Adding atypical antipsychotics to antidepressants for major depression offered an uneven trade-off — while some medications were better at easing symptoms, others were easier for patients to tolerate.

A systematic review and network meta-analysis evaluated five FDA-approved antipsychotic adjunctive therapies for adults with major depressive disorder (MDD) who had an inadequate response to antidepressant treatment alone.

Given that nearly two thirds of patients fail to achieve remission with initial antidepressant therapy, the investigators emphasized the need for comparative data that balance efficacy with treatment acceptability and tolerability, including patients’ ability to continue treatment.

“These results address an important knowledge gap and provide decision support to practitioners and persons with lived experience,” the investigators with lead author Roger S. McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, Toronto, Ontario, Canada, wrote.

The stakes are high the investigators noted because the “hazards of nonremission” include impaired functioning, lower quality of life, suicidality, higher healthcare use, and patient frustration and dissatisfaction with treatment.

The study was published online on May 6 in JAMA Psychiatry.

Weighing Risk Against Acceptability

The review included 22 short-term, double-blind, randomized clinical trials involving 10,962 adults. Investigators compared five atypical antipsychotics: aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine extended release (XR).

Lumateperone stood out for symptom response, showing the strongest results compared with placebo (risk ratio [RR], 1.72). Aripiprazole ranked second for response (RR, 1.53), followed by brexpiprazole, cariprazine, and quetiapine XR.

Lumateperone’s advantage on symptom relief did not carry over to treatment acceptability, defined in the study as all-cause discontinuation, or stopping treatment for any reason. On that measure, lumateperone ranked the lowest, with more than twice the risk for dropout seen with placebo (RR, 2.30).

Aripiprazole showed a different profile. It had the most favorable acceptability profile (RR, 1.16) while also ranking second for symptom response, placing it near the top for both efficacy and acceptability. Cariprazine, brexpiprazole, and quetiapine XR followed in the acceptability hierarchy.

Secondary outcomes reinforced the same trade-off. Lumateperone showed the strongest results for remission and overall reduction in depression severity, followed by aripiprazole. Discontinuation because of adverse events was highest with lumateperone, followed by quetiapine XR.

The tolerability findings were not uniform. Although lumateperone had the lowest overall acceptability, it was the only drug not associated with an increased risk for weight gain of at least 7% compared with placebo.

Dose-specific analyses pointed in the same direction. Lumateperone 42 mg had the greatest effect size for symptom response, followed by aripiprazole 11 mg. The same lumateperone dose also had the lowest acceptability, followed by quetiapine XR 300 mg and brexpiprazole 2 mg.

Several design differences may help explain the findings, the authors noted. Aripiprazole, brexpiprazole, cariprazine, and quetiapine XR were studied across multiple fixed-dose or flexible-dose designs, whereas lumateperone was evaluated only at 42 mg. Whether starting lumateperone at a lower dose and titrating upward would improve tolerability remains unknown, the authors said.

Important Caveats and Gaps

The researchers identified several limitations, including limited evidence on long-term maintenance treatment. Because most trials assessed outcomes at about 6 weeks, the analysis could not determine how well benefits and treatment continuation hold up over time.

The evidence base also relied heavily on industry-sponsored studies: 21 of the 22 randomized clinical trials had industry sponsorship.

Additionally, the findings may not apply to all patient groups. The main analysis excluded one study limited to older adults because of potential heterogeneity, although it was included in a sensitivity analysis. The review also did not address pediatric patients or cost-effectiveness.

The authors emphasized that the rankings should be interpreted cautiously. Differences across the trials, including baseline depression severity, duration of illness, treatment history, and placebo response, could have affected how the drugs appeared to perform. The analysis also did not determine whether specific drugs work better for particular depressive features, such as mixed features, anxious distress, anhedonia, or rumination.

No funding was reported. Disclosure information for study authors is available in the original study publication.