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Meta-Analysis
. 2023 Mar;37(3):268-278.
doi: 10.1177/02698811221104058. Epub 2022 Jul 21.

Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression

Fraser Scott  1 , Elliot Hampsey  2 , Sam Gnanapragasam  1 , Ben Carter  3 , Lindsey Marwood  2 , Rachael W Taylor  2 , Cansu Emre  2 , Lora Korotkova  2 , Jonatan Martín-Dombrowski  2 , Anthony J Cleare  1   2 , Allan H Young  1   2 , Rebecca Strawbridge  2
Affiliations
Meta-Analysis

Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression

Fraser Scott et al. J Psychopharmacol. 2023 Mar.

Abstract

Background: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below).

Methods: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions.

Results: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09-2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23-1.73) and risperidone (ES = 1.42, 95% CI: 1.29-1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81-0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses.

Conclusions: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option.

Keywords: Major depressive disorder; augmentation; combination; meta-analysis; treatment resistant depression.

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Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LM is currently an employee at COMPASS Pathways plc. This work is unrelated to COMPASS Pathways plc. In the last 3 years, AJC has received honoraria for speaking from Janssen, honoraria for consulting from Allergan, Janssen and NICE, and research grant support from the Medical Research Council (UK), Wellcome Trust (UK), the National Institute for Health Research (UK) and Protexin Probiotics International Ltd. RS declares an honorarium from Lundbeck. AHY declares honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. No other conflicts of interest are declared.

Figures

Figure 1.
Figure 1.
PRISMA flow diagram. TRD: treatment-resistant depression.
Figure 2.
Figure 2.
Forest plot displaying ESs for treatments examined in >3 studies.
See this image and copyright information in PMC

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