Real-world effectiveness of antipsychotic doses for relapse prevention in patients with first-episode schizophrenia in Finland: a nationwide, register-based cohort study

Background Antipsychotic doses for relapse prevention in patients with first-episode schizophrenia that have the highest likelihood of success are unknown. We aimed to study the evolution of antipsychotic dose and risk of severe relapse indicated by psychiatric rehospitalisation associated with antipsychotic use and specific dose categories. Methods We did a nationwide, register-based cohort study in Finland. Patients were identified from the nationwide Hospital Discharge register, which records all inpatient hospital stays. Patients with first-episode schizophrenia diagnosed as inpatients and who were 45 years or younger were followed-up for 5 years of illness or until a fifth relapse episode. The primary measure was rehospitalisation due to psychosis, which was used as a marker of relapse and defined as inpatient hospital care with an ICD-10 code of F20-F29 diagnosis recorded as the main discharge diagnosis. Time between relapses was required to be at least 30 days to be considered a next relapse. Antipsychotic use was derived from the prescription register. Dose was summed from all concomitant antipsychotics. Antipsychotic effectiveness for preventing rehospitalisation was studied using within-individual analyses to eliminate selection bias, stratifying time to before and after the second relapse. Findings In total, the study population comprised 5367 patients, of whom 3444 (64.2%) were men and 1923 (35.8%) were women, with a mean age of 29.5 years (SD 7.8) at the start of follow-up. Ethnicity data were not available. 3058 (57.0%) of 5367 patients required hospitalisations. In these patients, the mean dose increased gradually after each new relapse from 1.22 defined daily doses per day (95% CI 1.18-1.26) before the first relapse to 1.56 defined daily doses per day (1.48-1.64) before the fifth relapse. Adjusted hazard ratio (aHR) for rehospitalisation with antipsychotic use versus non-use increased from 0.42 (95% CI 0.35-0.51) before the second relapse to 0.78 (0.62-0.99) after the second relapse (p<0.0001), indicating markedly decreased effectiveness. Analysing specific dose categories revealed a U-shaped curve, showing the lowest rehospitalisation risk during use of the standard dose (0.9 to <1.1 defined daily doses per day) before but not after the second relapse. Low dose (<0.6 defined daily doses per day) was associated with substantially higher rehospitalisation risk (aHR 1.54 [95% CI 1.06-2.24]) versus standard dose before the second relapse, but not after the second relapse (1.11 [0.76-1.62]), owing to reduced effectiveness of all doses after the second relapse. Interpretation The effectiveness of antipsychotics for relapse prevention decreased substantially after the second relapse. Therefore, prevention of the second relapse is essential, and all patients should receive sufficient antipsychotic doses and enhanced relapse prevention efforts after their first relapse. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Automated summary

This study indicates that the effectiveness of antipsychotics for preventing relapse in patients with first-episode schizophrenia substantially decreases after the second relapse. Therefore, preventing the second relapse is essential, and all patients should receive sufficient antipsychotic doses and enhanced relapse prevention efforts after their first relapse.