Assessing Antipsychotics as Antidepressant Adjuncts

Atypical antipsychotics that are FDA-approved as antidepressant adjuncts are differentiated by efficacy, acceptability and tolerability in the treatment of major depressive disorder (MDD), in a new network meta-analysis¹ (NMA).

Roger S. McIntyre, MD, FRCPC, Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada, and colleagues explain that the analysis was conducted because clinical differences between the agents as antidepressant adjuncts "is currently unknown and is highly relevant to shared decision-making."

McIntyre discussed their findings with Psychiatric Times. "The key message is that there are clinically meaningful differences across the agents in their efficacy," he said. "These aspects need to be discussed with patients and considered by practitioners and payers in the algorithmic selection and sequencing of treatment."

The investigators identified 22 randomized, double-blind, placebo-controlled clinical trials (RCTs) assessing outcomes from adding an atypical antipsychotic when antidepressant response is inadequate. Although the trial participants had demonstrated inadequate response rather than treatment resistance, McIntyre and colleagues note that distinction "is imprecise and undoubtedly includes overlapping populations."

The 22 trials comprised 10,962 participants, of whom 1297 received aripiprazole, 1973 brexpiprazole, 1894 cariprazine, 483 lumateperone, and 719 quetiapine XR; and 4596 participants received placebo. Trials with the fixed combination of olanzapine-fluoxetine were excluded, as the product is approved for patients meeting criteria for treatment-resistant depression.

The primary measures were efficacy and acceptability; with the former defined as ≥50% improvement in overall depressive symptom severity on the Montgomery-Ȧsberg Depression Rating Scale (MADRS) at week 6, and the latter by rate of all-cause discontinuation. The investigators noted that the assessment at six weeks corresponds to the regulatory measure of acute adjunctive efficacy.

Secondary outcomes included remission defined by MADRS total score of ≤8 or ≤10, change in overall severity of depressive symptoms, and discontinuation due to adverse event. Additional measures that were explored included Clinical Global Impression (CGI) ratings of severity and of improvement, the Sheehan Disability Scale (SDS) scores, and the occurrence of weight gain and extrapyramidal symptoms.

The investigators reported that lumateperone 42 mg had the greatest effect size for efficacy (RR 1.73; 95% CrI, 1.42-2.16), followed by aripiprazole 11 mg (RR 1.67, 1.36-2.04) and aripiprazole 3 mg (RR 1.49, 1.09-2.03). The highest efficacy ranking might be further separated, McIntyre suggested, given the different levels of placebo response in the trials.

"This is a critical point, the placebo response was the lowest for aripiprazole and brexpiprazole; it was relatively higher for lumaterperone and the other agents," he recounted. "Hence, practitioners should be aware that although aripiprazole is second on efficacy, it also had the lowest placebo response, which effectively increases the response estimate of aripiprazole."

Although lumaterperone 42 mg ranked highest in efficacy, it appeared lowest in acceptability among the agents compared with placebo (RR 2.35, 1.49-3.81). Quetiapine XR 300 mg was next (RR 1.80, 1.25 to 2.68), followed by brexpiprazole 2 mg (RR 1.63, 1.24 to 2.16). The lower acceptability ranking of lumaterperone, however, was also qualified by McIntyre.

"The principal reason why lumateperone had a lower relative acceptability is because the dropout rate was higher, especially in one of the two studies," he noted, adding that it is "the only atypical that has no weight gain, no prolactin (increase), no sexual dysfunction, no EPS."

McIntyre also pointed out that the lumateperone studies were the only studies to use a fixed dose design (eg, 42 mg). "Whenever there is a flexible dose design, used with the other drugs, the rate of side effects is lower as the investigators have the opportunity to lower the range of the dose, which was not possible in the lumaterperone design," he explained.

The secondary outcomes were generally congruent with the primary, with lumateperone having the greatest effect size for remission compared with placebo (RR 1.87, 1.31 to 2.69), and in reduction in overall severity of depressive symptoms (MD, -4.83, -6.42 to -3.21); followed by aripiprazole (RR 1.58, 1.28 to 1.95 and MD -2.34, 03.33 to -1.37). Lumateperone also had a relatively higher rate of discontinuation for adverse effects (RR 16.50, 4.57 to 80.50) followed by quetiapine XR (RR 6.70, 2.90 to 17.90).

The investigators conclude that their results "address an important knowledge gap and provide decision support to practitioners and persons with lived experience, as well as providing data to inform treatment algorithms, policy, and reimbursement considerations."

McIntyre acknowledged limitations of the NMA and in the reported hierarchies, observing "we do not have long-term maintenance data for any of these agents, which is a knowledge gap in this field."

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

Reference

1. McIntyre RS, Stahl SM, Shim SR, et al. Adjunctive antipsychotics in major depressive disorder: A systematic review and network meta-analysis. JAMA Psychiatry. 2026;83(7):741-750.