Abstract
Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation. Clozapine’s main metabolite, N-desmethylclozapine (NDMC), has potent 5-HT2C antagonist properties which may explain this metabolic dysfunction, thus the CLZ:NDMC ratio is of particular interest. High insulin resistance states could be associated with CYP1A2 induction and lower CLZ:NDMC ratios. Additionally, lower CLZ:NDMC ratios have been associated with better cognitive, but worse metabolic functioning. This study investigated associations between metabolic and cognitive parameters with the CLZ/NDMC ratio. Primary outcomes included relationships between the CLZ:NDMC ratio to the homeostatic model assessment for insulin resistance (HOMA-IR) and Brief Assessment of Cognition in Schizophrenia (BACS) composite z-scores. Secondary outcomes assessed relationships between CLZ:NDMC ratios to fasting insulin, BMI, weight, fasting glucose, and BACS digit sequencing z-scores. 38 patients who were overweight or obese with schizophrenia or schizoaffective disorder completed fasting bloodwork, anthropometric, psychopathological, and cognitive assessments. Multivariate regressions found a statistically significant inverse association between the CLZ/NDMC ratio and HOMA-IR (B = − 1.028, SE B = .473, β = − 0.348 p = 0.037), which may have been driven by fasting insulin levels (B = − 27.124, SE B = 12.081, β = − 0.351 p = 0.031). The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine.
Highlights
Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation
Our results show that the CLZ:NDMC ratio is associated with insulin resistance [i.e. a lower ratio or relative increases in NDMC metabolite levels was associated with whole body insulin resistance (Fig. 2)]
These findings complement those of other studies which have found higher CLZ:NDMC ratios to be associated with better metabolic functioning[20,21,28]
Summary
Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation. The primary aims of this cross-sectional study were to investigate the association between the homeostatic model assessment for insulin resistance (HOMA-IR) and cognition (assessed by composite z-scores on the Brief Assessment of Cognition in Schizophrenia (BACS)) in relation to the CLZ:NDMC ratio. The relationships between the ratio and other metabolic measures, namely fasting glucose levels, body mass index (BMI), and serum insulin levels, as well as the BACS digit sequencing subtest z-scores, were investigated.
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