Comparative effectiveness of antipsychotic treatment strategies for relapse prevention in first-episode schizophrenia in Finland: a population-based cohort study.

Background: The best pharmacological treatment practices for relapse prevention in patients with first-episode schizophrenia are unclear. We aimed to assess different treatment strategies used before and after the first relapse, and their associations with subsequent relapse risk.

Methods: In this population-based cohort study, we enrolled individuals (aged ≤45 years) with first-episode schizophrenia who were hospitalised and subsequently relapsed between 1996 and 2014 from the nationwide Finnish Hospital Discharge Register. Individuals who had not been taking antipsychotics within the year preceeding initial hospitalisation and who had a relapse within 5 years of discharge were included in the analyses. Treatment strategies were assessed during the 30 days before hospitalisation for the first relapse and 30 days after discharge and were categorised as either long-acting injectable, clozapine, non-clozapine oral antipsychotic monotherapy, non-clozapine oral antipsychotic polypharmacy, and antipsychotic non-use. Adjusted hazard ratios (aHRs) of the risk of second relapse based on treatment type were analysed with Cox regression models for 2 years after the first relapse, or until death or end of data linkage (Dec 31, 2017). People with lived experience of schizophrenia were not involved in the research and writing process.

Findings: Between Jan 31, 1996 and Dec 31, 2017, 3000 individuals had their first psychosis relapse and were eligible for analysis. Mean age was 30·0 years (SD 7·6), 1069 (35·6%) of patients were women and 1931 (64·4%) men. No ethnicity data were available. 2148 (71·7%) had a second relapse within 2 years. Before first relapse, most individuals were either not using antipsychotics (n=1366 [45·5%]), or were using non-clozapine oral antipsychotic monotherapy (n=973 [32·4%]). Compared with continuing the same treatment strategy used before the first relapse, switching to clozapine was associated with the lowest risk of second relapse compared with continuing any non-clozapine oral antipsychotic monotherapy (aHR 0·66, 95% CI 0·49-0·89; relapse rate 73·2% with oral non-clozapine antipsychotic monotherapy continuation vs 57·1% with switch to clozapine). Switching to another non-clozapine oral antipsychotic monotherapy (0·99, 0·76-1·28) was approximately as unhelpful in preventing the next relapse as switching to antipsychotic non-use (1·07, 0·80-1·42).

Interpretation: In patients with first-episode schizophrenia having their first psychosis relapse despite use of non-clozapine oral antipsychotics, continuation with the same antipsychotic modality or switch to another non-clozapine oral antipsychotic did not show evidence of being beneficial in relapse prevention, suggesting that clozapine should be started instead. This finding, together with existing knowledge of decreased risk of mortality associated with clozapine, challenges current treatment guidelines that recommend clozapine as a third-line treatment, resulting in treatment practices characterised by long delays to clozapine initiation.

Funding: Sigrid Jusélius Foundation.