Cited by 167Treatment of Major DepressionMental Health Treatment and AccessPsychological Treatments and Disorders

The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index; 3 of the 96 sources its claims cite were checked for support.

Should antidepressants be used for major depressive disorder?

Open access
Jakobsen, Janus Christian, Gluud, Christian, Kirsch, Irving·2020·BMJ Evidence-Based Medicine

Abstract

Background: Major depressive disorder is estimated by the WHO to affect more than 300 million people globally, making depression the leading cause of disability worldwide. Antidepressants are commonly used to treat depression. Objective: The study aimed to provide an update on the evidence on the effects of antidepressants compared with placebo. Should antidepressants be used for adults with major depressive disorder? Study selection: We searched the Cochrane Library, BMJ Best Practice and PubMed up to June 2019 with the search terms ‘depression’ and ‘antidepressants’ targeting reviews published in English since 1990. Findings: Several reviews have assessed the effects of antidepressants compared with placebo for depression. Generally, all the previous reviews show that antidepressants seem to have statistically significant effects on depressive symptoms, but the size of the effect has questionable importance to most patients. Antidepressants seem to have minimal beneficial effects on depressive symptoms and increase the risk of both serious and non-serious adverse events. Conclusions: The benefits of antidepressants seem to be minimal and possibly without any importance to the average patient with major depressive disorder. Antidepressants should not be used for adults with major depressive disorder before valid evidence has shown that the potential beneficial effects outweigh the harmful effects.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that antidepressants for adults with major depressive disorder produce statistically significant but clinically minimal symptom reductions and increase adverse events, so benefits may not outweigh harms. The authors conclude antidepressants should not be used for major depressive disorder until valid evidence shows net benefit.

Key findings

  • Across reviews, antidepressants versus placebo show statistically significant effects on depressive symptoms, but effect sizes are below clinical significance thresholds. In the authors’ 2017 systematic review, SSRIs versus placebo reduced HDRS by 1.94 points (95% CI −2.50 to −1.37) or SMD −0.23 (95% CI −0.31 to −0.14), below NICE’s 3-point/0.5 SMD threshold and far from a 7-point HDRS/0.875 SMD “minimal improvement.”
  • A large network meta-analysis found overall antidepressants versus placebo SMD 0.30 (95% credibility interval 0.26 to 0.34), which the authors call presumably without clinical relevance; only 18% of included trials were assessed at low risk of bias.
  • SSRIs significantly increased the risk of both serious and non-serious adverse events; common long-term adverse effects include gastrointestinal problems, sleep disturbances, and sexual dysfunction, and withdrawal symptoms can persist more than 2 weeks and sometimes several months. Longer-term effects (SMD 0.34) and NICE results (SMD 0.28) seemed as small as short-term effects.
  • Industry involvement and bias were prominent: industry-sponsored studies more often showed benefits (RR 1.27, 95% CI 1.17 to 1.37) and favorable conclusions (RR 1.34, 95% CI 1.19 to 1.51), and meta-analyses with a manufacturer-employed author were 22-fold less likely to have negative statements. In STAR*D, 77.8% of patients would have been excluded from conventional trials, with HDRS improvement of 6.6 points after 3 months of SSRI treatment versus 14.8 points in conventional comparator trials.

Methods

  • Narrative review: two investigators independently searched the Cochrane Library, BMJ Best Practice, and PubMed up to June 2019 for English reviews published since 1990 using the terms “depression” and “antidepressants”; they included any review assessing benefits and harms of any antidepressant versus placebo in adults, plus references and relevant guideline recommendations.
  • No protocol was published before the literature search. The synthesis is narrative rather than systematic, and it focuses on adults with a primary diagnosis of major depressive disorder, excluding primary somatic disorders or other disorders.
  • Main analysis is a narrative synthesis of identified reviews, with attention to clinical significance thresholds, risk of bias, industry involvement, and harms.

Limitations

  • Stated: no protocol was published before the literature search; the majority of previous antidepressant trials were at high or unclear risk of bias; evidence has low generalisability because trials include highly selected patients; short-term trials likely underestimate adverse effects; the HDRS is psychometrically and conceptually flawed; and no studies clearly identify who will respond to antidepressants.
  • Stated: the authors’ GRADE assessment of the certainty of evidence was very low certainty.
  • Evident: as a narrative review without a protocol or systematic meta-analysis, selection and interpretation of included reviews may be susceptible to bias, and the paper relies on existing reviews rather than new primary data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/bmjebm-2019-111238

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

66 Not checked yet · 17 Own interpretation · 6 No basis given · 5 Own method · 2 Supported · 1 Partly supported · accuracy not yet measured

Verify all 93 references — free account

Show all 56 claims

  • It may state two separate claims as one. 33
  • Probably not a substantial claim. 13
41 of 41
  • The paper relies on this without support.

    The DSM-5 and ICD-10 diagnostic criteria for major depressive disorder are largely comparable.

    “These two sets of diagnostic criteria are largely comparable.”
  • The paper relies on this without support.

    There are no objective tests or laboratory tests for depression or for validating the diagnosis.

    “There are no objective tests and no laboratory test (eg, blood tests, MRI scans) for depression or for validating the diagnosis.”
  • The paper relies on this without support.

    The HDRS is the most commonly used depression rating scale and is recommended by psychiatrists worldwide.

    “The HDRS is the most commonly used depression rating scale and is the recommended scale by psychiatrists worldwide.”
  • The paper relies on this without support.

    Theoretically and in clinical practice, some patients might benefit significantly from antidepressants.

    “theoretically and in clinical practice some patients might benefit significantly from antidepressants.”
  • The paper relies on this without support.

    Adverse effects of other types of antidepressant than SSRIs are not thoroughly assessed in systematic reviews.

    “Adverse effects of other types of antidepressant than SSRIs (eg, serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants (TCAs)) are not thoroughly assessed in systematic reviews”
5 of 5

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Metadata

Authors
Jakobsen, J. C., Gluud, C., & Kirsch, I.
Affiliations
  • University of Southern Denmark (DK)
  • Copenhagen University Hospital (DK)
  • Harvard University (US)
Corresponding author
Jakobsen, Janus Christian
Venue
BMJ Evidence-Based Medicine
Publisher
BMJ
Published
2019-09-25
Volume
25
Issue
4
Pages
130-130
ISSN
  • 1356-5524 (ISSN-L)
  • 2515-446X
  • 2515-4478
OpenAlex
W2976089272
Cited by
162
References
67
Citations by year
2026: 13 · 2025: 28 · 2024: 21 · 2023: 38 · 2022: 22 · 2021: 24 · 2020: 14 · 2019: 2
FWCI
1.99
Type
journal article
Language
en
Open access
Locations
  • BMJ Evidence-Based Medicine (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc)
Topics
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Mental Health Treatment and Access
  • Social Sciences › Psychology › Clinical Psychology › Psychological Treatments and Disorders
Keywords
antidepressants, major depressive disorder, depression, antidepressant efficacy, antidepressant side effects, placebo comparison, risk-benefit assessment, treatment decision-making
MeSH terms
Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Humans, Treatment Outcome

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