Genetic Dissection of Atypical Antipsychotic-Induced Weight Gain: Novel Preliminary Data on the Pharmacogenetic Puzzle

Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychoticsin the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despitetheir benefits, use is limited by the occurrence of adverse reactions such as sedation and weightgain. This article provides a comprehensive review and discussion of obesity-related pathways andintegrates these with the known mechanisms of atypical antipsychotic action to identify candidatemolecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presentedto genetically dissect these obesity pathways and elucidate the genetic contribution of these candidatemolecules to clozapine-induced weight gain. There is considerable variability among individuals withrespect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-inducedweight gain has been suggested. Therefore, genetic variation in these candidate molecules may predictpatient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 geneticpolymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes(HTR2C/2A/1A); the histamine H₁ and H₂ receptor genes (H1R/H2R); the cytochrome P450 1A2gene (CYP1A2); the β3 and α_1a-adrenergic receptor genes (ADRB3/ADRA1A); and tumor necrosisfactor α (TNF-α). Prospective weight gain data were obtained for 80 patients with schizophrenia whocompleted a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-α, andHTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatricpharmacogenetics will in the future aid clinical practice in the prediction of response and sideeffects, such as antipsychotic-induced weight gain, and minimize the current “trial and error” approachto prescribing.