Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

Abstract

Background and purpose: Antipsychotics (APs) are the primary method of treatment for schizophrenia and other psychotic disorders. Unfortunately, lengthy trial-and-error approaches are typically required to find the optimal medication and dosage due to a large interindividual variability with outcome to AP treatment. The literature has shown abundant evidence for a genetic component in individuals' responses to APs. Pharmacogenetic studies analyze specific genetic markers and their association with symptom improvement and occurrence of side effects with APs. This research aims to optimize AP drug treatment by usage of predictive testing and to personalize medicine. Recent findings: This review will highlight the most consistent findings in pharmacogenetics of APs and will update the reader on the clinical implications. This will include how genetic variants modulate AP drug levels, side effects, and therapeutic symptom improvement (i.e. response) to AP treatment. Summary: Several promising findings were obtained implicating gene variants of the dopamine receptor genes in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect sizes appear to be particularly high in the genetics of side effects compared to response. One example is antipsychotic-induced weight gain where the leptin, HTR2C and in particular the melanocortin-4-receptor (MC4R) genes have been implicated in weight gain in children and adolescents. Consistent findings were also obtained for genes implicated in tardive dyskinesia and agranulocytosis. However, the most clinically relevant findings pertain to genes involved in drug metabolism such as the CYP2D6 and CYP2C19 genes which have been included in the first genetic test kits such as the Amplichip †

Toward a Global Roadmap for Precision Medicine in Psychiatry: Challenges and Opportunities

“…To date, many candidate gene-based association studies and genome-wide association studies (GWAS) have sought to identify genetic variants associated with psychotropic treatment response and these are discussed next. (Changasi et al, 2014;Fabbri and Serretti, 2015;Porcelli et al, 2011). Variations within the drug metabolizing gene CYP2D6 have been most extensively investigated in terms of pharmacokinetics of psychotropic medication (Porcelli et al, 2011).…”

Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia

“…We selected genes shown to be associated with antipsychotic drug response from pharmacodynamic candidate gene studies and genome-wide association studies. eTable 2 in Supplement 2 lists the most promising candidate genes, as reviewed by Changasi et al, and the genes shown to be associated with drug response from the 2 published genome-wide association studies …”

Selected single-nucleotide variants in GRIN1, GRIN2A, and GRIN2B encoding subunits of the NMDA receptor are not biomarkers of schizophrenia resistant to clozapine: exploratory study

“…In studies on clozapine, it was possible to identify single-nucleotide variants (SNVs) in the human leukocyte antigen (HLA)—the 6672G/C nucleotide variant, which is being tried to be used as a marker of the effectiveness of schizophrenia. The test had a high specificity; however, it was obsolete for commercial use due to low market interest [ 11 ]. Similarly, on daily basis practice, the testing of polymorphisms in CYP2D6 with regard to the metabolism of clozapine and determining its effective dose is used [ 12 ].…”