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Meta-Analysis
. 2024 Jan 22;27(1):e300730.
doi: 10.1136/bmjment-2023-300730.

Beneficial and harmful effects of tricyclic antidepressants for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis

Caroline Barkholt Kamp  1   2 , Johanne Juul Petersen  3 , Pascal Faltermeier  3   4 , Sophie Juul  3   5 , Faiza Siddiqui  3 , Marija Barbateskovic  3 , Andreas Torp Kristensen  6 , Joanna Moncrieff  7   8 , Mark Abie Horowitz  7   8 , Michael Pascal Hengartner  9 , Irving Kirsch  10 , Christian Gluud  3   2 , Janus Christian Jakobsen  3   2
Affiliations
Meta-Analysis

Beneficial and harmful effects of tricyclic antidepressants for adults with major depressive disorder: a systematic review with meta-analysis and trial sequential analysis

Caroline Barkholt Kamp et al. BMJ Ment Health. .

Abstract

Question: Tricyclic antidepressants are used to treat depression worldwide, but the adverse effects have not been systematically assessed. Our objective was to assess the beneficial and harmful effects of all tricyclic antidepressants for adults with major depressive disorder.

Study selection and analysis: We conducted a systematic review with meta-analysis and trial sequential analysis. We searched CENTRAL, MEDLINE, Embase, LILACS and other sources from inception to January 2023 for randomised clinical trials comparing tricyclic antidepressants versus placebo or 'active placebo' for adults with major depressive disorder. The primary outcomes were depressive symptoms measured on the 17-item Hamilton Depression Rating Scale (HDRS-17), serious adverse events and quality of life. The minimal important difference was defined as three points on the HDRS-17.

Findings: We included 103 trials randomising 10 590 participants. All results were at high risk of bias, and the certainty of the evidence was very low or low. All trials only assessed outcomes at the end of the treatment period at a maximum of 12 weeks after randomisation. Meta-analysis and trial sequential analysis showed evidence of a beneficial effect of tricyclic antidepressants compared with placebo (mean difference -3.77 HDRS-17 points; 95% CI -5.91 to -1.63; 17 trials). Meta-analysis showed evidence of a harmful effect of tricyclic antidepressants compared with placebo on serious adverse events (OR 2.78; 95% CI 2.18 to 3.55; 35 trials), but the required information size was not reached. Only 2 out of 103 trials reported on quality of life and t-tests showed no evidence of a difference.

Conclusions: The long-term effects of tricyclic antidepressants and the effects on quality of life are unknown. Short-term results suggest that tricyclic antidepressants may reduce depressive symptoms while also increasing the risks of serious adverse events, but these results were based on low and very low certainty evidence.

Prospero registration number: CRD42021226161.

Keywords: adult psychiatry; depression & mood disorders; psychiatry.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; MAH is a co-applicant and member of the DSMB of the RELEASE trial in Australia, funded by the Medical Research Future Fund (MRFF). MAH is co-founder and consultant for Outro Health, a digital clinic helping patients to stop unnecessary antidepressant medication. MAH has been paid honoraria by several NHS Trusts for grand rounds presentations, and by Salomon’s University and the University of Washington. MAH is a member of the Critical Psychiatry Network and the International Institute of Psychiatric Drug Withdrawal (IIPDW). JM is a co-investigator on REDUCE (programme grant studying discontinuation of antidepressants) and Chief Investigator on RADAR (programme grant to explore antipsychotic reduction and discontinuation). JM has been paid honoraria by University of Basel, Alberta Psychiatric Association, and Case Western University. JM receives royalties from Palgrave Macmillan and PCCS Books for three books about psychiatric drugs. JM is a co-chair person (unfunded position) of Critical Psychiatry Network. MPH receives royalties from Palgrave Macmillan for a book about antidepressants; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Figure 1
Figure 1
PRISMA flow diagram. From: Page et al.
Figure 2
Figure 2
Risk of bias (RoB) assessments.
Figure 3
Figure 3
Summary of findings table. HDRS, Hamilton Depression Rating Scale; GRADE, Grading Recommendations Assessment Development Evaluation; RCT, randomised clinical trial.
Figure 4
Figure 4
Meta-analysis of tricyclic antidepressants versus placebo on serious adverse events.
Figure 5
Figure 5
Meta-analysis of tricyclic antidepressants (TCA) versus placebo on non-serious adverse events.
See this image and copyright information in PMC

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