Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia

被引:13
作者
Costa-Dookhan, Kenya A. [1 ,2 ]
Rajji, Tarek K. [1 ,2 ,4 ]
Tran, Veronica N. [5 ]
Bowden, Sylvie [3 ]
Mueller, Daniel J. [1 ,2 ,4 ]
Remington, Gary J. [1 ,2 ,4 ]
Agarwal, Sri Mahavir [1 ,2 ,4 ,6 ]
Hahn, Margaret K. [1 ,2 ,4 ,6 ,7 ]
机构
[1] Univ Toronto, Inst Med Sci, Toronto, ON, Canada
[2] Ctr Addict & Mental Hlth, Schizophrenia Dept, Toronto, ON, Canada
[3] Univ Toronto, Dept Med, Toronto, ON, Canada
[4] Univ Toronto, Dept Psychiat, Toronto, ON, Canada
[5] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON, Canada
[6] Univ Toronto, Banting & Best Diabet Ctr, Toronto, ON, Canada
[7] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada
关键词
N-DESMETHYLCLOZAPINE; WEIGHT-GAIN; ANTIPSYCHOTICS; NORCLOZAPINE; FLUVOXAMINE; RECEPTORS; AGONISM; UNIQUE;
D O I
10.1038/s41598-021-81493-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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, beta=-0.348 p=0.037), which may have been driven by fasting insulin levels (B=-27.124, SE B=12.081, beta=-0.351 p=0.031). The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine.
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页数:7
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