Precautions for implementation of PGx in clinical practice
While PGx testing, is promising in the treatment of schizophrenia, certain limitations should be considered when clinicians rely on PGx tests without knowing their limitations. For example, a clinical case report published in the American Journal of Psychiatry provided a warning regarding the potential warrant of implementation of PGx testing in clinical practice.4 It described a male patient with treatment-resistant schizophrenia, aged 25 years, who showed rapid improvement following clozapine administration despite the fact that the PGx test used for the patient did not recommend clozapine for his treatment. He was judged to be a poor responder to clozapine based on the assessment of several genetic variants, including the DRD2, UGT2B15, CYP2C19, CYP2D6, HLA-B15.02, HTR2C, and MTHFR genes.
However, it should be noted that none of these genes reached Level 1A or 1B based on PharmGKB evaluations. Thus, most of the genetic information collected in this case was of limited use regarding prediction of clozapine response while other clinical factors were not considered. Consequently, PGx testing should be seen as a companion decision-support tool, under consideration of all available individual clinical and demographic information available, and not be interpreted as an alternative or substitute to protocol-based care for clinicians in their attempt to optimize pharmacological treatment.
That availability of commercial PGx tests is increasing at a rapid pace. However, it is also important to consider that tests are not standardized for gene and alleles and the interpretation is therefore inconsistent across the available PGx tests. Consistent with this notion, a recent study reported on the level of agreement in psychotropic medication recommendations across four PGx tests (CNSDose®, Genecept®, GeneSight®, and Neuropharmagen®).5 The agreement was generally modest (eg, antidepressants, 56%; anxiolytics/hypnotics, 56%; antipsychotics, 55%), which indicates that PGx tests are not interchangeable and that standardization across these tests is warranted. Taken together, these findings reflect the need for further standardization of genetic-based phenotyping across PGx tests.
PGx of antipsychotic treatment response and specific adverse effects
A number of genetic variants associated with antipsychotic response and adverse effects (eg, tardive dyskinesia, antipsychotic-induced weight gain, and clozapine-induced agranulocytosis) have been found.6,7 For example, among several gene variants associated with tardive dyskinesia, the association of the vesicular monoamine transporter 2 (VMAT2) gene with tardive dyskinesia is consistent with recent clinical evidence that showed that a novel selective VMAT2 inhibitor, valbenazine, improved tardive dyskinesia.8
Other findings from research that focused on antipsychotic-induced weight suggest consistent results for several genes implicated in appetite/satiety regulation.9 Our group is currently developing a multi-gene panel to assess individual risk of antipsychotic-induced weight gain, and the preliminary results have been promising.10 Nevertheless, further research is needed to apply recommendations based on pharmacodynamic variants for antipsychotics to clinical practice. Notably, polygenic risk scores, which represent the total number of risk alleles carried by an individual, weighted by the effect size from the genome-wide association studies, have been suggested to be associated with antipsychotic treatment response in patients with schizophrenia.11,12
However, to date, these PGx markers for antipsychotic response and adverse effects are not sufficiently validated to be used in clinical practice yet. Nevertheless, given the rapid advance in the genomic field, future research will find clinically actionable PGx markers to predict antipsychotic response and adverse effects by incorporating identified genetic variants and non-genetic factors.
In summary, PGx has the potential to optimize antipsychotic treatments and overcome conventional “trial-and-error” approaches. PGx testing has already been implemented in clinical practice. In fact, at least five major US medical centers (St. Jude Children’s Research Hospital, Vanderbilt University Medical Center, University of Florida Health Shands Hospital, Mayo Clinic, and Mount Sinai Medical Center) have implemented PGx testing into clinical care based on available expert consensus recommendations.13 For the time being, only recommendations for CYP2D6 metabolizer status and several antipsychotics (eg, aripiprazole, haloperidol, pimozide, risperidone, and zuclopenthixol) would meet sufficient evidence-based criteria for clinical utility (Table).
With advancements in the available technology and applied methods, including genome-wide association studies and targeted gene approaches, a number of new gene variants associated with antipsychotic responses and adverse effects have been identified and may be associated with clinical efficacy to predict clinical phenotypes.6,7 Additional well-designed randomized controlled trials with large sample sizes of patients from a variety of ethnicity groups, standardized clinical PGx guidelines, and increased awareness of the benefit and limitations of PGx will be needed to implement fully in clinical practice.
Dr Yoshida is a Postdoctoral Research Fellow, Centre for Addiction and Mental Health, Toronto, ON, Canada, and a Psychiatrist, Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; Dr Müller is Head, Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health, and Professor, Department of Psychiatry, University of Toronto, ON. The authors report no conflicts of interest concerning the subject matter of this article.
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