Benefits From Antidepressants: Synthesis of 6-Week Patient-Level Outcomes From Double-blind Placebo-Controlled Randomized Trials of Fluoxetine and Venlafaxine
Open accessAbstract
CONTEXT: Some meta-analyses suggest that efficacy of antidepressants for major depression is overstated and limited to severe depression. OBJECTIVE: To determine the short-term efficacy of antidepressants for treating major depressive disorder in youth, adult, and geriatric populations. DATA SOURCES: Reanalysis of all intent-to-treat person-level longitudinal data during the first 6 weeks of treatment of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride. STUDY SELECTION: All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. DATA EXTRACTION: Children's Depression Rating Scale-Revised scores (youth population), Hamilton Depression Rating Scale scores (adult and geriatric populations), and estimated response and remission rates at 6 weeks were analyzed for 2635 adults, 960 geriatric patients, and 708 youths receiving fluoxetine and for 2421 adults receiving immediate-release venlafaxine and 2461 adults receiving extended-release venlafaxine. DATA SYNTHESIS: Patients in all age and drug groups had significantly greater improvement relative to control patients receiving placebo. The differential rate of improvement was largest for adults receiving fluoxetine (34.6% greater than those receiving placebo). Youths had the largest treated vs control difference in response rates (24.1%) and remission rates (30.1%), with adult differences generally in the 15.6% (remission) to 21.4% (response) range. Geriatric patients had the smallest drug-placebo differences, an 18.5% greater rate of improvement, 9.9% for response and 6.5% for remission. Immediate-release venlafaxine produced larger effects than extended-release venlafaxine. Baseline severity could not be shown to affect symptom reduction. CONCLUSIONS: To our knowledge, 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first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies.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 depressive disorder in all age groups, although more so in youths and adults compared with geriatric patients. Baseline severity was not significantly related to degree of treatment advantage over placebo.
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Seventeen pharmacotherapy trials with suicidal behavior as an outcome, including twelve adult studies, five pediatric studies, and seven RCT meta-analyses, have appeared since the FDA adopted black box warnings in 2004 and 2006.
“Seventeen pharmacotherapy trials with suicidal behavior as an outcome (Table S2a), including twelve studies in adults, five pediatric studies and seven RCT meta-analyses(48–54), have appeared since the FDA(51) adopted black box warnings in 2004 and 2006 regarding psychotropic medication-related suicide risk in children and young adults, respectively.”
From Improving Suicide Prevention Through Evidence-Based Strategies: A Systematic Review (2021) · cites this paper as [49]
The Discussion (page unavailable) mentions a black-box warning concerning suicidal thinking and antidepressants in children, supporting part of the FDA-warning clause to which this citation is attached. It does not give the 2004 and 2006 dates or mention a warning for young adults. The Methods describe different trial counts and do not establish the citing sentence’s counts of trials with suicidal behavior as an outcome or RCT meta-analyses. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA meta-analysis of all FDA-registered randomized placebo-controlled studies of fluoxetine and venlafaxine found these medications decreased suicidal ideation and behavior.
“A meta-analysis of all FDA-registered randomized placebo-controlled studies of fluoxetine and venlafaxine found these medications decreased suicidal ideation and behavior.(49, 52)”
From Improving Suicide Prevention Through Evidence-Based Strategies: A Systematic Review (2021) · cites this paper as [49]
The Discussion (page unavailable) says the paper analyzed sponsor-conducted, placebo-controlled trials of fluoxetine and venlafaxine. Its reported benefits concern depressive symptoms, response, and remission—not a decrease in suicidal ideation or behavior. The passage also does not establish that the trials were all FDA-registered. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMost subsequent meta-analyses and epidemiological studies in pediatric and adult populations reported a more favorable risk-benefit ratio than FDA analyses, including benefits for suicidal behavior.
“One systematic review of antidepressants in pediatric populations found SSRIs increased odds of a suicide attempt,(53) but most subsequent meta-analyses and epidemiological studies in both pediatric(48),(50) and adult populations(49, 52, 66, 67, 86) reported a more favorable risk-benefit ratio than the FDA analyses,(51, 87) including benefits for suicidal behavior.”
From Improving Suicide Prevention Through Evidence-Based Strategies: A Systematic Review (2021) · cites this paper as [49]
The Discussion reports antidepressant benefits in youth and adults and says the findings should prompt reconsideration of the risk–benefit equation behind the warning about suicidal thinking in children. It does not report a benefit for suicidal behavior or establish what most subsequent meta-analyses and epidemiological studies found; this paper analyzes trial data for fluoxetine and venlafaxine. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBoth pediatric and adult studies of antidepressant effects on suicidal behavior show reductions in suicidal behavior in meta-analyses more readily than in individual RCTs.
“Both pediatric and adult studies of antidepressant effects on suicidal behavior show reductions in suicidal behavior in meta-analyses, more readily than in individual RCTs, probably because the low base rate of suicide attempts requires larger sample sizes.”
From Improving Suicide Prevention Through Evidence-Based Strategies: A Systematic Review (2021) · cites this paper as [49]
The Discussion (page unavailable) reports improved depression response and remission in youth and adults, but does not report reductions in suicidal behavior. A separate Discussion passage mentions the pediatric warning about suicidal thinking; neither it nor the Methods passages establish the claimed comparison between meta-analyses and individual RCTs. Searches for suicidal behavior, suicide attempts, and the proposed low-base-rate explanation found no supporting passage. (LLM, conf=0.76)
Experimental — accuracy not yet measuredOne small individual patient data meta-analysis found support for increasing benefit with increasing severity of depression, but three larger individual patient data meta-analyses did not find any such effect of antidepressants compared with placebo on depression severity.
“One small individual patient data meta-analysis found support for increasing benefit with increasing severity of depression,20 but three larger individual patient data meta-analyses did not find any such effect of antidepressants compared with placebo on depression severity .44–46”
From Should antidepressants be used for major depressive disorder? (2020) · cites this paper as [44]
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- Authors
- Gibbons, R. D., Hur, K., Brown, C. H., Davis, J. M., & Mann, J. J.
- Affiliations
- University of Chicago (US)
- Edward Hines, Jr. VA Hospital (US)
- University of Miami (US)
- University of Illinois Chicago (US)
- New York State Psychiatric Institute (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2012-06-01
- Volume
- 69
- Issue
- 6
- Pages
- 572-9
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3371295
- OpenAlex
- W2169679251
- Cited by
- 271
- References
- 24
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 6 · 2023: 10 · 2022: 15 · 2021: 15 · 2020: 13 · 2019: 24 · 2018: 26 · 2017: 18 · 2016: 21 · 2015: 30 · 2014: 26 · 2013: 43 · 2012: 14
- FWCI
- 26.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Justice
- U.S. Department of Veterans Affairs
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- University of Miami
- University of Chicago
- University of South Florida
- Agency for Healthcare Research and Quality (1U18HS01697, U18HS016973)
- Department of Psychiatry, Columbia University
- Pfizer Pharmaceuticals
- National Institute of Mental Health (MH8012201, MH-062185, R56MH078580, MH040859, R01MH040859, P50MH062185)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Social Psychology › Mental Health Treatment and Access
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- antidepressants, major depressive disorder, fluoxetine, venlafaxine, antidepressant efficacy, depression severity, adolescent depression, geriatric depression, placebo comparison, age differences in treatment response
- MeSH terms
- Venlafaxine Hydrochloride, Adolescent, Adult, Aged, Cyclohexanols, Depressive Disorder, Major, Major Depressive Disorder, Fluoxetine, Humans, Randomized Controlled Trials as Topic, Selective Serotonin Reuptake Inhibitors
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