Polymorphisms of the LEP- and LEPR genes, metabolic profile after prolonged clozapine administration and response to the antidiabetic metformin

Schizophr Res. 2010 Aug;121(1-3):213-7. doi: 10.1016/j.schres.2010.06.001. Epub 2010 Jun 29.


Background: The role of leptin in atypical antipsychotic-induced metabolic dysfunction was explored by assessing the anthropometric and metabolic profile and the response to metformin (MET) of clozapine- (CLZ) treated schizophrenia patients according to their single nucleotide polymorphisms (SNPs) in the leptin promoter (LEP2548/GA) and leptin receptor (LEPR Q223R) genes.

Methods: Phase 1. Body mass index (BMI), waist circumference, serum glucose, HbA1C, lipids, leptin, cortisol, insulin resistance index (HOMA-IR), metabolic syndrome and the frequencies of SNPs were assessed in 56 CLZ-treated patients (78.6% males). Phase 2. Fifty two phase 1 subjects were randomly assigned to MET XR (n=23) (1000 mg/day) or placebo (n=29) for 14 weeks. Changes in anthropometric and biochemical variables were compared between the SNPs.

Results: Phase 1. The QQ group displayed the lowest triglyceride levels (p<0.05). No other significant difference was observed. Phase 2. Change in anthropometric variables did not differ between the genotypes in any treatment group. After MET, glucose levels significantly increased in the GG group (p<0.05), whereas the HOMA-IR and the low density cholesterol significantly decreased in the QQ- but not in the (QR+RR) group (p<0.05). No differences were observed after placebo.

Conclusions: BW response to CLZ was not related to LEP- and LEPR-SNPs. The GG and (QR+RR) genotypes showed an unexpectedly opposite and blunted response to MET administration respectively.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / administration & dosage*
  • Blood Glucose / drug effects
  • Body Mass Index
  • Clozapine / administration & dosage*
  • Double-Blind Method
  • Female
  • Genotype
  • Humans
  • Hydrocortisone / blood
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance
  • Leptin / genetics*
  • Male
  • Metabolic Diseases / chemically induced*
  • Metformin / therapeutic use*
  • Middle Aged
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Leptin / genetics*
  • Schizophrenia* / drug therapy
  • Schizophrenia* / genetics
  • Schizophrenia* / physiopathology
  • Venezuela / epidemiology


  • Antipsychotic Agents
  • Blood Glucose
  • Hypoglycemic Agents
  • Leptin
  • Receptors, Leptin
  • Metformin
  • Clozapine
  • Hydrocortisone