Antipsychotic use in both adults and children has increased substantially over the past several decades. Weight gain and metabolic comorbidities remain a significant health risk associated with these drugs, particularly clozapine and olanzapine, with greatest severity in pediatric settings.
Within the first month of therapy, pronounced weight gain occurs in many, but not all patients. Recent research underscores genetic factors underlying profound inter-individual variability, pointing to genetic clues that allow physicians to preemptively identify patients at high risk for the condition. A meta-analysis by Zhang et al.  reported 13 single-nucleotide polymorphisms significantly associated with susceptibility, with variants in ADRA2A, DRD2, 5-HTR2C and MC4R genes showing the greatest impact. These variants are liked to altered adenosine, dopamine, serotonin and melanocortin-mediated cell signaling, respectively, which are pharmacodynamic targets of the drugs themselves.
For patients carrying a predisposing genetic variant whose non-genetic risk-benefit analysis still justifies use of these drugs, complementary therapies are imperative to minimize onset and severity of the condition, which typically develops within several weeks of starting the medication.
Dayabandara and colleagues summarized the most effective management strategies in a comprehensive review . Switching medication, adding an insulin sensitizing adjuvant such as metformin, and lifestyle modifications are all effective ways to prevent or mitigate the condition. Genetic testing may help to justify ongoing nutritional and lifestyle counseling to provide support, ensure compliance and successful care.
- Zhang JP, Lencz T, Zhang RX, et al. Pharmacogenetic associations of antipsychotic drug-related weight gain: a systematic review and meta-analysis. Schizophr Bull. 2016;42(6):1418–1437. https://www.ncbi.nlm.nih.gov/pubmed/28883731
- Dayabandara M, Hanwella R, Ratnatunga S, Seneviratne S, Suraweera C, de Silva VA. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat. 2017 Aug 22;13:2231-2241.