Abstract

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.

Highlights

  • Clozapine is known to constitute a second-generation antipsychotic (SGA; known as an atypical antipsychotic) employed in cases of schizoaffective disorder and schizophrenia in which treatment was previously unsuccessful [1]

  • Higher fatty liver scores were discovered in the clozapine group, and scholars reported a link between this SGA and liver-based adipogenesis caused by related proteins (e.g., fatty acid synthase (FASN) and PNPLA3) as well as by the activation of SREBP1 and fatty acid-binding protein 4 (FABP4) in clozapinetreated mice

  • Our clozapine group differed from our control group in weight gain, food efficiency, adipocyte size, fat tissue weight, renal and retinal pathology, serum AST and ALT levels, serum and hepatic triglyceride levels, and fatty liver disease severity

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Summary

Introduction

Clozapine is known to constitute a second-generation antipsychotic (SGA; known as an atypical antipsychotic) employed in cases of schizoaffective disorder and schizophrenia in which treatment was previously unsuccessful [1]. Most crucially, compared with that of conventional neuroleptics, it is more efficacious and less likely to induce tardive dyskinesia and extrapyramidal side effects [1,2]. Among those for whom typical antipsychotics did not have an effect, 30–60% respond positively to clozapine [2]. Clozapine has severe and lethal side effects, such as serotonin syndrome [9]. Another critical factor is that SGAs were reported to exert significant metabolic side effects, such as elevated type 2 diabetes mellitus (T2DM) risk [10]

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