The Risks of Adverse Events with Mirtazapine for Adults with Major Depressive Disorder: a Systematic Review with Meta-analysis and Trial Sequential Analysis

Overview

Journal BMC Psychiatry

Publisher Biomed Central

Date 2025 Jan 23

PMID 39844067

Authors

Caroline Barkholt Kamp

Johanne Juul Petersen

Pascal Faltermeier

Sophie Juul

Christina Dam Bjerregaard Sillassen

Faiza Siddiqui

Rebecca Kjaer Andersen

Joanna Moncrieff

Mark Abie Horowitz

Michael Pascal Hengartner

Irving Kirsch

Christian Gluud

Janus Christian Jakobsen

Affiliations

Soon will be listed here.

Abstract

Background: Mirtazapine is used to treat depression worldwide, and the effects of mirtazapine on depression rating scales are well-known. Our primary objective was to assess the risks of adverse events with mirtazapine for major depressive disorder.

Methods: We searched relevant sources from inception to 7 March 2024 for randomised clinical trials comparing mirtazapine versus placebo in adults with major depressive disorder. The primary outcomes were suicides or suicide attempts, serious adverse events, and non-serious adverse events. Data were synthesised using meta-analysis and Trial Sequential Analysis.

Results: We included 17 trials randomising 2,131 participants to mirtazapine versus placebo. All results were at high risk of bias, and the certainty of the evidence was very low. The included trials assessed outcomes at a maximum of 12 weeks after randomisation. Meta-analysis and Trial Sequential Analysis showed insufficient information to determine the effects of mirtazapine on the risks of suicides or suicide attempts and serious adverse events. Meta-analyses showed that mirtazapine increased the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite but decreased the risk of headaches.

Conclusions: There is a lack of evidence on the effects of mirtazapine on suicides and serious adverse events. Mirtazapine increases the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite. Mirtazapine might decrease the risk of headaches. The long-term effects of mirtazapine are unknown.

Prospero Id: CRD42022315395.

References

Funaki K, Nakajima S, Suzuki T, Mimura M, Uchida H . Early Improvements in Individual Symptoms to Predict Later Remission in Major Depressive Disorder Treated With Mirtazapine. J Clin Pharmacol. 2016; 56(9):1111-9. DOI: 10.1002/jcph.710. View

Wetterslev J, Thorlund K, Brok J, Gluud C . Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2007; 61(1):64-75. DOI: 10.1016/j.jclinepi.2007.03.013. View

Johnson C, Macdonald H, Atkinson P, Buchanan A, Downes N, Dougall N . Reviewing long-term antidepressants can reduce drug burden: a prospective observational cohort study. Br J Gen Pract. 2012; 62(604):e773-9. PMC: 3481518. DOI: 10.3399/bjgp12X658304. View

Kasper S . Clinical efficacy of mirtazapine: a review of meta-analyses of pooled data. Int Clin Psychopharmacol. 1995; 10 Suppl 4:25-35. DOI: 10.1097/00004850-199512004-00005. View

Jakobsen J, Wetterslev J, Winkel P, Lange T, Gluud C . Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014; 14:120. PMC: 4251848. DOI: 10.1186/1471-2288-14-120. View

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4:1. PMC: 4320440. DOI: 10.1186/2046-4053-4-1. View

Kinrys G, Gold A, Pisano V, Freeman M, Papakostas G, Mischoulon D . Tachyphylaxis in major depressive disorder: A review of the current state of research. J Affect Disord. 2018; 245:488-497. DOI: 10.1016/j.jad.2018.10.357. View

Hrobjartsson A, Thomsen A, Emanuelsson F, Tendal B, Hilden J, Boutron I . Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. CMAJ. 2013; 185(4):E201-11. PMC: 3589328. DOI: 10.1503/cmaj.120744. View

Juul S, Siddiqui F, Barbateskovic M, Jorgensen C, Hengartner M, Kirsch I . Beneficial and harmful effects of antidepressants versus placebo, 'active placebo', or no intervention for adults with major depressive disorder: a protocol for a systematic review of published and unpublished data with meta-analyses and trial.... Syst Rev. 2021; 10(1):154. PMC: 8152051. DOI: 10.1186/s13643-021-01705-6. View

10.

Malhi G, Bell E, Bassett D, Boyce P, Bryant R, Hazell P . The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2020; 55(1):7-117. DOI: 10.1177/0004867420979353. View

11.

Papakostas G, Homberger C, Fava M . A meta-analysis of clinical trials comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. J Psychopharmacol. 2008; 22(8):843-8. DOI: 10.1177/0269881107083808. View

12.

Claghorn J, Earl C, Walczak D, Stoner K, Wong L, Kanter D . Fluvoxamine maleate in the treatment of depression: a single-center, double-blind, placebo-controlled comparison with imipramine in outpatients. J Clin Psychopharmacol. 1996; 16(2):113-20. DOI: 10.1097/00004714-199604000-00003. View

13.

Altman D, Royston P . The cost of dichotomising continuous variables. BMJ. 2006; 332(7549):1080. PMC: 1458573. DOI: 10.1136/bmj.332.7549.1080. View

14.

Keus F, Wetterslev J, Gluud C, van Laarhoven C . Evidence at a glance: error matrix approach for overviewing available evidence. BMC Med Res Methodol. 2010; 10:90. PMC: 2959031. DOI: 10.1186/1471-2288-10-90. View

15.

Qin P . The impact of psychiatric illness on suicide: differences by diagnosis of disorders and by sex and age of subjects. J Psychiatr Res. 2011; 45(11):1445-52. DOI: 10.1016/j.jpsychires.2011.06.002. View

16.

Siddiqui F, Barbateskovic M, Juul S, Katakam K, Munkholm K, Gluud C . Duloxetine versus 'active' placebo, placebo or no intervention for major depressive disorder; a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Syst Rev. 2021; 10(1):171. PMC: 8191126. DOI: 10.1186/s13643-021-01722-5. View

17.

Jorgensen C, Juul S, Siddiqui F, Horowitz M, Moncrieff J, Munkholm K . The risks of adverse events with venlafaxine and mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder: a protocol for two separate systematic reviews with meta-analysis and Trial Sequential.... Syst Rev. 2023; 12(1):57. PMC: 10061867. DOI: 10.1186/s13643-023-02221-5. View

18.

Hengartner M, Ploderl M . Estimates of the minimal important difference to evaluate the clinical significance of antidepressants in the acute treatment of moderate-to-severe depression. BMJ Evid Based Med. 2021; 27(2):69-73. DOI: 10.1136/bmjebm-2020-111600. View

19.

Watanabe N, Omori I, Nakagawa A, Cipriani A, Barbui C, Churchill R . Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011; (12):CD006528. PMC: 4158430. DOI: 10.1002/14651858.CD006528.pub2. View

20.

Liberati A, Altman D, Tetzlaff J, Mulrow C, Gotzsche P, Ioannidis J . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700. PMC: 2714672. DOI: 10.1136/bmj.b2700. View