Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis

Pharmacogenet Genomics. 2005 Apr;15(4):195-200. doi: 10.1097/01213011-200504000-00002.


Objectives: Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. Two recent studies in the same cohort of Chinese Han subjects have shown that polymorphisms of the promoter regions of both the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor and the leptin genes, are associated with antipsychotic-induced weight gain over 10 weeks. We have investigated whether these effects remain true in a Caucasian population and following longer term treatment.

Methods: Seventy-three Spanish caucasian patients with a first-episode psychosis and initially drug-naive were genotyped for the 5-HT2C receptor -759C/T and leptin -2548A/G polymorphisms. Body mass index and plasma leptin levels were monitored after 6 weeks, 3 months and 9 months of antipsychotic treatment.

Results: Patients with the -759T variant allele showed significantly less weight gain than those without this allele. This effect held true in the smaller group of patients receiving olanzapine. The -2548 leptin polymorphism was not associated with short-term (6 week and 3 month) weight increases but did show significant association with 9-month antipsychotic-induced weight gain. The 5-HT2C -759 genotype was significantly associated with pre-treatment plasma leptin levels.

Conclusions: These findings confirm the importance of two genetic factors associated with long-term antipsychotic-induced weight increases in schizophrenia, and implicate a role for leptin in the 5-HT receptor-mediated weight regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Affective Disorders, Psychotic / complications
  • Affective Disorders, Psychotic / drug therapy*
  • Alleles
  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / pharmacology*
  • Benzodiazepines / pharmacology
  • Body Mass Index
  • Female
  • Genetic Variation
  • Genotype
  • Humans
  • Leptin / blood
  • Leptin / genetics*
  • Male
  • Models, Genetic
  • Olanzapine
  • Pharmacogenetics
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic
  • Receptor, Serotonin, 5-HT2C / genetics*
  • Receptors, Leptin
  • Schizophrenia / drug therapy
  • Time Factors
  • Weight Gain / drug effects*
  • Weight Gain / genetics


  • Antipsychotic Agents
  • LEPR protein, human
  • Leptin
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Leptin
  • Benzodiazepines
  • Olanzapine