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Conceivable Mechanisms of Clozapine Propagated Dyslipidemia- A Short Review

Pearl Pinto, Sivaprakasam Chinnarasu, Mohanraj Sadasivam, Louis Cojandaraj*

Clozapine is the most effective drug for the treatment of refractory schizophrenia, showing a good response in the treatment of patients with resistant schizophrenia, especially reducing violent, aggressive, and suicidal tendencies. However, treatment with clozapine has been associated with hyperlipidemia especially high triglycerides, obesity, diabetes, and cardiovascular disease. Elevated level of lipids has a direct impact on the improvement of symptoms in schizophrenics treated with clozapine. Although the mechanism is not clear, there is a possibility of serum lipids playing a major part in enhancing clozapine's therapeutic activity. The effect of clozapine on phospholipids might indicate that this rise is related to its therapeutic benefit as well. Increase in fatty acids accompanied by a sharp rise in triglycerides may alsocontribute, pointing towards the possible involvement of lipases which are involved in the storage and release of fatty acids and triglycerides in the adipose tissue. An increase in hepatic lipid synthesis can be one other cause for hyperlipidaemia, leading to weight gain after a long term therapy. Lipogenesis and myelin synthesis could also become targets in schizophrenia since myelination and synaptogenesis is essential in the central nervous system. Hence a focus is put on the upregulation of several genes involved in cholesterol and fatty acid biosynthesis, which are proven to be controlled by Sterol Regulating Element Binding Protein transcription factors (SREBP). The antipsychotic drug Clozapine activates this SREBP system. This activation increases lipogenesis which could be one of the mechanisms of action, which in turn could explain the metabolic side effects produced by clozapine.