Predictors of multiple treatment failure of antipsychotics in early-onset psychosis

Abstract

Background: In adult-onset psychosis, a number of factors are associated with poor clinical outcomes, which include the severity of negative symptoms at illness onset, the presence of premorbid difficulties, and a family history of psychotic disorder [1]. If and how these factors effect psychosis prognosis in children and adolescents is unclear [2]. Objective: Using a retrospective cohort design and data from a large electronic case register, we sought to investigate, in a sample of children and adolescents with first-episode psychosis (FEP), the prospective association of demographic and clinical variables at first presentation to services with reduced antipsychotic effectiveness. We used multiple treatment failure (MTF) as a proxy for reduced treatment effectiveness, defined as the initiation of a third trial of novel antipsychotic as a result of insufficient response, nontolerable adverse effects or non-adherence. We hypothesized that presence of premorbid difficulties (e.g. comorbid neurodevelopmental disorders), baseline negative symptoms and family history of psychosis would be positively associated with MTF. Methods: Data were obtained from a clinical cohort of 638 children (51% male) with FEP, aged 10−17 years, referred to inpatient and community-based services in South London, UK, using the Clinical Record Interactive Search (CRIS) system. Age, sex, ethnicity, adaptive function, inpatient status, presence of negative symptoms at first presentation, first degree family history of psychosis, co-morbid neurodevelopmental disorders (autism spectrum disorders [ASD], intellectual disability [ID], and hyperkinetic disorders), unique antipsychotic medications prescribed in a 5-year observation period, and reasons for MTF were extracted from electronic patient records. The effect of neurodevelopmental comorbidity, presenting with two or more Marder Negative Symptoms, and family history of psychosis, on the development of MTF over a 5-year period was modelled using Cox regression. Results: One hundred and twenty-four children with FEP (19.3% of the sample) developed MTF prior to the age of eighteen. Of those, 10.5% (n = 13) showed a persistently insufficient response to two consecutive trials of different antipsychotics, 14.5% (n = 18) experienced persistently non-tolerable adverse effects, 4% (n = 5) showed persistent non-adherence, and 78% (n = 77) showed a combination of these reasons. After controlling for a range of potential confounders, a fully adjusted cox proportional hazards model found that co-morbid ASD (adjusted hazard ratio [aHR] 1.89; 95% CI 1.03–3.46; p<0.05) was significantly associated with MTF. The presence of two or more NS around the first episode (aHR 2.00; 1.16– 3.42; p<0.05), family history of psychosis (aHR 2.08; 1.15–3.75; p<0.05), and Black ethnicity, relative to white British ethnicity (aHR 2.09; 1.31–3.33; p<0.05) were all significantly associated with an increased risk of MTF over a 5 year follow-up period. Adaptive function score was inversely associated with MTF (aHR 0.98; 0.97–0.99, p<0.05). Conclusion: Prominent negative symptoms, co-morbid ASD and first degree family history of psychosis at first presentation can delineate a subset of children and adolescents with psychosis who have a higher risk of reduced antipsychotic effectiveness. Children with these risk factors may require early optimisation of current therapeutic approaches or early alternatives to conventional antipsychotic treatment to improve their prognosis.