A very large number of children and adults with autism are treated with antipsychotic drugs that are more commonly prescribed to patients with schizophrenia, bipolar disorder, depression, and post-traumatic stress disorder. Although these drugs can improve behavioral problems such as agitation, stereotypic behavior, temper tantrums, and self-injury, they come at the expense of serious metabolic disturbances, which include excessive weight gain and altered lipid profile. Children are especially vulnerable to an early weight gain, which foretells increased risk of youth-onset diabetes and cardiovascular disease. The general consensus is that these metabolic disturbances result from the exclusive action of the drugs on certain receptors within the brain. Unexpectedly, we discovered that the same receptors are also expressed in human fat cells. Furthermore, we found that incubation of human fat samples and isolated fat cells with several types of antipsychotic drugs caused major changes in the release of hormones that control appetite and insulin sensitivity. To support our premise that fat tissue is a critical target of antipsychotic drugs, we will undertake two objectives: (1) to examine whether drugs that have variable metabolic profile directly accelerate the formation of mature fat cells, increase fat accumulation, and alter the release of fat-derived hormones that regulate appetite, insulin sensitivity, and inflammation, and (2) to use rats, which can be experimentally manipulated, to verify whether the drugs suppress leptin, a fat-derived hormone that regulates appetite, leading to increased food intake followed by weight gain. The proposed collaboration between experts in adipocyte biology, psychiatry, and body weight regulation, together with the use of unique reagents, human fat cells, and a responsive animal model, provides us with an exceptional opportunity for characterizing a previously unrecognized site of action of the antipsychotics. This research should yield both conceptual innovation and practical outcomes. Conceptually, it will generate a more comprehensive understanding of the mechanisms by which these drugs cause metabolic disturbances. In practice, human fat cells can be easily incorporated into the screening paradigms by drug companies for the identification of a new generation of antipsychotic drugs that are devoid of metabolic side effects. Our ultimate goal is to provide much safer drugs to autistic patients who benefit from treatment with such medications.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
