Abstract
Background
Cognitive impairment is a key feature in schizophrenia that affects employability and quality of life. While clozapine is effective in reducing symptoms and relapse in treatment-resistant schizophrenia, it appears to have contradictory effects on cognition. Despite its high anticholinergic burden, clozapine is linked to cognitive advantages over other neuroleptics. This may be mediated by its primary metabolite, norclozapine, which has different neurotransmitter receptor affinities. The clozapine:norclozapine ratio is crucial in therapeutic drug monitoring and clozapine titration, potentially improving therapeutic outcomes and minimizing side effects. However, current evidence regarding the association between the clozapine:norclozapine ratio and cognition and employability is mixed.
Aims & Objectives
We aim to investigate if the clozapine:norclozapine ratio predicts cognitive performance and employment status.
Method
This study was conducted at a tertiary mental health institution in Singapore from January 2016 to August 2022, involving 86 patients aged 21 to 67 years on clozapine for schizophrenia. Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia-Short Form (BACS-SF), while specific psychopathology was rated using the Positive and Negative Syndrome Scale (PANSS). Employability was measured via a questionnaire. Linear and logistic regression were performed to examine relationships between clozapine:norclozapine ratio and cognitive function, and employment status.
Results
Linear regression analysis indicated that the clozapine:norclozapine ratio was not a significant predictor of cognitive performance (Beta = -0.034, p = 0.731). However, total PANSS score was a significant negative predictor of BACS score (Beta = -0.415, p < 0.001). Logistic regression analysis revealed that the clozapine:norclozapine ratio was not a significant predictor of employment status (B = -0.197, p = 0.325). Higher PANSS scores were associated with lower employment (B = -0.044, p = 0.026). Age, sex and antipsychotic dose was not associated with employment or cognition.
Discussion & Conclusions
Our study found no significant association between the clozapine:norclozapine ratio and cognitive performance or employment status. The lack of a direct relationship between the clozapine:norclozapine ratio and outcomes might reflect the complex pharmacodynamics of clozapine. While the ratio may provide information on clozapine metabolism, its direct impact on clinical outcomes may be moderated by various factors such as individual patient characteristics and duration of treatment. Hence, a single pharmacological measure, such as the clozapine:norclozapine ratio, might not show a strong direct effect. Results showed that symptom severity, measured by PANSS score, significantly influenced employment outcomes and cognitive performance in schizophrenia, consistent with existing literature. The small sample size (N=86) may limit the study's power to detect subtle effects and cross-sectional design limits the ability to assess dynamic changes of cognition and employment status over time. Our findings underscore the complexity of treatment-resistant schizophrenia and highlight the need for multifaceted approaches in therapeutic strategies.