Antipsychotic treatment algorithms in first-episode psychosis (FEP) typically reserve clozapine for patients who fail two trials, despite evidence of declining response rates with each subsequent medication. A recent randomized, sequential trial (SMART-CAT) evaluated whether clozapine should be considered earlier - after just one failed antipsychotic trial - in patients aged 16 to 45 with FEP.

In the first phase, response rates were highest with risperidone (63.4%), amisulpride (61.8%), and olanzapine (60.5%), and significantly lower with aripiprazole (44.3%) and perphenazine (45.7%). Among nonresponders who entered phase 2, clozapine demonstrated the highest response rate (62.5%), compared to amisulpride (44.7%) and olanzapine (31.7%). Clozapine also showed greater symptom reduction on the Positive and Negative Syndrome Scale (PANSS) compared to both agents, although differences in all-cause discontinuation were not observed. Notably, across both phases, approximately two-thirds of patients achieved response. However, long-term discontinuation rates remained high, with lack of efficacy as the primary driver.

These findings suggest that earlier use of clozapine after a single failed trial may improve outcomes in FEP, particularly when rapid symptom control is needed. While current guidelines recommend waiting for two failed trials, this study supports reconsideration of that threshold. Clinicians should weigh the benefits of earlier efficacy against monitoring burden and safety considerations, particularly in patients with poor initial response.

Reference:

Li X et al. JAMA Psychiatry. 2026:e260086. Abstract