Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis

Abstract

Objective: To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents.

Methods: We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model.

Results: A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB.

Limitations: Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.

Conclusions: This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD.

Keywords: Efficacy; Mood disorders; Network Meta-analysis; Treatment resistant; Unipolar depression.

Conflict of interest statement

Declaration of Competing Interest

NA Nuñez is supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. MA Frye reports grant support from Assurex Health, Mayo Foundation and intellectual property licensed to Chymia LLC. with rights to receive future royalties. B Singh reports grant support from Mayo Clinic. All other authors report no financial relationships with commercial interests. All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Elsevier B.V. All rights reserved.

Figures

Fig. 1.

Flow diagram. Full-text articles were excluded due to the following reasons: (14) were open label studies; (18) were articles that did not report data on depressive symptoms focused on neuroimaging (10) wrong publication type, (5) were not treatment resistant and (7) articles fell under the exclusion criteria listed in the section above.

Fig. 2.

Network graph of the included studies to enable visualization of the geometry of the treatment network according to measured outcomes. (A) Response (B) Remission. Each of the connected line represent a comparison between 2 interventions. The thickness of each line corresponds to the number of trials comparing every pair of treatments.