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, 76 (12), 1241-1255
[Online ahead of print]

Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review


Association of Antidepressant Use With Adverse Health Outcomes: A Systematic Umbrella Review

Elena Dragioti et al. JAMA Psychiatry.


Importance: Antidepressant use is increasing worldwide. Yet, contrasting evidence on the safety of antidepressants is available from meta-analyses, and the credibility of these findings has not been quantified.

Objective: To grade the evidence from published meta-analyses of observational studies that assessed the association between antidepressant use or exposure and adverse health outcomes.

Data sources: PubMed, Scopus, and PsycINFO were searched from database inception to April 5, 2019.

Evidence review: Only meta-analyses of observational studies with a cohort or case-control study design were eligible. Two independent reviewers recorded the data and assessed the methodological quality of the included meta-analyses. Evidence of association was ranked according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant.

Results: Forty-five meta-analyses (17.9%) from 4471 studies identified and 252 full-text articles scrutinized were selected that described 120 associations, including data from 1012 individual effect size estimates. Seventy-four (61.7%) of the 120 associations were nominally statistically significant at P ≤ .05 using random-effects models. Fifty-two associations (43.4%) had large heterogeneity (I2 > 50%), whereas small-study effects were found for 17 associations (14.2%) and excess significance bias was found for 9 associations (7.5%). Convincing evidence emerged from both main and sensitivity analyses for the association between antidepressant use and risk of suicide attempt or completion among children and adolescents, autism spectrum disorders with antidepressant exposure before and during pregnancy, preterm birth, and low Apgar scores. None of these associations remained supported by convincing evidence after sensitivity analysis, which adjusted for confounding by indication.

Conclusions and relevance: This study's findings suggest that most putative adverse health outcomes associated with antidepressant use may not be supported by convincing evidence, and confounding by indication may alter the few associations with convincing evidence. Antidepressant use appears to be safe for the treatment of psychiatric disorders, but more studies matching for underlying disease are needed to clarify the degree of confounding by indication and other biases. No absolute contraindication to antidepressants emerged from this umbrella review.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fusar-Poli reported receiving grants and personal fees from Lundbeck outside the submitted work. Dr Vieta reported receiving grants and serving as a consultant, advisor, or continuing medical education speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Galenica, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, CIBERSAM, the Seventh European Framework Programme and Horizon 2020, and the Stanley Medical Research Institute. Dr Young reported receiving grants and personal fees from Janssen; receiving personal fees from Lundbeck, Allegan, Sunovion, Livanova, Johnson & Johnson, and Bionomics outside the submitted work; being employed by King's College London and an honorary consultant for SLaM (NHS United Kingdom); receiving fees for lectures and service on advisory boards for the following companies with drugs for affective and related disorders: AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, and Bionomics; being a consultant to Johnson & Johnson and Livanova; not having share holdings in pharmaceutical companies; being lead investigator for the Embolden Study (AstraZeneca), BCI Neuroplasticity Study, and Aripiprazole Mania Study and participating in investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck, Wyeth, and Janssen; and receiving past and present grant funding from the National Institute of Mental Health, Canadian Institutes of Health Research, National Alliance for Research on Schizophrenia and Depression, Stanley Medical Research Institute, Medical Research Council, Wellcome Trust, Royal College of Physicians, British Medical Association, Vancouver General Hospital and University of Bristish Columbia Hospital Foundation, Western Economic Diversification Canada, Canadian Cancer Society Depression Research Fund, Michael Smith Foundation for Health Research, National Institute for Health Research (NIHR), and Janssen. Dr Correll reported receiving personal fees from Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gedeon Richter, Indivior, LB Pharma, Lundbeck, MedAvante-ProPhase, Merck, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, and Supernus; receiving grants and personal fees from Janssen/Johnson & Johnson and Teva outside the submitted work; serving on a data safety monitoring board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva; providing expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka; receiving royalties from UpToDate and grant support from Janssen and Takeda; and being shareholder of LB Pharma. No other disclosures were reported.

Comment in

  • JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2019.2193

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