Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice

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.

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice

“…Compared with the TAA group, serum IL-1β was 22% lower ( Figure 4 a) and serum TNF-α was 42% lower in the SSd group ( Figure 4 b). Serum FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation [ 36 , 37 , 38 ]. Compared with the TAA group, serum FGF21 was 2.21-fold higher ( Figure 4 c) and serum CRP was 24% lower in the SSd group ( Figure 4 d).…”

“…H&E staining was used to study fat infiltration into the liver. The scoring was as follows: 0 = no fat infiltration; 1 = <5% fat infiltration; 2 = 5–25% fat infiltration; 3 = 25–50% fat infiltration; and 4 = >50% fat infiltration [ 19 , 38 , 93 ]. A high-resolution digital microscope was used to perform imaging (Moticam 2300; Motic Instruments, Richmond, BC, Canada), and Motic Images Plus version 2.0 software (Motic Instruments, Richmond, BC, Canada) was used to determine the histology and morphometry of liver.…”

The development of the Metabolic-associated Fatty Liver Disease during pharmacotherapy of mental disorders - a review

“…Mice fed with HFD and to whom clozapine was administered, showed a 1.4 times greater fatty liver scores than mice taking only HFD [99].…”

“…In separate studies for clozapine and risperidone, an increase in serum leptin concentrations was associated with reduced leptin receptor concentration and increased food intake. Long-term use of both clozapine and risperidone leads to resistance to leptin, causing inhibition of leptin signaling, which under normal conditions should be associated with a decrease in appetite [99,100]. In the study of Perez-Iglesias et al, serum leptin and insulin levels, body weight and BMI, among patients taking haloperidol, olanzapine or risperidone for one year, were monitored.…”

Imipramine Accelerates Nonalcoholic Fatty Liver Disease, Renal Impairment, Diabetic Retinopathy, Insulin Resistance, and Urinary Chromium Loss in Obese Mice

“…One study highlighted that symptoms of depression could be related to reduced kidney function and dialysis commencement; such symptoms should be monitored in all disease stages in CKD patients [25]. Long-term hyperglycemia and IR are among the key factors related to bloodretina barrier dysfunction and retina damage linked to diabetes [26]. The retina is crucial to human vision, and diabetes is, of course, a risk factor for diabetic retinopathy (DR).…”