Clozapine induces mitochondrial alterations and the secretion of proinflammatory cytokines in insulin‐sensitive cell types

Abstract

Clozapine is an effective treatment for schizophrenia but causes side effects like weight gain and diabetes. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for clozapine side effects as well as the development of obesity and insulin resistance. Prior investigations have focused on the brain and neurons. In this study, the effect of clozapine on insulin responsive cell types and cells associated with obesity was examined. Cultured myoblasts, adipocytes, and hepatocytes were treated with 0, 25, 50 and 75 μM clozapine. After 24 hours, a mitochondrial selective probe was used to assess morphology and membrane potential (ΔΨm). ATP lysates were also prepared and culture media collected for cytokine analyses by multiplex array. Clozapine caused mitochondria fission in all cell types. In addition, it altered mitochondria ΔΨm (p<0.05), volume (p<0.05), and ATP levels (p<0.05) relative to controls. Clozapine also significantly induced the production of the proinflammatory cytokines MCP‐1, IL‐6, and GM‐CSF. In conclusion, clozapine damages mitochondria and promotes inflammation in insulin responsive cells. Understanding how clozapine alters metabolism may provide insight on the origin of metabolic disease in the general population. Supported by Biaggini Research Fellowship, St. Mary's Univ. to VC‐S & Friends for Psychiatric Research Grant, Dept. of Psychiatry to CW‐B.