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Antipsychotic drugs have alleviated the debilitating symptoms of thousands of patients with schizophrenia and bipolar disorder, but often at a high price. These drugs can also trigger excessive weight gain, leading to life-threatening complications such as diabetes or heart disease. Now scientists at Johns Hopkins University have uncovered the mechanism by which these drugs stimulate the appetite—a finding that could lead to new agents without the side effect of constant hunger.
Neuroscientists Solomon H. Snyder and Sangwon Kim found that when they administered clozapine, a powerful antipsychotic, to mice, the animals experienced a spike of the appetite-stimulating enzyme AMPK. Then they discovered that blocking a receptor for histamine caused a boost in AMPK similar to the effects of clozapine. Histamine, well known for causing allergy symptoms, has been long suspected to play a role in weight control, but the mechanism has been unknown. The researchers confirmed their finding by administering clozapine to mice genetically engineered to lack the histamine receptor, and these rodents showed no increase in AMPK.
“This is the first time histamine and AMPK have been linked,” Kim says. By blocking histamine receptors, clozapine and other antipsychotics prevent cells from receiving the body's signal to turn off AMPK production. As a result, AMPK builds up in the hypothalamus and continues to stimulate appetite, even when enough food has been consumed. He suggests that pharmaceutical companies may be able to screen out antipsychotic drugs with antihistamine properties and thereby avoid the side effects of weight gain. The researchers say their work may also lead to safer weight-loss drugs.