Schizophrenia: Clozapine a better fit for second relapse prevention

A population-based cohort study in Finland has revealed that clozapine initiation after a first-episode schizophrenia relapse is associated with a lower risk of second relapse compared with continuation with the same antipsychotic or switching to another non-clozapine oral antipsychotic. These findings challenge current guidelines that recommend clozapine as a third-line treatment.

Half of the patients with one prior schizophrenia relapse were estimated to have a second relapse after 1.23 years. Despite increases in antipsychotic dosages following each subsequent relapse, their effectiveness tends to diminish, highlighting the importance of preventing a second relapse. [BMC Psychiatry 2021;21:634; Lancet Psychiatry 2025;12:122-130]

Clozapine better for 2^nd relapse prevention

To assess the effectiveness of different treatment strategies for second relapse prevention, the researchers conducted a population-based cohort study using the national registry of Finland. They included 3,000 patients with first-episode schizophrenia (mean age, 30.0 years; female, 35.6 percent) who were hospitalized and subsequently experienced a relapse between 1996 and 2014. [Lancet Psychiatry 2025;12:122-130]

Within 2 years, 71.7 percent of patients had a second relapse. Most patients were either not using antipsychotics (45.5 percent) or were using non-clozapine oral antipsychotic monotherapy (32.4 percent) before the first relapse.

Switching to clozapine was associated with a substantially decreased risk of second relapse vs continuing any non-clozapine oral antipsychotic monotherapy used before the first relapse (relapse rate, 57.1 vs 73.2 percent; adjusted hazard ratio [aHR], 0.66; 95 percent confidence interval [CI], 0.49–0.89).

Switching to another non-clozapine oral antipsychotic monotherapy (HR, 0.99; 95 percent CI, 0.76–1.28) and switching to antipsychotic non-use (HR, 1.07; 95 percent CI, 0.80–1.42) were both ineffective in preventing a second relapse vs non-clozapine oral antipsychotic monotherapy continuation.

Guidelines challenged

A previous systematic review showed that clozapine was associated with a substantially decreased risk of death vs other antipsychotics. [Pharmacol Ther 2022;236:108236] “If death had been included in the outcome, the [benefits] associated with clozapine use would likely have been even more distinct,” commented the researchers.

“Results of our study suggested that only a switch to clozapine was associated with a decreased risk of the second relapse,” remarked the researchers. “This finding, together with existing knowledge of decreased risk of mortality associated with clozapine, challenges current treatment guidelines, which uniformly state that clozapine should be used after ≥2 different non-clozapine antipsychotics.” [Am J Psychiatry 2020;177:868-872; NICE Clinical guideline CG178; Am J Psychiatry 2017;174:216-229; Lancet Psychiatry 2025;12:122-130]

“Current guidelines prioritize the risk of side effects associated with clozapine, particularly focusing on severe but rare and monitorable adverse effects, rather than the common risk of relapse, which has potentially severe acute and long-term consequences,” commented the researchers.

Current guideline recommendations have resulted in long delays to clozapine initiation in real-world clinical practice. As evidenced in the current study, only 10.4 percent and 12.6 percent of patients used clozapine before and after the first relapse, respectively. “Instead, clozapine initiation should be considered as part of shared decision-making with patients with schizophrenia and their caregivers,” recommended the researchers.