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

doi:10.1001/jamapsychiatry.2019.2859

. 2019 Dec 1;76(12):1241-1255.

doi: 10.1001/jamapsychiatry.2019.2859.

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

Elena Dragioti^{1

2}, Marco Solmi^{3

4

5}, Angela Favaro^{3

4}, Paolo Fusar-Poli^{5

6

7}, Paola Dazzan^{8

9}, Trevor Thompson¹⁰, Brendon Stubbs^{11

12}, Joseph Firth^{13

14

15}, Michele Fornaro¹⁶, Dimitrios Tsartsalis¹⁷, Andre F Carvalho¹⁸, Eduard Vieta¹⁹, Philip McGuire⁵, Allan H Young^{12

20}, Jae Il Shin²¹, Christoph U Correll^{22

23

24

25}, Evangelos Evangelou^{2

26}

Affiliations

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

PMID: 31577342
PMCID: PMC6777224
DOI: 10.1001/jamapsychiatry.2019.2859

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

Elena Dragioti et al. JAMA Psychiatry. 2019.

. 2019 Dec 1;76(12):1241-1255.

doi: 10.1001/jamapsychiatry.2019.2859.

Authors

Affiliations

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

PMID: 31577342
PMCID: PMC6777224
DOI: 10.1001/jamapsychiatry.2019.2859

Erratum in

Data Errors in Table.
[No authors listed] [No authors listed] JAMA Psychiatry. 2021 May 1;78(5):569. doi: 10.1001/jamapsychiatry.2021.0314. JAMA Psychiatry. 2021. PMID: 33760059 Free PMC article. No abstract available.

Abstract

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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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.

Figures

**Figure 1.. Flowchart of the Literature Search and Evaluation Process for 45 Published Meta-analyses and Systematic Reviews**

**Figure 2.. Percentages of the Reported 13 Adverse Health Outcome Domains Associated With Antidepressant Exposure in 45 Published Meta-analyses**

See this image and copyright information in PMC

Comment in

Selective Serotonin Reuptake Inhibitor Use During Pregnancy-Associated With but Not Causative of Autism in Offspring.
Flores JM, Avila-Quintero VJ, Bloch MH. Flores JM, et al. JAMA Psychiatry. 2019 Dec 1;76(12):1225-1227. doi: 10.1001/jamapsychiatry.2019.2193. JAMA Psychiatry. 2019. PMID: 31577332 No abstract available.

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References

1. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005-2008. NCHS Data Brief. 2011;(76):1-8. - PubMed
1. Davey CG, Chanen AM. The unfulfilled promise of the antidepressant medications. Med J Aust. 2016;204(9):348-350. doi:10.5694/mja16.00194 - DOI - PubMed
1. Skapinakis P, Caldwell DM, Hollingworth W, et al. . Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2016;3(8):730-739. doi:10.1016/S2215-0366(16)30069-4 - DOI - PMC - PubMed
1. Locher C, Koechlin H, Zion SR, et al. . Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(10):1011-1020. doi:10.1001/jamapsychiatry.2017.2432 - DOI - PMC - PubMed
1. Bighelli I, Castellazzi M, Cipriani A, et al. . Antidepressants versus placebo for panic disorder in adults. Cochrane Database Syst Rev. 2018;4:CD010676. doi:10.1002/14651858.CD010676.pub2 - DOI - PMC - PubMed

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[1] Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005-2008. NCHS Data Brief. 2011;(76):1-8. - PubMed

[2] Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005-2008. NCHS Data Brief. 2011;(76):1-8. - PubMed

[3] Davey CG, Chanen AM. The unfulfilled promise of the antidepressant medications. Med J Aust. 2016;204(9):348-350. doi:10.5694/mja16.00194 - DOI - PubMed

[4] Davey CG, Chanen AM. The unfulfilled promise of the antidepressant medications. Med J Aust. 2016;204(9):348-350. doi:10.5694/mja16.00194 - DOI - PubMed

[5] Skapinakis P, Caldwell DM, Hollingworth W, et al. . Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2016;3(8):730-739. doi:10.1016/S2215-0366(16)30069-4 - DOI - PMC - PubMed

[6] Skapinakis P, Caldwell DM, Hollingworth W, et al. . Pharmacological and psychotherapeutic interventions for management of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2016;3(8):730-739. doi:10.1016/S2215-0366(16)30069-4 - DOI - PMC - PubMed

[7] Locher C, Koechlin H, Zion SR, et al. . Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(10):1011-1020. doi:10.1001/jamapsychiatry.2017.2432 - DOI - PMC - PubMed

[8] Locher C, Koechlin H, Zion SR, et al. . Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(10):1011-1020. doi:10.1001/jamapsychiatry.2017.2432 - DOI - PMC - PubMed

[9] Bighelli I, Castellazzi M, Cipriani A, et al. . Antidepressants versus placebo for panic disorder in adults. Cochrane Database Syst Rev. 2018;4:CD010676. doi:10.1002/14651858.CD010676.pub2 - DOI - PMC - PubMed

[10] Bighelli I, Castellazzi M, Cipriani A, et al. . Antidepressants versus placebo for panic disorder in adults. Cochrane Database Syst Rev. 2018;4:CD010676. doi:10.1002/14651858.CD010676.pub2 - DOI - PMC - PubMed

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

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