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Schizophrenia often requires long-term treatment with antipsychotic medication. This study aims to measure the continuity of antipsychotic treatment over the course of illness in schizophrenia, as well as factors involved in the interruption of treatment. For this, we followed up a national cohort of first-episode psychosis patients in Finland for up to 18 years. Stratified Cox proportional hazards regressions were conducted for "within-participant" risk of discontinuation of subsequent treatments compared to the first, and by specific antipsychotic compared to oral olanzapine, the most prescribed antipsychotic in this cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated. Among 3343 participants followed up for a mean of 8 years (SD = 4.93), the median number of continuous treatment episodes was 6 (interquartile range [IQR] = 3–11) with a median duration of 11.4 months (IQR = 5.3–25.6). In the first year after diagnosis, the incidence rate of treatment discontinuation was 30.12 (95% CI = 29.89–30.35) events per 100 participant-years, decreasing to 8.90 (95% CI = 8.75–9.05) in the 10th year. The risk of discontinuation progressively decreased over successive treatment episodes (aHR = 0.30; 95% CI = 0.20–0.46 for episodes after the 15th compared to the first). Individuals were 67% less likely to interrupt treatment with long-acting injectable than oral antipsychotics (aHR = 0.33; 95% CI = 0.27–0.41). Treatment for schizophrenia over the long term is often characterized by recurrent cycles of interruptions and reintroductions of antipsychotic medication, which is typically not recommended by management guidelines. Greater utilization of long-acting injectable formulations earlier in the course of illness may facilitate the continuity of antipsychotic treatment in schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction Long-acting injectable antipsychotics (LAIs) are associated with multiple positive outcomes in psychosis, but it is unclear whether LAIs are associated with worse outcomes if neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect, occurs. Methods We used nationwide and nationally representative databases of healthcare encounters in Finland to study the incidence and outcome predictors of NMS in patients diagnosed with schizophrenia/schizoaffective disorder between January 01, 1972 and December 31, 2017. Using a nested case-control design, we also explored differences by antipsychotic formulation (LAI vs oral antipsychotic [OAP]) and class (first-generation antipsychotic [FGA] vs second-generation antipsychotic [SGA]). Results One hundred seventy-two NMS cases and 1441 sex-, age-, and diagnosis-matched controls were included (age = 58.8 ± 13.1 years, males = 59.9%). Incidence of NMS was 1.99 (1.98–2.00) per 10 000 person-years. The likelihood of developing NMS did not differ by antipsychotic formulation (adjusted odds ratio [aOR]: 0.89, 95% confidence intervals [95% CI]: 0.59–1.33, for LAIs vs OAPs) or class (FGA-OAP vs SGA-OAP [aOR: 1.08, 95% CI: 0.66–1.76], FGA-LAI [aOR: 0.89, 95% CI: 0.52–1.53], SGA-LAI [aOR: 1.35, 95% CI: 0.58–3.12]). NMS risk factors included antipsychotic treatment change: increased number (odds ratios [OR]: 5.00, 95% CI: 2.56–9.73); decreased number/switch (OR: 2.43, 95% CI: 1.19–4.96); higher antipsychotic dose (>2DDDs–OR: 3.15, 95% CI: 1.61–6.18); co-treatment with anticholinergics (OR: 2.26, 95% CI: 1.57–3.24), lithium (OR: 2.16, 95% CI: 1.30–3.58), benzodiazepines (OR: 2.02, 95% CI: 1.44–3.58); and comorbid cardiovascular disease (OR: 1.73, 95% CI: 1.22–2.45). Within 30 days, 4.7% of cases with NMS died (15.1% within 1 year) without differences by antipsychotic formulation. NMS reoccurred in 5 of 119 subjects (4.2%), after a median = 795 (range = 77–839) days after rechallenge with antipsychotics. Conclusion NMS remains a potentially life-threatening risk, yet these results should further contribute to mitigate concerns about LAI safety regarding NMS onset or outcomes, including mortality. [ABSTRACT FROM AUTHOR]

Background: There is uncertainty about the incidence of breakthrough psychosis in treatment adherent patients, and the role that factors, such as cumulative antipsychotic exposure, play in this phenomenon. Methods: In a nationwide cohort of individuals treated for schizophrenia-spectrum disorders in Finland between 1 January 1996 and 31 December 2015, 'Breakthrough Psychosis on Antipsychotic Maintenance Medication' (BAMM) was defined as hospitalization for psychosis despite ongoing continuous treatment with long-acting injectable antipsychotics (LAIs) or oral antipsychotics (OAPs) for ⩾8 weeks. Incidence rates, survival curves, and risk factors were presented. Results: In a cohort of 16 031 continuous LAI treatment episodes with virtually assured adherence [median duration = 441 days, interquartile range (IQR) = 155–1277], BAMM incidence was 31.5%. For 42 867 OAPs treatment episodes (median duration = 483 days, IQR = 167–1491), for whom adherence was modeled by the PRE2DUP method, BAMM incidence was 31.1%. Factors related to illness instability at treatment onset were associated with BAMM, although median time to BAMM was 291 days (IQR = 121–876) for LAIs and 344 days (IQR = 142–989) for OAPs, and 27.4% (N = 1386) of the BAMM events in the LAI, and 32.9% (N = 4378) in the OAP group occurred despite >1 year since last hospitalization at treatment onset. Cumulative antipsychotic exposure was not a consistent risk factor. Conclusion: BAMM was relatively common even when adherence was confirmed with LAIs. Illness instability at treatment onset accounted for most cases, but relapse after years of continuous treatment was still prevalent. There was insufficient evidence to support causality between cumulative antipsychotic exposure and BAMM. Future research needs to address the role of symptom severity and neurobiology in BAMM. [ABSTRACT FROM AUTHOR]

Background: Agranulocytosis is a life-threatening side-effect of clozapine, the only approved drug for treatment-resistant schizophrenia. The long-term profile of this complication has not yet been well established. Here we aim to describe the risk of clozapine-induced agranulocytosis over the long term., Methods: We used the entire population of Finland to identify people diagnosed with schizophrenia or schizoaffective disorder between 1972 and 2014 and developed a Kaplan-Meier model of time to diagnosis of agranulocytosis during clozapine versus non-clozapine treatment over a 22-year observation period (1996 to 2017). Next, we developed a nested case-control model for agranulocytosis matching by sex, age, time since diagnosis, and being in the incident cohort on a 1 to 5 ratio. Various durations of use for clozapine and non-clozapine antipsychotic treatment were compared to the modal antipsychotic use duration, deriving adjusted odds ratios (aORs) in a multivariable regression model. Recurrence and lethality rates for clozapine-induced agranulocytosis were described. These data reflect on all individuals with lived experience of schizophrenia in Finland during the study time, although individuals with lived experience were not included in the design of the study., Findings: We identified 61 769 people with schizophrenia or schizoaffective disorder (14 037 individuals treated with clozapine and 47 732 individuals treated with non-clozapine antipsychotics), with a mean age of 46·67 years (IQR 34·44-57·61), of whom 30 721 (49·7%) were female and 31 048 (50·3%) were male (data on ethnicity not available). Among those, 398 individuals were diagnosed with agranulocytosis (231 individuals treated with clozapine and 167 individuals treated with non-clozapine antipsychotics), representing a cumulative incidence of agranulocytosis for 1·37% (95% CI 0·58-3·16) on clozapine and 0·13% (0·04-0·23) on non-clozapine antipsychotics. In the case (n=398) versus control (n=1987) model, the risk of clozapine-induced agranulocytosis decreased steeply over time from an aOR of 36·01 (95% CI 16·79-77·22) for less than 6 months on clozapine to 4·38 (1·86-10·34) for clozapine use of 54 months or more. Only one of 3559 individuals starting clozapine died because of clozapine-induced agranulocytosis., Interpretation: The risk of clozapine-induced agranulocytosis decreases steeply over time but might be persistently greater than that of non-clozapine antipsychotics. This long-term risk excess seems small in absolute terms compared with the known magnitude of the advantages of clozapine in relevant outcomes, including life expectancy. Given the widespread underuse of clozapine, relaxing the long-term neutrophil monitoring could favour the advantages of long-term clozapine use, including greater life expectancy, without incurring the intolerable risk of clozapine-induced agranulocytosis., Funding: Northwell Health and Sigrid Jusèlius Foundation., Competing Interests: Declaration of interests JMR has received honoraria from Teva, Karuna, and Janssen; royalties from UpToDate; and grant support from Saladax and Alkermes. JMK has received consulting fees or honoraria for lectures from Alkermes, Allergan, Boehringer Ingelheim, Cerevel, Click Therapeutics, Dainippon Sumitomo, H Lundbeck, Health Rhythms, HLS Therapeutics, Indivior, Intracellular Therapies, Janssen, Johnson and Johnson, Karuna, LB Pharmaceuticals, Merck, Minerva, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion, and Teva; grant support from Click Therapeutics, H Lundbeck, Janssen, Otsuka, Saladax, Sunovion, and Valera; and is a stockholder for Cerevel, Health Rhythms, Karuna, LB Pharmaceuticals, North Shore Therapies, and the Vanguard Research Group. JT, HT, and AT have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly paid to their institution. JT has been a consultant or advisor to or has received honoraria from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Orion, Otsuka, Mediuutiset, Sidera, and Sunovion. HT has received personal fees from Janssen-Cilag and Otsuka., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)