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Original Investigation
October 2, 2019

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

Author Affiliations
  • 1Pain and Rehabilitation Centre, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden
  • 2Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, University Campus, Ioannina, Greece
  • 3Department of Neuroscience, University of Padua, Padua, Italy
  • 4Padova Neuroscience Center (PNC), University of Padua, Padua, Italy
  • 5Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
  • 6OASIS Service, South London and Maudsley NHS (National Health Service) Foundation Trust, London, United Kingdom
  • 7Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
  • 8Section of Imaging, Neurobiology, and Psychosis, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom
  • 9National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, London, United Kingdom
  • 10Department of Psychology, Social Work and Counselling, University of Greenwich, Greenwich, United Kingdom
  • 11Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, United Kingdom
  • 12Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
  • 13NICM Health Research Institute, School of Science and Health, University of Western Sydney, Sydney, Australia
  • 14Division of Psychology and Mental Health, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
  • 15Centre for Youth Mental Health, University of Melbourne, Melbourne, Australia
  • 16Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II University, Naples, Italy
  • 17Department of Clinical Physiology, Linköping University, Linköping, Sweden
  • 18Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
  • 19Department of Psychiatry and Psychology, Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, the Spanish Ministry of Science and Innovation (CIBERSAM), Barcelona, Catalonia, Spain
  • 20South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, Kent, United Kingdom
  • 21Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
  • 22Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York
  • 23Department of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, New York
  • 24Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, New York
  • 25Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Department of Child and Adolescent Psychiatry, Berlin Institute of Health, Berlin, Germany
  • 26Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
JAMA Psychiatry. 2019;76(12):1241-1255. doi:10.1001/jamapsychiatry.2019.2859
Key Points

Question  Is antidepressant use associated with adverse health outcomes, and how credible is the evidence behind this association in published meta-analyses of real-world data?

Findings  In this systematic umbrella review of 45 meta-analyses of observational studies, convincing evidence was found for the associations between antidepressant use and suicide attempt or completion among individuals younger than 19 years and between antidepressant use and autism risk among the offspring. However, none of these associations remained at the convincing evidence level after a sensitivity analysis that adjusted for confounding by indication.

Meaning  This study’s findings suggest that claimed adverse health outcomes associated with antidepressants may not be supported by strong evidence and may be exaggerated by confounding by indication; no absolute contraindication to the use of antidepressants was found to be currently supported by convincing evidence.


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.

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    1 Comment for this article
    No evidence that antidepressants are safe and some cause for concern
    Michael Hengartner, PhD | Zurich University of Applied Sciences, Switzerland
    Dragioti et al conclude that antidepressant use appears to be safe (1). We believe that this confidence in the safety profile of antidepressants is unwarranted. Although they found little convincing evidence of harm outcomes in their review, this in no way implies that they found convincing evidence that antidepressants are safe.
    Sexual dysfunction - the most prevalent adverse event caused by antidepressant use, was not included in their review but has been convincingly documented in placebo-controlled trials (2) and sexual dysfunction can even remain long after the drug was stopped (3). Withdrawal reactions from antidepressants were also excluded, despite
    their relatively high incidence in long-term users and that they can be severe and long-lasting, as has been demonstrated in both placebo-controlled trials and observational studies (4).
    Dragioti et al found no convincing evidence that antidepressants protect against suicide in adults, but selectively emphasise this favourable outcome in their discussion instead of the various highly suggestive adverse outcomes, including, for instance, osteoporotic fractures, upper gastrointestinal bleeding, preterm birth, and lower Apgar score (1). Moreover, meta-analyses of placebo-controlled trials in adults provide no evidence that antidepressants protect against suicides or suicide attempts (2); some even indicate that antidepressants increase the risk of suicide attempts (5). Recent well-controlled longitudinal cohort studies in real-world primary care patients with depression likewise found significantly increased suicide risk with antidepressants (6).
    Meta-analyses of placebo-controlled trials further show that antidepressants increase the rate of serious adverse events (2), and meta-analyses of observational studies suggest they increase all-cause mortality and the risk of cardiovascular events (7). Surprisingly, the meta-analysis by Maslej et al (7) on all-cause mortality and cardiovascular events was not included in Dragioti et al for unknown reasons.
    Dragioti et al suggest that confounding by indication has exaggerated the reported effect sizes (1). However, in the four studies reported in Dragioti et al that adjusted for confounding by indication, the effect sizes for adverse events remained almost unchanged. This suggests that there is little reason to assume that confounding by indication inflated the reported associations. The meta-analysis by Maslej et al on all-cause mortality likewise found no evidence for confounding by indication (7).
    There are plenty of well-controlled observational studies that found elevated rates of serious adverse events that were not addressed in this umbrella review of systematic reviews, including obesity, diabetes, cardiovascular disease, hyponatremia, liver damage, and dementia. Therefore, we cannot be confident that antidepressants are safe, and we need to remain mindful that antidepressants can cause severe harm.

    1. Dragioti E, et al. JAMA Psychiatry. 2019.
    2. Jakobsen JC, et al. BMC Psychiatry. 2017;17(1):58.
    3. Healy D. Int J Risk Saf Med. 2018;29(3-4):135-147.
    4. Davies J, Read J. Addict Behav. 2019;97:111-121.
    5. Fergusson D, et al. BMJ. 2005;330(7488):396.
    6. Coupland C, et al. BMJ. 2015;350:h517.
    7. Maslej MM, et al. Psychother Psychosom. 2017;86(5):268-282.