Importance There is an urgent need for algorithm trials that address treatment steps in schizophrenia sequentially. Moreover, there is a debate about whether clozapine should be used after 1 failed antipsychotic drug trial. Objective To investigate whether switching to clozapine is effective in patients with first-episode psychosis (FEP) who have not responded to 1 previous antipsychotic drug. Design, Setting, and Participants This was a sequential, assessor-blind trial with 2 randomizations conducted across 7 centers in China from February 2019 to October 2022. Included were individuals aged 16 to 45 years and with FEP (schizophrenia, schizophreniform disorder, or schizoaffective disorder). In phase 1, patients with FEP were randomized to receive oral olanzapine, risperidone, amisulpride, aripiprazole, or perphenazine for 8 weeks. In phase 2, nonresponders were rerandomized to receive olanzapine, amisulpride, or clozapine for another 8 weeks. Responders entered a 1-year naturalistic follow-up. Study data were analyzed from February to August 2025. Interventions Specific antipsychotic drugs. Main Outcomes and Measures The primary outcomes were as follows (1) symptomatic response, defined as the proportion of patients achieving a greater than or equal to 40% reduction in Positive and Negative Syndrome Scale (PANSS) total score and (2) time to all-cause discontinuation, defined as discontinuation of antipsychotic drugs for any reason. Results A total of 762 participants were randomized, and 654 (mean SD age, 26.9 7.5 years; 328 male 50.2%) were eligible for the study. Of the eligible participants, 556 (85.4%) completed phase 1, and 359 (55.1%) responded to treatment. Response rates were 60.5% (78 of 129) for olanzapine, 63.4% (83 of 131) for risperidone, 61.8% (81 of 131) for amisulpride, 44.3% (58 of 131) for aripiprazole, and 45.7% (59 of 129) for perphenazine (χ 2 = 18.3; P = .001). In phase 2, 111 nonresponders were rerandomized (41 taking olanzapine, 38 taking amisulpride, and 32 taking clozapine). A total of 92 patients (82.9%) completed phase 2, and the following achieved a response: 13 (31.7%) taking olanzapine vs 17 (44.7%) taking amisulpride and 20 (62.5%) taking clozapine (χ 2 = 6.9; P = .03). Conclusions and Relevance The majority of patients with FEP responded to an initial antipsychotic drug trial, with risperidone and amisulpride being superior to aripiprazole and perphenazine. In those who initially did not respond to antipsychotic treatment, clozapine was more efficacious than olanzapine and amisulpride based on the PANSS ratings criteria outcome. This study provides some evidence for clinicians to consider regarding use of clozapine as the next sequential treatment after patients have failed an adequate trial with 1 of the more traditional antipsychotics. Trial Registration ClinicalTrials.gov Identifier: NCT03510325
Li et al. (2026) studied this question.