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JAMA Psychiatry. 2019 Oct 2. doi: 10.1001/jamapsychiatry.2019.2859. [Epub ahead of print]

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

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Pain and Rehabilitation Centre, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, University Campus, Ioannina, Greece.
Department of Neuroscience, University of Padua, Padua, Italy.
Padova Neuroscience Center (PNC), University of Padua, Padua, Italy.
Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
OASIS Service, South London and Maudsley NHS (National Health Service) Foundation Trust, London, United Kingdom.
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Section of Imaging, Neurobiology, and Psychosis, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, London, United Kingdom.
Department of Psychology, Social Work and Counselling, University of Greenwich, Greenwich, United Kingdom.
Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, United Kingdom.
Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
NICM Health Research Institute, School of Science and Health, University of Western Sydney, Sydney, Australia.
Division of Psychology and Mental Health, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
Centre for Youth Mental Health, University of Melbourne, Melbourne, Australia.
Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II University, Naples, Italy.
Department of Clinical Physiology, Linköping University, Linköping, Sweden.
Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Department of Psychiatry and Psychology, Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, the Spanish Ministry of Science and Innovation (CIBERSAM), Barcelona, Catalonia, Spain.
South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, Kent, United Kingdom.
Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York.
Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York.
Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, New York.
Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Department of Child and Adolescent Psychiatry, Berlin Institute of Health, Berlin, Germany.
Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.



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.


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.


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.

[Available on 2020-10-02]

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