norclozapine and Insulin-Resistance

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.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cognition; Female; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Psychotic Disorders; Schizophrenia; Young Adult

The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine.. Adult female rats were treated with a range of doses of clozapine and norclozapine (0.5, 2, 8 & 20 mg/kg, i.p.) and then subjected to the intraperitoneal glucose tolerance test (IGTT), where glucose levels were recorded for 2 h following a glucose challenge. In parallel, rats were tested with two doses of clozapine and norclozapine (2 & 20 mg/kg, i.p.) in the hyperinsulinemic-euglycemic clamp (HIEC), to measure whole body insulin resistance.. In the IGTT, clozapine demonstrated dose-dependent effects on fasting glucose levels and total glucose area-under-the-curve following the glucose challenge, with the two highest doses strongly increasing glucose levels. Only the highest dose of norclozapine increased fasting glucose levels, and caused a non-significant increase in glucose levels following the challenge. By contrast, both doses of clozapine and norclozapine caused a potent and long-lasting decrease in the glucose infusion rate in the HIEC, indicating that both compounds cause whole body insulin resistance.. While not as potent as its parent compound, norclozapine clearly exerts acute metabolic effects, particularly on insulin resistance. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Topics: Animals; Antipsychotic Agents; Clozapine; Female; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Rats, Sprague-Dawley