Suicidal Thoughts and Behavior With Antidepressant Treatment: Reanalysis of the Randomized Placebo-Controlled Studies of Fluoxetine and Venlafaxine
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CONTEXT: The US Food and Drug Administration issued a black box warning for antidepressants and suicidal thoughts and behavior in children and young adults. OBJECTIVE: To determine the short-term safety of antidepressants by standard assessments of suicidal thoughts and behavior in youth, adult, and geriatric populations and the mediating effect of changes in depressive symptoms. DATA SOURCES: All intent-to-treat person-level longitudinal data 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: The suicide items from the Children's Depression Rating Scale-Revised and the Hamilton Depression Rating Scale as well as adverse event reports of suicide attempts and suicide during active treatment were analyzed in 9185 patients (fluoxetine: 2635 adults, 960 geriatric patients, 708 youths; venlafaxine: 2421 adults with immediate-release venlafaxine and 2461 adults with extended-release venlafaxine) for a total of 53 260 person-week observations. DATA SYNTHESIS: Suicidal thoughts and behavior decreased over time for adult and geriatric patients randomized to fluoxetine or venlafaxine compared with placebo, but no differences were found for youths. In adults, reduction in suicide ideation and attempts occurred through a reduction in depressive symptoms. In all age groups, severity of depression improved with medication and was significantly related to suicide ideation or behavior. CONCLUSIONS: 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.
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A 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 [52]
The Study Selection section describes sponsor-conducted randomized trials of fluoxetine and venlafaxine, and the Conclusions report decreased suicidal thoughts and behavior in adult and geriatric patients. The claim omits the important qualifier that no significant treatment effect was found in youths. Our copy also describes the trials as sponsor-conducted, rather than establishing that they 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 [52]
The COMMENT section reports significantly lower suicide-risk measures with antidepressant treatment in adult and geriatric patients. But it says those adult findings largely agree with the FDA’s, rather than showing a more favorable result, and that the study could not analyze suicidal behavior separately from ideation. It therefore supports an adult suicide-risk benefit, not the full comparison or a distinct benefit for suicidal behavior. (LLM, conf=0.86)
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 [52]
The COMMENT reports significant reductions in suicide-risk measures for treated adults in an analysis combining trial data, and the METHODS notes that suicide attempts and deaths were too few for well-powered comparisons. But the RESULTS > YOUTH FLUOXETINE STUDIES found no significant treatment effect in youths. The paper also says it lacked power to analyze suicidal behavior separately from ideation, so it does not establish the claimed reduction in suicidal behavior for both age groups or directly compare meta-analyses with individual RCTs. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSeventeen 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 [52]
The safety profile of antidepressants is controversial.
“The safety profile of antidepressants is controversial.”
From Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review (2019) · cites this paper as [8]
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- Authors
- Gibbons, R. D., Brown, C. H., Hur, K., Davis, J. M., & Mann, J. J.
- Affiliations
- University of Chicago (US)
- University of Miami (US)
- United States Department of Veterans Affairs (US)
- Corresponding author
- Gibbons, Robert D.
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2012-06-01
- Volume
- 69
- Issue
- 6
- Pages
- 580
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3367101
- OpenAlex
- W2146935353
- Cited by
- 291
- References
- 15
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 17 · 2023: 16 · 2022: 13 · 2021: 18 · 2020: 14 · 2019: 17 · 2018: 14 · 2017: 17 · 2016: 30 · 2015: 28 · 2014: 37 · 2013: 42 · 2012: 19
- FWCI
- 45.69
- 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
- Agency for Healthcare Research and Quality (U18HS016973, 1U18HS016973)
- National Institute of Mental Health (MH8012201, MH-062185, R56MH078580, MH040859, R01MH040859, P50MH062185)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- antidepressant safety, suicidal ideation, suicide attempts, fluoxetine, venlafaxine, major depressive disorder, depressive symptoms, mediation analysis, youth, elderly patients, black box warning
- MeSH terms
- Venlafaxine Hydrochloride, Cyclohexanols, Major Depressive Disorder, Fluoxetine, Humans, Suicide, Randomized Controlled Trials as Topic, Selective Serotonin Reuptake Inhibitors
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