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.
Highlights
Despite intensive effort in neuroscience research, very few new psychopharmacological agents have entered the market during recent decades
At this point, CYP2C19 and CYP2D6 enzymes seem to be more important for pharmacogenetics in psychiatry, since they contribute significantly to the phase I metabolism of more than two thirds of all currently available psychiatric drugs [19]
The cumulative allelic frequency of all CYP2C19 and CYP2D6 alleles that influence enzymatic capacity varies by ethnicity, but it is always substantial; the total number of affected patients is considerable
Summary
Despite intensive effort in neuroscience research, very few new psychopharmacological agents have entered the market during recent decades. One recently published and adequately powered study suggests that the CYP1A2 SNP rs2472297 may predict clozapine exposure [20] and potentially affect clozapine treatment At this point, CYP2C19 and CYP2D6 enzymes seem to be more important for pharmacogenetics in psychiatry, since they contribute significantly to the phase I metabolism of more than two thirds of all currently available psychiatric drugs [19]. Possible obstacles in terms of feasibility include the availability of an efficient system to generate, deliver and implement genotyping in the clinical prescription of psychiatric medication At this time, despite gene-dosing advice for many antidepressants (Tables 3 and 4) and antipsychotics (Table 5) these are all prescribed to patients with almost no preemptive genotyping or genetic analyses during treatment, not even when side effects occur or when the pharmacotherapy is inefficacious. Regulatory and legislative frameworks should be developed and implemented to guide this process
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