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. 2021 Mar;66(3):274-288.
doi: 10.1177/0706743720970857. Epub 2020 Nov 11.

Comparative Efficacy and Tolerability of Adjunctive Pharmacotherapies for Acute Bipolar Depression: A Systematic Review and Network Meta-analysis

Anees Bahji  1   2 , Dylan Ermacora  2 , Callum Stephenson  3 , Emily R Hawken  4   5 , Gustavo Vazquez  4   5
Affiliations

Comparative Efficacy and Tolerability of Adjunctive Pharmacotherapies for Acute Bipolar Depression: A Systematic Review and Network Meta-analysis

Anees Bahji et al. Can J Psychiatry. 2021 Mar.

Abstract
in English, French

Objective: We investigated the comparative efficacy and tolerability of augmentation strategies for bipolar depression.

Data sources: We conducted a systematic review and network meta-analysis of 8 electronic databases for double-blind, randomized controlled trials of adjunctive pharmacotherapies for acute bipolar depression.

Data extraction and synthesis: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and applied the Cochrane risk of bias tool for study quality appraisal. Two reviewers independently abstracted data. We resolved all discrepancies by consensus.

Main outcomes and measures: Primary outcomes were response and completion of treatment. We estimated summary rate ratios (RRs) and standardized mean differences (SMDs) relative to placebo controls using frequentist random-effects network meta-analysis.

Results: We identified 69 trials meeting eligibility criteria (8,007 participants, 42.8 years, 58.0% female). Adjunctive racemic intravenous ketamine, coenzyme Q10, pramipexole, fluoxetine, and lamotrigine were more effective than placebo. Summary RRs for response ranged between 1.51 (95% confidence interval [CI], 1.11 to 2.06) for fluoxetine and 12.49 (95% CI, 3.06 to 50.93) for racemic intravenous ketamine. For completion of treatment, risperidone appeared less tolerable than placebo (RR = 0.59; 95% CI, 0.38 to 0.94), while fluoxetine seemed more tolerable than placebo (RR = 1.13; 95% CI, 1.02 to 1.24). None of the investigated agents were associated with increased treatment-emergent mood switches.

Conclusions and relevance: The evidence for augmentation strategies in bipolar depression is limited to a handful of agents. Fluoxetine appeared to have the most consistent evidence base for both efficacy and tolerability. There remains a need for additional research exploring novel treatment strategies for bipolar depression, particularly head-to-head studies.

Objectif:: Nous avons investigué l’efficacité et la tolérabilité comparatives des stratégies d’augmentation pour la dépression bipolaire.

Sources des données:: Nous avons mené une revue systématique et une méta-analyse de réseau de 8 bases de données électroniques en quête d’essais à double insu, randomisés et contrôlés de pharmacothérapies d’appoint pour la dépression bipolaire aiguë.

Extraction et synthèse des données:: Nous avons suivi les directives PRISMA et utilisé l’outil du risque de biais de Cochrane pour évaluer la qualité des études. Deux réviseurs ont analysé les données indépendamment. Nous avons réglé toutes les disparités par consensus.

Principaux résultats et mesures:: Les principaux résultats étaient la réponse au traitement et la fin de celui-ci. Nous avons estimé les rapports de cotes (RC) sommaires et les différences moyennes normalisées (DMN) relatifs aux contrôles par placebo utilisant une méta-analyse de réseau fréquentiste à effets aléatoires.

Résultats:: Nous avons identifié 69 essais qui satisfaisaient aux critères d’admissibilité (8 007 participants, 42,8 ans, 58,0% de femmes). La kétamine racémique intraveineuse d’appoint, la coenzyme Q10, le pramipexole, la fluoxétine, et la lamotrigine étaient plus efficaces que le placebo. Les RC sommaires pour la réponse jouaient entre 1,51 (IC à 95% 1,11 à 2,06) pour la fluoxétine et 12,49 (3,06 à 50,93) pour la kétamine racémique intraveineuse. Pour terminer le traitement, la rispéridone semblait moins tolérable que le placebo (RR = 0,59, 0,38 à 0,94), alors que la fluoxétine semblait plus tolérable que le placebo (RR = 1,13, 1,02 à 1,24). Aucun des agents investigués n’était associé à des sautes d’humeur accrues attribuables au traitement.

Keywords: bipolar disorder; comparative effectiveness; depression; meta-analysis; pharmacotherapies; review.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review flow diagram.
Figure 2.
Figure 2.
Network graph of the included studies to enable visualization of the geometry of the treatment network.
Figure 3.
Figure 3.
Contrast plots for rate ratios of depression response at primary study end point versus placebo.
Figure 4.
Figure 4.
Contrast plots for rate ratios of completion of treatment at primary study end point versus placebo.
See this image and copyright information in PMC

References

    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, Virginia: American Psychiatric Association; 2013.
    1. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387(10027):1561–1572. - PubMed
    1. Merikangas KR, Jin R, He J-P, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68(3):241–251. - PMC - PubMed
    1. Ferrari AJ, Stockings E, Khoo J-P, et al. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18(5):440–450. - PubMed
    1. Cloutier M, Greene M, Guerin A, Touya M, Wu E. The economic burden of bipolar I disorder in the United States in 2015. J Affect Disord. 2018;226:45–51. - PubMed

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