Lumateperone-Induced Mania

The antipsychotic triggered mania in three patients within two weeks

STUDY: Mudgal V et al, Indian Journal of Psychiatry 2026

STUDY TYPE: Case series

FUNDING: Independent

Background

Most antipsychotics are linked to mania in case reports. It’s a rare, paradoxical reaction. This is the first report for lumateperone.

Lumateperone combines serotonin 2A blockade, partial dopamine agonism, and mild serotonin reuptake inhibition.

Update (9/24/26): Shortly after I posted this the first trial of lumateperone in mania was presented at a conference.

The Cases

• Three adults with bipolar I or II disorder, all in a depressive episode and already on mood stabilizers or antipsychotics, started lumateperone 42 mg daily. Two were also taking an antidepressant, and one was taking fluoxetine (which elevates lumateperone’s levels).
• All developed manic symptoms within 10 to 14 days, with mania scale (YMRS) scores of 26 to 29, well into the severe range.

Other Antipsychotics

Here’s the the number of case reports of manic induction on second-generation antipsychotics:

• Quetiapine: 22
• Lurasidone: 12
• Olanzapine: 12
• Ziprasidone: 12
• Aripiprazole: 9
• Risperidone: 9
• Lumateperone: 3
• Paliperidone: 2
• Brexpiprazole: 1
• Cariprazine: 1
• Clozapine: 1
• Asenapine, iloperidone: 0

The problem may be more likely in the lower dose range used for depression.

With quetiapine, there’s a clearer mechanism. This antipsychotic is metabolized into an antidepressant-like compound (norquetiapine) through CYP3A4, so anything that speeds up that enzyme (eg, carbamazepine) can induce mania by converting quetiapine too rapidly.

Practice Implications

1. Watch out for this rare possibility, particularly in patients taking fluoxetine or other CYP3A4 inhibitors that raise lumateperone (and other antipsychotic) levels.
2. Paradoxical reactions can occur with antipsychotics, where they treat a problem in many but cause it in a few. Antipsychotics both cause and treat mania, OCD, and depression.

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

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