Aripiprazole at high doses directly induces the unfolded protein response.

Schizophrenia is a mental disease which results in a decreased life expectancy and wellbeing by promoting obesity and sedentary lifestyle. Schizophrenia is treated by antipsychotic medications. While the second generation of antipsychotic (SGA), Olanzapine and Aripiprazole, have greater effectiveness in treating Schizophrenia, they display a higher risk of metabolic side effects, mostly the development of insulin resistance and dyslipidemia.

The unfolded protein response (UPR) is activated in response to endoplasmic reticulum (ER) stress and plays an important role in chronic metabolic diseases, including obesity, insulin resistance, and diabetes. We therefore hypothesize that mild, chronic ER stress conditions develop upon SGA treatment and contribute to the side effects.

We observed a full-fledged activation of ER stress by aripiprazole and not olanzapine. This occurred at variable intensities in different cell types, such as hepatocellular carcinoma, melanoma and others. Mechanistically, aripiprazole caused the depletion of calcium from the ER, resulting in the activation of IRE1 and PERK, two major transducers of the UPR. Apoptosis occurred at the concentrations of UPR induction. Deletion of both IRE1 and PERK, but not individually, from HepG2 cells facilitated the induction of apoptosis by aripiprazole. Our study reveals for the first time a cytotoxic effect of aripiprazole that involves the induction of ER stress. Impaired UPR promotes the cell death.