Developed in 1952, chlorpromazine was the first antipsychotic. Back then it was called a neuroleptic and the first reported use was in a manic patient.
After a first psychotic mania, lithium or valproate prevented rehospitalization better than an antipsychotic alone
STUDY: Szmulewicz AG et al, Lancet Psychiatry 2026
STUDY TYPE: Cohort study (target trial emulation)
FUNDING: ASISA (Spain) and National Institute of Mental Health
Background
Guidelines suggest that traditional mood stabilizers work as well for psychotic mania as antipsychotics, and this study tests the idea.
The Study
- 371 patients (median age 22) with bipolar I disorder after a first manic episode with psychotic features, treated at early psychosis clinics in the US, Canada, Chile, and Spain.
- Compared starting a mood stabilizer alone (lithium or valproate), a second-generation antipsychotic alone, or both with methods designed to mimic a randomized trial.
- Primary outcome: psychiatric hospitalization or emergency visit over 2 years.
Results
Mood stabilizers offered greater protection. The two-year risk of hospitalization or emergency visits was:
- Mood stabilizer alone: 42%
- Combination: 42%
- Antipsychotic alone: 50%
Mood stabilizers resulted in 7 fewer hospitalizations per 100 patients (risk ratio 0.82), and depression accounted for much of the difference.
Manic relapses were about the same in all groups, but depressive relapses or suicide-related events were more common with an antipsychotic alone (19% vs 12 to 14%). Adding an antipsychotic to a mood stabilizer brought no extra benefit.
Limitations
This is observational data. Patients started on antipsychotics alone were sicker at baseline, a third were lost to follow-up, and quetiapine, which prevents both poles, was lumped in with the others.
Practice Implications
- Earlier trials showed similar acute benefits with antipsychotics vs mood stabilizers in psychotic mania, though these were not head to head.
- Also, most antipsychotics failed to prevent depression in bipolar trials, such as risperidone, aripiprazole, and cariprazine (but not quetiapine or asenapine)
- Use antipsychotics as add-on if needed, but mood stabilizers for prevention. Lithium has the strongest maintenance record: start it early and aim for a level of 0.6 to 0.8 mEq/L.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
