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Clozapine\u2019s main metabolite, <jats:italic>N<\/jats:italic>-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\u2009=\u2009\u2212\u20091.028, SE B\u2009=\u2009.473, \u03b2\u2009=\u2009\u2212\u20090.348 p\u2009=\u20090.037), which may have been driven by fasting insulin levels (B\u2009=\u2009\u2212\u200927.124, SE B\u2009=\u200912.081, \u03b2\u2009=\u2009\u2212\u20090.351 p\u2009=\u20090.031). The CLZ\/NDMC ratio may predict insulin resistance\/metabolic comorbidity among patients with TRS receiving clozapine.<\/jats:p>","DOI":"10.1038\/s41598-021-81493-0","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T11:03:39Z","timestamp":1611227019000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Associations between plasma clozapine\/N-desmethylclozapine ratio, insulin resistance and cognitive performance in patients with co-morbid obesity and ultra-treatment resistant schizophrenia"],"prefix":"10.1038","volume":"11","author":[{"given":"Kenya A.","family":"Costa-Dookhan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek K.","family":"Rajji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica N.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Bowden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary J.","family":"Remington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sri Mahavir","family":"Agarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret K.","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"81493_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1185\/03007999709113338","volume":"14","author":"HY Meltzer","year":"1997","unstructured":"Meltzer, H. 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Dr. Remington has received research support from HLS Therapeutics for work not related to this project, as well as the Canadian Institutes of Health Research, and consultant fees from HLS therapeutics for work not related to this project. All other authors declare no conflicts of interest. Funding for this study was provided by the Ministry of Health and Long-Term Care, Alternative Funding Plan fund.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2004"}}