Research

Drug-induced Metabolic Syndrome

Second-generation antipsychotics (SGAs) are essential medications for millions of schizophrenia patients worldwide. Moreover, the last decade has witnessed an exponential increase in their uses for other neuropsychiatric conditions such as bipolar disorder, major depressive disorder, and autism. Despite their broad efficacy and low risks for extrapyramidal symptoms, most SGAs have been linked to the drug-induced metabolic syndrome that is characterized by excessive weight gain, dyslipidemia, and type-2 diabetes. Obesity and diabetes often develop shortly after SGA treatment. Moreover, the risk for metabolic syndrome is significantly higher in female subjects. The rapid disease onset as well as the gender difference strongly suggest a distinct etiology underlying SGA-induced metabolic syndrome. Unfortunately, while tremendous resources and efforts have been spent combating obesity and diabetes in the general population, little progress has been made toward understanding or treating drug-induced metabolic disturbances.

Genome-wide association studies in human patients have indicated a role for several brain monoamine receptors in SGA-induced metabolic syndrome. However, a critical obstacle for testing their potential contributions has been the difficulty to replicate clinical symptoms in rodents. To this end, we adopted a paradigm that reproduces hyperphagia, obesity, and diabetes in SGA-fed mice. We then use a combination of neurochemical, pharmacological, and behavioral analyses to interrogate the contribution of individual candidate genes and neural pathways in genome-edited mice. This multidiscipline approach recently allowed us to identify the serotonin 2c receptor (Htr2c), among others, as one critical mediator of the SGA-induced metabolic syndrome. We further show that lorcaserin, an Htr2c specific agonist, suppresses weight gain and improves glucose profile in SGA-treated mice.

Ongoing research in our laboratory aims to:

  1. Investigate the brain sites that mediate SGAs’ metabolic effects
  2. Determine whether SGAs’ psychotropic and metabolic effects can be segregated and targeted individually, and
  3. Identify novel therapeutic targets to alleviate or eliminate SGAs’ adverse metabolic effects.