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

Nicolas A. Nuñez, Boney Joseph, Mehak Pahwa, Rakesh Kumar, Manuel Gardea Resendez, Larry J. Prokop, Marin Veldic, Ashok Seshadri, Joanna M. Biernacka, Mark A. Frye, Zhen Wang, Balwinder Singh

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)385-400
Number of pages16
JournalJournal of Affective Disorders
StatePublished - Apr 1 2022


  • Efficacy
  • Mood disorders
  • Network Meta-analysis
  • Treatment resistant
  • Unipolar depression

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health


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