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

Buspirone is a partial serotonin 5-HT1A receptor agonist that also raises prefrontal dopamine and promotes hippocampal neurogenesis.

Early controlled trials showed promise in schizophrenia, for cognition, psychotic symptoms, and extrapyramidal side effects, and this trial adds to that limited database.

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 (effect size, 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, possibly due to small sample size.

Side Effects

Well tolerated, with dizziness the most common complaint.

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.
3. Some antipsychotics are also partial serotonin 5-HT1A receptor agonist, like aripiprazole, asenapine, brexpiprazole, lurasidone, quetiapine, and ziprasidone. Surprisingly, so is clozapine, so buspirone may be adding to an existing mechanism.