Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?

Abstract

In recent decades, very few new psychiatric drugs have entered the market. Thus, improvement in the use of antidepressant and antipsychotic therapy has to focus mainly on enhanced and more personalized treatment with the currently available drugs. One important aspect of such individualization is emphasizing interindividual differences in genes relevant to treatment, an area that can be termed neuropsychopharmacogenomics. Here, we review previous efforts to identify such critical genetic variants and summarize the results obtained to date. We conclude that most clinically relevant genetic variation is connected to phase I drug metabolism, in particular to genetic polymorphism of CYP2C19 and CYP2D6. To further improve individualized pharmacotherapy, there is a need to take both common and rare relevant mutations into consideration; we discuss the present and future possibilities of using whole genome sequencing to identify patient-specific genetic variation relevant to treatment in psychiatry. Translation of pharmacogenomic knowledge into clinical practice can be considered for specific drugs, but this requires education of clinicians, instructive guidelines, as well as full attention to polypharmacy and other clinically relevant factors. Recent large patient studies (n > 1,000) have replicated previous findings and produced robust evidence warranting the clinical utility of relevant genetic biomarkers. To further judge the clinical and financial benefits of preemptive genotyping in psychiatry, large prospective randomized trials are needed to quantify the value of genetic-based patient stratification in neuropsychopharmacotherapy and to demonstrate the cost-effectiveness of such interventions.

Keywords: CYP2C19; CYP2D6; NGS; depression; genotyping; schizophrenia.

Figure 1

Scheme for NGS-based sequencing for determination of global genomic variations of importance for preemptive pharmacogenetics advice. Common variants might also be directly detected by using standard genotyping techniques and conventional sequencing. The gene of interest might have its origin in a complex locus like the CYP2D locus and for proper sequencing e.g. long range PCR methods are necessary. From the (NGS, common known mutations will be evident but also rare mutations. These can be classified by subjecting the sequences to specific algorithms that can classify the mutations according to expected functional impact.