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Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression: Adjunctive therapies for non-responsive depression

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
JournalJournal of Psychopharmacology
Accepted/In press10 May 2022

King's Authors


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 ISI 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 heterogenous study designs independent of comparator interventions.
Results: 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 (ES) 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 6 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.

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