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

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 exp...

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Autores principales:	Kenya A. Costa-Dookhan, Tarek K. Rajji, Veronica N. Tran, Sylvie Bowden, Daniel J. Mueller, Gary J. Remington, Sri Mahavir Agarwal, Margaret K. Hahn
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4facbfff40714bdaa240ff203aa63723
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spelling	oai:doaj.org-article:4facbfff40714bdaa240ff203aa637232021-12-02T13:50:41ZAssociations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia10.1038/s41598-021-81493-02045-2322https://doaj.org/article/4facbfff40714bdaa240ff203aa637232021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81493-0https://doaj.org/toc/2045-2322Abstract 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.Kenya A. Costa-DookhanTarek K. RajjiVeronica N. TranSylvie BowdenDaniel J. MuellerGary J. RemingtonSri Mahavir AgarwalMargaret K. HahnNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kenya A. Costa-Dookhan Tarek K. Rajji Veronica N. Tran Sylvie Bowden Daniel J. Mueller Gary J. Remington Sri Mahavir Agarwal Margaret K. Hahn Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia
description	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.
format	article
author	Kenya A. Costa-Dookhan Tarek K. Rajji Veronica N. Tran Sylvie Bowden Daniel J. Mueller Gary J. Remington Sri Mahavir Agarwal Margaret K. Hahn
author_facet	Kenya A. Costa-Dookhan Tarek K. Rajji Veronica N. Tran Sylvie Bowden Daniel J. Mueller Gary J. Remington Sri Mahavir Agarwal Margaret K. Hahn
author_sort	Kenya A. Costa-Dookhan
title	Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia
title_short	Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia
title_full	Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia
title_fullStr	Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia
title_full_unstemmed	Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia
title_sort	associations between plasma clozapine/n-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4facbfff40714bdaa240ff203aa63723
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Associations between plasma clozapine/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia

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