Adjunctive Atypical Antipsychotics May Differ in Efficacy and Acceptability in Resistant Depression: JAMA
Canada: A systematic review and network meta-analysis have found that adjunctive atypical antipsychotics differ in both efficacy and acceptability when used for adults with major depressive disorder (MDD) who have an inadequate response to antidepressants. Treatment selection should therefore balance potential benefits with tolerability and patient acceptance.
The findings help guide clinicians, patients, policymakers, and reimbursement decisions by addressing an important evidence gap in comparative effectiveness. The review focused on FDA-approved agents, though approval status varies internationally. For example, in Europe, only Quetiapine XR is approved for MDD augmentation. A major unresolved issue is the lack of strong long-term maintenance efficacy data for most adjunctive atypical antipsychotics, which have limited approvals in some regions.
The study was published in JAMA Psychiatry by Roger S. McIntyre, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada, and colleagues.
Major depressive disorder remains one of the leading causes of disability worldwide, and many patients fail to achieve remission despite treatment with standard antidepressants. To improve outcomes, atypical antipsychotics are often prescribed as adjunctive therapy. However, direct comparisons among approved agents have been limited.
To address this gap, the researchers conducted a systematic review and network meta-analysis comparing FDA-approved atypical antipsychotics used alongside antidepressants in adults with MDD. The investigators searched PubMed/MEDLINE, PsycINFO, Embase, and the Cochrane Library through July 2025. A total of 22 short-term studies involving 10,962 participants were included in the analysis.
The medications evaluated included aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine extended release (XR), along with placebo groups. The primary outcomes were treatment efficacy, defined as at least a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and acceptability, measured by rates of treatment discontinuation for any reason.
Key Findings:
- Lumateperone showed the highest efficacy among the adjunctive atypical antipsychotics evaluated for major depressive disorder.
- Aripiprazole and brexpiprazole ranked next in efficacy following lumateperone.
- Cariprazine also demonstrated significant therapeutic benefit in patients with MDD.
- Quetiapine XR showed comparatively lower efficacy estimates than the other agents studied.
- Aripiprazole demonstrated the highest overall acceptability, indicating better treatment continuation among patients.
- Cariprazine and brexpiprazole also showed favorable acceptability profiles.
- Lumateperone and quetiapine XR were associated with comparatively higher treatment discontinuation rates.
- Secondary outcomes, including symptomatic remission, were generally consistent with the primary efficacy findings.
- Exploratory analyses assessing tolerability, including clinically significant weight gain, also showed differences among the medications.
The authors noted that treatment selection should balance efficacy, tolerability, and patient acceptance rather than focusing on symptom improvement alone.
They also highlighted the lack of robust long-term maintenance data for most adjunctive atypical antipsychotics as a key evidence gap that may influence international regulatory approvals. Overall, the findings indicate that FDA-approved adjunctive atypical antipsychotics differ in efficacy and acceptability, supporting individualized treatment approaches for MDD.
Reference:
McIntyre RS, Stahl SM, Shim SR, et al. Adjunctive Antipsychotics in Major Depressive Disorder: A Systematic Review and Network Meta-Analysis. JAMA Psychiatry. Published online May 06, 2026. doi:10.1001/jamapsychiatry.2026.0658
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