Treatment-resistant Schizophrenia and Clozapine:a Pharmacoepidemiological Study of Predictors and Outcomes
Year: 2016
Type: dissertation
Study design: Observational Study
Abstract: Background Treatment-resistant schizophrenia (TRS) is generally defined as an insufficient treatment response to at least two first-line antipsychotics and it has been estimated that TRS affects approximately one third of all individuals with schizophrenia. Clozapine is the recommended treatment in TRS, but it is considered to be underused or postponed in favour of alternative treatment strategies such as antipsychotic polypharmacy, despite no sound evidence base for its efficacy in TRS. A longer duration of untreated psychosis or ineffective treatment has consistently been found to be associated with a worse prognosis in schizophrenia. Predictors of TRS are needed to identify individuals who may not respond sufficiently to first-line antipsychotic treatment and who might benefit from clozapine. Aim The aim of this thesis was to identify sociodemographic, clinical, and genetic predictors of treatment resistance in schizophrenia and to study time to death and selfharm in individuals treated with clozapine and in individuals meeting criteria for TRS but not treated with clozapine. Methods Four Danish register-based cohort studies were performed using longitudinal survival techniques. All studies included individuals born in Denmark after 1955 and with a first schizophrenia diagnosis in 1996 or later. Cohort size varied among studies according to data availability: 8624 (Study 1), 13,349 (Study 2), and 862 (Study 3) individuals. Study 4 was restricted to a cohort of 2370 individuals meeting criteria for TRS. TRS was identified using a pharmacoepidemiological proxy defined based on register data and knowledge from clinical treatment guidelines and treatment practice. Results Study 1: Approximately 20% of individuals with a schizophrenia diagnosis met criteria for TRS during a median follow-up of 9 years. Proportions ranged from 10% to 45%, depending on criteria used. Several factors were identified to be associated with TRS, such as lower age at schizophrenia diagnosis, living in less urban areas, psychiatric hospitalization, prior diagnosis of personality disorder, and prior episode of suicide attempt. Study 2: The 5-year risk of TRS was estimated to be significantly higher for individuals living in rural areas being diagnosed with schizophrenia than for individuals living in the capital area (18% vs 11%). Study 3: No evidence of a significant association between the polygenic risk score for schizophrenia and TRS was found. Study 4: Current clozapine treatment was found to be associated with decreased rates of all-cause mortality and self-harm in TRS. However, the association between mortality was not statistically significant when clozapine was compared with other antipsychotics. Highest rate of death was observed during periods of no antipsychotic treatment and in periods after clozapine discontinuation. Conclusion and perspectives The first study identified candidate predictors which could potentially be included in a future prediction model for TRS, including sociodemographic, clinical, and genetic information on an individual level. Whereas several disease-related factors were significantly associated with increased rates of TRS, little or no evidence was found for an association between known risk factors for schizophrenia and TRS based on a multivariable model. Remarkably, an inverse association between urbanicity and TRS was observed, compared with the well-establish finding of an association between urbanicity and schizophrenia. This supports the hypothesis that TRS might constitute a subtype of schizophrenia that has a distinct aetiology. It could, however, also to a great extent reflect different treatment practice across the country. This emphasizes the need for optimized, harmonized, and specialized care and treatment in TRS, with special focus on interventions in rural areas. In line with other studies, no statistically significant evidence of an association between the polygenic risk score for schizophrenia and TRS was found. The genetic liability for TRS should thus be investigated further as more genetic data become available. The last study indicated that being treated with clozapine decreases the risk of death and self-harm in individuals with TRS. Future research should focus on evaluation of clozapines’ efficacy and safety compared with alternative treatment strategies that are recommended or commonly used in TRS. This research should place special emphasis on the role of adherence to antipsychotic medication and clozapine discontinuation in order to improve life quality and prevent deaths among patients with TRS.
Institution: Aarhus University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4412304484