Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism

Physiol Behav. 2011 Sep 26;104(4):590-8. doi: 10.1016/j.physbeh.2011.05.033. Epub 2011 Jun 12.


The atypical antipsychotics (AAPs) are associated with weight gain and an increased incidence of metabolic disease including type 2 diabetes mellitus. Epidemiological, cross-sectional and prospective studies suggest that two of the AAPs, olanzapine and clozapine, cause the most dramatic weight gain and metabolic impairments including increased fasting glucose, insulin and triglycerides. Relative to the other AAPs, both olanzapine and clozapine exhibit a particularly high antagonistic affinity for histamine and muscarinic receptors which have been hypothesized as mediators of the reported increase in weight and glucose abnormalities. In this article, we review the current evidence for the AAP associated weight gain and abnormal glucose metabolism. We postulate that the effects of the AAPs on food intake and peripheral metabolism are initially independently regulated but with increasing body adiposity, the early AAP-induced impairments in peripheral metabolism will be exacerbated, thereby establishing a vicious cycle such that the effects of the AAP are magnified by the known pathophysiological consequences of obesity. Furthermore, we examine how inhibition of the histaminergic pathway may mediate increases in food intake and the potential role of the vagus nerve in the reported peripheral metabolic effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / pharmacology*
  • Appetite Regulation / drug effects*
  • Appetite Regulation / physiology*
  • Benzodiazepines / adverse effects
  • Benzodiazepines / pharmacology
  • Clozapine / adverse effects
  • Clozapine / pharmacology
  • Glucose / metabolism*
  • Histamine
  • Histamine Antagonists / pharmacology
  • Humans
  • Models, Biological
  • Muscarinic Antagonists / pharmacology
  • Obesity / chemically induced
  • Obesity / metabolism
  • Olanzapine
  • Receptors, Histamine
  • Vagus Nerve / physiology
  • Weight Gain / drug effects*
  • Weight Gain / physiology


  • Antipsychotic Agents
  • Histamine Antagonists
  • Muscarinic Antagonists
  • Receptors, Histamine
  • Benzodiazepines
  • Histamine
  • Glucose
  • Clozapine
  • Olanzapine