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

Abstract

BackgroundMetabolic 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.ResultsSignificant 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).ConclusionsThese 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.

Associations of Genetic Variants of Methylenetetrahydrofolate Reductase and Serum Folate Levels with Metabolic Parameters in Patients with Schizophrenia

“…Certain regions of DNA methylation at birth were associated with obesity and insulin resistance in childhood [ 33 ]. In addition, site-specific DNA methylation has been shown to be associated with metabolic alternations in patients treated with antipsychotics [ 34 , 35 ]. Therefore, analysis of DNA methylation is essential when studying the associations between one-carbon metabolism and metabolic abnormalities.…”

Deletion ofCrtc1leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

“…Understanding how genetic and environmental factors interact in metabolic diseases and how they impact normal brain and behavior is central for better diagnosing and treating related mood disorders. Because of its central role in regulating brain metabolism and its strong association with features of MeS in psychiatric patients [11][12][13][14] , Crtc1 is a key candidate gene to understand how (neuro-)metabolic alterations can affect normal behavior. In this study, we have been able to identify reduced hippocampal energy metabolism in Crtc1-deficient mice that translated into measurable in vivo neuroimaging markers.…”

New Insights Into the Pivotal Role of CREB-Regulated Transcription Coactivator 1 in Depression and Comorbid Obesity

“…The presence of the SNP and/or DNA methylation correlated with CRTC1 gene expression, which in turn, related to BMI and fat distribution. Delacretaz et al, 2019 Human, psychiatric patients with psychotropic treatment Significant methylation changes observed in three CRTC1 CpG sites in the blood of patients with early and important weight gain. One of these 3 CpG sites was significantly associated with early weight gain in patients carrying the G allele of rs4808844A > G, a SNP associated with this methylation site.…”

“…Although the human CRTC1 polymorphisms studied so far were not clearly associated with depression, they were associated with obesity markers [body mass index (BMI), fat mass] in psychiatric cohorts and in individuals with MDD ( Choong et al, 2013 ; Quteineh et al, 2016 ). With regard to obesity, further human genetic investigations showed that the CRTC1 locus links fat mass to cardiometabolic diseases ( Lu et al, 2016 ) and that genetic and epigenetic control of CRTC1 transcription affects fat distribution and eating behavior ( Booij, 2019 ; Delacretaz et al, 2019 ; Rohde et al, 2019 ; Wang et al, 2021 ). Altogether, these observations strengthen the hypothesis that CRTC1 may represent a pivotal transcription coactivator regulating both MDD and obesity etiological pathways (see Tables 1 , 2 ).…”