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

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 our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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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

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Stanford Prevention Research Center, Department of Medicine, 1265 Welch Road, 3rd floor, Stanford 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 University, Hamilton, Ontario, Canada, L8S 4K1 4 Department of Anesthesia, 1200 Main Street West, HSC 2U1, McMaster University, Hamilton, Ontario, Canada, L8S 4K1 5 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 Education, 252 Bloor Street West, University of Toronto, Toronto, Ontario, Canada, M5S 1V6 7 Department of Rehabilitation Science, 500 University Ave, University of Toronto, Toronto, Ontario 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 9 Department of Statistics, 390 Serra Mall, Stanford University School of Humanities and Sciences, 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: [email protected], Tel: +1 (650) 725-5465

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.

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

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.

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

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were employees of the assessed drug manufacturer and 147 (79%) had some industry link (sponsorship or authors who were industry employees and/or had conflicts of interest). Only 58 meta-analyses (31%) 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). Conclusion: There is a massive production of meta-analyses of antidepressants for depression authored by or linked to the industry, and they almost never report any caveats about antidepressants in their

assessed products.

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

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

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

pharmaceuticals, for the management of depression. •

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

Our study shows the massive presence of the industry in generating a factory of meta-analyses 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 their abstracts about the antidepressants assessed.

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

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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

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syntheses become more influential in shaping guidelines and clinical practice, the biopharmaceutical 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 be performed with more limited resources and faster than randomized trials, it is conceivable that the

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

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 extremely high visibility between 2005 and early 2008, causing heated debates about serious risks (e.g., suicidality [9, 10]) or questionable effectiveness in patients without severe depression [11]. However,

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

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sponsorship by the industry? Do industry-related meta-analyses reach more favorable conclusions in their abstracts than other meta-analyses? To answer these questions, we aimed to examine 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 4

ACCEPTED MANUSCRIPT 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

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

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

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by the industry may focus on a single medication, including pooled analyses with individual-level data [12].

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

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interventions). We excluded meta-analyses that compared antidepressants against non-drug interventions only (e.g., diet, psychotherapy or cognitive interventions). Meta-analyses were also eligible regardless of whether they focused on benefits, harms, mortality, treatment discontinuation or

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

Eligible approved antidepressants included selective serotonin reuptake inhibitors (SSRIs), serotonin 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 5

ACCEPTED MANUSCRIPT 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-

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analysis).

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

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citalopram[title/abstract] OR Escitalopram[title/abstract] OR Fluoxetine[title/abstract] OR Fluvoxamine[title/abstract] OR Paroxetine[title/abstract] OR Sertraline[title/abstract] OR Venlafaxine[title/abstract] OR Desvenlafaxine[title/abstract] OR Duloxetine[title/abstract] OR Bupropion[title/abstract] OR Trazodone[title/abstract] OR Mirtazapine[title/abstract] OR Nefazodone[title/abstract] OR Amitriptyline[title/abstract] OR Clomipramine[title/abstract] OR

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Doxepin[title/abstract] OR Imipramine[title/abstract] OR Trimipramine[title/abstract] OR Desipramine[title/abstract] OR Nortriptyline[title/abstract] OR Protriptyline[title/abstract] OR Amoxapine[title/abstract] OR Maprotiline[title/abstract] OR Isocarboxazid[title/abstract] OR

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

papers.

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

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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ACCEPTED MANUSCRIPT 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

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corresponding author; publication date; journal; disease/condition; any mention of a literature search; 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-forprofit, government, not reported); whether any author was employed by a for-profit organization (and if

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so, whether this is a manufacturer of an assessed drug(s)); whether any author was receiving or had received any support by for-profit organizations (consulting, conference and speaker fees, provided 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 any conflicts in the published meta-analysis, under-reporting of industry tries is a potential issue [13]. Thus, we searched a random sample of 3 articles published by the corresponding author in the same

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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, we extended the search to the author’s papers published within +/-1 year.

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 7

ACCEPTED MANUSCRIPT 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

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evidence might be of low quality, limited, uncertain or inconclusive was not counted as a negative statement. Discrepancies between data extractors were discussed and consensus was reached with an

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arbitrator.

Statistical Analysis

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We described data as proportions and ranges, as appropriate. We calculated the proportion of metaanalyses funded or sponsored by a for-profit organization; funded or sponsored by a manufacturer of an 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 forprofit organization; with author(s) with a conflict of interest with the manufacturer of the assessed

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

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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; and use of individual-level data. We provide the results of all tests separately for all meta-analyses and 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 8

ACCEPTED MANUSCRIPT 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-

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analyses (Table 1, Appendix A).

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

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

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and SNRIs (30%). Most comparisons were against placebo (74%). About a third of the meta-analyses did not use a systematic literature review and a similar proportion used individual level data; these meta-analyses typically reflected pooled analyses of single medications.

Sponsorship, employment and conflicts of interest

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

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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.

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 9

ACCEPTED MANUSCRIPT 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

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drug(s).

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

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included in our evaluation.

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 use a literature review (21% vs. 91%, p<0.001), to use individual level data (79% vs. 11%, p<0.001), to

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

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

Negative statements in the conclusion of the abstract 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 10

ACCEPTED MANUSCRIPT 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.

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Associations of negative statements 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).

Among all 185 meta-analyses, those published in the USA, published in psychiatric specialty journals, 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).

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

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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 manufacturer of the assessed drug was still significantly associated with fewer negative statements (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

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involvement from industry (sponsorship, industry authors, or authors with industry conflicts of interest) 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 specific manufactured drug. Industry-authored meta-analyses almost never include any negative

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concluding statement in the abstract that summarizes the conclusions of the work about the antidepressants assessed, while more than half of those without any discernible industry involvement 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. Given the importance of these tools for evidence-based medicine and decision-making, it is logical that the industry would be very much interested in their results. For randomized trials, industry-sponsored

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

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owned by the same sponsor) [21], that result in favorable results. Multiple reviews have shown that industry-sponsored trials are associated with higher treatment success and report more favorable 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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ACCEPTED MANUSCRIPT 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

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reviews and/or meta-analyses, respectively, of which 26-40% had ties to the industry [3, 4, 22]. The first two evaluations pertained to various drugs, while the third included all meta-analyses on antihypertensives 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 sponsoring and favorable inferences. Our study adds to this previous work by showing an even more

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massive impact of the manufacturers in writing and shaping a large meta-analysis agenda with 147 industry-linked meta-analyses published on a single drug class over just 7 years. The number and 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 may be due to the fact that we also considered pooled analyses without systematic reviews, and these

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types of papers are almost exclusively done by the industry. However, these papers are also influential. 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) were mostly done with meta-analyses published before the time frame that we examined, it would be 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 13

ACCEPTED MANUSCRIPT reviews, it is perhaps not surprising that similar inflations in production may be seen now for industrysponsored meta-analyses as were seen previously with expert-based pieces.

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Only one meta-analysis with a manufacturer author reported a negative statement in the conclusion of 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 causing any major concerns alone. Moreover, we found that even when restricting our analyses to

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studies with non-industry employed authors, conflicts of interest with the manufacturer of the assessed drug were still strongly associated with fewer negative statements in the abstracts. Journals and 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 and declarations are rarely verified [13]. Correspondingly, we found that a quarter of meta-analyses

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including authors reporting no conflicts in fact had some temporally concurrent industry ties.

Organizations such as the Cochrane Collaboration, the Institute of Medicine, and the Agency for

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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 sponsors should be entirely excluded from the conduct and authorship of meta-analyses because of 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 meta14

ACCEPTED MANUSCRIPT 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

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

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

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point for summarizing the final take-home message offered by a scientific paper. Efforts to capture the presence of negative statements in the very different contexts where they could appear in the full paper 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 positive aspects. Fourth, having many meta-analyses is not necessarily bad in principle, but having too

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much of a good thing may be damaging [32], especially if this literature is biased.

Empirical studies in other fields beyond antidepressants may be helpful to probe the breadth of the

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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

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Sciences and Humanities Research Council Doctoral Scholarship, and CM by a graduate scholarship 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 manuscript for publication. SE and JPAI had full access to all the data in the study and take

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responsibility for the integrity of the data and the accuracy of the data analysis. We thank Ms. Kelsey Vercammen for assisting with article retrieval; no compensation was received for completing this work.

Conflict of interest

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All authors declare no conflicts of interests.

Authors’ contributions

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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, CM and JPAI revised it critically for important intellectual content. All authors approved the final version to be published.

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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.

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,

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32(2):237-245.

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

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Yank V, Rennie D, Bero LA: Financial ties and concordance between results and conclusions in meta-analyses: retrospective cohort study. BMJ 2007, 335(7631):1202-1205. 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 systematic reviews. Annals of internal medicine 2014, 161(7):513-518. 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 of published articles. PLoS Med 2011, 8(3):e1000425. 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 wellperformed meta-analyses. Intensive Care 2012, 38(8):1258-1271.

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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. 19

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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,

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33(5):393-407. 28.

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

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Finding what works in health care: standards for systematic reviews

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

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

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

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

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

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Figure 1 – Flow chart of eligible meta-analyses

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Records identified through MEDLINE search: (1111)

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Figure 1 – Flow chart of eligible meta-analyses

Records excluded after title and abstract screening (849)

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Records screened (1111)

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)

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 7: Did not evaluate an indication of depression or did not report outcomes separately for depression 4: Non-English 1: Duplicate

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Eligible articles (185)

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Table 1 – Description of Eligible Meta-analyses

Metaanalyses without industry employee authors (n=128)

2 (3.5) 1 (1.8) 5 (9) 12 (21) 1 (2) 0 (0) 8 (14) 27 (47)

0 (0) 16 (12.5) 8 (6) 50 (39) 4 (3) 2 (2) 9 (7) 39 (31)

0.002*

15 (8) 104 (56) 66 (35)

1 (2) 36 (63) 20 (35)

14 (11) 67 (52) 46 (36)

0.15*

13 (7) 24 (13) 29 (16) 26 (14) 32 (17) 20 (11) 32 (17) 9 (5)

7 (12) 4 (7) 13 (23) 10 (18) 8 (14) 3 (5) 9 (16) 3 (5)

6 (5) 20 (16) 16 (13) 16 (13) 24 (19) 17 (13) 23 (18) 6 (5)

0.21*

152 (82) 6 (3)

56 (98) 1 (2)

96 (75) 5 (4)

0.01*

14 (8)

1 (2)

13 (10)

1 (0.5) 3 (1.6) 2 (1) 1 (0.5)

1 (2) 0 (0) 0 (0) 0 (0)

0 (0) 3 (2) 2 (2) 1 (1)

Country(ies) of corresponding author Africa Asia Canada Europe Oceania South America UK USA

2 (1) 17 (9) 13 (7) 62 (33) 5 (3) 2 (1) 17 (9) 66 (35)

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Publication Year 2007 2008 2009 2010 2011 2012 2013 2014 (until March 5)

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Journal General medical journals Psychiatric journals Other specialty journals

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Characteristics

All metaanalyses (n=185)

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n (%) Metaanalyses with industry employee authors (n=57)

Disease/condition of evaluated patients Major depression only Major depression comorbid with psychiatric disorders Major depression comorbid with non-psychiatric disorders Other Depression not-specified Interferon-alpha associated depression Minor depression or dysthymia Persistent or recurrent depression

Pvalue

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Comparators evaluated# Placebo Other antidepressant Other active intervention

2 (2) 1 (1) 3 (2)

83 (45) 55 (30)

20 (35) 23 (40)

63 (49) 32 (25)

27 (15) 28 (16) 9 (5) 7 (4)

8 (14) 3 (5) 3 (5) 2 (4)

19 (15) 25 (20) 6 (5) 5 (4)

1.00 0.01 1.00 1.00

5 (3) 23 (12)

2 (4) 0 (0)

3 (2) 23 (18)

0.64 <0.001

44 (77) 32 (56) 3 (5)

93 (73) 68 (53) 22 (17)

0.59 0.75 0.04

171 (91) 86 (46) 13 (7) 91 (49)

53 (93) 24 (42) 2 (3.5) 21 (37)

118 (92) 62 (48) 11 (9) 70 (55)

1.00 0.52 0.35 0.03

128 (69)

12 (21)

116 (91)

<0.001

59 (32)

45 (79)

14 (11)

<0.001

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137 (74) 100 (54) 25 (14)

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Type of outcomes reported# Benefit Harm Mortality Treatment discontinuation Use of literature review

0 (0) 0 (0) 0 (0)

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Type of antidepressant(s) evaluated# Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) Atypical antidepressants Tricyclic and tetracyclic antidepressants Monoamine Oxidase Inhibitors (MAOIs) Melatonergic and non-melatonergic antidepressants Antipsychotics approved for antidepressants Antidepressants not specified

2 (1) 1 (0.5) 3 (1.6)

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Post-stroke depression Postpartum depression Psychotic depression

Use of individual patient data

0.08 0.04

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*P-value comparing the two groups across all categories; #not mutually exclusive categories/ multiple 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

Odds ratio (95% CI)

3/46 (7) 55/139 (40)

0.10 (0.03 to 0.36)

5/48 (10) 53/137 (39)

0.18 (0.07 to 0.50)

1/54 (2) 57/131 (44)

0.02 (0.003 to 0.18)

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P-value

0.50 (0.09 to 2.66)

0.47

<0.001

4/9 (44) 52/119 (44)

1.03 (0.26 to 4.03)

0.61

<0.001

--

--

--

<0.001

--

--

--

0.27 (0.14 to 0.52)

<0.001

22/68 (32) 34/60 (57)

0.37 (0.18 to 0.75)

0.007

36/134 (27) 22/51 (43)

0.48 (0.25 to 0.95)

0.05

35/88 (40) 21/40 (53)

0.60 (0.28 to 1.27)

0.19

24/124 (19) 34/61 (56)

0.19 (0.10 to 0.37)

<0.001

23/70 (33) 33/58 (57)

0.37 (0.18 to 0.76)

0.008

39/147 (27)

0.36 (0.17 to 0.75)

0.01

37/90 (41)

0.70 (0.33 to 1.50)

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2/57 (3.5) 56/128 (44)

<0.001

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2/7 (29) 54/121 (45)

23/113 (20) 35/72 (49)

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Sponsored by the manufacturer of assessed drug(s) Yes No Sponsored by any for-profit organization Yes No Author(s) employee(s) of the manufacturer of drug(s) Yes No Author(s) employee(s) of any for-profit organization Yes No Conflicts of interest with manufacturer of assessed drug(s) Yes No Conflicts of interest with any for-profit organization Yes No Any involvement* of manufacturer of assessed drug(s) Yes No Any involvement* of any for-profit organization Yes

Negative statements, n/N (%)

0.05 (0.01 to 0.20)

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Among 128 meta-analyses without industry employee authors Negative Odds ratio statements, (95% CI) n/N (%) P-value

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19/38 (50)

19/38 (50) 0.46 (0.23 to 0.92)

0.03

13/39 (33) 43/89 (48)

0.54 (0.24 to 1.17)

0.13

9/15 (60) 23/103 (22) 25/66 (38)

3.70 (1.25 to 10.96) 0.39 (0.20 to 0.73) 1.58 (0.84 to 3.01)

0.004

9/14 (64) 22/67 (33) 24/46 (52)

2.57 (0.81 to 8.15) 0.39 (0.19 to 0.80) 1.71 (0.82 to 3.53)

0.04

1/13 (8) 6/24 (25) 8/29 (28) 13/26 (50) 11/32 (34) 7/20 (35) 11/32 (34) 1/9 (11)

0.17 (0.21 to 1.33) 0.70 (0.26 to 1.86) 0.81 (0.34 to 1.95) 2.53 (1.09 to 5.89) 1.18 (0.53 to 2.65) 1.20 (0.45 to 3.20) 1.18 (0.53 to 2.65) 0.26 (0.03 to 2.14)

0.37

1/6 (17) 6/20 (30) 8/16 (50) 12/16 (75) 10/24 (42) 7/17 (41) 11/23 (48) 1/6 (17)

0.24 (0.03 to 2.15) 0.50 (0.18 to 1.39) 1.33 (0.47 to 3.81) 4.64 (1.41 to 15.29) 0.90 (0.37 to 2.21) 0.89 (0.31 to 2.50) 1.22 (0.50 to 3.02) 0.24 (0.03 to 2.15)

0.77

46/152 (30) 12/33 (36)

0.76 (0.35 to 1.67)

0.54

44/96 (45) 12/32 (38)

1.41 (0.62 to 3.20)

0.54

1.10 (0.59 to 2.06)

0.87

27/63 (43)

0.93 (0.46 to 1.87)

0.86

0.97 (0.49 to 1.92)

1.00

16/32 (50)

1.40 (0.63 to 3.13)

0.42

0.34 (0.11 to 1.02) 1.51 (0.66 to 3.48)

0.046 0.38

4/19 (21) 11/25 (44)

0.29 (0.09 to 0.94) 1.01 (0.42 to 2.44)

0.04 1.00

0.61 (0.12 to 3.04)

0.72

2/6 (33)

0.63 (0.11 to 3.57)

0.70

4/7 (57)

3.06 (0.66 to 14.15)

0.21

3/5 (60)

1.98 (0.32 to 12.28)

0.65

1/5 (20)

0.54 (0.06 to 4.94)

1.00

1/3 (33)

0.64 (0.06 to 7.20)

1.00

11/23 (48)

2.24 (0.93 to 5.44)

0.09

11/23 (48)

1.22 (0.50 to 3.02)

0.82

26/100 (26) 32/85 (38)

0.58 (0.31 to 1.09)

0.11

24/49 (49) 32/79 (41)

1.41 (0.69 to 2.89)

0.37

17/55 (31)

2/9 (22)

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4/27 (15) 11/28 (39)

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27/83 (33)

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14/66 (21) 44/119 (37)

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No Country USA Other Journal$ General medical Psychiatric specialty Other specialty Publication year$ 2007 2008 2009 2010 2011 2012 2013 2014 Focus on major depression only Yes No Type of antidepressant evaluated# Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) Atypical antidepressants Tricyclic and tetracyclic antidepressants Monoamine Oxidase Inhibitors (MAOIs) Melatonergic and nonmelatonergic antidepressants Antipsychotics approved for antidepressants Antidepressants not specified Assessed one antidepressant only Yes No Type of comparator evaluated#

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0.69 (0.34 to 1.37) 1.07 (0.57 to 1.99) 1.89 (0.80 to 4.46)

0.29 0.88 0.17

38/93 (41) 30/68 (44) 11/22 (50)

0.65 (0.30 to 1.43) 1.03 (0.51 to 2.08) 1.36 (0.54 to 3.40)

0.32 1.00 0.64

50/171 (29) 32/86 (37) 4/13 (31) 32/91 (35)

0.31 (0.10 to 0.94) 1.66 (0.89 to 3.11) 0.97 (0.29 to 3.29) 1.42 (0.76 to 2.65)

0.04 0.12 1.00 0.34

49/118 (42) 30/62 (48) 4/11 (36) 30/70 (43)

0.30 (0.08 to 1.24) 1.44 (0.72 to 2.91) 0.71 (0.20 to 2.57) 0.92 (0.46 to 1.86)

0.10 0.37 0.76 0.86

52/128 (41) 6/57 (11)

5.82 (2.33 to 14.54)

<0.001

51/116 (44) 5/12 (42)

1.10 (0.33 to 3.66)

1.00

6/59 (10) 52/126 (41)

0.16 (0.06 to 0.40)

<0.001

5/14 (36) 51/114 (45)

0.69 (0.22 to 2.18)

0.58

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40/137 (29) 32/100 (32) 11/25 (44)

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Placebo Other antidepressant Other active intervention Type of outcome# Benefit Harm Mortality Treatment discontinuation Use of literature review Yes No Use of individual level data Yes No

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

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Appendix A - List of Eligible Studies 1.

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Ali MK, Lam RW. Comparative efficacy of escitalopram in the treatment of major depressive disorder. Neuropsychiatric disease and treatment 2011;7:39-49. Alkhafaji AA, Trinquart L, Baron G, Desvarieux M, Ravaud P. Impact of evergreening on patients and health insurance: a meta analysis and reimbursement cost analysis of citalopram/escitalopram antidepressants. BMC medicine 2012;10:142. Apler A. Citalopram for major depressive disorder in adults: a systematic review and meta-analysis of published placebo-controlled trials. BMJ open 2011;1:e000106. Arroll B, Elley CR, Fishman T, et al. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev 2009:Cd007954. Aursnes I, Gjertsen MK. Common adverse events associated with an SSRI: metaanalysis of early paroxetine data. Pharmacoepidemiology and drug safety 2008;17:707-13. Baldessarini RJ, Faedda GL, Offidani E, et al. Antidepressant-associated moodswitching and transition from unipolar major depression to bipolar disorder: a review. Journal of affective disorders 2013;148:129-35. 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 controlled trial database. Human psychopharmacology 2009;24:269-75. Ball SG, Desaiah D, Spann ME, et al. Efficacy of duloxetine on painful physical symptoms in major depressive disorder for patients with clinically significant painful physical symptoms at baseline: a meta-analysis of 11 double-blind, placebo-controlled clinical trials. The primary care companion to CNS disorders 2011;13. 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. 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. Barbui C, Cipriani A, Patel V, Ayuso-Mateos JL, van Ommeren M. Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis. The British journal of psychiatry : the journal of mental science 2011;198:11-6, sup 1. 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. 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. Bauer M, McIntyre RS, Szamosi J, Eriksson H. Evaluation of adjunct extendedrelease 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 (CINP) 2013;16:1755-65. Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N. The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis. European archives of psychiatry and clinical neuroscience 2009;259:172-85. Baumeister H, Hutter N, Bengel J. Psychological and pharmacological interventions for depression in patients with diabetes mellitus and depression. Cochrane Database Syst Rev 2012;12:Cd008381. Beasley CM, Jr., Ball SG, Nilsson ME, et al. Fluoxetine and adult suicidality revisited: an updated meta-analysis using expanded data sources from placebocontrolled trials. Journal of clinical psychopharmacology 2007;27:682-6. Bradley AJ, Lenox-Smith AJ. Does adding noradrenaline reuptake inhibition to 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;27:74058. 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. Bschor T, Baethge C. No evidence for switching the antidepressant: systematic review and meta-analysis of RCTs of a common therapeutic strategy. Acta psychiatrica Scandinavica 2010;121:174-9. Carandang C, Jabbal R, Macbride A, Elbe D. A review of escitalopram and citalopram in child and adolescent depression. Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent 2011;20:315-24. Chen J, Gao K, Kemp DE. Second-generation antipsychotics in major depressive disorder: update and clinical perspective. Current opinion in psychiatry 2011;24:10-7. Chuluunkhuu G, Nakahara N, Yanagisawa S, Kamae I. The efficacy of reboxetine 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. 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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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. 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. Cipriani A, Koesters M, Furukawa TA, et al. Duloxetine versus other antidepressive agents for depression. Cochrane Database Syst Rev 2012;10:Cd006533. Cipriani A, La Ferla T, Furukawa TA, et al. Sertraline versus other antidepressive agents for depression. Cochrane Database Syst Rev 2009:Cd006117. Cipriani A, Purgato M, Furukawa TA, et al. Citalopram versus other antidepressive agents for depression. Cochrane Database Syst Rev 2012;7:Cd006534. Cipriani A, Santilli C, Furukawa TA, et al. Escitalopram versus other antidepressive agents for depression. Cochrane Database Syst Rev 2009:Cd006532. Citrome L. Vilazodone for major depressive disorder: a systematic review of the 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 harmed? International journal of clinical practice 2012;66:356-68. Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the 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 harmed? International journal of clinical practice 2013;67:1089-104. Citrome L. Vortioxetine for major depressive disorder: a systematic review of the 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 harmed? International journal of clinical practice 2014;68:60-82. Citrome L, Goldberg JF, Portland KB. Placing transdermal selegiline for major depressive disorder into clinical context: number needed to treat, number needed to harm, and likelihood to be helped or harmed. Journal of affective disorders 2013;151:409-17. Clayton AH, Campbell BJ, Favit A, et al. Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale. The Journal of clinical psychiatry 2007;68:1860-6. 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. 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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De Crescenzo F, Perelli F, Armando M, Vicari S. Selective serotonin reuptake inhibitors (SSRIs) for post-partum depression (PPD): a systematic review of randomized clinical trials. Journal of affective disorders 2014;152-154:39-44. de Silva VA, Hanwella R. Efficacy and tolerability of venlafaxine versus specific serotonin reuptake inhibitors in treatment of major depressive disorder: a metaanalysis of published studies. International clinical psychopharmacology 2012;27:8-16. Demyttenaere K, Corruble E, Hale A, Quera-Salva MA, Picarel-Blanchot F, Kasper S. A pooled analysis of six month comparative efficacy and tolerability in four randomized clinical trials: agomelatine versus escitalopram, fluoxetine, and sertraline. CNS spectrums 2013;18:163-70. Deshauer D, Moher D, Fergusson D, Moher E, Sampson M, Grimshaw J. Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2008;178:1293-301. Dolder CR, Nelson M, Snider M. Agomelatine treatment of major depressive disorder. The Annals of pharmacotherapy 2008;42:1822-31. Dowlati Y, Herrmann N, Swardfager WL, Reim EK, Lanctot KL. Efficacy and tolerability of antidepressants for treatment of depression in coronary artery disease: a meta-analysis. Canadian journal of psychiatry Revue canadienne de psychiatrie 2010;55:91-9. Ehret M, Sobieraj DM. Prevention of interferon-alpha-associated depression with antidepressant medications in patients with hepatitis C virus: a systematic review and meta-analysis. International journal of clinical practice 2014;68:255-61. Emslie GJ, Findling RL, Yeung PP, Kunz NR, Li Y. Venlafaxine ER for the treatment of pediatric subjects with depression: results of two placebo-controlled trials. Journal of the American Academy of Child and Adolescent Psychiatry 2007;46:479-88. Eyding D, Lelgemann M, Grouven U, et al. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. Bmj 2010;341:c4737. Farahani A, Correll CU. Are antipsychotics or antidepressants needed for psychotic depression? A systematic review and meta-analysis of trials comparing antidepressant or antipsychotic monotherapy with combination treatment. The Journal of clinical psychiatry 2012;73:486-96. Fishbain DA, Detke MJ, Wernicke J, Chappell AS, Kajdasz DK. The relationship between antidepressant and analgesic responses: findings from six placebocontrolled trials assessing the efficacy of duloxetine in patients with major depressive disorder. Current medical research and opinion 2008;24:3105-15. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA : the journal of the American Medical Association 2010;303:47-53.

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Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev 2011:Cd006528. Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressants in the acute-phase treatment of adults with major depression: systematic review and meta-analysis. The Journal of clinical psychiatry 2008;69:1404-15. Watanabe N, Omori IM, Nakagawa A, et al. Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression: systematic review and meta-analysis. CNS drugs 2010;24:35-53. Wightman DS, Foster VJ, Krishen A, Richard NE, Modell JG. Meta-analysis of suicidality in placebo-controlled clinical trials of adults taking bupropion. Primary care companion to the Journal of clinical psychiatry 2010;12. Wijkstra J, Lijmer J, Burger H, Geddes J, Nolen WA. Pharmacological treatment for psychotic depression. Cochrane Database Syst Rev 2013;11:Cd004044. Williams N, Simpson AN, Simpson K, Nahas Z. Relapse rates with long-term antidepressant drug therapy: a meta-analysis. Human psychopharmacology 2009;24:401-8. Yi ZM, Liu F, Zhai SD. Fluoxetine for the prophylaxis of poststroke depression in patients with stroke: a meta-analysis. International journal of clinical practice 2010;64:1310-7. Zhuang J, Wang X, Xu L, Wu T, Kang D. Antidepressants for polycystic ovary syndrome. Cochrane Database Syst Rev 2013;5:Cd008575.

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Abstract Conclusions

Abstract included any negative statements expressing caveats or did not include any positive statements about the effectiveness or safety/toxicity of the assessed antidepressant(s)

Author(s) directly employed by an industry

Author(s) with a conflict of interest with an industry

Ali 2011

Based on pooled and meta-analysis studies, escitalopram demonstrates superior efficacy compared with citalopram and with SSRIs combined. Escitalopram shows similar efficacy to serotonin noradrenaline reuptake inhibitors but the number of trials in these comparisons is limited. Efficacy differences are modest but clinically relevant, especially in more severely depressed patients.

No

No

Yes

Alkhafaji 2012

The clinical benefit of escitalopram versus citalopram remains uncertain. In our case of evergreening, escitalopram represented a substantially high proportion of the overall reimbursement cost burden as compared with citalopram and the generic forms.

Yes

No

No

Apler 2011

Data concerning remission rates for citalopram, relative to placebo, are inconclusive. Response rates and symptom reduction scores in citalopram-treated patients with MDD are 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 effectiveness of citalopram for MDD.

No

No

No

Arroll 2009

Both TCAs and SSRIs are effective for depression treated in primary care.

No

Yes

Yes

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Appendix B – Description of negative statement appraisal and industry authorship or industry-related conflicts

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Frequently occurring adverse reactions that are included in today’s SPC for paroxetine 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 mentioned in the SPC of today. Meta-analyses of adverse effects should be mandatory at the stage of first registration of a drug.

Yes

No

No

Baldessarini 2013

AD-treatment was associated with new mania-like responses in 8.18% of patients diagnosed with unipolar MDD. Contributions to mood-switching due to unrecognized BPD versus mood-elevating pharmacological effects, as well as quantitative associations between switching and later diagnosis of BPD not associated with AD-treatment remain uncertain.

Yes

No

No

Baldwin 2009

The pattern of response in these RCTs suggests that in patients with MDD, GAD or SAD in wider clinical practice, a period of at least 4 weeks is worthwhile before considering further intervention.

No

Yes

No

Ball 2011

According to this meta-analysis, duloxetine 60 mg once daily is as effective in improving painful physical symptoms as it is for depression in patients with MDD and clinically 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 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. However, the results do not address its efficacy compared to other alternatives, as in all studies the comparator was placebo.

No

Yes

Yes

Ball 2013

These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective 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 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 controlled trials may not generalize well to real clinical practice.

No

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Aursnes 2008

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No

No

Yes

No

Yes

There is evidence showing there is unlikely to be a clinically important advantage for 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.

Yes

No

No

Bauer 2009

This meta analysis provides evidence of the clinical efficacy of venlafaxine in achieving therapeutic response and remission in patients with major depression. Venlafaxine appears more effective than SSRIs, and at least as effective as tricyclic antidepressants, in the treatment of major depressive 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.

No

No

Yes

Bauer 2013

Adjunct quetiapine XR improved sleep disturbance and quality vs. placebo in patients with MDD and an inadequate response to on-going antidepressant treatment, and was effective against depressive symptoms in patients experiencing high sleep disturbance.

No

Yes

Yes

Bauer 2014

In conclusion, in patients with MDD and inadequate response to ongoing antidepressant, adjunct quetiapine XR (150 and 300 mg/day) was effective in both SSRI and SNRI subgroups.

No

No

Yes

To summarize, this meta-analysis was designed to get an overview as fair as possible of the comparative efficacy of duloxetine and active comparators in MDD by combining the summary results of 6 pivotal RCTs under a multitreatment framework. Our main 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 evidence regarding the comparative efficacy of duloxetine across different dose ranges.

Barbui 2008

Among adults with moderate to severe major depression in the clinical trials we reviewed, paroxetine was not superior to placebo in terms of overall treatment effectiveness and acceptability. These results were not biased by selective inclusion of published studies.

Barbui 2011

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Ballesteros 2007

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Psychological and pharmacological interventions have a moderate and clinically significant effect on depression outcomes in diabetes patients. Glycaemic control improved moderately in pharmacological trials, while the evidence is inconclusive for psychological 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 substantial risk of bias and the heterogeneity of examined populations and interventions.

No

No

No

Beasley 2007

Fluoxetine treatment led to greater benefit rather than risk for suicidality.

No

Yes

No

Bradley 2013

There is sufficient current evidence that demonstrates an increase in efficacy, when noradrenaline reuptake is added to serotonin (5-HT) reuptake, to suggest that patients with 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 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.

No

Yes

No

Brunton 2010

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

Yes

Yes

Yes

Bschor 2010

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 we recommend that physicians rely on more thoroughly evaluated strategies.

Yes

No

Yes

Carandang 2011

At present, escitalopram and citalopram should be considered a second-line option for adolescent depression. The US Food and Drug Administration approval of escitalopram for treatment of adolescent depression was based on a single positive RCT. This is less evidence than typically required for approval of a drug for a new indication.

No

No

Yes

Chen 2011

Both SGA monotherapy and adjunctive therapy showed greater efficacy in the treatment of 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.

No

No

Yes

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Baumeister 2012

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These results suggest that the efficacy of the reboxetine and the other antidepressants (SSRI, TCA and SNRI) on both measures does not differ while it is significantly superior to placebo.

Cipriani 2007

We found a substantial body of evidence regarding the benefits and harms of ADs in the treatment of depressive disorder. Nonetheless, there remains considerable residual uncertainty. The evidence is inadequate for generally applicable recommendations; in most 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.

Cipriani 2008

No

No

Yes

No

Yes

The results of this review suggest that sertraline may be a candidate as the initial choice of antidepressant for people with major depression.

No

No

Yes

Cipriani 2009a

Clinically important differences exist between commonly prescribed antidepressants for 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 cost.

No

No

Yes

Cipriani 2009b

Some statistically significant differences favouring escitalopram over other antidepressive agents for the acute phase treatment of major depression were found, in terms of efficacy (citalopram and fluoxetine) and acceptability (duloxetine). There is insufficient evidence to detect a difference between escitalopram and other antidepressants in early response to 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 treatment effect due to sponsorship bias should also be borne in mind. This systematic review and meta-analysis highlighted a trend in favour of sertraline over other antidepressive agents both in terms of efficacy and acceptability, using 95% 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 the protocol of this review. Outcomes of clear relevance to patients and clinicians were not reported in any of the included studies.

No

No

Yes

No

No

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Chuluunkhu u 2008

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Some statistically significant differences between citalopram and other antidepressants for 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 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 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.

No

Cipriani 2012b

Duloxetine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. No differences in 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 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 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 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 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 economic estimates of antidepressant treatment effect should be considered to better inform healthcare policy.

Yes

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Vilazodone represents another option for the treatment of MDD. Vilazodone appears to 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 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.

No

No

Yes

Citrome 2013a

NNT for transdermal selegiline for efficacy is similar to that for other antidepressant regimens for which similar analyses have been published. There appear to be no clinically relevant effects of selegiline on weight or sexual functioning.

No

Yes

Yes

Citrome 2013b

Levomilnacipran represents another option for the treatment of MDD. Levomilnacipran appears to have a favourable weight-gain profile. Additional controlled data regarding long-term efficacy and comparative effectiveness will help characterise this new agent

No

No

Yes

Citrome 2014

Vortioxetine represents another option for the treatment of MDD. Vortioxetine appears to 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 better characterise this agent. Pending clinical trials include those examining cognitive dysfunction that can accompany MDD

No

No

Yes

Clayton 2007

This meta-analysis suggests that short-term therapy with STS 6mg/24 hours does not impair any aspect of sexual function in MDD patients as measured using a patient-rated questionnaire. Bupropion treatment at the EU-approved dose of ≤300 mg/day may offer advantages over SSRIs in the resolution of sleepiness and fatigue in remitted MDD patients

No

Yes

Yes

No

Yes

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Citrome 2012

SSRIs appear to be efficacious and well tolerated in the treatment of post partum depression, but the available evidence fails to demonstrate a clear superiority over other treatments.

No

No

No

de Silva 2012

The superior efficacy of venlafaxine over SSRIs is of clinical importance. However, higher 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.

Yes

No

Yes

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The present pooled analysis shows that, from a clinical point of view, agomelatine is at least as efficacious as the investigated SSRIs with a trend to fewer discontinuations due to adverse events.

Deshauer 2008

There is a lack of classic randomized controlled trials of serotonin reuptake inhibitors 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 following initial recovery but provide no guidance for longer treatment.

Dolder 2008

No

No

Yes

No

No

No

Overall, agomelatine is a promising and well-tolerated medication for the treatment of major depressive disorder. More large-scale controlled trials are needed to gain a better understanding of the relative efficacy and safety of agomelatine.

No

No

No

Dowlati 2010

Treatment with ADs for depression in CAD results in significant therapeutic effects without substantially increased rates of discontinuation.

No

No

Yes

Ehret 2014

SSRIs prevent depression in patients with HCV treated with INF-a therapy. The impact of SSRIs on completion of antiviral therapy or on the development of adverse events is less clear.

No

No

No

Emslie 2007

Venlafaxine ER may be effective in depressed adolescents. However, its safety and efficacy in pediatric patients has not been established. Prescribers should monitor for signs of suicidal ideation and hostility in pediatric patients taking venlafaxine ER.

No

Yes

Yes

Eyding 2010

Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.

Yes

No

No

Farahani 2012

Antidepressant-antipsychotic cotreatment was superior to monotherapy with either drug 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.

No

No

Yes

Fishbain 2008

Duloxetine’s analgesic effect is independent of the drug’s antidepressant effect. Additionally, faster onset of the analgesic effect appears to be a population specific phenomenon that is unmodified in the presence of active agents.

No

Yes

Yes

Fournier 2010

The magnitude of benefit of antidepressant medication compared with placebo increases 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.

Yes

No

Yes

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Demyttenaer e 2013

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Adverse event profiles are similar among second-generation antidepressants. However, different frequencies of specific adverse events might be clinically relevant and influence the choice of a treatment.

Gartlehner 2009

Current evidence does not warrant the choice of duloxetine over other second-generation antidepressants based on greater efficacy or safety for patients with acute-phase MDD with or without accompanying symptoms such as pain.

Gartlehner 2011

Yes

No

Yes

Yes

No

Yes

Current evidence does not warrant recommending a particular second-generation antidepressant on the basis of differences in efficacy. Differences in onset of action and adverse events may be considered when choosing a medication.

Yes

No

Yes

Gibbons 2012a

This is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that antidepressants show little benefit except for severe depression. The antidepressants fluoxetine and venlafaxine are efficacious for major depression, in all age 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.

No

No

Yes

Gibbons 2012b

Fluoxetine and venlafaxine decreased suicidal thoughts and behavior for adult and geriatric patients. This protective effect is mediated by decreases in depressive symptoms with 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 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.

No

No

Yes

Glue 2010

This meta-analysis emphasizes the importance of continuation treatment following acute response in depressive disorders. The robust findings of relapse prevention designs contrast with acute antidepressant efficacy studies, and may be due to enrichment of the patient population.

No

Yes

Yes

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Gartlehner 2008

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This present systematic review indicates that amitriptyline is at least as efficacious as other 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 less well tolerated, and although counterbalanced by a higher proportion of responders, the difference was not statistically significant.

Yes

No

No

Guaiana 2013

Agomelatine did not seem to provide a significant advantage in efficacy over other 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 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, 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 the efficacy and tolerability of agomelatine.

Yes

No

No

Hansen 2008

This review demonstrates the overall benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants and emphasizes the need for additional studies of comparative differences among drugs.

No

No

Yes

Hazel 2013

Data suggest tricyclic drugs are not useful in treating depression in children. There is marginal evidence to support the use of tricyclic drugs in the treatment of depression in adolescents.

Yes

No

Yes

Hetrick 2007

Caution is required to interpret the results. First, there were methodological issues, including high attrition, issues regarding measurement instruments and clinical usefulness 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 with SSRIs. It is unclear what the effect of SSRIs is on suicide completion. While untreated 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.

Yes

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Guaiana 2007

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No

No

No

No

No

Yes

No

Yes

These results support the utility of certain antidepressants (tricyclics, nefazodone) in treating depression in patients with comorbid alcohol use disorders. More data on the use of newer antidepressants, including the SSRIs, for this select patient population are needed.

No

No

Yes

Antidepressants are effective for MDD in patients who present with co-morbid axis-III 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.

No

No

Yes

Caution is required in interpreting the results given the methodological limitations of the 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 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 evidence of an increased risk of suicide-related outcomes in those treated with antidepressant medications.

Hou 2013

Prophylactic SSRI antidepressants can significantly reduce the incidence of PEG-IFNa/RBV-associated depression in patients with CHC, with good safety and tolerability, without reduction of SVR.

Howland 2011

Agomelatine was generally well tolerated compared with placebo. Its adverse effect profile is different to that of other antidepressant drugs, but its overall tolerability in studies with 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. 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 clinically significant advantages compared with other antidepressant drugs, and it has certain limitations and disadvantages. Because of the unique pharmacology of agomelatine 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.

Iovieno 2011a

Iovieno 2011b

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There was evidence of an increased risk in suicide-related outcomes on antidepressant treatments, while antidepressant treatments were also shown to be efficacious.

Yes

No

Yes

Kantrowitz 2008

Although rare, the present study indicates that tricyclic monotherapy may be temporally associated with an exacerbation of psychotic symptoms in patients with unipolar MDDP, potentially worsening prognosis.

Yes

No

Yes

Kasper 2009

Escitalopram is a good therapeutic option for the long-term treatment of MDD, particularly in severely depressed patients.

No

Yes

Yes

Kasper 2010

Our results based on pooled data from 15 placebo-controlled, short-term studies of 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 significantly lower suicidality risk compared to placebo.

No

Yes

Yes

Katzman 2007

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

No

Yes

Yes

Kaymaz 2008

Antidepressants robustly reduce relapse risk in the maintenance phase, regardless of a 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.

No

No

Yes

Kennedy 2009

In this meta-analysis, superior efficacy of escitalopram compared to SSRIs and SNRIs was confirmed, although the superiority over SSRIs was largely explained by differences between escitalopram and citalopram.

No

Yes

Yes

Khan 2012

In conclusion, the combination of psychotherapy and antidepressants for depression may 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 important than getting depressed patients involved in an active therapeutic program. Future research should consider whether certain patient profiles might justify a specific treatment modality.

No

No

Yes

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Julious 2013

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Newer generation antidepressant medications clearly differ in their efficacy as a function of baseline symptom severity. The selective serotonin reuptake inhibitor escitalopram had superior efficacy in the treatment of more severe depression, perhaps attributable to differential efficacy related to symptoms of negativistic thinking.

No

Yes

Yes

Kirsch 2008

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship 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.

Yes

No

Yes

Koesters 2011

There were no significant differences between venlafaxine and selective serotonin reuptake inhibitor on any of these parameters. Analyses of publication bias were inconclusive. 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 use of their research potential Chinese, researchers will have to improve trial reporting and the peer-review process.

Yes

No

No

Koesters 2013

We found evidence suggesting that a clinically important difference between agomelatine and placebo in patients with unipolar major depression is unlikely. There was evidence of substantial publication bias

Yes

No

Yes

Kok 2011

Continuing treatment with antidepressants in elderly patients is efficacious compared with placebo in preventing relapses and recurrences. Efficacy and tolerability during long-term treatment does not differ between TCAs and SSRIs.

No

No

Yes

Kok 2012

Antidepressant treatment in older depressed patients is efficacious. We could not demonstrate differences in effectiveness between different classes of antidepressants; this was also the case in more severely depressed patients.

No

No

Yes

Kornstein 2009

This pooled analysis indicates that escitalopram is at least as effective as the SNRIs (venlafaxine XR and duloxetine), even in severe depression, and escitalopram treatment was better tolerated.

No

Yes

Yes

Kornstein 2010

Desvenlafaxine generally improved depressive symptoms across age and sex subgroups.

No

Yes

Yes

Krebs 2008

The authors found insufficient evidence to support the choice of one second-generation antidepressant over another in patients with pain accompanying depression.

Yes

No

No

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Kilts 2009

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Several evidence-based acute pharmacological, psychotherapeutic, and combined treatments for persistent depressive disorder are available with significant differences between them.

Lam 2008

This pooled analysis shows that over an 8-week treatment period, escitalopram (10–20 mg/day) is superior in both effectiveness and tolerability compared with duloxetine (60 mg/day).

Lam 2010

No

No

Yes

No

Yes

Yes

In conclusion, escitalopram is associated with a better efficacy and tolerability profile than SNRIs (duloxetine and venlafaxine) when used as a second step treatment in patients with MDD. These results should be confirmed in prospective randomized clinical trials.

No

Yes

Yes

Laoutidis 2013

This meta-analysis suggests that antidepressants can be effective in treating depressive symptoms beside clinical depression. When considering the risk of side effects and interactions and the heterogeneity among the mostly small studies, a general recommendation cannot be made until well-controlled studies are conducted.

No

No

No

Laughren 2011

Vilazodone is a new treatment for MDD, but it is unknown whether it has any advantages compared to other drugs in the antidepressant class.

Yes

No

No

Lenox-Smith 2009

In this model, venlafaxine was shown to be a cost-effective alternative to generic fluoxetine 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 primary care in the UK.

No

Yes

Yes

Leucht 2012

Amitriptyline is an efficacious antidepressant drug. It is, however, also associated with a number of side effects. Degree of placebo response and severity of depression at baseline may moderate drug-placebo efficacy differences.

Yes

No

Yes

Levkovitz 2011

These results support the utility of antidepressants for dysthymic disorder. In fact, the 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 antidepressants are essential.

No

No

Yes

Lieberman 2008

Adverse events were comparable to those found with other drugs sharing a similar mechanism of action. These data support the efficacy, safety, and tolerability of desvenlafaxine in the treatment of major depressive disorder.

No

Yes

Yes

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Kriston 2014

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Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the treatment of MDD in placebo-controlled trials. A long-term study is underway to further explore desvenlafaxine 50 mg/d for MDD.

Liu 2013

There is insufficient evidence to support antidepressant efficacy for SSRIs, pramipexole, 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 benefits and acceptability, followed by pramipexole and SNRIs, SSRIs might be the last choice.

Ma 2013

No

Yes

Yes

Yes

No

No

Sertraline and mirtazapine exhibited optimally balanced efficacy, acceptability, and safety for first-line acute treatment of child and adolescent MDD.

No

No

No

Macedo 2011

This systematic review and meta-analysis showed that all RCTs included reported efficacy outcomes for pirlindole comparable to those of its comparators, and that pirlindole was 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.

No

Yes

Yes

Magni 2013

The present study detected differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is 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 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 efficacy data, treatment decisions should also be based on considerations of drug toxicity, patient acceptability and cost.

Yes

No

Yes

Mallinckrodt 2007

Potentially important differences in symptom response patterns were found between duloxetine and the combined SSRIs depending on symptom severity, and different HAMD 17 items responded differently to duloxetine compared with SSRIs. Understanding these differences may be useful in tailoring antidepressant therapy for individual patients.

No

Yes

No

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Liebowitz 2010

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According to the limited data obtained from three RCTs, bupropion XL is as effective and tolerable as venlafaxine XR for adult patients with MDD. Further studies in this area should be conducted to confirm these findings.

Maneeton 2012

Based on the limited evidence obtained from three RCTs, quetiapine XR is effective for 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 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.

Marangell 2011

No

No

Yes

Yes

No

Yes

In conclusion, consistent with our hypothesis, duloxetine produced a substantial direct effect on pain improvement and change in mood exerted a modest indirect effect on pain 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 comorbid patients with duloxetine.

No

Yes

Yes

Montgomery 2011

In this meta-analysis, the statistically significant superior efficacy of escitalopram compared to citalopram was shown to be clinically relevant.

No

Yes

Yes

Mukai 2009

The available data, although limited, suggest that the dual-action agents (TCAs and SNRIs) do not appear to confer any additional benefits in efficacy over single-action agents (SSRIs) in the treatment of depression in the elderly.

Yes

No

No

Nakagawa 2008

The overall effectiveness and tolerability of milnacipran versus other antidepressants does 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 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.

No

No

Yes

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Maneeton 2013

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Currently, there is inadequate evidence to conclude whether milnacipran is superior, 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 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 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.

Yes

No

Yes

Nelson 2008

Antidepressants are more effective than placebo in elderly depressed subjects although effects are modest and vary. Identification of the characteristics of responders and nonresponders will be crucial to improving treatment outcomes

No

No

Yes

Nelson 2009

In randomized, placebo-controlled trials, anxiety in late-life depression was not associated with decreased response to second generation antidepressants

No

No

Yes

Nelson 2010

Duloxetine was more effective than placebo in achieving response and remission in both anxious and nonanxious patients. Anxious status did not affect the magnitude of the drug effect.

No

No

Yes

Nelson 2011

The evidence for antidepressant treatment of people with depression and dementia, although suggestive, does not confirm efficacy. All of the trials were significantly underpowered to detect differences, resulting in inconclusive findings. Variable trial methods, comorbid conditions, and differences in antidepressants employed further confounded findings.

Yes

No

Yes

Nelson 2013

Older patients with a long illness duration and moderate to severe depression appear to benefit from antidepressants as compared with placebo. Antidepressants do not appear to be effective for older patients with short illness duration.

No

No

Yes

Nieuwenhuij sen 2008

Based on a heterogeneous sample of studies, there is currently no evidence of an effect of medication alone, enhanced primary care, psychological interventions or the combination 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.

Yes

No

No

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Nakagawa 2009

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These safety results may better inform clinicians providing individualized care to elderly patients with major depressive disorder.

No

Yes

Yes

Offidani 2013

Risks of excessive mood elevation during antidepressant treatment, including maniahypomania, 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 monitoring for potential risk of future bipolar disorder.

Yes

No

No

Omori 2009

There were no large differences between fluvoxamine and any other antidepressants in 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 those in side-effect profiles.

Yes

No

Yes

Omori 2010

We found no strong evidence that fluvoxamine was either superior or inferior to any other 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, including these differences in side effect profiles.

Yes

No

Yes

Pae 2013

STS appears to be comparably efficacious and tolerable in atypical and nonatypical subtypes of MDD. Adequately powered, controlled, clinical trials are necessary to confirm our findings.

No

Yes

Yes

Pani 2010

There is low evidence, at the present, supporting the clinical use of antidepressants for the 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 to allow comparison of results.

Yes

No

No

Papakostas 2007a

These results suggest that milnacipran and the SSRIs do not differ with respect to their overall efficacy in the treatment of MDD.

No

No

Yes

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Oakes 2013

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These results suggest that the 5HT2-receptor antagonists trazodone and nefazodone and the 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 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.

No

No

Yes

Papakostas 2007c

Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage 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 dualaction 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 relevance given the large number of depressed patients treated with SSRI /serotoninnorepinephrine reuptake inhibitor (SNRI) antidepressant drugs. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms.

No

No

Yes

Papakostas 2007d

There does not appear to be any statistically detectable difference in the rapidity of antidepressant effect between bupropion and the SSRIs overall or escitalopram specifically.

No

Yes

Yes

Papakostas 2008a

These results suggest that mirtazapine and the SSRIs differ with respect to their side-effect profile but not their overall efficacy in the treatment of MDD.

No

No

Yes

Papakostas 2008b

Contrary to clinician impression, there does not appear to be any difference in the anxiolytic efficacy of bupropion and the SSRIs when used to treat MDD.

No

Yes

No

Papakostas 2008c

These results suggest a modest yet statistically significant advantage in remission rates 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 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 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.

No

No

Yes

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Papakostas 2007b

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Initiating treatment with SSRIs at doses higher than those typically used in clinical trials/settings is associated with higher response rates but also higher rates of discontinuation due to intolerance. Developing treatment strategies allowing clinicians to deliver higher initial SSRI doses while enhancing the tolerability of treatment may represent an alternative approach to improving the efficacy of treatment of MDD.

Yes

No

Yes

Papakostas 2011

Escitalopram was more effective than placebo, and as effective as the SSRIs andSNRIs, in 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 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.

No

Yes

No

Papakostas 2012

Subdividing patients with severe major depressive disorder into those with versus without 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, of yet undetermined clinical relevance, and warrant replication and further exploration.

No

Yes

Yes

Pedrelli 2011

These results show no difference in the depressive outcome of patients with comorbid opiateuse disorders on MMTwhether they are on medication or placebo. Future studies examining the effectiveness of antidepressants while controlling for several variables such as psychosocial treatment and assessing the specific classes of antidepressants are needed.

Yes

No

Yes

Pizzi 2011

A significantly greater improvement in depression symptoms was always apparent in 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.

No

No

No

Pjrek 2009

Thus escitalopram and reboxetine were equally effective in treating SAD on all primary 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.

No

No

Yes

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Papakostas 2010

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Antidepressants are effective for the treatment of depression in patients with neurological disorders but the evidence for the efficacy of antidepressants in improving quality of life, and functional and cognitive outcomes is inconclusive.

Pritchett 2007

The effect size analyses demonstrate that duloxetine 40 mg has minimum efficacy, and that 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 MDD.

Ramsberg 2012

Of the investigated antidepressants, escitalopram has the highest probability of remission 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.

Rayner 2010

No

No

No

No

Yes

No

No

Yes

No

This review provides evidence that antidepressants are superior to placebo in treating depression in physical illness. However, it is likely that publication and reporting biases exaggerated the effect sizes obtained. Further research is required to determine the comparative efficacy and acceptability of particular antidepressants in this population.

No

No

No

Rayner 2011

This review provides evidence that antidepressants are effective in treating depression in palliative care. Their superiority over placebo is apparent within 4–5 weeks and increases with continued use. It is probable that the effect sizes yielded in this review overestimate the efficacy of antidepressants due to biases such as selective reporting and publication. Nevertheless, the magnitude and consistency of the effect suggests genuine benefit.

No

Information on COI not available

No

Reddy 2010

Desvenlafaxine 50 mg/d has demonstrated efficacy, safety, and tolerability for the 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 CYP2D6, lack of interaction with p-glycoprotein, and low protein binding.

No

Yes

No

Reed 2012

Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are supported by subgroup analysis and open-label, long-term effectiveness data.

No

Yes

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Price 2011

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Because of the indirect nature of the comparisons, the often wide credible intervals, and the 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 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.

Yes

No

Yes

Robinson 2013

Results demonstrate that improvement in pain and mood contributes to functional improvement, and pain reduction and functional improvement increase the likelihood of remission of depressive symptoms with duloxetine treatment in patients with both MDD and PPS at baseline.

No

Yes

Yes

Robinson 2008

A comprehensive review of safety from the clinical development program suggests that the STS is safe and well tolerated, with an improved safety margin compared with orally administered MAOIs.

No

No

Yes

Rocha 2012

The results suggest that antidepressant combination is more efficient than a single antidepressant without a significant decrease in tolerability. However, the small number of clinical trials and methodological problems precludes definitive conclusions

No

No

Yes

Rocha 2013

The results suggest antidepressants may be efficacious in the treatment of dPD. However, the results were unstable. In fact, the small number of trials and methodological drawbacks preclude definitive conclusions about their efficacy and tolerability in dPD.

No

No

Yes

Rooney 2010

No high-quality studies have examined the value of any drug treatment of depression in 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.

Yes

No

No

Salter 2013

The early initiation of antidepressant therapy, in nondepressed stroke patients, may reduce 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 require additional examination.

No

No

No

Sarkar 2013

Antidepressant pretreatment with selective serotonin reuptake inhibitors lowers the incidence and severity of IFN-associated depression in patients with chronic hepatitis C infection or malignant melanoma.

No

No

Yes

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Reichenpfad er 2014

64

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In conclusion, these analyses demonstrate that venlafaxine may be superior to SSRIs in 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 pronounced clinical benefit that may be achieved with venlafaxine in severely depressed patients.

No

Yes

Yes

Schueler 2011

Rather than being a first-line option, venlafaxine appears to be a valid alternative in patients who do not tolerate or respond to SSRIs or TCAs. Duloxetine does not seem to be indicated as a first-line treatment.

Yes

No

Yes

Seitz 2010

Currently there are few studies directly comparing citalopram to other antidepressants for 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 antidepressants. Well designed studies comparing citalopram to other antidepressants for LLD are required.

Yes

No

No

Serretti 2011

Our results, though significant, were generally observed with small estimate values, their 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 samples.

Yes

No

Yes

Signorovitch 2011

Treatment of adult MDD patients with escitalopram was significantly more likely to result 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 which individual patient data were not obtained.

No

Yes

Yes

Singh 2011

Although there is evidence of the superiority of agomelatine over placebo and selected antidepressants, it is questionable whether the magnitude of effect size is clinically significant and sample characteristics are relevant to the general patient population with major depressive disorder.

Yes

Yes

No

Skapinakis 2010

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

Yes

No

Yes

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Schmitt 2009

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Desvenlafaxine therapy resulted in significant improvements in functioning and well-being among MDD patients.

No

Yes

Yes

Stein 2011

Additional research assessing the comparative effects of antidepressants with 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.

No

Yes

Yes

Stein 2013

Once-a-day oral agomelatine is a new, efficacious alternative option for the treatment of anxiety in patients with major depression.

No

Yes

Yes

Stone 2009

Risk of suicidality associated with use of antidepressants is strongly age dependent. 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 25-64 and to reduce the risk of both suicidality and suicidal behaviour in those aged ≥65.

Yes

No

No

Szegedi 2009

The results indicate that early improvement with antidepressant medication can predict subsequent treatment outcome with high sensitivity in patients with major depressive 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 should be considered earlier than conventionally thought.

No

Yes

Yes

Taylor 2011

Antidepressants are efficacious and safe in the treatment of depression occurring in the 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 cardiovascular disease.

No

No

Yes

Tedeschini 2011

The present meta-analysis suggests that antidepressants are efficacious in late-life MDD, but significant study heterogeneity suggests that other factors may contribute to these findings. A secondary analysis raises the possibility that efficacy of these agents may be reduced in trials involving patients aged 65 years or older. Why antidepressants may be less efficacious in elderly versus younger subjects remains unclear.

No

No

Yes

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Soares 2009

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No

Yes

Yes

No

Yes

No

Yes

Yes

In conclusion, the findings indicate that mirtazapine may be a more rapidly effective antidepressant than SSRIs.

No

Yes

Yes

Thompson 2007

Antidepressant treatment for depression in AD is efficacious, with rates of discontinuation that are comparable to placebo. Nonetheless, clinicians must be vigilant regarding the potential side effects of antidepressants in this population.

No

No

Yes

Tondo 2010

Use of ADs in adults with BPD or MDD was highly prevalent and moderately increased the risk of mania overall, with little protection by mood stabilizers.

Yes

No

Yes

Tourian 2009

EP

ACCEPTED MANUSCRIPT

The current study failed to meet its primary efficacy end point based on the a priori 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 both doses to be effective for MDD compared with placebo. Desvenlafaxine was associated with significantly greater improvement in anxiety symptoms compared with placebo in patients with MDD.

No

Yes

No

No

Yes

Yes

Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared 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 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 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 SGAs for SAD withdrew from the studies early due to adverse effects. The overall quality of evidence in this review is very low.

Thaler 2012

Evidence guiding the selection of an SGA based on accompanying symptoms of depression is limited. Very few trials were designed and adequately powered to answer questions about accompanying symptoms; analyses were generally of subgroups in larger MDD trials. Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose response effect on tolerability was observed.

Thase 2010

Yes

Tourian 2010

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Thaler 2011

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Tsapakis 2008

Presently, the claims about clinically relevant superiority of escitalopram over citalopram in short-to-medium term treatment of major depressive disorder are not supported by evidence. Antidepressants of all types showed limited efficacy in juvenile depression, but fluoxetine 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 readily accessible treatments for juvenile depression are urgently required.

Yes

No

Yes

No

No

Yes

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Trkulja 2010

Most add-on interventions demonstrated comparable efficacy in patients with MDD and an 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.

No

Yes

Yes

Undurraga 2012

Study findings generally support moderate efficacy of clinically employed antidepressants 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 clinical assessments.

No

No

No

Undurraga 2013

Responses to imipramine in its earliest controlled trials were much larger than in recent antidepressant trials. Drug-placebo differences declined significantly between 1959 and 1965, with rising placebo-associated responses. Frequent failure to find superior drug-overplacebo 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.

Yes

No

Yes

Usala 2008

Nevertheless, additional RCTs with sound methodological designs, validated diagnostic instruments, large sample sizes, and consistent outcomes are necessary to determine the role of SSRIs, alone or in combination with psychological interventions in the treatment of depression in children and adolescents.

No

No

Yes

van den Broek 2009

From our review, no significant difference in treatment effect between low 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.

No

No

Yes

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Turner 2014

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The treatment of depression in people with diabetes is a necessary step, but improvement of the general medical condition including glycemic control is likely to require simultaneous attention to both conditions. Further research is needed.

Vieta 2013

Quetiapine XR as a monotherapy (150mg/day at Weeks 2 and 4) or adjunct to ongoing antidepressant therapy (150 and 300 mg/day at Weeks 2 and 4) increased sustained response rates versus placebo.

von Wolff 2013

Yes

No

Yes

No

Yes

Yes

This systematic review provides evidence for the efficacy of both SSRIs and TCAs in the treatment of chronic depression and showed a better acceptability of SSRIs.

No

No

No

Wade 2009

A higher probability of achieving remission is associated with responding after 8 weeks and with completing 6 months of treatment.

No

Yes

Yes

Watanabe 2008

Although mirtazapine is likely to have a faster onset of action than SSRIs, no significant 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.

No

No

Yes

Watanabe 2010

The study confirmed the paucity of adequate safety reporting in trials comparing mirtazapine with other types of antidepressant in the acutephase treatment of depression in adults. Based on the available evidence, mirtazapine appears to have a unique adverseevent profile. Using these findings, clinicians can inform their patients, not only of the 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.

Yes

No

Yes

Watanabe 2011

Some statistically significant and possibly clinically meaningful differences between 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 the acute-phase treatment. Dropouts occur similarly in participants treated with mirtazapine and those treated with other antidepressants, although the adverse event profile of mirtazapine is unique.

No

No

Yes

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van der FeltzCornelis 2010

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

No

Yes

Yes

Wijkstra 2013

Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone.

No

No

Yes

Williams 2009

Prophylactic antidepressant drug therapy appears efficacious in preventing future relapses 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.

No

No

Yes

Yi 2010

Fluoxetine was beneficial for the prophylaxis of poststroke depression in patients with stroke but not in reducing symptom severity of PSD.

No

No

No

Zhuang 2013

There is no evidence on the effectiveness and safety of antidepressants in treating depression and other symptoms in women with PCOS.

Yes

No

No

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Wightman 2010

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