Article

Pharmacogenetics of antipsychotic-induced weight gain: Review and clinical implications

Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Molecular Psychiatry (Impact Factor: 14.5). 09/2011; 17(3):242-66. DOI: 10.1038/mp.2011.109
Source: PubMed

ABSTRACT

Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application.

7 Followers
 · 
78 Reads
  • Source
    • "Although widely prescribed, risperidone use has some risks and few studies have evaluated its pharmacokinetic effects in children and adolescents or adverse drug reactions in these populations [4]. The possibility of weight gain, cardiovascular effects, and metabolic effects associated with hepatotoxicity, insulin and leptin resistance, hyperglycemia, and hyperinsulinemia is associated with increased cardiovascular and cancer morbimortality in adulthood [5] [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective. To identify the frequency of obesity and metabolic complications in child and adolescent users of risperidone. Potential associations with clinical parameters and SNPs of the HTR2C, DRD2, LEP, LEPR, MC4R, and CYP2D6 genes were analyzed. Methods. Samples from 120 risperidone users (8–20 years old) were collected and SNPs were analyzed, alongside assessment of chronological and bone ages, prescribed and weight-adjusted doses, use of other psychotropic drugs, waist circumference, BMI 𝑧-scores, blood pressure, HOMA-IR index, fasting levels of serum glucose, insulin, cholesterol, triglycerides, transaminases, and leptin. Results. Thirty-two (26.7%) patients were overweight and 5 (4.2%) obese. Hypertension was recorded in 8 patients (6.7%), metabolic syndrome in 6 (5%), and increased waist circumference in 20 (16.7%). The HOMA-IR was high for 22 patients (18.3%), while total cholesterol and triglycerides were high in 20 (16.7%) and 41 (34.2%) patients, respectively. SNP associations were found for LEP, HTR2C, and CYP2D6 with BMI; CYP2D6 with blood pressure, ALT, and HOMA-IR; HTR2C and LEPR with leptin levels; MC4R and DRD2 with HOMA-IR; HTR2C with WC; and LEP with ALT. Conclusions. Although not higher than in the general pediatric population, a high frequency of patients was overweight/obese, with abnormalities in metabolic parameters and some pharmacogenetic associations
    Full-text · Article · Jan 2016 · Journal of Child and Adolescent Psychopharmacology
  • Source
    • "Although widely prescribed, risperidone use has some risks and few studies have evaluated its pharmacokinetic effects in children and adolescents or adverse drug reactions in these populations [4]. The possibility of weight gain, cardiovascular effects, and metabolic effects associated with hepatotoxicity, insulin and leptin resistance, hyperglycemia, and hyperinsulinemia is associated with increased cardiovascular and cancer morbimortality in adulthood [5] [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective. To identify the frequency of obesity and metabolic complications in child and adolescent users of risperidone. Potential associations with clinical parameters and SNPs of the HTR2C, DRD2, LEP, LEPR, MC4R, and CYP2D6 genes were analyzed. Methods. Samples from 120 risperidone users (8–20 years old) were collected and SNPs were analyzed, alongside assessment of chronological and bone ages, prescribed and weight-adjusted doses, use of other psychotropic drugs, waist circumference, BMI z -scores, blood pressure, HOMA-IR index, fasting levels of serum glucose, insulin, cholesterol, triglycerides, transaminases, and leptin. Results. Thirty-two (26.7%) patients were overweight and 5 (4.2%) obese. Hypertension was recorded in 8 patients (6.7%), metabolic syndrome in 6 (5%), and increased waist circumference in 20 (16.7%). The HOMA-IR was high for 22 patients (18.3%), while total cholesterol and triglycerides were high in 20 (16.7%) and 41 (34.2%) patients, respectively. SNP associations were found for LEP, HTR2C, and CYP2D6 with BMI; CYP2D6 with blood pressure, ALT, and HOMA-IR; HTR2C and LEPR with leptin levels; MC4R and DRD2 with HOMA-IR; HTR2C with WC; and LEP with ALT. Conclusions. Although not higher than in the general pediatric population, a high frequency of patients was overweight/obese, with abnormalities in metabolic parameters and some pharmacogenetic associations.
    Full-text · Article · Jan 2016 · International Journal of Endocrinology
  • Source
    • "In humans, risperidone may promote weight gain through appetite stimulation, although many animal studies comparing SGAs challenge this hypothesis (Baptista et al., 2004; F. Li et al., 2013; Pouzet et al., 2003; Smith et al., 2012). Risperidone-induced weight gain is thought to be multifaceted, involving genetic, metabolic, and environmental contributors (Correll et al., 2011; Lett et al., 2011). Recent data implicates alterations in the gut microbiome as the mechanism by which SGAs impact metabolism and weight gain (Davey et al., 2013; Morgan et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Risperidone is a second-generation antipsychotic that causes weight gain. We hypothesized that risperidone-induced shifts in the gut microbiome are mechanistically involved in its metabolic consequences. Wild-type female C57BL/6J mice treated with risperidone (80μg/day) exhibited significant excess weight gain, due to reduced energy expenditure, which correlated with an altered gut microbiome. Fecal transplant from risperidone-treated mice caused a 16% reduction in total resting metabolic rate in naïve recipients, attributable to suppression of non-aerobic metabolism. Risperidone inhibited growth of cultured fecal bacteria grown anaerobically more than those grown aerobically. Finally, transplant of the fecal phage fraction from risperidone-treated mice was sufficient to cause excess weight gain in naïve recipients, again through reduced energy expenditure. Collectively, these data highlight a major role for the gut microbiome in weight gain following chronic use of risperidone, and specifically implicates the modulation of non-aerobic resting metabolism in this mechanism.
    Full-text · Article · Oct 2015 · EBioMedicine
Show more