This adds a third antipsychotics to the options for both poles
STUDY: Cutler AJ et al, poster presented at Psych Congress 2026, September 15–19, New Orleans (unpublished)
STUDY TYPE: Randomized, double-blind, placebo-controlled phase 3 trial
FUNDING: Johnson & Johnson (manufacturer of lumateperone); five of eight authors are company employees
Background
Among the antipsychotics, only cariprazine and quetiapine are effective in both the depressive and manic phases of the illness, and only quetiapine has robust preventative data for the maintenance phase.
Lumateperone (Caplyta) is FDA approved for bipolar I and II depression, schizophrenia, and as an add-on for major depressive disorder. It blocks serotonin 2A receptors, modulates dopamine D2 receptors, and mildly inhibits serotonin reuptake. Its antidepressant properties raised the question of whether it would ease mania or provoke it.
The Study
- 354 hospitalized adults with bipolar I in a manic episode; 15% had mixed features and about a third had psychotic features.
- Randomized to lumateperone 42 mg or placebo for three weeks; 327 (92%) completed.
- Primary outcome: change in the Mania scale (YMRS) at day 22.
Results
Mania scores fell 4.8 points more with lumateperone than placebo (effect size 0.69), with separation by day 3. Response rates were 46% vs 21% (NNT 4), and remission rates 31% vs 16% (NNT 7). Global severity scores (CGI-S) improved more by day 8 (effect size 0.62).
Side Effects
Headache (15% vs 8%), dry mouth (8% vs 3%), and nausea (8% vs 2%) led the list. Somnolence was low at 4%. Under 2% stopped because of side effects.
Limitations
- Unpublished and not peer reviewed
- Industry-funded and largely industry-authored
- Three weeks long, so we don’t know if it prevents mania
Practice Implications
- When choosing an antipsychotic for acute mania, aim for one that will also treat the depressed phases that are so common in this illness.
- Quetiapine rises to the top for efficacy there, with unique preventative data, but has problems with weight gain and sedation.
- Cariprazine and lumateperone are also options, though more expensive. Among them, lumateperone’s data is more robust in bipolar depression. Cariprazine unfortunately failed in the maintenance phase (2024, NCT03573297). Lumateperone is untested in the maintenance phase, but does have more robust data in bipolar depression than cariprazine, with a larger effect size and efficacy in both bipolar I and II.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
