Genetics of Common Antipsychotic-Induced Adverse Effects

Abstract

The effectiveness of antipsychotic drugs is limited due to accompanying adverse effects which can pose considerable health risks and lead to patient noncompliance. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual susceptibility to antipsychotic-induced adverse effects (AAEs), thereby improving clinical outcomes. We reviewed the literature on the PGx of common AAEs from 2010 to 2015, placing emphasis on findings that have been independently replicated and which have additionally been listed to be of interest by PGx expert panels. Gene-drug associations meeting these criteria primarily pertain to metabolic dysregulation, extrapyramidal symptoms (EPS), and tardive dyskinesia (TD). Regarding metabolic dysregulation, results have reaffirmed HTR2C as a strong candidate with potential clinical utility, while MC4R and OGFR1 gene loci have emerged as new and promising biomarkers for the prediction of weight gain. As for EPS and TD, additional evidence has accumulated in support of an association with CYP2D6 metabolizer status. Furthermore, HSPG2 and DPP6 have been identified as candidate genes with the potential to predict differential susceptibility to TD. Overall, considerable progress has been made within the field of psychiatric PGx, with inroads toward the development of clinical tools that can mitigate AAEs. Going forward, studies placing a greater emphasis on multilocus effects will need to be conducted.

Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

“…Indeed, MC4R function is implicated in energy expenditure as well as regulation of food intake independently of changes in body weight (Xu et al, 2013 ; Mountjoy, 2015 ). Furthermore, a single nucleotide polymorphism (SNP) in MC4R, rs17782313, has been associated with overeating as well as APD-induced weight gain (Yilmaz et al, 2015 ; Macneil and Muller, 2016 ). Two additional SNPs, rs8087522, and rs1801133, have also been linked to APD-induced weight gain (Malhotra et al, 2012 ; Macneil and Muller, 2016 ), suggesting that the MC4R locus may be an attractive candidate for predicting APD-induced weight gain and metabolic disruption.…”

A comprehensive analysis of mitochondrial genes variants and their association with antipsychotic-induced weight gain

“…The heritability of AIWG has been suggested to be between 60 and 80% based on twin and family studies, indicating the role of genetic factors in the pathophysiology of AIWG (Gebhardt et al, 2010). Several studies have addressed the genetic basis of AIWG in terms of the nuclear genome, and it is a well-established area of research (MacNeil and Muller, 2016; Muller et al, 2013; Muller and Kennedy, 2006). …”

Influence of polygenic risk scores on lipid levels and dyslipidemia in a psychiatric population receiving weight gain-inducing psychotropic drugs

“…Of note, it is very likely that the consideration of additional genetic variants (e.g. SNPs associated with psychotropic drug-induced weight gain and metabolic abnormalities in genes such as FTO, LEP, LEPR or HTR2C [46,47]) in the wGRS may help to improve the predictive power of wGRS on dyslipidemia.…”