Accepted Manuscript

Meta-analyses with industry involvement are massively published and report no

caveats for antidepressants

Shanil Ebrahim, PhD, Sheena Bance, MSc, Abha Athale, MSc, Cindy Malachowski,
MSc, John P.A. Ioannidis, MD

PII: S0895-4356(15)00429-1
DOI: 10.1016/j.jclinepi.2015.08.021
Reference: JCE 8982

To appear in: Journal of Clinical Epidemiology

Received Date: 27 January 2015

Revised Date: 6 August 2015
Accepted Date: 26 August 2015

Please cite this article as: Ebrahim S, Bance S, Athale A, Malachowski C, Ioannidis JPA, Meta-analyses
with industry involvement are massively published and report no caveats for antidepressants, Journal of
Clinical Epidemiology (2015), doi: 10.1016/j.jclinepi.2015.08.021.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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 ACCEPTED MANUSCRIPT

Meta-analyses with industry involvement are massively published and

report no caveats for antidepressants
Shanil Ebrahim PhD1,2,3,4,5, Sheena Bance MSc6, Abha Athale MSc7, Cindy Malachowski MSc8, John
P.A. Ioannidis MD1,2,8,9
1
Stanford Prevention Research Center, Department of Medicine, 1265 Welch Road, 3rd floor, Stanford

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University, Stanford, CA 94305, USA
2
Meta-Research Innovation Center at Stanford (METRICS), Stanford University, 1265 Welch Rd,
Stanford, CA 94305, USA
3
Department of Clinical Epidemiology & Biostatistics, 1200 Main Street West, Room 2C, McMaster

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University, Hamilton, Ontario, Canada, L8S 4K1
4
Department of Anesthesia, 1200 Main Street West, HSC 2U1, McMaster University, Hamilton,
Ontario, Canada, L8S 4K1

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Department of Anaesthesia and Pain Medicine, 555 University Ave, Hospital for Sick Children,
Toronto, Ontario, Canada, M5G 1X8
6
Department of Applied Psychology and Human Development, Ontario Institute for Studies in

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Education, 252 Bloor Street West, University of Toronto, Toronto, Ontario, Canada, M5S 1V6
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Department of Rehabilitation Science, 500 University Ave, University of Toronto, Toronto, Ontario
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Canada, M5G 1V7
8
Department of Health Research and Policy, Redwood Building T152, 150 Governor's Lane, Stanford
University School of Medicine, Stanford, California, United States of America, 94305
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Department of Statistics, 390 Serra Mall, Stanford University School of Humanities and Sciences,
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Stanford, CA 94305, USA

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Corresponding Author: John P.A. Ioannidis, 1265 Welch Road, Medical School Office Building
Room X306, Stanford, CA 94305, USA. E-mail: jioannid@stanford.edu, Tel: +1 (650) 725-5465
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Abstract word count: 200

Manuscript word count: 3255

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Abstract

Objective: To identify the impact of industry involvement in the publication and interpretation of

meta-analyses of antidepressant trials in depression.

Study design and setting: Using MEDLINE, we identified all meta-analyses evaluating

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antidepressants for depression published in 1/2007-3/2014. We extracted data pertaining to author

affiliations, conflicts of interest and whether the conclusion of the abstract included negative statements

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on whether the antidepressant(s) were effective or safe.

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Results: We identified 185 eligible meta-analyses. Fifty-four (29%) meta-analyses had authors who

were employees of the assessed drug manufacturer and 147 (79%) had some industry link (sponsorship

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or authors who were industry employees and/or had conflicts of interest). Only 58 meta-analyses (31%)
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had negative statements in the concluding statement of the abstract. Meta-analyses including an author

who were employees of the manufacturer of the assessed drug were 22-times less likely to have
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negative statements about the drug than other meta-analyses (1/54 [2%] vs. 57/131 [44%], p<0.001).
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Conclusion: There is a massive production of meta-analyses of antidepressants for depression authored

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by or linked to the industry, and they almost never report any caveats about antidepressants in their

abstracts. Our findings add a note of caution for meta-analyses with ties to the manufacturers of the
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assessed products.

Keywords: Industry sponsor, conflicts of interest, competing interests, meta-analyses, antidepressants,

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depression
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Running title: Meta-analyses with industry involvement are massively published and report no caveats

for antidepressants

Word count: 3255

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“What is new”

• No studies have systematically assessed the extent and implications of industry involvement in

meta-analyses of trials evaluating antidepressants, one of the largest markets of

pharmaceuticals, for the management of depression.

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• Our study shows the massive presence of the industry in generating a factory of meta-analyses

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in this field (147 of 185 [79%] meta-analyses published in the last 7 years).

• Industry-authored meta-analyses almost never include any negative concluding statement in

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their abstracts about the antidepressants assessed.

• Caution is needed in interpreting meta-analyses with ties to the manufacturers of the assessed

products.
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Background

Meta-analyses are often considered the highest level of evidence in the hierarchy of evidence-based

medicine. The number of meta-analyses being conducted is growing rapidly [1]. As these data

syntheses become more influential in shaping guidelines and clinical practice, the biopharmaceutical

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industry may have an enhanced interest in them [2]. There is some evidence that randomized trials and

systematic reviews performed or sponsored by the industry may lead to more favorable conclusions

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than non-industry-related trials and systematic reviews [3-7]. Given that influential meta-analyses can

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be performed with more limited resources and faster than randomized trials, it is conceivable that the

industry could easily help generate a large number of meta-analyses to support its products.

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Antidepressants comprise one of the largest markets of pharmaceuticals, with several blockbuster

drugs, and a market of $9.4 billion per year in the U.S alone in 2013 [8]. A few meta-analyses of
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antidepressants published by the FDA and other non-industry sponsored investigators reached
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extremely high visibility between 2005 and early 2008, causing heated debates about serious risks (e.g.,
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suicidality [9, 10]) or questionable effectiveness in patients without severe depression [11]. However,

there is no systematic study of industry-related meta-analyses in this field. Some important questions
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may be asked. Is there a large current meta-analysis literature of antidepressants under control or

sponsorship by the industry? Do industry-related meta-analyses reach more favorable conclusions in

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their abstracts than other meta-analyses? To answer these questions, we aimed to examine
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systematically the extent and implications of industry involvement in meta-analyses of trials evaluating

antidepressants for the management of depression published between 2007 and 2014.

Methods

Eligibility criteria
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We considered all meta-analyses of randomized controlled trials evaluating drugs approved as

antidepressants in patients with depressive conditions and published since 2007. Publications were

eligible regardless of whether they used either group-level or individual-patient information.

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Meta-analyses were defined as analyses that quantitatively combine results from multiple trials to

produce a summary treatment effect. A thorough systematic review component was not required (e.g.,

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pooled analyses of multiple trials on a given drug would qualify, regardless of whether additional trials

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on the same or similar drugs might exist or not). We anticipated that several meta-analyses performed

by the industry may focus on a single medication, including pooled analyses with individual-level data

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[12].
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Meta-analyses qualified regardless of whether they included only inactive comparators
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(placebo/standard treatment) or active comparators (other antidepressants or against other active drug

interventions). We excluded meta-analyses that compared antidepressants against non-drug

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interventions only (e.g., diet, psychotherapy or cognitive interventions). Meta-analyses were also
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eligible regardless of whether they focused on benefits, harms, mortality, treatment discontinuation or

multiple outcomes. We excluded meta-analyses only focusing on predictors of outcomes.

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Eligible approved antidepressants included selective serotonin reuptake inhibitors (SSRIs), serotonin
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and norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, tricyclic and tetracyclic

antidepressants, monoamine oxidase (MAO) inhibitors, melatonergic and non-melatonergic

antidepressants, and any antipsychotics approved for antidepressants (e.g., quetiapine).

In this paper, sponsorship refers specifically to the act of an industry funding the meta-analysis that

involves one or more of the drugs that it manufactures; whereas conflict of interest refers to all the
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situations where one or more authors are either company employees of the industry or received any

support from the industry for any of their work (not necessarily sponsoring for the specific meta-

analysis).

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Search

We completed an electronic search of MEDLINE from January 1, 2007 to March 5, 2014 (last update)

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using a combination of relevant MeSH terms of antidepressants and specific drug names:

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(trial*[title/abstract] OR RCT[title/abstract]) AND (antidepressant*[title/abstract] OR

citalopram[title/abstract] OR Escitalopram[title/abstract] OR Fluoxetine[title/abstract] OR

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Fluvoxamine[title/abstract] OR Paroxetine[title/abstract] OR Sertraline[title/abstract] OR
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Venlafaxine[title/abstract] OR Desvenlafaxine[title/abstract] OR Duloxetine[title/abstract] OR

Bupropion[title/abstract] OR Trazodone[title/abstract] OR Mirtazapine[title/abstract] OR

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Nefazodone[title/abstract] OR Amitriptyline[title/abstract] OR Clomipramine[title/abstract] OR

Doxepin[title/abstract] OR Imipramine[title/abstract] OR Trimipramine[title/abstract] OR

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Desipramine[title/abstract] OR Nortriptyline[title/abstract] OR Protriptyline[title/abstract] OR

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Amoxapine[title/abstract] OR Maprotiline[title/abstract] OR Isocarboxazid[title/abstract] OR

Phenelzine[title/abstract] OR Tranylcypromine[title/abstract] OR Selegiline[title/abstract]) AND (meta-

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analysis[ptyp] OR systematic[sb] OR pooled[title/abstract]). We excluded non-English language

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papers.
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Study selection

Four reviewers (SE, SB, AA, CM) independently screened titles and abstracts of identified citations to

flag potentially eligible studies. Of those flagged, reviewers independently applied eligibility criteria to

the full-text of studies.

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Data extraction

To inform data extraction items, we piloted a sample of 36 articles. Using standardized forms, data

extractors captured the following information from all eligible meta-analyses: country of affiliation of

corresponding author; publication date; journal; disease/condition; any mention of a literature search;

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use of any individual-level data; type(s) of antidepressant(s); comparator(s) (placebo/non-treatment,

other antidepressant, other active intervention); outcome(s) assessed (benefits, harms, mortality,

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treatment discontinuation); funding source (manufacturer of assessed drug(s), other for-profit, not-for-

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profit, government, not reported); whether any author was employed by a for-profit organization (and if

so, whether this is a manufacturer of an assessed drug(s)); whether any author was receiving or had

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received any support by for-profit organizations (consulting, conference and speaker fees, provided
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testimony, monies for publications, grants/support for other studies, or other); and whether any author

had received any support specifically by manufacturers of products assessed in the meta-analysis.
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For meta-analyses where no author was affiliated with a for-profit organization and no author reported
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any conflicts in the published meta-analysis, under-reporting of industry tries is a potential issue [13].
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Thus, we searched a random sample of 3 articles published by the corresponding author in the same

year as the publication of the meta-analysis. We captured whether the corresponding author declared
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any relevant conflicts of interest in these articles. If the author published <3 articles in the same year,
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we extended the search to the author’s papers published within +/-1 year.
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Two investigators, blind to the authorship of the meta-analysis or author’s potential affiliation with

industry, independently extracted whether the abstract of the meta-analysis included any negative

statements expressing caveats about the effectiveness or safety/toxicity of the assessed

antidepressant(s) (e.g., “drug X is not effective” or “drug X causes harms”). When no such negative

statements were made, we noted whether there were any positive statements for effectiveness and/or
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safety/toxicity. If there were no such positive statements, we counted as negative any statements that

stated the evidence was of low quality, limited, uncertain or inconclusive. When positive statements

existed about the effectiveness and/or safety/toxicity of the assessed drug, simply adding that the

evidence might be of low quality, limited, uncertain or inconclusive was not counted as a negative

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statement. Discrepancies between data extractors were discussed and consensus was reached with an

arbitrator.

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Statistical Analysis

We described data as proportions and ranges, as appropriate. We calculated the proportion of meta-

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analyses funded or sponsored by a for-profit organization; funded or sponsored by a manufacturer of an
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assessed drug(s); with author(s) directly employed by a for-profit organization; with author(s) directly

employed by the manufacturer of an assessed drug; with author(s) with a conflict of interest with a for-
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profit organization; with author(s) with a conflict of interest with the manufacturer of the assessed

drug; or with combinations of these affiliations and conflicts. We evaluated with exact tests, whether
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the conclusions of the meta-analysis differed according to the presence or not of industry sponsorships,
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specific industry affiliations and/or conflicts of authors; country of affiliation (USA vs. other); journal;

publication year; focus on patients with major depression only; type of antidepressant evaluated; focus
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on a single antidepressant only; type of comparators evaluated; outcome type; use of literature search;
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and use of individual-level data. We provide the results of all tests separately for all meta-analyses and
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for meta-analyses without industry employed authors. We report the odds ratios and 95% confidence

intervals (CIs) and two-tailed p-values for these comparisons. We completed all analyses using SPSS

Statistics software 22.0.0.

Results

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Our search identified 1111 citations. Three articles were unavailable [14-16] and we scrutinized 259 in

full-text. Of these, 74 were excluded (figure 1). Our evaluation thus consisted of 185 eligible meta-

analyses (Table 1, Appendix A).

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After 2007, every year, 20 to 32 eligible meta-analyses were published. The majority of the

publications were published by corresponding authors from the USA (35%) and Europe (33%),

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assessed benefit (92%), evaluated patients with major depression only (82%), and appeared in

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psychiatric specialty journals (56%). The most frequently evaluated antidepressants were SSRIs (45%)

and SNRIs (30%). Most comparisons were against placebo (74%). About a third of the meta-analyses

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did not use a systematic literature review and a similar proportion used individual level data; these
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meta-analyses typically reflected pooled analyses of single medications.
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Sponsorship, employment and conflicts of interest

Forty-six (25%) meta-analyses were sponsored by the manufacturer of the assessed drug, 3 (2%) by a
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for-profit organization and not the manufacturer of the assessed drug, 20 (11%) by a not-for-profit
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organization, 33 (18%) by a government agency, 41 (22%) received no funding, and for 51 (28%)

sponsorship was not reported in the publication. Of those 51 however, 11 (22%) meta-analyses had
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authors who were industry employees.

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Fifty-seven (31%) meta-analyses included an author employed by a for-profit organization (54 were

employed by the manufacturer of the assessed drug). Overall, 134 meta-analyses (72%; n=121 conflicts

reported in the meta-analysis; n=13 conflicts reported in other publications that we retrieved by the

same corresponding author) included an author with a conflict of interest with a for-profit organization,

of which 113 meta-analyses (61%; n=104 conflicts reported in the meta-analysis; 9 conflicts reported

in other publications that we retrieved) were receiving or had received support from the manufacturer
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of the assessed drug. Overall, 145 of the 185 meta-analyses (78%) had authors who were industry

employees or had conflicts of interest with for-profit organizations; 122 of the 145 had authors who

were employees of the manufacturer or had conflicts of interest with the manufacturer of the assessed

drug(s).

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For meta-analyses where no author was affiliated with a for-profit organization and no author reported

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any conflicts (n=53), we identified 13 (25%) that had conflicts after searching a random sample of 3

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articles published by the corresponding author in the same year as the meta-analysis; these were

included in our evaluation.

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Comparison of meta-analyses with industry authors versus other meta-analyses

Meta-analyses with industry authors (n=57) were more likely than other meta-analyses (n=128) to not
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use a literature review (21% vs. 91%, p<0.001), to use individual level data (79% vs. 11%, p<0.001), to

come from the USA rather than Europe or Asia, to focus on major depression only (98% vs. 75%,
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p<0.001), and to evaluate SNRIs (40% vs. 25%, p=0.04) rather than other drugs. They were also less
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likely to use other active interventions as a comparator (5% vs. 17%, p=0.04) and report treatment

discontinuation as an outcome (37% vs. 55%, p=0.03) (Table 1).

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Negative statements in the conclusion of the abstract

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One hundred and twenty-seven (69%) articles concluded without any negative statements about the

assessed antidepressant(s). The kappa coefficient between the two independent extractors regarding the

presence or absence of negative statements was 0.81 (95% CI of 0.71 to 0.90). Of the 58 that did

include a negative statement, 20 concluded no or inferior effectiveness and 20 concluded inferior

safety/toxicity profile (3 had negative statements on both effectiveness and safety/toxicity). Another 21

(36%) made no clear positive statement about effectiveness or safety and stated the evidence was of
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low quality, limited amount, uncertain or inconclusive. Appendix B provides a description of the

negative statement appraisal and industry authorship or industry-related conflicts of all meta-analyses.

Associations of negative statements

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Among all 185 meta-analyses, the strongest association with abstract conclusions was seen for author

industry employment (Table 2). Including an author employed by the manufacturer of the assessed

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drug was associated with a 22-fold lower chance of reporting a negative statement (1/54 [2%] vs.

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57/131 [44%], p<0.001).

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Among all 185 meta-analyses, those published in the USA, published in psychiatric specialty journals,
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those evaluating atypical antidepressants, those without a literature search and those using individual

level data had a significantly lower frequency of negative statements. Conversely, there was a higher
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frequency of negative statements in general medical journals (Table 3).

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When the 57 meta-analyses with industry employee authors were excluded, among the remaining 128
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meta-analyses, sponsorship from the industry, conflicts of interest of non-industry employee authors,

country of author affiliation, not using a literature search, and using individual level data were no
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longer significantly associated with fewer negative statements. However, conflict of interest with the
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manufacturer of the assessed drug was still significantly associated with fewer negative statements
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(22/68 vs. 34/60, p=0.007). Among the 38 meta-analyses without any involvement from industry, half

(19/38) had some negative statement. Also, those published in psychiatric specialty journals (33% vs.

56%) and those evaluating atypical antidepressants (21% vs. 48%) still had a nominally significantly

lower frequency of negative statements.

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Discussion

Over the past seven years, there have been nearly 200 published meta-analyses assessing the

effectiveness of antidepressants for depression. Approximately 80% of these meta-analyses had a direct

involvement from industry (sponsorship, industry authors, or authors with industry conflicts of interest)

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and one-third were written by industry employee authors. This represents a massive presence of the

industry in generating a prolific production of meta-analyses in this field. Meta-analyses by industry

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authors often lack a systematic review and focus on pooling individual data from industry trials on a

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specific manufactured drug. Industry-authored meta-analyses almost never include any negative

concluding statement in the abstract that summarizes the conclusions of the work about the

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antidepressants assessed, while more than half of those without any discernible industry involvement
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do include such statements in the abstract.
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There is extensive debate about the involvement of the industry in randomized trials and meta-analyses.
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Given the importance of these tools for evidence-based medicine and decision-making, it is logical that
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the industry would be very much interested in their results. For randomized trials, industry-sponsored

studies seem to be of better quality versus other trials [17-19]. However, industry-sponsored studies
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may also tend to selectively choose outcome data [20], or comparators (e.g., placebo, interventions

owned by the same sponsor) [21], that result in favorable results. Multiple reviews have shown that
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industry-sponsored trials are associated with higher treatment success and report more favorable
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efficacy results [5, 6], even when the results of industry-sponsored studies were not really that

favorable [22]. It seems that the same enhancement of favorable conclusions is operating also in the

level of meta-analyses.

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Some previous empirical evaluations [3, 4, 22] have also shown that industry-sponsored systematic

reviews tend to yield more favorable conclusions than non-industry sponsored systematic reviews, even

though the results are largely similar. These evaluations had assessed 39, 24, and 124 systematic

reviews and/or meta-analyses, respectively, of which 26-40% had ties to the industry [3, 4, 22]. The

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first two evaluations pertained to various drugs, while the third included all meta-analyses on anti-

hypertensives over several decades. Another recent evaluation [23] identified 26 systematic reviews of

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neuraminidase inhibitors (performing 37 assessments) also showed an association between industry

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sponsoring and favorable inferences. Our study adds to this previous work by showing an even more

massive impact of the manufacturers in writing and shaping a large meta-analysis agenda with 147

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industry-linked meta-analyses published on a single drug class over just 7 years. The number and
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annual rate of publication of meta-analyses in our survey are larger than in previous evaluations and the

proportion of meta-analyses with industry involvement is more than double. Some of this difference
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may be due to the fact that we also considered pooled analyses without systematic reviews, and these

types of papers are almost exclusively done by the industry. However, these papers are also influential.
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Moreover, even if we were to exclude them, the mass of antidepressants’ meta-analyses and the
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proportion of industry involvement still remain impressive.

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Given that the previous empirical studies (with the exception of the one on neuraminidase inhibitors)
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were mostly done with meta-analyses published before the time frame that we examined, it would be
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interesting to examine the penetration of the industry in the recent years across meta-analyses of

diverse types of blockbuster medications. Apparently meta-analyses have become so popular, that they

can become a prime marketing tool. There is evidence that even for reviews without meta-analyses [24,

25] or even for editorials [26], industry-supported authors often generate a massive literature that

attempts to promote specific products. As meta-analyses become easier to produce (given the diffusion

of methods and user-friendly software) and as they acquire more influence than simple opinion-based
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reviews, it is perhaps not surprising that similar inflations in production may be seen now for industry-

sponsored meta-analyses as were seen previously with expert-based pieces.

Only one meta-analysis with a manufacturer author reported a negative statement in the conclusion of

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the abstract and this statement was not considered a major caveat. Specifically, the authors reported

that duloxetine-treated patients had a higher risk of treatment-emergent adverse events versus placebo-

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treated patients [27], a statement that can be expected practically for any active treatment without

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causing any major concerns alone. Moreover, we found that even when restricting our analyses to

studies with non-industry employed authors, conflicts of interest with the manufacturer of the assessed

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drug were still strongly associated with fewer negative statements in the abstracts. Journals and
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conferences have attempted to regulate this source of bias by asking authors to declare all competing

interests in their published reports. However, authors do not always declare their conflicts of interests
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and declarations are rarely verified [13]. Correspondingly, we found that a quarter of meta-analyses

including authors reporting no conflicts in fact had some temporally concurrent industry ties.
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Organizations such as the Cochrane Collaboration, the Institute of Medicine, and the Agency for

Healthcare Research and Quality (AHRQ) have tried to address issues of potential conflict and its
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reporting in meta-analyses [4, 28, 29]. Some authors have even argued that content experts and
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sponsors should be entirely excluded from the conduct and authorship of meta-analyses because of
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unavoidable conflicts [30]. A more extreme view has been that industry-sponsored research in general

should not be published by medical journals [31].

There are some limitations to our study. First, for meta-analyses including authors with no conflicts, we

probed further by reviewing previous recent publications of the corresponding author. We did not

complete this search for every author included in the meta-analysis and thus the total number of meta-
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analyses with industry ties is likely to be an underestimate. Second, we searched only MEDLINE for

meta-analyses of antidepressant trials. There is a possibility that other databases such as PsycINFO or

EMBASE could include some additional meta-analyses and antidepressants may be used also for other

indications besides depression. If anything, this means that the factory of meta-analyses is probably

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more prolific than we have recorded. Third, we used an operational definition for identifying the

presence of negative statements focusing only in the conclusions of the abstract. The dichotomy of

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yes/no probably underestimates the rich, subtle diversity that may exist in the presentation and

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discussion of a full paper and its results. However, the conclusions of the abstract are clearly a central

point for summarizing the final take-home message offered by a scientific paper. Efforts to capture the

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presence of negative statements in the very different contexts where they could appear in the full paper
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would have entailed more subjectivity. Moreover, even if some negative statements appear in the full

text, these are likely to be far less influential if the conclusion of the abstract focuses only on the
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positive aspects. Fourth, having many meta-analyses is not necessarily bad in principle, but having too

much of a good thing may be damaging [32], especially if this literature is biased.
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Empirical studies in other fields beyond antidepressants may be helpful to probe the breadth of the

problem. Our findings add a note of caution when interpreting and using meta-analyses with ties to the
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manufacturers of the assessed products.

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Acknowledgements

No funds were received for this study. SE is supported by a MITACS Elevate and SickKids

Restracomp Postdoctoral Fellowship Awards, SB by an Ontario Graduate Scholarship and Social

Sciences and Humanities Research Council Doctoral Scholarship, and CM by a graduate scholarship

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from the Ontario Mental Health Association. Sponsors providing individual financial support to authors

did not have a role in the design and conduct of the study; collection, management, analysis, and

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interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the

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manuscript for publication. SE and JPAI had full access to all the data in the study and take

responsibility for the integrity of the data and the accuracy of the data analysis. We thank Ms. Kelsey

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Vercammen for assisting with article retrieval; no compensation was received for completing this work.
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Conflict of interest
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All authors declare no conflicts of interests.

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Authors’ contributions

SE and JPAI conceived and designed the study. SE, SB, AA, and CM made substantial contributions to
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the acquisition, analysis, or interpretation of data for the work. SE drafted the manuscript and SB, AA,
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CM and JPAI revised it critically for important intellectual content. All authors approved the final
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version to be published.

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[http://www.researchandmarkets.com/research/p35qmw/u_s]

9. Hammad TA, Laughren T, Racoosin J: Suicidality in pediatric patients treated with

antidepressant drugs. Archives of general psychiatry 2006, 63:332-339.

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10. Relationship between psychotropic drugs and pediatric suicidality: review and evaluation

of clinical data [http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-

Hammads-Review.pdf]

11. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT: Initial severity

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and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug

Administration. Plos Med 2008, 5(2):e45.

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12. Haidich AB, Pilalas D, Contopoulos-Ioannidis DG, Ioannidis JP: Most meta-analyses of drug

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interventions have narrow scopes and many focus on specific agents. J Clin Epidemiol

2013, 66(4):371-378.

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13. Chimonas S, Frosch Z, Rothman DJ: From disclosure to transparency: the use of company
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payment data. Arch Intern Med 2011, 171(1):81-86.

14. Guay DR: Vilazodone hydrochloride, a combined SSRI and 5-HT1A receptor agonist for
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major depressive disorder. The Consultant pharmacist : the journal of the American Society

of Consultant Pharmacists 2012, 27(12):857-867.

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15. Fleurence R, Williamson R, Jing Y, Kim E, Tran QV, Pikalov AS, Thase ME: A systematic
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review of augmentation strategies for patients with major depressive disorder.

Psychopharmacology bulletin 2009, 42(3):57-90.

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16. Robinson DS, Gilmor ML, Yang Y, Moonsammy G, Azzaro AJ, Oren DA, Campbell BJ:
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Treatment effects of selegiline transdermal system on symptoms of major depressive

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disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials.

Psychopharmacology bulletin 2007, 40(3):15-28.

17. Reynolds T: Industry-Funded Versus Publicly Funded Trials: Are the Standards the

Same? JNCI J Natl Cancer Inst 2001, 93(21):1590-1592.

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18. Thomas O, Thabane L, Douketis J, Chu R, Westfall AO, Allison DB: Industry funding and

the reporting quality of large long-term weight loss trials. Int J Obes (Lond) 2008,

32(10):1531-1536.

19. Khan NA, Lombeida JI, Singh M, Spencer HJ, Torralba KD: Association of industry funding

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with the outcome and quality of randomized controlled trials of drug therapy for

rheumatoid arthritis. Arthritis Rheum 2012, 64(7):2059-2067.

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20. Peura P, Martikainen JA, Purmonen TT, Turunen JH: Sponsorship-related outcome selection

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bias in published economic studies of triptans: systematic review. Med Decis Making 2012,

32(2):237-245.

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21. Lathyris D, Patsopoulos NA, Salanti G, Ioannidis JP: Industry sponsorship and selection of
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comparators in randomized clinical trials. Eur J Clin Invest 2010, 40(2):172-182.

22. Yank V, Rennie D, Bero LA: Financial ties and concordance between results and
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conclusions in meta-analyses: retrospective cohort study. BMJ 2007, 335(7631):1202-1205.

23. Dunn AG, Arachi D, Hudgins J, Tsafnat G, Coiera E, Bourgeois FT: Financial conflicts of
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interest and conclusions about neuraminidase inhibitors for influenza: an analysis of

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systematic reviews. Annals of internal medicine 2014, 161(7):513-518.

24. Fugh-Berman A, McDonald CP, Bell AM, Bethards EC, Scialli AR: Promotional tone in
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reviews of menopausal hormone therapy after the Women's Health Initiative: an analysis
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of published articles. PLoS Med 2011, 8(3):e1000425.

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25. Hartog CS, Skupin H, Natanson C, Sun J, Reinhart K: Systematic analysis of hydroxyethyl

starch (HES) reviews: proliferation of low-quality reviews overwhelms the results of well-

performed meta-analyses. Intensive Care 2012, 38(8):1258-1271.

26. Tatsioni A, Siontis GC, Ioannidis JP: Partisan perspectives in the medical literature: a study

of high frequency editorialists favoring hormone replacement therapy. J Gen Intern Med

2010, 25(9):914-919.
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27. Brunton S, Wang F, Edwards SB, Crucitti AS, Ossanna MJ, Walker DJ, Robinson MJ: Profile

of adverse events with duloxetine treatment: a pooled analysis of placebo-controlled

studies. Drug safety : an international journal of medical toxicology and drug experience 2010,

33(5):393-407.

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28. Report development [http://www.ahrq.gov/clinic/epc/]

29. Finding what works in health care: standards for systematic reviews

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[http://www.nap.edu/catalog.php?record_id=13059]

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30. Gøtzsche PC, Ioannidis JP: Content area experts as authors: helpful or harmful for

systematic reviews and meta-analyses? BMJ 2012, 345:e7031.

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31. Smith R, Gøtzsche PC, Groves T: Should journals stop publishing research funded by the
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drug industry? BMJ 2014, 348:g171.

32. Siontis KC, Hernandez-Boussard T, Ioannidis JP: Overlapping meta-analyses on the same
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topic: survey of published studies. BMJ 2013, 347:f4501.

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Figure Legend

Figure 1 – Flow chart of eligible meta-analyses

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Figure 1 – Flow chart of eligible meta-analyses

Records identified through MEDLINE search:

(1111)

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Records screened Records excluded after title and abstract

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(1111) screening (849)

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Unable to retrieve meta-analyses (3)
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Full-text articles assessed
for eligibility (259) Full-text articles excluded for failing to
meet eligibility criteria (74)
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22: Not a meta-analysis or a pooled analysis

4: Did not evaluate antidepressants
27: Did not evaluate the efficacy of antidepressants
9 evaluated co-therapy of antidepressant and
another drug vs. antidepressants only
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7: Did not evaluate an indication of depression or

did not report outcomes separately for depression
4: Non-English
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1: Duplicate

Eligible articles
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(185)
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Table 1 – Description of Eligible Meta-analyses

n (%)
Meta- Meta-
analyses analyses
with without

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All meta- industry industry
analyses employee employee P-
Characteristics (n=185) authors authors value

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(n=57) (n=128)
Country(ies) of corresponding author
Africa 2 (1) 2 (3.5) 0 (0) 0.002*

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Asia 17 (9) 1 (1.8) 16 (12.5)
Canada 13 (7) 5 (9) 8 (6)
Europe 62 (33) 12 (21) 50 (39)
Oceania 5 (3) 1 (2) 4 (3)

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South America 2 (1) 0 (0) 2 (2)
UK 17 (9) 8 (14) 9 (7)
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USA 66 (35) 27 (47) 39 (31)

Journal
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General medical journals 15 (8) 1 (2) 14 (11) 0.15*

Psychiatric journals 104 (56) 36 (63) 67 (52)
Other specialty journals 66 (35) 20 (35) 46 (36)
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Publication Year
2007 13 (7) 7 (12) 6 (5) 0.21*
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2008 24 (13) 4 (7) 20 (16)

2009 29 (16) 13 (23) 16 (13)
2010 26 (14) 10 (18) 16 (13)
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2011 32 (17) 8 (14) 24 (19)

2012 20 (11) 3 (5) 17 (13)
2013 32 (17) 9 (16) 23 (18)
2014 (until March 5) 9 (5) 3 (5) 6 (5)
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Disease/condition of evaluated patients

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Major depression only 152 (82) 56 (98) 96 (75) 0.01*

Major depression comorbid with psychiatric 6 (3) 1 (2) 5 (4)
disorders
Major depression comorbid with non-psychiatric 14 (8) 1 (2) 13 (10)
disorders
Other
Depression not-specified 1 (0.5) 1 (2) 0 (0)
Interferon-alpha associated depression 3 (1.6) 0 (0) 3 (2)
Minor depression or dysthymia 2 (1) 0 (0) 2 (2)
Persistent or recurrent depression 1 (0.5) 0 (0) 1 (1)

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Post-stroke depression 2 (1) 0 (0) 2 (2)

Postpartum depression 1 (0.5) 0 (0) 1 (1)
Psychotic depression 3 (1.6) 0 (0) 3 (2)

Type of antidepressant(s) evaluated#

Selective Serotonin Reuptake Inhibitors (SSRIs) 83 (45) 20 (35) 63 (49) 0.08
Serotonin and Norepinephrine Reuptake 55 (30) 23 (40) 32 (25) 0.04
Inhibitors (SNRIs)

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Atypical antidepressants 27 (15) 8 (14) 19 (15) 1.00
Tricyclic and tetracyclic antidepressants 28 (16) 3 (5) 25 (20) 0.01
Monoamine Oxidase Inhibitors (MAOIs) 9 (5) 3 (5) 6 (5) 1.00

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Melatonergic and non-melatonergic 7 (4) 2 (4) 5 (4) 1.00
antidepressants
Antipsychotics approved for antidepressants 5 (3) 2 (4) 3 (2) 0.64

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Antidepressants not specified 23 (12) 0 (0) 23 (18) <0.001

Comparators evaluated#
Placebo 137 (74) 44 (77) 93 (73) 0.59

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Other antidepressant 100 (54) 32 (56) 68 (53) 0.75
Other active intervention 25 (14) 3 (5) 22 (17) 0.04
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Type of outcomes reported#
Benefit 171 (91) 53 (93) 118 (92) 1.00
Harm 86 (46) 24 (42) 62 (48) 0.52
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Mortality 13 (7) 2 (3.5) 11 (9) 0.35

Treatment discontinuation 91 (49) 21 (37) 70 (55) 0.03
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Use of literature review 128 (69) 12 (21) 116 (91) <0.001

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Use of individual patient data 59 (32) 45 (79) 14 (11) <0.001

*P-value comparing the two groups across all categories; #not mutually exclusive categories/ multiple
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categories may have been evaluated in the eligible trials

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Table 2 - Association of negative statements made in meta-analyses with industry sponsorship,

authors, and conflicts of interest
Among all 185 meta-analyses Among 128 meta-analyses without industry
employee authors

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Characteristic Negative Odds ratio Negative Odds ratio
statements, (95% CI) statements, (95% CI)

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n/N (%) P-value n/N (%) P-value
Sponsored by the manufacturer of
assessed drug(s)

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Yes 3/46 (7) 0.10 (0.03 to 0.36) <0.001 2/7 (29) 0.50 (0.09 to 2.66) 0.47
No 55/139 (40) 54/121 (45)
Sponsored by any for-profit organization

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Yes 5/48 (10) 0.18 (0.07 to 0.50) <0.001 4/9 (44) 1.03 (0.26 to 4.03) 0.61
No 53/137 (39) 52/119 (44)

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Author(s) employee(s) of the
manufacturer of drug(s)
Yes 1/54 (2) 0.02 (0.003 to 0.18) <0.001 -- -- --

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No 57/131 (44)
Author(s) employee(s) of any for-profit

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organization
Yes 2/57 (3.5) 0.05 (0.01 to 0.20) <0.001 -- -- --

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No 56/128 (44)
Conflicts of interest with manufacturer of
assessed drug(s)
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Yes 23/113 (20) 0.27 (0.14 to 0.52) <0.001 22/68 (32) 0.37 (0.18 to 0.75) 0.007
No 35/72 (49) 34/60 (57)
Conflicts of interest with any for-profit
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organization
Yes 36/134 (27) 0.48 (0.25 to 0.95) 0.05 35/88 (40) 0.60 (0.28 to 1.27) 0.19
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No 22/51 (43) 21/40 (53)

Any involvement* of manufacturer of
assessed drug(s)
Yes 24/124 (19) 0.19 (0.10 to 0.37) <0.001 23/70 (33) 0.37 (0.18 to 0.76) 0.008
No 34/61 (56) 33/58 (57)
Any involvement* of any for-profit
organization
Yes 39/147 (27) 0.36 (0.17 to 0.75) 0.01 37/90 (41) 0.70 (0.33 to 1.50) 0.44

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No 19/38 (50) 19/38 (50)

Country
USA 14/66 (21) 0.46 (0.23 to 0.92) 0.03 13/39 (33) 0.54 (0.24 to 1.17) 0.13
Other 44/119 (37) 43/89 (48)
Journal$
General medical 9/15 (60) 3.70 (1.25 to 10.96) 0.004 9/14 (64) 2.57 (0.81 to 8.15) 0.04

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Psychiatric specialty 23/103 (22) 0.39 (0.20 to 0.73) 22/67 (33) 0.39 (0.19 to 0.80)
Other specialty 25/66 (38) 1.58 (0.84 to 3.01) 24/46 (52) 1.71 (0.82 to 3.53)
Publication year$

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2007 1/13 (8) 0.17 (0.21 to 1.33) 0.37 1/6 (17) 0.24 (0.03 to 2.15) 0.77
2008 6/24 (25) 0.70 (0.26 to 1.86) 6/20 (30) 0.50 (0.18 to 1.39)

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2009 8/29 (28) 0.81 (0.34 to 1.95) 8/16 (50) 1.33 (0.47 to 3.81)
2010 13/26 (50) 2.53 (1.09 to 5.89) 12/16 (75) 4.64 (1.41 to 15.29)
2011 11/32 (34) 1.18 (0.53 to 2.65) 10/24 (42) 0.90 (0.37 to 2.21)

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2012 7/20 (35) 1.20 (0.45 to 3.20) 7/17 (41) 0.89 (0.31 to 2.50)
2013 11/32 (34) 1.18 (0.53 to 2.65) 11/23 (48) 1.22 (0.50 to 3.02)

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2014 1/9 (11) 0.26 (0.03 to 2.14) 1/6 (17) 0.24 (0.03 to 2.15)
Focus on major depression only
Yes 46/152 (30) 0.76 (0.35 to 1.67) 0.54 44/96 (45) 1.41 (0.62 to 3.20) 0.54

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No 12/33 (36) 12/32 (38)
Type of antidepressant evaluated#

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Selective Serotonin Reuptake 27/83 (33) 1.10 (0.59 to 2.06) 0.87 27/63 (43) 0.93 (0.46 to 1.87) 0.86
Inhibitors (SSRIs)

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Serotonin and Norepinephrine 17/55 (31) 0.97 (0.49 to 1.92) 1.00 16/32 (50) 1.40 (0.63 to 3.13) 0.42
Reuptake Inhibitors (SNRIs)
Atypical antidepressants 4/27 (15) 0.34 (0.11 to 1.02) 0.046 4/19 (21) 0.29 (0.09 to 0.94) 0.04
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Tricyclic and tetracyclic 11/28 (39) 1.51 (0.66 to 3.48) 0.38 11/25 (44) 1.01 (0.42 to 2.44) 1.00
antidepressants
Monoamine Oxidase 2/9 (22) 0.61 (0.12 to 3.04) 0.72 2/6 (33) 0.63 (0.11 to 3.57) 0.70
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Inhibitors (MAOIs)
Melatonergic and non- 4/7 (57) 3.06 (0.66 to 14.15) 0.21 3/5 (60) 1.98 (0.32 to 12.28) 0.65
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melatonergic antidepressants
Antipsychotics approved for 1/5 (20) 0.54 (0.06 to 4.94) 1.00 1/3 (33) 0.64 (0.06 to 7.20) 1.00
antidepressants
Antidepressants not specified 11/23 (48) 2.24 (0.93 to 5.44) 0.09 11/23 (48) 1.22 (0.50 to 3.02) 0.82
Assessed one antidepressant only
Yes 26/100 (26) 0.58 (0.31 to 1.09) 0.11 24/49 (49) 1.41 (0.69 to 2.89) 0.37
No 32/85 (38) 32/79 (41)
Type of comparator evaluated#

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Placebo 40/137 (29) 0.69 (0.34 to 1.37) 0.29 38/93 (41) 0.65 (0.30 to 1.43) 0.32
Other antidepressant 32/100 (32) 1.07 (0.57 to 1.99) 0.88 30/68 (44) 1.03 (0.51 to 2.08) 1.00
Other active intervention 11/25 (44) 1.89 (0.80 to 4.46) 0.17 11/22 (50) 1.36 (0.54 to 3.40) 0.64
Type of outcome#
Benefit 50/171 (29) 0.31 (0.10 to 0.94) 0.04 49/118 (42) 0.30 (0.08 to 1.24) 0.10
Harm 32/86 (37) 1.66 (0.89 to 3.11) 0.12 30/62 (48) 1.44 (0.72 to 2.91) 0.37

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Mortality 4/13 (31) 0.97 (0.29 to 3.29) 1.00 4/11 (36) 0.71 (0.20 to 2.57) 0.76
Treatment discontinuation 32/91 (35) 1.42 (0.76 to 2.65) 0.34 30/70 (43) 0.92 (0.46 to 1.86) 0.86

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Use of literature review
Yes 52/128 (41) 5.82 (2.33 to 14.54) <0.001 51/116 (44) 1.10 (0.33 to 3.66) 1.00
No 6/57 (11) 5/12 (42)

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Use of individual level data
Yes 6/59 (10) 0.16 (0.06 to 0.40) <0.001 5/14 (36) 0.69 (0.22 to 2.18) 0.58
No 52/126 (41) 51/114 (45)

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*Sponsorship, author employee, or author conflict of interest for 185 meta-analyses, and sponsorship or author conflict of interest
for 128 meta-analyses; $P-value comparing the frequency of negative statements across all categories; #not mutually exclusive

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categories/ multiple categories may have been evaluated in the eligible trials

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Appendix A - List of Eligible Studies

1. Ali MK, Lam RW. Comparative efficacy of escitalopram in the treatment of
major depressive disorder. Neuropsychiatric disease and treatment 2011;7:39-49.
2. Alkhafaji AA, Trinquart L, Baron G, Desvarieux M, Ravaud P. Impact of
evergreening on patients and health insurance: a meta analysis and reimbursement

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cost analysis of citalopram/escitalopram antidepressants. BMC medicine
2012;10:142.
3. Apler A. Citalopram for major depressive disorder in adults: a systematic review
and meta-analysis of published placebo-controlled trials. BMJ open

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2011;1:e000106.
4. Arroll B, Elley CR, Fishman T, et al. Antidepressants versus placebo for
depression in primary care. Cochrane Database Syst Rev 2009:Cd007954.

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5. Aursnes I, Gjertsen MK. Common adverse events associated with an SSRI: meta-
analysis of early paroxetine data. Pharmacoepidemiology and drug safety
2008;17:707-13.
6. Baldessarini RJ, Faedda GL, Offidani E, et al. Antidepressant-associated mood-

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switching and transition from unipolar major depression to bipolar disorder: a
review. Journal of affective disorders 2013;148:129-35.
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7. Baldwin DS, Stein DJ, Dolberg OT, Bandelow B. How long should a trial of
escitalopram treatment be in patients with major depressive disorder, generalised
anxiety disorder or social anxiety disorder? An exploration of the randomised
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controlled trial database. Human psychopharmacology 2009;24:269-75.

8. Ball SG, Desaiah D, Spann ME, et al. Efficacy of duloxetine on painful physical
symptoms in major depressive disorder for patients with clinically significant
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painful physical symptoms at baseline: a meta-analysis of 11 double-blind,

placebo-controlled clinical trials. The primary care companion to CNS disorders
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2011;13.
9. Ball SG, Desaiah D, Zhang Q, Thase ME, Perahia DG. Efficacy and safety of
duloxetine 60 mg once daily in major depressive disorder: a review with expert
commentary. Drugs in context 2013;2013:212245.
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10. Ballesteros J, Callado LF, Gutierrez M. An independent meta-analysis using

summary data for clinical response, remission, and discontinuation for any reason
from the 6 pivotal phase III randomized clinical trials of duloxetine in major
depressive disorder. Journal of clinical psychopharmacology 2007;27:219-21.
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11. Barbui C, Cipriani A, Patel V, Ayuso-Mateos JL, van Ommeren M. Efficacy of

antidepressants and benzodiazepines in minor depression: systematic review and
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meta-analysis. The British journal of psychiatry : the journal of mental science

2011;198:11-6, sup 1.
12. Barbui C, Furukawa TA, Cipriani A. Effectiveness of paroxetine in the treatment
of acute major depression in adults: a systematic re-examination of published and
unpublished data from randomized trials. CMAJ : Canadian Medical Association
journal = journal de l'Association medicale canadienne 2008;178:296-305.
13. Bauer M, Demyttenaere K, El-Khalili N, et al. Pooled analysis of adjunct
extended-release quetiapine fumarate in patients with major depressive disorder

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according to ongoing SSRI or SNRI treatment. International clinical

psychopharmacology 2014;29:16-25.
14. Bauer M, McIntyre RS, Szamosi J, Eriksson H. Evaluation of adjunct extended-
release quetiapine fumarate on sleep disturbance and quality in patients with
major depressive disorder and an inadequate response to on-going antidepressant
therapy. The international journal of neuropsychopharmacology / official
scientific journal of the Collegium Internationale Neuropsychopharmacologicum

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(CINP) 2013;16:1755-65.
15. Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N. The effect of
venlafaxine compared with other antidepressants and placebo in the treatment of

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major depression: a meta-analysis. European archives of psychiatry and clinical
neuroscience 2009;259:172-85.
16. Baumeister H, Hutter N, Bengel J. Psychological and pharmacological

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interventions for depression in patients with diabetes mellitus and depression.
Cochrane Database Syst Rev 2012;12:Cd008381.
17. Beasley CM, Jr., Ball SG, Nilsson ME, et al. Fluoxetine and adult suicidality
revisited: an updated meta-analysis using expanded data sources from placebo-

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controlled trials. Journal of clinical psychopharmacology 2007;27:682-6.
18. Bradley AJ, Lenox-Smith AJ. Does adding noradrenaline reuptake inhibition to
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selective serotonin reuptake inhibition improve efficacy in patients with
depression? A systematic review of meta-analyses and large randomised
pragmatic trials. Journal of psychopharmacology (Oxford, England) 2013;27:740-
58.
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19. Brunton S, Wang F, Edwards SB, et al. Profile of adverse events with duloxetine
treatment: a pooled analysis of placebo-controlled studies. Drug safety : an
international journal of medical toxicology and drug experience 2010;33:393-407.
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20. Bschor T, Baethge C. No evidence for switching the antidepressant: systematic

review and meta-analysis of RCTs of a common therapeutic strategy. Acta
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psychiatrica Scandinavica 2010;121:174-9.

21. Carandang C, Jabbal R, Macbride A, Elbe D. A review of escitalopram and
citalopram in child and adolescent depression. Journal of the Canadian Academy
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of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de

psychiatrie de l'enfant et de l'adolescent 2011;20:315-24.
22. Chen J, Gao K, Kemp DE. Second-generation antipsychotics in major depressive
disorder: update and clinical perspective. Current opinion in psychiatry
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2011;24:10-7.
23. Chuluunkhuu G, Nakahara N, Yanagisawa S, Kamae I. The efficacy of reboxetine
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as an antidepressant, a meta-analysis of both continuous (mean HAM-D score)

and dichotomous (response rate) outcomes. The Kobe journal of medical sciences
2008;54:E147-58.
24. Cipriani A, Furukawa TA, Geddes JR, et al. Does randomized evidence support
sertraline as first-line antidepressant for adults with acute major depression? A
systematic review and meta-analysis. The Journal of clinical psychiatry
2008;69:1732-42.

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25. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability
of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet
2009;373:746-58.
26. Cipriani A, Geddes JR, Furukawa TA, Barbui C. Metareview on short-term
effectiveness and safety of antidepressants for depression: an evidence-based
approach to inform clinical practice. Canadian journal of psychiatry Revue
canadienne de psychiatrie 2007;52:553-62.

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27. Cipriani A, Koesters M, Furukawa TA, et al. Duloxetine versus other anti-
depressive agents for depression. Cochrane Database Syst Rev
2012;10:Cd006533.

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28. Cipriani A, La Ferla T, Furukawa TA, et al. Sertraline versus other antidepressive
agents for depression. Cochrane Database Syst Rev 2009:Cd006117.
29. Cipriani A, Purgato M, Furukawa TA, et al. Citalopram versus other anti-

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depressive agents for depression. Cochrane Database Syst Rev 2012;7:Cd006534.
30. Cipriani A, Santilli C, Furukawa TA, et al. Escitalopram versus other
antidepressive agents for depression. Cochrane Database Syst Rev
2009:Cd006532.

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31. Citrome L. Vilazodone for major depressive disorder: a systematic review of the
efficacy and safety profile for this newly approved antidepressant - what is the
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number needed to treat, number needed to harm and likelihood to be helped or
harmed? International journal of clinical practice 2012;66:356-68.
32. Citrome L. Levomilnacipran for major depressive disorder: a systematic review of
the efficacy and safety profile for this newly approved antidepressant--what is the
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number needed to treat, number needed to harm and likelihood to be helped or

harmed? International journal of clinical practice 2013;67:1089-104.
33. Citrome L. Vortioxetine for major depressive disorder: a systematic review of the
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efficacy and safety profile for this newly approved antidepressant - what is the
number needed to treat, number needed to harm and likelihood to be helped or
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harmed? International journal of clinical practice 2014;68:60-82.

34. Citrome L, Goldberg JF, Portland KB. Placing transdermal selegiline for major
depressive disorder into clinical context: number needed to treat, number needed
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to harm, and likelihood to be helped or harmed. Journal of affective disorders

2013;151:409-17.
35. Clayton AH, Campbell BJ, Favit A, et al. Symptoms of sexual dysfunction in
patients treated for major depressive disorder: a meta-analysis comparing
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selegiline transdermal system and placebo using a patient-rated scale. The Journal
of clinical psychiatry 2007;68:1860-6.
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36. Cooper C, Katona C, Lyketsos K, et al. A systematic review of treatments for

refractory depression in older people. The American journal of psychiatry
2011;168:681-8.
37. Cooper JA, Tucker VL, Papakostas GI. Resolution of sleepiness and fatigue: A
comparison of bupropion and selective serotonin reuptake inhibitors in subjects
with major depressive disorder achieving remission at doses approved in the
European Union. Journal of psychopharmacology (Oxford, England)
2014;28:118-24.

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 ACCEPTED MANUSCRIPT

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C EP
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Appendix B – Description of negative statement appraisal and industry authorship or

industry-related conflicts

PT
Author year Abstract Conclusions Abstract included Author(s) Author(s)
any negative directly with a

RI
statements employed conflict of
expressing caveats by an interest

SC
or did not include industry with an
any positive industry
statements about
the effectiveness

U
or safety/toxicity
of the assessed

AN
antidepressant(s)

Ali 2011 Based on pooled and meta-analysis studies, escitalopram demonstrates superior efficacy No No Yes

M
compared with citalopram and with SSRIs combined. Escitalopram shows similar efficacy
to serotonin noradrenaline reuptake inhibitors but the number of trials in these comparisons

D
is limited. Efficacy differences are modest but clinically relevant, especially in more
severely depressed patients.

TE
Alkhafaji The clinical benefit of escitalopram versus citalopram remains uncertain. In our case of Yes No No
2012 evergreening, escitalopram represented a substantially high proportion of the overall
reimbursement cost burden as compared with citalopram and the generic forms.
EP
Apler 2011 Data concerning remission rates for citalopram, relative to placebo, are inconclusive. No No No
Response rates and symptom reduction scores in citalopram-treated patients with MDD are
C

significantly better relative to placebo treatment, according to a meta-analysis of published

reports. Evaluation of unpublished data is necessary to assess more definitively the
AC

effectiveness of citalopram for MDD.

Arroll 2009 Both TCAs and SSRIs are effective for depression treated in primary care. No Yes Yes

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Aursnes Frequently occurring adverse reactions that are included in today’s SPC for paroxetine Yes No No
2008 were evident and documented already in the early studies accompanying the application for
marketing authorization in 1989. Some other adverse effects observed then are still not

PT
mentioned in the SPC of today. Meta-analyses of adverse effects should be mandatory at
the stage of first registration of a drug.

RI
Baldessarini AD-treatment was associated with new mania-like responses in 8.18% of patients Yes No No
2013 diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD
versus mood-elevating pharmacological effects, as well as quantitative associations

SC
between switching and later diagnosis of BPD not associated with AD-treatment remain
uncertain.
Baldwin The pattern of response in these RCTs suggests that in patients with MDD, GAD or SAD No Yes No

U
2009 in wider clinical practice, a period of at least 4 weeks is worthwhile before considering
further intervention.

AN
Ball 2011 According to this meta-analysis, duloxetine 60 mg once daily is as effective in improving No Yes Yes
painful physical symptoms as it is for depression in patients with MDD and clinically

M
significant painful physical symptoms. The results of this meta-analysis indicate that
duloxetine has small effect sizes in reducing painful physical symptoms and depressive
symptoms in patients with MDD and clinically significant pain levels at baseline. Thus, the

D
results of the study permit one to conclude that duloxetine has a clinically significant
impact on painful physical symptoms and in reducing the severity of depressive symptoms.

TE
However, the results do not address its efficacy compared to other alternatives, as in all
studies the comparator was placebo.
EP
Ball 2013 These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective No Yes Yes
short- and long-term treatment for adults with MDD. The evidence of the independent
analgesic effect of duloxetine 60 mg/day supports its use as a treatment for patients with
C

PPS associated with depression. This review is limited by the fact that it included
randomized clinical trials with different study designs. Furthermore, data from randomized
AC

controlled trials may not generalize well to real clinical practice.

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Ballesteros To summarize, this meta-analysis was designed to get an overview as fair as possible of the No No No
2007 comparative efficacy of duloxetine and active comparators in MDD by combining the
summary results of 6 pivotal RCTs under a multitreatment framework. Our main

PT
finding concerns with the appropriateness of reviewing the dose range currently
recommended for duloxetine, and this issue will be either supported or rejected by further
research. At the moment, we sincerely think more research is needed to clarify the current

RI
evidence regarding the comparative efficacy of duloxetine across different dose ranges.

SC
Barbui 2008 Among adults with moderate to severe major depression in the clinical trials we reviewed, Yes No Yes
paroxetine was not superior to placebo in terms of overall treatment effectiveness and
acceptability. These results were not biased by

U
selective inclusion of published studies.

AN
Barbui 2011 There is evidence showing there is unlikely to be a clinically important advantage for Yes No No
antidepressants over placebo in individuals with minor depression. For benzodiazepines, no
evidence is available, and thus it is not possible to determine their potential therapeutic role
in this condition.

M
Bauer 2009 This meta analysis provides evidence of the clinical efficacy of venlafaxine in achieving No No Yes
therapeutic response and remission in patients with major depression. Venlafaxine appears

D
more effective than SSRIs, and at least as effective as tricyclic antidepressants, in the
treatment of major depressive

TE
episode. Venlafaxine appeared more effective than comparators in treatment resistant
depression. In addition, venlafaxine effective in reducing relapse when given long term
after major depressive episode.
EP
Bauer 2013 Adjunct quetiapine XR improved sleep disturbance and quality vs. placebo No Yes Yes
in patients with MDD and an inadequate response to on-going antidepressant treatment,
C

and was effective against depressive symptoms in patients experiencing high sleep
disturbance.
AC

Bauer 2014 In conclusion, in patients with MDD and inadequate response to ongoing antidepressant, No No Yes
adjunct quetiapine XR (150 and 300 mg/day) was effective in both SSRI and SNRI
subgroups.

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Baumeister Psychological and pharmacological interventions have a moderate and clinically significant No No No
2012 effect on depression outcomes in diabetes patients. Glycaemic control improved
moderately in pharmacological trials, while the evidence is inconclusive for psychological

PT
interventions. Adherence to diabetic treatment regimens, diabetes complications, death
from any cause, health economics and QoL have not been investigated sufficiently.
Overall, the evidence is sparse and inconclusive due to several low-quality trials with

RI
substantial risk of bias and the heterogeneity of examined populations and interventions.

Beasley Fluoxetine treatment led to greater benefit rather than risk for suicidality. No Yes No

SC
2007
Bradley There is sufficient current evidence that demonstrates an increase in efficacy, when No Yes No
2013 noradrenaline reuptake is added to serotonin (5-HT) reuptake, to suggest that patients with

U
severe depression or those who have failed to reach remission with a SSRI may benefit
from treatment with a SNRI. However, as these conclusions are drawn from the evidence

AN
derived from meta-analyses and pragmatic trials, large adequately powered RCTs using
optimal dosing regimens and clinically relevant outcome measures in severe depression
and SSRI treatment failures are still required to confirm these findings.

M
Brunton Duloxetine treatment is associated with significantly higher rates of common TEAEs Yes Yes Yes
2010 versus placebo, regardless of indication or demographic subgroup. Differences across

D
indications are likely to be attributable to the underlying condition rather than duloxetine,
as suggested by the similar trends observed in placebo- and duloxetine-treated patients.

Bschor 2010
TE
There is a discrepancy between the published evidence and the frequent decision to switch
antidepressants, indicating an urgent need for more controlled studies. Pending such studies
Yes No Yes
EP
we recommend that physicians rely on more thoroughly evaluated strategies.

Carandang At present, escitalopram and citalopram should be considered a second-line option for No No Yes
2011 adolescent depression. The US Food and Drug Administration approval of escitalopram for
C

treatment of adolescent depression was based on a single positive RCT. This is less
AC

evidence than typically required for approval of a drug for a new indication.
Chen 2011 Both SGA monotherapy and adjunctive therapy showed greater efficacy in the treatment of No No Yes
MDD than placebo, but augmentation is more widely utilized in treatment resistant
depression. Clinicians should routinely monitor for cardiometabolic side effects and extra
pyramidal symptoms during SGA therapy.

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Chuluunkhu These results suggest that the efficacy of the reboxetine and the other antidepressants No No No
u 2008 (SSRI, TCA and SNRI) on both measures does not differ while it is significantly superior
to placebo.

PT
Cipriani We found a substantial body of evidence regarding the benefits and harms of ADs in the Yes No Yes
2007 treatment of depressive disorder. Nonetheless, there remains considerable residual
uncertainty. The evidence is inadequate for generally applicable recommendations; in most

RI
cases, the balance between risks and benefits will need to be considered for individual
patients. Clinicians should also be guided by the recommendations and warning issued by
drug regulatory authorities.

SC
Cipriani The results of this review suggest that sertraline may be a candidate as the No No Yes
2008 initial choice of antidepressant for people with major depression.

U
Cipriani Clinically important differences exist between commonly prescribed antidepressants for No No Yes

AN
2009a both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be
the best choice when starting treatment for moderate to severe major depression in adults
because it has the most favourable balance between benefits, acceptability, and acquisition

M
cost.

Cipriani Some statistically significant differences favouring escitalopram over other antidepressive No No Yes
2009b agents for the acute phase treatment of major depression were found, in terms of efficacy

D
(citalopram and fluoxetine) and acceptability (duloxetine). There is insufficient evidence to
detect a difference between escitalopram and other antidepressants in early response to

TE
treatment (after two weeks of treatment). Cost effectiveness information is also needed in
the field of antidepressant trials. Furthermore, as with most standard systematic reviews,
the findings rely on evidence from direct comparisons. The potential for overestimation of
EP
treatment effect due to sponsorship bias should also be borne in mind.
Cipriani This systematic review and meta-analysis highlighted a trend in favour of sertraline over No No Yes
2009c other antidepressive agents both in terms of efficacy and acceptability, using 95%
C

confidence intervals and a conservative approach, with a random effects analysis.

However, the included studies did not report on all the outcomes that were pre-specified in
AC

the protocol of this review. Outcomes of clear relevance to patients and clinicians were not
reported in any of the included studies.

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Cipriani Some statistically significant differences between citalopram and other antidepressants for No No Yes
2012a the acute phase treatment of major depression were found in terms of efficacy, tolerability
and acceptability. Citalopram was more efficacious than paroxetine and reboxetine and

PT
more acceptable than tricyclics, reboxetine and venlafaxine, however, it seemed to be less
efficacious than escitalopram. As with most systematic reviews in psychopharmacology,
the potential for overestimation of treatment effect due to sponsorship bias and publication

RI
bias should be borne in mind when interpreting review findings. Economic analyses were
not reported in the included studies, however, cost effectiveness information is needed in
the field of antidepressant trials.

SC
Cipriani Duloxetine did not seem to provide a significant advantage in efficacy over other Yes No Yes
2012b antidepressive agents for the acute-phase treatment of major depression. No differences in

U
terms of efficacy were found, even though duloxetine was worse than some SSRIs (most of
all, escitalopram) and newer antidepressants (like venlafaxine) in terms of acceptability and

AN
tolerability. Unfortunately, we only found evidence comparing duloxetine with a handful of
other active antidepressive agents and only a few trials per comparison were found (in
some cases we retrieved just one trial). This limited the power of the review to detect
moderate, but clinically meaningful differences between the drugs. As many statistical tests

M
have been used in the review, the findings from this review are better thought of as
hypothesis forming rather than hypothesis testing and it would be very comforting to see
the conclusions replicated in future trials. Most of included studies were sponsored by the

D
drug industry manufacturing duloxetine. As for all other new investigational compounds,
the potential for overestimation of treatment effect due to sponsorship bias should be borne

TE
in mind. In the present review no trials reported economic outcomes. Given that several
SSRIs and the great majority of antidepressants are now available as generic formulation
(only escitalopram, desvenlafaxine and duloxetine are still on patent), more comprehensive
EP
economic estimates of antidepressant treatment effect should be considered to better inform
healthcare policy.
C
AC

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Citrome Vilazodone represents another option for the treatment of MDD. Vilazodone appears to No No Yes
2012 have a favourable weight-gain profile based on short-term studies. Sexual side-effects were
not consistently demonstrated when assessed using clinical rating scales but spontaneously

PT
reported AEs related to sexual functioning were observed. Additional controlled data
regarding long-term efficacy and effectiveness will help characterise this new agent when
used in maintenance treatment.

RI
Citrome NNT for transdermal selegiline for efficacy is similar to that for other antidepressant No Yes Yes
2013a regimens for which similar analyses have been published. There appear to be no clinically

SC
relevant effects of selegiline on weight or sexual functioning.

Citrome Levomilnacipran represents another option for the treatment of MDD. Levomilnacipran No No Yes

U
2013b appears to have a favourable weight-gain profile. Additional controlled data regarding
long-term efficacy and comparative effectiveness will help characterise this new agent

AN
Citrome Vortioxetine represents another option for the treatment of MDD. Vortioxetine appears to No No Yes
2014 have a favourable weight-gain profile. Additional information regarding the time course of
response/remission and for the commonly occurring AE of nausea would be helpful to

M
better characterise this agent. Pending clinical trials include those examining cognitive
dysfunction that can accompany MDD

D
Clayton This meta-analysis suggests that short-term therapy with STS 6mg/24 hours does not No Yes Yes
2007 impair any aspect of sexual function in MDD patients as measured using a patient-rated

TE
questionnaire.
Cooper 2014 Bupropion treatment at the EU-approved dose of ≤300 mg/day may offer advantages over No Yes Yes
SSRIs in the resolution of sleepiness and fatigue in remitted MDD patients
EP
De SSRIs appear to be efficacious and well tolerated in the treatment of post partum No No No
Crescenzo depression, but the available evidence fails to demonstrate a clear superiority over other
C

2014 treatments.
AC

de Silva The superior efficacy of venlafaxine over SSRIs is of clinical importance. However, higher Yes No Yes
2012 rates of discontinuation due to adverse events for venlafaxine compared with SSRIs are a
disadvantage. Findings of this meta-analysis that included only published studies were
similar to those from meta-analysis that included unpublished data.

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Demyttenaer The present pooled analysis shows that, from a clinical point of view, agomelatine is at No No Yes
e 2013 least as efficacious as the investigated SSRIs with a trend to fewer discontinuations due to
adverse events.

PT
Deshauer There is a lack of classic randomized controlled trials of serotonin reuptake inhibitors No No No
2008 lasting more than 1 year for the treatment of depression. The results of our systematic
review support current recommendations for 6–8 months of antidepressant treatment

RI
following initial recovery but provide no guidance for longer treatment.
Dolder 2008 Overall, agomelatine is a promising and well-tolerated medication for the treatment of No No No

SC
major depressive disorder. More large-scale controlled trials are needed to gain a better
understanding of the relative efficacy and safety of agomelatine.
Dowlati Treatment with ADs for depression in CAD results in significant therapeutic effects No No Yes

U
2010 without substantially increased rates of discontinuation.

AN
Ehret 2014 SSRIs prevent depression in patients with HCV treated with INF-a therapy. The impact of No No No
SSRIs on completion of antiviral therapy or on the development of adverse events is less
clear.

M
Emslie 2007 Venlafaxine ER may be effective in depressed adolescents. However, its safety and No Yes Yes
efficacy in pediatric patients has not been established. Prescribers should monitor for signs
of suicidal ideation and hostility in pediatric patients taking venlafaxine ER.

D
Eyding 2010 Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published Yes No No

TE
evidence is affected by publication bias, underlining the urgent
need for mandatory publication of trial data.
Farahani Antidepressant-antipsychotic cotreatment was superior to monotherapy with either drug No No Yes
EP
2012 class in the acute treatment of psychotic depression. These results support recent treatment
guidelines, but more studies are needed to assess specific combinations and
maintenance/relapse-prevention efficacy.
C

Fishbain Duloxetine’s analgesic effect is independent of the drug’s antidepressant effect. No Yes Yes
2008 Additionally, faster onset of the analgesic effect appears to be a population specific
AC

phenomenon that is unmodified in the presence of active agents.

Fournier The magnitude of benefit of antidepressant medication compared with placebo increases Yes No Yes
2010 with severity of depression symptoms and may be minimal or nonexistent, on average, in
patients with mild or moderate symptoms. For patients with very severe depression, the
benefit of medications over placebo is substantial.

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Gartlehner Adverse event profiles are similar among second-generation antidepressants. However, Yes No Yes
2008 different frequencies of specific adverse events might be clinically relevant and influence
the choice of a treatment.

PT
Gartlehner Current evidence does not warrant the choice of duloxetine over other second-generation Yes No Yes
2009 antidepressants based on greater efficacy or safety for patients with acute-phase MDD with
or without accompanying symptoms such as pain.

RI
Gartlehner Current evidence does not warrant recommending a particular second-generation Yes No Yes
2011 antidepressant on the basis of differences in efficacy. Differences in onset of action and

SC
adverse events may be considered when choosing a medication.
Gibbons This is the first research synthesis in this area to use complete longitudinal person-level No No Yes
2012a data from a large set of published and unpublished studies. The results do not support

U
previous findings that antidepressants show little benefit except for severe depression. The
antidepressants fluoxetine and venlafaxine are efficacious for major depression, in all age

AN
groups although more so in youth and adults compared with geriatric patients. Baseline
severity was not significantly related to degree of treatment advantage over placebo.

M
Gibbons Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric No No Yes
2012b patients. This protective effect is mediated by decreases in depressive symptoms with

D
treatment. For youths, no significant effects of treatment on suicidal thoughts and behavior
were found, although depression responded to treatment. No evidence of increased suicide

TE
risk was observed in youths receiving active medication. To our knowledge, this is the first
research synthesis of suicidal thoughts and behavior in depressed patients treated with
antidepressants that examined the mediating role of depressive symptoms using complete
longitudinal person-level data from a large set of published and unpublished studies.
C EP

Glue 2010 This meta-analysis emphasizes the importance of continuation treatment No Yes Yes
following acute response in depressive disorders. The robust findings of relapse prevention
AC

designs contrast with acute antidepressant efficacy studies, and may be due to enrichment
of the patient population.

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Guaiana This present systematic review indicates that amitriptyline is at least as efficacious as other Yes No No
2007 tricyclics or newer compounds. However, the burden of side-effects in patients receiving it
was greater. In comparison with selective serotonin reuptake inhibitors amitriptyline was

PT
less well tolerated, and although counterbalanced by a higher proportion of responders, the
difference was not statistically significant.

Guaiana Agomelatine did not seem to provide a significant advantage in efficacy over other Yes No No

RI
2013 antidepressive agents for the acute-phase treatment of major depression. Agomelatine was
better tolerated than paroxetine and venlafaxine in terms of overall side effects, and fewer

SC
participants treated with agomelatine dropped out of the trials due to side effects compared
to sertraline and venlafaxine, but data were limited because the number of included studies
was small. We found evidence that compared agomelatine with only a small number of
other active antidepressive agents, and there were only a few trials for each comparison,

U
which limits the generalisability of the results. Moreover, the overall methodological
quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning

AN
the efficacy and tolerability of agomelatine.

Hansen 2008 This review demonstrates the overall benefits of continuation- and maintenance-phase No No Yes

M
treatment of major depression with second-generation antidepressants and emphasizes the
need for additional studies of comparative differences among drugs.

D
Hazel 2013 Data suggest tricyclic drugs are not useful in treating depression in children. There is Yes No Yes
marginal evidence to support the use of tricyclic drugs in the treatment of depression in

TE
adolescents.
Hetrick 2007 Caution is required to interpret the results. First, there were methodological issues, Yes No No
including high attrition, issues regarding measurement instruments and clinical usefulness
EP
of outcomes, often variously defined across trials. Second, patients seen in clinical practice
are likely to be more unwell, and at greater risk of suicide, compared to those in the trials,
and it is unclear how this group would respond to SSRIs. This needs to be considered,
along with the evidence of an increased risk of suicide related outcomes in those treated
C

with SSRIs. It is unclear what the effect of SSRIs is on suicide completion. While untreated
AC

depression is associated with the risk of completed suicide and impacts on functioning, it is
unclear whether SSRIs would modify this risk in a clinically meaningful way.

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Hetrick 2012 Caution is required in interpreting the results given the methodological limitations of the Yes No No
included trials in terms of internal and external validity. Further, the size and clinical
meaningfulness of statistically significant results are uncertain. However, given the risks of

PT
untreated depression in terms of completed suicide and impacts on functioning, if a
decision to use medication is agreed, then fluoxetine might be the medication of first
choice given guideline recommendations. Clinicians need to keep in mind that there is

RI
evidence of an increased risk of suicide-related outcomes in those treated with
antidepressant medications.

SC
Hou 2013 Prophylactic SSRI antidepressants can significantly reduce the incidence of PEG-IFN- No No No
a/RBV-associated depression in patients with CHC, with good safety and tolerability,
without reduction of SVR.

U
Howland Agomelatine was generally well tolerated compared with placebo. Its adverse effect profile Yes No Yes
2011 is different to that of other antidepressant drugs, but its overall tolerability in studies with

AN
other antidepressants as active control drugs did not appear to be substantially better than
the controls. Agomelatine is contraindicated in patients with impaired liver function and in
patients taking drugs that potently inhibit cytochrome P450 1A2 metabolic enzymes.

M
Because elevated liver enzymes are common, and there is a rare risk of more serious liver
reactions, routine laboratory monitoring of liver function is recommended periodically
throughout treatment. Based on this comprehensive review, agomelatine does not have

D
clinically significant advantages compared with other antidepressant drugs, and it has
certain limitations and disadvantages. Because of the unique pharmacology of agomelatine

TE
and its reported tolerability profile, it should only be considered as an alternative drug for
patients who do not respond to or cannot tolerate other antidepressant drugs.
EP
Iovieno These results support the utility of certain antidepressants (tricyclics, nefazodone) in No No Yes
2011a treating depression in patients with comorbid alcohol use disorders. More data on the use
C

of newer antidepressants, including the SSRIs, for this select patient population are needed.
AC

Iovieno Antidepressants are effective for MDD in patients who present with co-morbid axis-III No No Yes
2011b disorders and as effective (vs. placebo) in this population as they are in the general MDD
population. Higher general response rates observed in the co-morbid MDD population are
intriguing, and require replication.

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Julious 2013 There was evidence of an increased risk in suicide-related outcomes on antidepressant Yes No Yes
treatments, while antidepressant treatments were also shown to be efficacious.
Kantrowitz Although rare, the present study indicates that tricyclic monotherapy may be temporally Yes No Yes

PT
2008 associated with an exacerbation of psychotic symptoms in patients with unipolar MDDP,
potentially worsening prognosis.

RI
Kasper 2009 Escitalopram is a good therapeutic option for the long-term treatment of MDD, No Yes Yes
particularly in severely depressed patients.

SC
Kasper 2010 Our results based on pooled data from 15 placebo-controlled, short-term studies of No Yes Yes
mirtazapine in MDD using the suicide item scores from the HAMD as a proxy outcome
measure for suicidality risk, demonstrate that mirtazapine was associated with statistically

U
significantly lower suicidality risk compared to placebo.

AN
Katzman There were no significant and valid differences between paroxetine and other No Yes Yes
2007 antidepressants to suggest that multiple modes of action improve clinical outcomes.

Kaymaz Antidepressants robustly reduce relapse risk in the maintenance phase, regardless of a No No Yes

M
2008 number of clinical and pharmacologic factors. There is evidence, however, that with the
increasing number of episodes, patients develop a relative resistance against the
prophylactic properties of antidepressant medication.

D
Kennedy In this meta-analysis, superior efficacy of escitalopram compared to SSRIs and SNRIs was No Yes Yes

TE
2009 confirmed, although the superiority over SSRIs was largely explained by differences
between escitalopram and citalopram.
Khan 2012 In conclusion, the combination of psychotherapy and antidepressants for depression may No No Yes
EP
provide a slight advantage whereas antidepressants alone and psychotherapy alone are not
significantly different from alternative therapies
or active intervention controls. These data suggest that type of treatment offered is less
C

important than getting depressed patients involved in an active therapeutic program. Future
research should consider whether certain patient profiles might justify a specific treatment
AC

modality.

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Kilts 2009 Newer generation antidepressant medications clearly differ in their efficacy as a No Yes Yes
function of baseline symptom severity. The selective serotonin reuptake inhibitor
escitalopram had superior efficacy in the treatment of more severe depression, perhaps

PT
attributable to differential efficacy related to symptoms of negativistic thinking.
Kirsch 2008 Drug–placebo differences in antidepressant efficacy increase as a function of baseline Yes No Yes
severity, but are relatively small even for severely depressed patients. The relationship

RI
between initial severity and antidepressant efficacy is attributable to decreased
responsiveness to placebo among very severely depressed patients, rather than to increased
responsiveness to medication.

SC
Koesters There were no significant differences between venlafaxine and selective serotonin reuptake Yes No No
2011 inhibitor on any of these parameters. Analyses of publication bias were inconclusive.

U
Chinese researchers have published a number of randomized controlled trials comparing
venlafaxine to active comparators, but study quality was found to be low. To make optimal

AN
use of their research potential Chinese, researchers will have to improve trial reporting and
the peer-review process.

M
Koesters We found evidence suggesting that a clinically important difference between agomelatine Yes No Yes
2013 and placebo in patients with unipolar major depression is unlikely. There was evidence of
substantial publication bias

D
Kok 2011 Continuing treatment with antidepressants in elderly patients is efficacious compared with No No Yes
placebo in preventing relapses and recurrences. Efficacy and tolerability during long-term

TE
treatment does not differ between TCAs and SSRIs.
Kok 2012 Antidepressant treatment in older depressed patients is efficacious. We could not No No Yes
demonstrate differences in effectiveness between different classes of antidepressants; this
EP
was also the case in more severely depressed patients.
Kornstein This pooled analysis indicates that escitalopram is at least as effective as the SNRIs No Yes Yes
C

2009 (venlafaxine XR and duloxetine), even in severe depression, and escitalopram treatment
was better tolerated.
AC

Kornstein Desvenlafaxine generally improved depressive symptoms across age and sex subgroups. No Yes Yes
2010
Krebs 2008 The authors found insufficient evidence to support the choice of one second-generation Yes No No
antidepressant over another in patients with pain accompanying depression.

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 ACCEPTED MANUSCRIPT

Kriston 2014 Several evidence-based acute pharmacological, psychotherapeutic, and combined No No Yes
treatments for persistent depressive disorder are available with significant differences
between them.

PT
Lam 2008 This pooled analysis shows that over an 8-week treatment period, escitalopram (10–20 No Yes Yes
mg/day) is superior in both effectiveness and tolerability compared with duloxetine (60
mg/day).

RI
Lam 2010 In conclusion, escitalopram is associated with a better efficacy and tolerability profile than No Yes Yes
SNRIs (duloxetine and venlafaxine) when used as a second step treatment in patients with

SC
MDD. These results should be confirmed in prospective randomized clinical trials.
Laoutidis This meta-analysis suggests that antidepressants can be effective in treating depressive No No No
2013 symptoms beside clinical depression. When considering the risk of side effects and

U
interactions and the heterogeneity among the mostly small studies, a general
recommendation cannot be made until well-controlled studies are conducted.

AN
Laughren Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages Yes No No
2011 compared to other drugs in the antidepressant class.

M
Lenox-Smith In this model, venlafaxine was shown to be a cost-effective alternative to generic fluoxetine No Yes Yes
2009 and amitriptyline when used as a first-line therapy. Thus, cost of therapy should not be a
barrier to use of venlafaxine as a first-line option in treating major depressive disorder in

D
primary care in the UK.

TE
Leucht 2012 Amitriptyline is an efficacious antidepressant drug. It is, however, also associated with a Yes No Yes
number of side effects. Degree of placebo response and severity of depression at baseline
may moderate drug-placebo efficacy differences.
EP
Levkovitz These results support the utility of antidepressants for dysthymic disorder. In fact, the No No Yes
2011 margin of efficacy of antidepressants for dysthymic disorder was larger than for MDD.
Future studies providing longer-term data on the treatment of dysthymic disorder with
C

antidepressants are essential.

AC

Lieberman Adverse events were comparable to those found with other drugs sharing a similar No Yes Yes
2008 mechanism of action. These data support the efficacy, safety, and tolerability of
desvenlafaxine in the treatment of major depressive disorder.

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Liebowitz Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the No Yes Yes
2010 treatment of MDD in placebo-controlled trials. A long-term study is underway to further
explore desvenlafaxine 50 mg/d for MDD.

PT
Liu 2013 There is insufficient evidence to support antidepressant efficacy for SSRIs, pramipexole, Yes No No
pergolide and SNRIs.TCAs might be the best choice when starting antidepressant treatment
in patients of Parkinson’s disease because it has the most favorable balance between

RI
benefits and acceptability, followed by pramipexole and SNRIs, SSRIs might be the last
choice.

SC
Ma 2013 Sertraline and mirtazapine exhibited optimally balanced efficacy, acceptability, and safety No No No
for first-line acute treatment of child and adolescent MDD.

Macedo This systematic review and meta-analysis showed that all RCTs included reported efficacy No Yes Yes

U
2011 outcomes for pirlindole comparable to those of its comparators, and that pirlindole was

AN
significantly better in terms of reducing anxiety symptoms. However, the analysis of these
results should take into account the quality of the original included articles, which had a
mean Jadad trial quality score of 3.7 (out of 5). Therefore, further clinical trials should be
conducted to evaluate the benefits of pirlindole.

M
Magni 2013 The present study detected differences in terms of efficacy and tolerability between Yes No Yes
fluoxetine and certain ADs, but the clinical meaning of these differences is

D
uncertain.Moreover, the assessment of quality with the risk of bias tool showed that the
great majority of included studies failed to report details on methodological procedures. Of

TE
consequence, no definitive implications can be drawn from the studies’ results. The better
efficacy profile of sertraline and venlafaxine (and possibly other ADs) over fluoxetine may
be clinically meaningful, as already suggested by other systematic reviews. In addition to
EP
efficacy data, treatment decisions should also be based on considerations of drug toxicity,
patient acceptability and cost.
C

Mallinckrodt Potentially important differences in symptom response patterns were found between No Yes No
2007 duloxetine and the combined SSRIs depending on symptom severity, and different HAMD
AC

17 items responded differently to duloxetine compared with SSRIs. Understanding these

differences may be useful in tailoring antidepressant therapy for individual patients.

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Maneeton According to the limited data obtained from three RCTs, bupropion XL is as effective and No No Yes
2013 tolerable as venlafaxine XR for adult patients with MDD. Further studies in this area
should be conducted to confirm these findings.

PT
Maneeton Based on the limited evidence obtained from three RCTs, quetiapine XR is effective for Yes No Yes
2012 adult patients with MDD. The high dropout rate due to adverse events suggests that some
MDD patients may not be able to tolerate quetiapine XR. Due to the balance of its efficacy

RI
benefit and risk of side effects, as the overall discontinuation rate shown, the acceptability
of this agent is not more than placebo. These results should be viewed as the very
preliminary one. Further studies in this area are warranted.

SC
Marangell In conclusion, consistent with our hypothesis, duloxetine produced a substantial direct No Yes Yes
2011 effect on pain improvement and change in mood exerted a modest indirect effect on pain

U
improvements in patients with fibromyalgia and MDD. Hence, both direct and indirect
analgesic and antidepressant properties appear to be relevant for the treatment of these

AN
comorbid patients with duloxetine.

Montgomery In this meta-analysis, the statistically significant superior efficacy of escitalopram No Yes Yes

M
2011 compared to citalopram was shown to be clinically relevant.

Mukai 2009 The available data, although limited, suggest that the dual-action agents (TCAs and SNRIs) Yes No No
do not appear to confer any additional benefits in efficacy over single-action agents

D
(SSRIs) in the treatment of depression in the elderly.

TE
Nakagawa The overall effectiveness and tolerability of milnacipran versus other antidepressants does No No Yes
2008 not seem to differ in the acute phase of treatment for major depresion. However, there is
some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due
EP
to adverse events and the rates of patients experiencing adverse events. Milnacipran may
benefit some patient populations who experience adverse effects from other antidepressants
in the acute phase of treatment for major depression.
C
AC

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Nakagawa Currently, there is inadequate evidence to conclude whether milnacipran is superior, Yes No Yes
2009 inferior or the same as other antidepressive agents in terms of efficacy, acceptability and
tolerability in the acute phase treatment of major depression. However, there is some

PT
evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events
(acceptability) and the rates of experiencing adverse events (tolerability). Information
about other clinically meaningful outcomes such as cost-effectiveness and social

RI
functioning, including the ability to return to work, is lacking. Further study is needed to
answer whether milnacipran would be the better choice of antidepressant for acute major
depression.

SC
Nelson 2008 Antidepressants are more effective than placebo in elderly depressed subjects although No No Yes
effects are modest and vary. Identification of the characteristics of responders and

U
nonresponders will be crucial to improving treatment outcomes

AN
Nelson 2009 In randomized, placebo-controlled trials, anxiety in late-life depression was not associated No No Yes
with decreased response to second generation antidepressants

Nelson 2010 Duloxetine was more effective than placebo in achieving response and remission in both No No Yes

M
anxious and nonanxious patients. Anxious status did not affect the magnitude of the drug
effect.

D
Nelson 2011 The evidence for antidepressant treatment of people with depression and dementia, Yes No Yes
although suggestive, does not confirm efficacy. All of the trials were

TE
significantly underpowered to detect differences, resulting in inconclusive findings.
Variable trial methods, comorbid conditions, and differences in antidepressants employed
further confounded findings.
EP
Nelson 2013 Older patients with a long illness duration and moderate to severe depression appear to No No Yes
benefit from antidepressants as compared with placebo. Antidepressants do not appear to
be effective for older patients with short illness duration.
C

Nieuwenhuij Based on a heterogeneous sample of studies, there is currently no evidence of an effect of Yes No No
sen 2008 medication alone, enhanced primary care, psychological interventions or the combination
AC

of those with medication on sickness absence of depressed workers. In future RCTs,

interventions should specifically address work issues, and occupational outcomes should be
used to measure the effect.

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Oakes 2013 These safety results may better inform clinicians providing individualized care to elderly No Yes Yes
patients with major depressive disorder.
Offidani Risks of excessive mood elevation during antidepressant treatment, including mania- Yes No No

PT
2013 hypomania, were much greater than with placebo, and similar in juvenileanxiety and
depressive disorders. Excessive arousalactivation in children or adolescents treated with
antidepressants for anxiety as well as depressive disorders calls for particular caution and

RI
monitoring for potential risk of future bipolar disorder.

Omori 2009 There were no large differences between fluvoxamine and any other antidepressants in Yes No Yes

SC
terms of efficacy and tolerability. There is evidence of differing side effect profiles,
especially when comparing gastrointestinal side effects between fluvoxamine and
tricyclics. Clinicians should focus on practically or clinically relevant differences including

U
those in side-effect profiles.

AN
Omori 2010 We found no strong evidence that fluvoxamine was either superior or inferior to any other Yes No Yes
antidepressants in terms of efficacy and tolerability in the acute phase treatment of
depression. However, differing side effect profiles were evident. Based on these findings,
we conclude that clinicians should focus on practical or clinically relevant considerations,

M
including these differences in side effect profiles.

Pae 2013 STS appears to be comparably efficacious and tolerable in atypical and nonatypical No Yes Yes

D
subtypes of MDD. Adequately powered, controlled, clinical trials are necessary to confirm
our findings.

TE
Pani 2010 There is low evidence, at the present, supporting the clinical use of antidepressants for the Yes No No
treatment of depressed opioid addicts in treatment with opioid agonists. There is a need of
larger randomised studies investigating relevant outcomes, safety issues and reporting data
EP
to allow comparison of results.
Papakostas These results suggest that milnacipran and the SSRIs do not differ with respect to their No No Yes
C

2007a overall efficacy in the treatment of MDD.

AC

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Papakostas These results suggest that the 5HT2-receptor antagonists trazodone and nefazodone and the No No Yes
2007b SSRIs do not differ with respect to their overall efficacy and tolerability in the treatment of
MDD. Although the sample size was relatively large and conveyed sufficient statistical

PT
power to test for differences in the overall sample, depression is a heterogeneous condition
and differences may exist between treatments in particular subgroups of patients.

RI
Papakostas Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage No No Yes
2007c compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one
indicator of clinical significance, nearly 24 patients would need to be treated with dual-

SC
action antidepressant drugs instead of SSRIs in order to obtain one additional responder.
This difference falls well below the mark of NNT 10 suggested by the United Kingdom’s
National Institute of Clinical Excellence but nonetheless might be of public health

U
relevance given the large number of depressed patients treated with SSRI /serotonin-
norepinephrine reuptake inhibitor (SNRI) antidepressant drugs. Further research is needed

AN
to examine whether larger differences between classes of antidepressant drugs might exist
in specific MDD sub-populations or for specific MDD symptoms.

M
Papakostas There does not appear to be any statistically detectable difference in the rapidity of No Yes Yes
2007d antidepressant effect between bupropion and the SSRIs overall or escitalopram specifically.

D
Papakostas These results suggest that mirtazapine and the SSRIs differ with respect to their side-effect No No Yes

TE
2008a profile but not their overall efficacy in the treatment of MDD.
Papakostas Contrary to clinician impression, there does not appear to be any difference in the No Yes No
2008b anxiolytic efficacy of bupropion and the SSRIs when used to treat MDD.
EP
Papakostas These results suggest a modest yet statistically significant advantage in remission rates No No Yes
2008c when switching patients with SSRI-resistant depression to a non-SSRI rather than an SSRI
antidepressant. With the number needed to treat (NNT) statistic as one indicator of clinical
C

significance, nearly 22 SSRI nonresponders would need to be switched to a non-SSRI

rather than a second SSRI antidepressant to obtain one additional remitter. This difference
AC

falls well below the mark of NNT 10 suggested by the United Kingdom’s National
Institute of Clinical Excellence but nonetheless might be of public health relevance given
the large number of SSRI-resistant patients switched to an SSRI versus a non-SSRI
antidepressant.

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Papakostas Initiating treatment with SSRIs at doses higher than those typically used in clinical Yes No Yes
2010 trials/settings is associated with higher response rates but also higher rates of
discontinuation due to intolerance. Developing treatment strategies allowing clinicians to

PT
deliver higher initial SSRI doses while enhancing the tolerability of treatment may
represent an alternative approach to improving the efficacy of treatment of MDD.

Papakostas Escitalopram was more effective than placebo, and as effective as the SSRIs andSNRIs, in No Yes No

RI
2011 the treatment of anxious MDD. The present analysis provides some evidence that the
presence of an anxious MDD subtype is a predictor of poor response. There was no

SC
difference in the response to treatment of patients with or without anxious MDD to
escitalopram, SSRIs, or SNRIs. The present analysis did not support the notion that SNRIs
are more effective than escitalopram in the treatment of anxious MDD, nor was there
evidence to support treatment moderating effects for anxious MDD.

U
Papakostas Subdividing patients with severe major depressive disorder into those with versus without No Yes Yes

AN
2012 anxious depression results in the characterization of sub-types that are particularly
“responsive” (severe non-anxious) and “unresponsive” (severe anxious) to selective
serotonin reuptake inhibitor therapy (relative to placebo). These findings are preliminary,

M
of yet undetermined clinical relevance, and warrant replication and further exploration.

Pedrelli These results show no difference in the depressive outcome of patients with comorbid Yes No Yes

D
2011 opiateuse disorders on MMTwhether they are on medication or placebo. Future studies
examining the effectiveness of antidepressants while controlling for several variables such

TE
as psychosocial treatment and assessing the specific classes of antidepressants are needed.

Pizzi 2011 A significantly greater improvement in depression symptoms was always apparent in No No No
EP
patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and
depression, SSRI medication decreases depression symptoms and may improve CHD
prognosis.
C

Pjrek 2009 Thus escitalopram and reboxetine were equally effective in treating SAD on all primary No No Yes
AC

and secondary outcome measures. Reboxetine displayed a faster onset of action, but was
associated with more pronounced side effects. Further studies comparing SSRI and NARI
in SAD are warranted.

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Price 2011 Antidepressants are effective for the treatment of depression in patients with neurological No No No
disorders but the evidence for the efficacy of antidepressants in improving quality of life,
and functional and cognitive outcomes is inconclusive.

PT
Pritchett The effect size analyses demonstrate that duloxetine 40 mg has minimum efficacy, and that No Yes No
2007 duloxetine 60–120 mg/day is effective in the treatment of patients with MDD. An initial
dose less than 60 mg/day might provide better tolerability for some patients diagnosed with

RI
MDD.
Ramsberg Of the investigated antidepressants, escitalopram has the highest probability of remission No Yes No

SC
2012 and is the most effective and cost-effective pharmacological treatment in a primary care
setting, when evaluated over a one year time horizon. Small differences in remission rates
may be important when assessing costs and cost-effectiveness of antidepressants.

U
Rayner 2010 This review provides evidence that antidepressants are superior to placebo in treating No No No
depression in physical illness. However, it is likely that publication and reporting biases

AN
exaggerated the effect sizes obtained. Further research is required to determine the
comparative efficacy and acceptability of particular antidepressants in this population.

M
Rayner 2011 This review provides evidence that antidepressants are effective in treating depression in No Information No
palliative care. Their superiority over placebo is apparent within 4–5 weeks and increases on COI not
with continued use. It is probable that the effect sizes yielded in this review overestimate available

D
the efficacy of antidepressants due to biases such as selective reporting and publication.
Nevertheless, the magnitude and consistency of the effect suggests genuine benefit.

TE
Reddy 2010 Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the No Yes No
treatment of MDD in two placebo-controlled trials. The metabolic profile of desvenlafaxine
suggests a low risk of drug–drug interactions owing to minimal inhibitory effects on
EP
CYP2D6, lack of interaction with p-glycoprotein, and low protein binding.
C

Reed 2012 Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant No Yes Yes
improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are
AC

supported by subgroup analysis and open-label, long-term effectiveness data.

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Reichenpfad Because of the indirect nature of the comparisons, the often wide credible intervals, and the Yes No Yes
er 2014 high variation in magnitude of outcome, we rated the overall strength of evidence with
respect to our findings as low. The current degree of evidence does not allow a precise

PT
estimate of comparative risk of SD associated with a specific antidepressant. In the absence
of such evidence, clinicians need to be aware of SD as a common adverse event and should
discuss patients’ preferences before initiating antidepressant therapy.

RI
Robinson Results demonstrate that improvement in pain and mood contributes to functional No Yes Yes
2013 improvement, and pain reduction and functional improvement increase the likelihood of
remission of depressive symptoms with duloxetine treatment in patients with both MDD

SC
and PPS at baseline.
Robinson A comprehensive review of safety from the clinical development program suggests that the No No Yes

U
2008 STS is safe and well tolerated, with an improved safety margin compared with orally
administered MAOIs.

AN
Rocha 2012 The results suggest that antidepressant combination is more efficient than a single No No Yes
antidepressant without a significant decrease in tolerability. However, the small number of
clinical trials and methodological problems precludes definitive conclusions

M
Rocha 2013 The results suggest antidepressants may be efficacious in the treatment of dPD. However, No No Yes
the results were unstable. In fact, the small number of trials and methodological drawbacks

D
preclude definitive conclusions about their efficacy and tolerability in dPD.
Rooney No high-quality studies have examined the value of any drug treatment of depression in Yes No No

TE
2010 patients with primary brain tumours. Detailed prospective studies and RCTs are needed to
inform the safe and effective treatment of this common and important complication of
brain tumours.
EP
Salter 2013 The early initiation of antidepressant therapy, in nondepressed stroke patients, may reduce No No No
the odds for development of PSD. Optimum timing and duration for treatment and the
identification of the most appropriate recipients for a program of indicated prevention
C

require additional examination.

AC

Sarkar 2013 Antidepressant pretreatment with selective serotonin reuptake inhibitors lowers the No No Yes
incidence and severity of IFN-associated depression in patients with chronic hepatitis C
infection or malignant melanoma.

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Schmitt In conclusion, these analyses demonstrate that venlafaxine may be superior to SSRIs in No Yes Yes
2009 achieving remission in both mild/moderate and severely depressed patients. The greater
difference in remission rates among patients with baseline HAM-D17 C 30 suggests a more

PT
pronounced clinical benefit that may be achieved with venlafaxine in severely depressed
patients.

Schueler Rather than being a first-line option, venlafaxine appears to be a valid alternative in Yes No Yes

RI
2011 patients who do not tolerate or respond to SSRIs or TCAs. Duloxetine does not seem to be
indicated as a first-line treatment.

SC
Seitz 2010 Currently there are few studies directly comparing citalopram to other antidepressants for Yes No No
LLD. The small number of studies and methodological issues in many studies limit any
conclusions about the relative efficacy and tolerability of citalopram compared to other

U
antidepressants. Well designed studies comparing citalopram to other antidepressants for
LLD are required.

AN
Serretti 2011 Our results, though significant, were generally observed with small estimate values, their Yes No Yes
clinical relevance is subtle since each feature is expected to influence marginally the whole
outcome, and probably amore pronounced effect could result only by analyzing very large

M
samples.
Signorovitch Treatment of adult MDD patients with escitalopram was significantly more likely to result No Yes Yes

D
2011 in remission without concurrent AEs compared to treatment with current SNRIs. Study
limitations include focus on only the initial 8 weeks of treatment and exclusion of trials for

TE
which individual patient data were not obtained.

Singh 2011 Although there is evidence of the superiority of agomelatine over placebo and selected Yes Yes No
antidepressants, it is questionable whether the magnitude of effect size is clinically
EP
significant and sample characteristics are relevant to the general patient population with
major depressive disorder.
C

Skapinakis These results suggest that there is insufficient evidence to reject the null hypothesis of no Yes No Yes
2010 differences in efficacy between SSRIs and placebo in the treatment of depression in PD.
AC

Due to the limited number of studies and the small sample sizes a type II error (false
negative) cannot be excluded. The comparison between SSRIs and TCAs is based on only
three studies and further trials with more pragmatic design are needed.

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Soares 2009 Desvenlafaxine therapy resulted in significant improvements in functioning and well-being No Yes Yes
among MDD patients.
Stein 2011 Additional research assessing the comparative effects of antidepressants with No Yes Yes

PT
polysomnography is needed. In the interim, from a clinical perspective, escitalopram
appears to be beneficial for the treatment of sleep problems in MDD and GAD.

RI
Stein 2013 Once-a-day oral agomelatine is a new, efficacious alternative option for the treatment of No Yes Yes
anxiety in patients with major depression.

SC
Stone 2009 Risk of suicidality associated with use of antidepressants is strongly age dependent. Yes No No
Compared with placebo, the increased risk for suicidality and suicidal behaviour among
adults under 25 approaches that seen in children and adolescents. The net effect seems to
be neutral on suicidal behaviour but possibly protective for suicidal ideation in adults aged

U
25-64 and to reduce the risk of both suicidality and suicidal behaviour in those aged ≥65.

AN
Szegedi The results indicate that early improvement with antidepressant medication can predict No Yes Yes
2009 subsequent treatment outcome with high sensitivity in patients with major depressive

M
disorder. The high negative predictive values indicate little chance of stable response or
stable remission in the absence of improvement within 2 weeks. A lack of improvement
during the first 2 weeks of therapy may indicate that changes in depression management

D
should be considered earlier than conventionally thought.

TE
Taylor 2011 Antidepressants are efficacious and safe in the treatment of depression occurring in the No No Yes
context of chronic physical health problems. The SSRIs are probably the antidepressants of
first choice given their demonstrable effect on quality of life and their apparent safety in
EP
cardiovascular disease.
Tedeschini The present meta-analysis suggests that antidepressants are efficacious in late-life MDD, No No Yes
2011 but significant study heterogeneity suggests that other factors may contribute to these
C

findings. A secondary analysis raises the possibility that efficacy of these agents may be
AC

reduced in trials involving patients aged 65 years or older. Why antidepressants may be
less efficacious in elderly versus younger subjects remains unclear.

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Thaler 2011 Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared Yes No Yes
with placebo, which shows a non-significant effect in favour of fluoxetine, and two small
trials comparing fluoxetine against light therapy, which suggest equivalence between the

PT
two interventions. The lack of available evidence precludes the ability to draw any overall
conclusions on the use of SGAs for SAD. Further larger RCTs are required to expand and
strengthen the evidence base on this topic, and should also include comparisons with

RI
pyschotherapy and other SGAs. Data on adverse events were sparse, and a comparative
analysis was not possible. Therefore the data we obtained on adverse effects is not robust
and our confidence in the data is limited. Overall, up to 27% of participants treated with

SC
SGAs for SAD withdrew from the studies early due to adverse effects. The overall quality
of evidence in this review is very low.

U
Thaler 2012 Evidence guiding the selection of an SGA based on accompanying symptoms of depression Yes No Yes
is limited. Very few trials were designed and adequately powered to answer questions

AN
about accompanying symptoms; analyses were generally of subgroups in larger MDD
trials.
Thase 2009 Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder No Yes Yes
across the range of doses studied. No evidence of greater efficacy was observed with doses

M
>50 mg/day; a strong dose response effect on tolerability was observed.
Thase 2010 In conclusion, the findings indicate that mirtazapine may be a more rapidly effective No Yes Yes

D
antidepressant than SSRIs.
Thompson Antidepressant treatment for depression in AD is efficacious, with rates of discontinuation No No Yes

TE
2007 that are comparable to placebo. Nonetheless, clinicians must be vigilant regarding the
potential side effects of antidepressants in this population.
EP
Tondo 2010 Use of ADs in adults with BPD or MDD was highly prevalent and moderately increased Yes No Yes
the risk of mania overall, with little protection by mood stabilizers.
Tourian The current study failed to meet its primary efficacy end point based on the a priori No Yes No
C

2009 analysis plan. Desvenlafaxine was generally well tolerated. A post hoc pooled analysis of
this trial and 2 previously published trials with both desvenlafaxine 50 and 100 mg/d found
AC

both doses to be effective for MDD compared with placebo.

Tourian Desvenlafaxine was associated with significantly greater improvement in anxiety No Yes Yes
2010 symptoms compared with placebo in patients with MDD.

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Trkulja 2010 Presently, the claims about clinically relevant superiority of escitalopram over citalopram Yes No Yes
in short-to-medium term treatment of major depressive disorder are not supported by
evidence.

PT
Tsapakis Antidepressants of all types showed limited efficacy in juvenile depression, but fluoxetine No No Yes
2008 might be more effective, especially in adolescents. Studies in children and in severely
depressed, hospitalised or suicidal juvenile patients are needed, and effective, safe and

RI
readily accessible treatments for juvenile depression are urgently required.
Turner 2014 Most add-on interventions demonstrated comparable efficacy in patients with MDD and an No Yes Yes

SC
inadequate response to initial antidepressants. However, there is currently a paucity of
high-quality data regarding the use of add-on treatments in patients with MDD who are
inadequate responders to antidepressants, with quetiapine XR presenting the most
comprehensive evidence base to date.

U
Undurraga Study findings generally support moderate efficacy of clinically employed antidepressants No No No

AN
2012 for acute major depression, but underscore limitations of meta-analyses of controlled trials
for ranking drugs by efficacy. We suggest that efficiency and drug–placebo differences
may be improved with fewer sites and subjects, and better quality-control of diagnostic and

M
clinical assessments.

Undurraga Responses to imipramine in its earliest controlled trials were much larger than in recent Yes No Yes

D
2013 antidepressant trials. Drug-placebo differences declined significantly between 1959 and
1965, with rising placebo-associated responses. Frequent failure to find superior drug-over-

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placebo outcomes may reflect patient characteristics and limited statistical power.
Antidepressant-trial methods have become much more standardized, samples larger and
more complex, and effect-sizes much smaller since the 1960s.
EP
Usala 2008 Nevertheless, additional RCTs with sound methodological designs, validated No No Yes
diagnostic instruments, large sample sizes, and consistent outcomes are necessary to
determine the role of SSRIs, alone or in combination with psychological interventions in
C

the treatment of depression in children and adolescents.

AC

van den From our review, no significant difference in treatment effect between low No No Yes
Broek 2009 dose of both venlafaxine and the TCAs could be found. In our opinion,
because of the heterogeneity of the odds ratios, one cannot conclude that
they are of equal efficacy.

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van der The treatment of depression in people with diabetes is a necessary step, but improvement Yes No Yes
Feltz- of the general medical condition including glycemic control is likely to require
Cornelis simultaneous attention to both conditions. Further research is needed.

PT
2010
Vieta 2013 Quetiapine XR as a monotherapy (150mg/day at Weeks 2 and 4) or adjunct to ongoing No Yes Yes
antidepressant therapy (150 and 300 mg/day at Weeks 2 and 4) increased sustained

RI
response rates versus placebo.
von Wolff This systematic review provides evidence for the efficacy of both SSRIs and TCAs in the No No No

SC
2013 treatment of chronic depression and showed a better acceptability of SSRIs.

Wade 2009 A higher probability of achieving remission is associated with responding after 8 weeks No Yes Yes
and with completing 6 months of treatment.

U
Watanabe Although mirtazapine is likely to have a faster onset of action than SSRIs, no significant No No Yes

AN
2008 differences were observed at the end of 6 to 12 weeks' treatment. Clinicians should focus
on other practically relevant considerations to tailor treatment to best fit the needs of
individual patients.

M
Watanabe The study confirmed the paucity of adequate safety reporting in trials comparing Yes No Yes
2010 mirtazapine with other types of antidepressant in the acutephase treatment of depression in

D
adults. Based on the available evidence, mirtazapine appears to have a unique adverse-
event profile. Using these findings, clinicians can inform their patients, not only of the

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simple frequency of adverse events with mirtazapine, but also of the relative difference in
the frequency of adverse events in comparison with that of other antidepressants, to aid
pragmatic clinical decisions.
EP
Watanabe Some statistically significant and possibly clinically meaningful differences between No No Yes
2011 mirtazapine and other antidepressive agents were found for the acute-phase treatment of
major depression. Mirtazapine is likely to have a faster onset of action than SSRIs during
C

the acute-phase treatment. Dropouts occur similarly in participants treated with mirtazapine
and those treated with other antidepressants, although the adverse event profile of
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mirtazapine is unique.

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Wightman Although no statistically significant differences were observed between bupropion and No Yes Yes
2010 placebo in expressed suicidal ideation or behavior, we believe that all patients treated with
antidepressants should receive careful monitoring for clinical worsening, suicidality, or

PT
unusual changes in behavior.
Wijkstra Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. No No Yes
2013 Some evidence indicates that combination therapy with an antidepressant plus an

RI
antipsychotic is more effective than either treatment alone or placebo. Evidence is limited
for treatment with an antidepressant alone or with an antipsychotic alone.

SC
Williams Prophylactic antidepressant drug therapy appears efficacious in preventing future relapses No No Yes
2009 across a range of illness severity as well as age. More studies are needed to explore the
effects of various acute antidepressant strategies and the direct influence of treatment
resistance on relapse outcomes.

U
Yi 2010 Fluoxetine was beneficial for the prophylaxis of poststroke depression in patients with No No No

AN
stroke but not in reducing symptom severity of PSD.
Zhuang There is no evidence on the effectiveness and safety of antidepressants in treating Yes No No

M
2013 depression and other symptoms in women with PCOS.

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