Mechanistic connections between glucose/ilipid disturbances and weight gain induced by antipsychotic drugs

Antipsychotic drugs produce an array of metabolic side effects including elevated serum lipids (especially triglycerides), hyperglycemia, significant weight gain and even diabetes in some patients. This review will focus on possible molecular mechanisms by which the drugs affect metabolic function. There appears to be a connection between the drug-induced lipid and glucose disturbances and weight gain in patients. The relationship between these metabolic effects stems from operation of the glucose-fatty acid cycle and the cooperative regulation of energy metabolism at the level of signaling pathways, including Akt and AMPK, which converge on forkhead and C/EBP transcription factors. Genetic studies have provided some insight into the possible pharmacological basis for drug-induced weight gain with apparent contributions by histamine H I and serotonergic (5-HT2C) receptors. However, additional targets of the drugs must be involved in the induction of the metabolic syndrome. These targets may include glucose transporters, cytochrome P450 enzymes, aryl hydrocarbon receptors, K+ channels, and glucose-sensing systems in general. Additional clues have emerged from animal models. Antipsychotic drugs produce hyperglycemia and weight gain in mice and rats. Moreover, the drugs stimulate lipid accumulation in the nematode, Caenorhaditis elegans, a valuable genetic tool for elucidation of molecular targets involved i in diverse biological responses. A better understanding of the drug-induced side effects may ultimately allow identification of risk factors in patients and prevention of weight gain and glucose disturbances with adjunctive approaches. Finally, knowledge of the molecular basis of these emergent syndromes may inspire the development of the next generation of antipsychotic drugs with minimal metabolic liability.