Mechanistic Connections between Glucose/Lipid Disturbances and Weight Gain induced by Antipsychotic Drugs

This chapter focuses on possible molecular mechanisms by which the drugs affect the 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 H1 and serotonergic (5‐HT2C) receptors. 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. The knowledge of the molecular basis of these emergent syndromes may inspire the development of the next generation of antipsychotic drugs with minimal metabolic liability.