Scientists Find the Brain Pathway Behind a Key Antipsychotic's Weight Gain

Researchers at UT Southwestern Medical Center have identified a brain signaling pathway that appears to drive the substantial weight gain often associated with clozapine, a widely used antipsychotic medication for treatment-resistant schizophrenia. The preclinical findings, published in Nature Communications, point to a potential way to reduce the drug's metabolic side effects.

"Clozapine can be life-changing for people whose symptoms do not respond to other antipsychotics, but its metabolic side effects can make long-term treatment difficult," said senior co-corresponding author Chen Liu, a principal investigator in the Center for Hypothalamic Research at UT Southwestern. To model the drug's effects, researchers incorporated clozapine into the diet of female mice, producing blood concentrations within the therapeutic range seen in patients; over 12 weeks, the mice ate more, especially at night, gained fat, developed fatty liver changes and showed impaired glucose control.

The team traced this response to the brain's melanocortin system, which regulates hunger and fullness. Neurons expressing the melanocortin 4 receptor (MC4R) in a brain region called the paraventricular hypothalamus normally suppress feeding, while a potassium channel called Kir7.1 in the same cells acts like an electrical brake, weakening that signal when it opens. The researchers found clozapine and risperidone, another antipsychotic, suppressed activity in these neurons, while ziprasidone, which is less likely to cause weight gain, did not. When Kir7.1 was genetically deleted from MC4R-expressing neurons, clozapine-induced weight gain was markedly reduced, though mice still gained weight on a different antipsychotic, olanzapine, suggesting different drugs act through distinct mechanisms.

The researchers tested two treatments to counteract clozapine's effects: setmelanotide, an MC4R-activating drug already approved for certain rare genetic forms of obesity, reduced food intake and weight in clozapine-treated mice, while an experimental Kir7.1 blocker called ML418 reduced eating, weight and fat mass and improved glucose tolerance in mice that had already become obese. "Clozapine acts on many receptors, so MC4R-Kir7.1 is not the whole story," Liu said, adding that targeting the pathway precisely could help manage metabolic side effects without weakening the drug's psychiatric benefits.