clin Psychopharmacol 2012;32(2):278-81. 

PMID: 22367652.

*Roshanaei-Moghaddam B, Pauly MC, Atkins DC, et 

al. Relative effects of CBT and pharmacotherapy in 

depression versus anxiety: is medication somewhat 

better for depression, and CBT somewhat better for 

anxiety? Depress Anxiety 2011;28(7):560-7. PMID: 

21608087.

Rubenstein LV, Williams JW, Jr., Danz M, Shekelle 

P, Suttorp M, Johnsen B. VA Evidence-based 

Synthesis Program Reports. Determining Key 

Features of Effective Depression Interventions. 

Washington (DC): Department of Veterans Affairs 

(US); 2009.

Samad Z, Brealey S, Gilbody S. The effectiveness of 

behavioural therapy for the treatment of depression in 

older adults: a meta-analysis. Int J Geriatr Psychiatry 

2011;26(12):1211-20. PMID: 21308789.

Schueler YB, Koesters M, Wieseler B, et al. A 

systematic review of duloxetine and venlafaxine in 

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Psychiatr Scand 2011;123(4):247-65. PMID: 

20831742.

Shinohara K, Honyashiki M, Imai H, et al. 

Behavioural therapies versus other psychological 

therapies for depression. Cochrane Database Syst 

Rev 2013;10:Cd008696. PMID: 24129886.

Silveira H, Moraes H, Oliveira N, Coutinho ES, Laks 

J, Deslandes A. Physical exercise and clinically 

depressed patients: a systematic review and metaanalysis. Neuropsychobiology. 2013;67(2):61-68. 

PMID: 23295766.

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computerised CBT really helpful for adult 

depression?-A meta-analytic re-evaluation of CCBT 

for adult depression in terms of clinical 

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Psychiatry 2013;13:113. PMID: 23587347.

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improvement in depressive symptoms with 

desvenlafaxine 50 mg/d as a predictor of treatment 

success in patients with major depressive disorder. J 

Clin Psychopharmacol. 2014;34(1):57-65 PMID: 

24346751

Spielmans GI, Berman MI, Usitalo AN. 

Psychotherapy versus second-generation 

antidepressants in the treatment of depression: a 

meta-analysis. J Nerv Ment Dis 2011;199(3):142-9. 

PMID: 21346483.
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Spijker J, van Straten A, Bockting CL, et al. 

Psychotherapy, antidepressants, and their 

combination for chronic major depressive disorder: a 

systematic review. Can J Psychiatry 2013;58(7):386-

92. PMID: 23870720.

Tedeschini E, Levkovitz Y, Iovieno N, et al. Efficacy 

of antidepressants for late-life depression: a metaanalysis and meta-regression of placebo-controlled 

randomized trials. J Clin Psychiatry 

2011;72(12):1660-8. PMID: 22244025.

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care to improve the management of depressive 

disorders: a community guide systematic review and 

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PMID: 22516495.

Trivedi RB, Nieuwsma JA, Williams JW, Jr. 

Examination of the utility of psychotherapy for 

patients with treatment resistant depression: a 

systematic review. J Gen Intern Med 2011;26(6):643-

50. PMID: 21184287.

van Hees ML, Rotter T, Ellermann T, et al. The 

effectiveness of individual interpersonal 

psychotherapy as a treatment for major depressive 

disorder in adult outpatients: a systematic review. 

BMC Psychiatry 2013;13:22. PMID: 23312024.

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Combination of pharmacotherapy and psychotherapy 

in the treatment of chronic depression: a systematic 

review and meta-analysis. BMC Psychiatry 

2012;12:61. PMID: 22694751.

von Wolff A, Holzel LP, Westphal A, et al. Selective 

serotonin reuptake inhibitors and tricyclic 

antidepressants in the acute treatment of chronic 

depression and dysthymia: a systematic review and 

meta-analysis. J Affect Disord 2013;144(1-2):7-15. 

PMID: 22963896.

Woltmann E, Grogan-Kaylor A, Perron B, et al. 

Comparative effectiveness of collaborative chronic 

care models for mental health conditions across 

primary, specialty, and behavioral health care 

settings: systematic review and meta-analysis. Am J 

Psychiatry 2012;169(8):790-804. PMID: 22772364

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