Psychotropic drug-induced genetic-epigenetic modulation of CRTC1 gene is associated with early weight gain in a prospective study of psychiatric patients

Clin Epigenetics. 2019 Dec 26;11(1):198. doi: 10.1186/s13148-019-0792-0.


Background: Metabolic side effects induced by psychotropic drugs represent a major health issue in psychiatry. CREB-regulated transcription coactivator 1 (CRTC1) gene plays a major role in the regulation of energy homeostasis and epigenetic mechanisms may explain its association with obesity features previously described in psychiatric patients. This prospective study included 78 patients receiving psychotropic drugs that induce metabolic disturbances, with weight and other metabolic parameters monitored regularly. Methylation levels in 76 CRTC1 probes were assessed before and after 1 month of psychotropic treatment in blood samples.

Results: Significant methylation changes were observed in three CRTC1 CpG sites (i.e., cg07015183, cg12034943, and cg 17006757) in patients with early and important weight gain (i.e., equal or higher than 5% after 1 month; FDR p value = 0.02). Multivariable models showed that methylation decrease in cg12034943 was more important in patients with early weight gain (≥ 5%) than in those who did not gain weight (p = 0.01). Further analyses combining genetic and methylation data showed that cg12034943 was significantly associated with early weight gain in patients carrying the G allele of rs4808844A>G (p = 0.03), a SNP associated with this methylation site (p = 0.03).

Conclusions: These findings give new insights on psychotropic-induced weight gain and underline the need of future larger prospective epigenetic studies to better understand the complex pathways involved in psychotropic-induced metabolic side effects.

Keywords: CRTC1; Early weight gain; Methylation; Psychiatric population; Psychotropic drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Alleles
  • Case-Control Studies
  • CpG Islands / drug effects
  • DNA Methylation / drug effects*
  • Epigenesis, Genetic
  • Female
  • Genetic Association Studies
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Obesity / chemically induced
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Psychotropic Drugs / adverse effects*
  • Psychotropic Drugs / pharmacology
  • Transcription Factors / genetics*
  • Weight Gain / genetics*


  • CRTC1 protein, human
  • Psychotropic Drugs
  • Transcription Factors