02. Which Adjunctive Antipsychotic Is Best for Major Depression?

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Which Adjunctive Antipsychotic Is Best for Depression?

You may have seen reviews of this new network meta-analysis because it’s gotten quite a bit of press. So I’ll offer a bigger picture view here. The research question was this: of five atypical antipsychotics now FDA approved for adjunctive treatment of major depressive disorder, which is best?

Obviously, a head-to-head comparison study would be ideal. But since those are fleetingly rare, let alone a five-medication horse race, a network meta-analysis gives us a sense of relative benefit and risk.

CANMAT Recommends Aripiprazole and Brexpiprazole

Let’s put this meta-analysis in context. First, what treatments of all kinds are recommended in international treatment guidelines for a patient with a partial response to an antidepressant? Knowing that, we can then narrow to ask what antipsychotics are recommended and compare those recommendations with these new network meta-analytic results.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Guidelines addressed depression not responding to an antidepressant in 2023. Their algorithm begins by suggesting the addition of psychological treatments “earlier rather than later.” First line are cognitive behavioral therapy, interpersonal therapy and behavioral activation

Then consider switching antidepressants, especially if there are side effect problems as well as inadequate response. Or consider augmenting, especially if there is a clear partial response. And for augmenting, aripiprazole and brexpiprazole are first line.

We’ll see those two again in this new network meta-analysis.

NICE Offers Four Equal Options

In England’s National Institute for Clinical Excellence Guidelines (NICE) one arrives at medication augmentation after considering personal and social factors, adherence, diagnosis, and psychotherapies including exercise. Four options are then given equal weight:

• Aripiprazole
• Olanzapine
• Quetiapine
• Lithium

Of those, only aripiprazole is included in the new network meta-analysis. Lithium was excluded because it is not an antipsychotic — though note that several meta-analyses have found it superior to placebo as an adjunct to an antidepressant, with a smaller effect size than antipsychotic augmentation. Lithium’s possible anti-suicide effect may also be worth clinical consideration.

Olanzapine and Quetiapine IR Excluded

Olanzapine was not included in the new meta-analysis either, even though it has demonstrated efficacy when adjunctive with fluoxetine. Quetiapine immediate release (IR) was also excluded — despite several randomized trials showing an antidepressant effect as monotherapy in unipolar depression — because it lacks an FDA indication. Only quetiapine extended release (XR) has one, so that formulation was included.

Study Skewed Toward Expensive Drugs

So by studying only FDA-approved medications, this new network meta-analysis is skewed toward newer, more expensive medications, and those with which we have less long-term clinical experience.

Thus, it’s important not to think of this new study as a guide to the best thing to do for antidepressant partial response.

Lumateperone Led on Response Rates,

All that said, let’s see the results: think of it as a race between five horses. As they round the bend toward the finish line at 6 weeks, we’re looking for the adjunctive antipsychotic with the best response rates. And at the wire, it’s lumateperone; aripiprazole was not far behind.

Discontinuation Favored Aripiprazole

But wait, there’s another parallel finish line: discontinuation rates reflect the side effect burden in that first 6 weeks. By that metric, lumateperone was last and aripiprazole first.

It might sound as though aripiprazole emerges as the best adjunctive antipsychotic, but it is not so simple. For example, lumateperone studies used a fixed 42 mg dose, whereas the multiple studies of aripiprazole used varying and titrated doses. So perhaps the lower tolerability of lumateperone was simply due to that fixed dosing. And lumateperone was the only one of the five — the others being aripiprazole, quetiapine, brexpiprazole, and cariprazine — not associated with concerning weight gain.

Cost Differences Are Dramatic

So the race results are not simple. But here’s one thing that is. Using the GoodRx website data reflecting US prices:

• Generic aripiprazole: $16 a month
• Quetiapine immediate release: $9 a month
• Brexpiprazole: about $1,500 a month
• Lumateperone: $1,800 a month

To justify this cost difference, one would want to see dramatic differences in efficacy, side effects, and risks. And such differences were not seen in this network meta-analysis.

Bottom Line for Clinicians

So to summarize: what to do for a patient with a partial response to an antidepressant? There are multiple options, including psychotherapies. But one conclusion from this new analysis seems clear.

Newer, expensive medications are not clearly superior to generic aripiprazole, or to the other medications that weren’t included.

Abstract

Adjunctive Antipsychotics in Major Depressive Disorder: A Systematic Review and Network Meta-Analysis

Roger S. McIntyre, M.D.; Stephen M. Stahl, M.D., PhD; Sung Ryul Shim, MPH, PhD & et al

Importance  Most adults living with major depressive disorder (MDD) fail to achieve remission with conventional antidepressants. The US Food and Drug Administration (FDA) has approved 5 atypical antipsychotics in MDD on the basis of their substantial evidence of efficacy and safety.

Objective  To compare the efficacy and acceptability of FDA-approved atypical antipsychotics for the adjunctive treatment of MDD in order to provide decision support to practitioners and persons with lived experience.

Data Sources  A systematic search was conducted using PubMed/MEDLINE, PsycINFO, the Cochrane Library, and Embase from database inception through July 15, 2025.

Study Selection  Six independent raters screened publications for eligibility. Inclusion criteria were atypical antipsychotics that are FDA approved in the adjunctive treatment of MDD.

Data Extraction and Synthesis  Two independent raters obtained data and examined risk of bias in accordance with the Cochrane criteria. Effect sizes were synthesized using random-effects models. Data were analyzed from August to September 2025.

Main Outcomes and Measures  The primary outcomes were efficacy (ie, ≥50% reduction from baseline in the total Montgomery-Åsberg Depression Rating Scale [MADRS] score) and acceptability (ie, all-cause discontinuation).

Results  A total of 22 short-term studies comprising 10 962 participants (aripiprazole: n = 1297; brexpiprazole: n = 1973; cariprazine: n = 1894; lumateperone: n = 483; quetiapine extended release [XR]: n = 719; and placebo: n = 4596) were included for analysis. Lumateperone had the highest effect size for efficacy (risk ratio [RR], 1.72; 95% credible interval [CrI], 1.40-2.15), followed by aripiprazole (RR, 1.53; 95% CrI, 1.32-1.77), brexpiprazole (RR, 1.38; 95% CrI, 1.18-1.65), cariprazine (RR, 1.20; 95% CrI, 1.07-1.36), and quetiapine XR (RR, 1.15; 95% CrI, 0.96-1.35). A hierarchy of acceptability was observed, with aripiprazole exhibiting the highest acceptability (RR, 1.16; 95% CrI, 0.89-1.50), followed by cariprazine (RR, 1.44; 95% CrI, 1.15-1.82), brexpiprazole (RR, 1.47; 95% CrI, 1.18-1.85), quetiapine XR (RR, 1.56; 95% CrI, 1.14-2.12), and lumateperone (RR, 2.30; 95% CrI, 1.45-3.84). Secondary outcomes (eg, symptomatic remission) and exploratory outcomes (eg, clinically significant weight gain) accorded with the coprimary outcomes.

Conclusions and Relevance  This systematic review and meta-analysis indicates that differences exist between adjunctive atypical antipsychotics in the treatment of MDD with respect to overall efficacy and acceptability, which should be simultaneously considered. The absence of adequate and well-controlled studies documenting maintenance efficacy of adjunctive atypical antipsychotics in MDD remains a knowledge gap.

Reference

McIntyre, R. M.D.; Stahl, S. M.D., PhD; Shim, S. MPH, PhD & et al. (2026). Adjunctive Antipsychotics in Major Depressive Disorder: A Systematic Review and Network Meta-Analysis. JAMA Psychiatry. 2026;83(7):741–750.