Buspirone Augments Clozapine in Schizophrenia

An old anxiolytic improves cognition and psychosis in a small trial

STUDY: Xia Y et al, Br J Clin Pharmacol 2026

STUDY TYPE: Randomized, double-blind, placebo-controlled trial

FUNDING: Independent

Background

Roughly 85% of patients with schizophrenia have some degree of cognitive impairment, and antipsychotics do little to fix it. Buspirone is a partial serotonin 5-HT1A receptor agonist, better known as an anxiolytic, that also raises prefrontal dopamine and promotes hippocampal neurogenesis. Those mechanisms make it a plausible cognitive booster in schizophrenia.

The Study

• 46 stable inpatients with schizophrenia on clozapine, randomized to clozapine plus placebo, clozapine plus buspirone 15 mg/day (5 mg three times a day), or clozapine plus buspirone 30 mg/day (10 mg three times a day).
• Double-blind, 12 weeks.

Results

Both buspirone doses outperformed clozapine alone on total PANSS scores by week 4 (Cohen’s d = 0.68 and 0.82). The higher dose improved positive and negative symptoms earlier, by week 4 rather than week 8. On cognition, both groups improved in immediate memory and visuospatial abilities by week 8 (d > 0.5 and d > 0.45, respectively), with language gains by week 12. The two buspirone doses didn’t differ significantly from each other on most measures, likely a sample-size issue.

Side Effects

Both doses were well tolerated. Dizziness was the most common complaint: 14% with low dose buspirone, 21% with the higher dose, and 11% with placebo. One patient in the higher-dose group withdrew due to persistent dizziness. No serious adverse events occurred.

Limitations

Only 46 patients across three groups. All were Chinese inpatients, limiting generalizability. Clozapine plasma levels weren’t monitored. The 12-week duration may have been too short to capture the full cognitive trajectory. The RBANS battery is less sensitive than the standard MATRICS battery for detecting nuanced cognitive change.

Practice Implications

1. The results are modest and the trial is small, but they’re consistent with prior data and the biology makes sense.
2. If augmenting clozapine with buspirone, start at 5 mg three times a day for a week, then increase to 10 mg three times a day to reduce early dizziness. Watch for sedation.