RESUMO
In four previous studies, a combinatorial multigene pharmacogenomic test (GeneSight) predicted those patients whose antidepressant treatment for major depressive disorder resulted in poorer efficacy and increased health-care resource utilizations. Here, we extended the analysis of clinical validity to the combined data from these studies. We also compared the outcome predictions of the combinatorial use of allelic variations in genes for four cytochrome P450 (CYP) enzymes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter (SLC6A4) and serotonin 2A receptor (HTR2A) with the outcome predictions for the very same subjects using traditional, single-gene analysis. Depression scores were measured at baseline and 8-10 weeks later for the 119 fully blinded subjects who received treatment as usual (TAU) with antidepressant standard of care, without the benefit of pharmacogenomic medication guidance. For another 96 TAU subjects, health-care utilizations were recorded in a 1-year, retrospective chart review. All subjects were genotyped after the clinical study period, and phenotype subgroups were created among those who had been prescribed a GeneSight panel medication that is a substrate for either CYP enzyme or serotonin effector protein. On the basis of medications prescribed for each subject at baseline, the combinatorial pharmacogenomic (CPGx™) GeneSight method categorized each subject into either a green ('use as directed'), yellow ('use with caution') or red category ('use with increased caution and with more frequent monitoring') phenotype, whereas the single-gene method categorized the same subjects with the traditional phenotype (for example, poor, intermediate, extensive or ultrarapid CYP metabolizer). The GeneSight combinatorial categorization approach discriminated and predicted poorer outcomes for red category patients prescribed medications metabolized by CYP2D6, CYP2C19 and CYP1A2 (P=0.0034, P=0.04 and P=0.03, respectively), whereas the single-gene phenotypes failed to discriminate patient outcomes. The GeneSight CPGx process also discriminated health-care utilization and disability claims for these same three CYP-defined medication subgroups. The CYP2C19 phenotype was the only single-gene approach to predict health-care outcomes. Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes. This clinical validity is likely to contribute to the clinical utility reported for combinatorial pharmacogenomic decision support.
Assuntos
Antidepressivos/administração & dosagem , Citocromo P-450 CYP2C19/genética , Depressão/tratamento farmacológico , Depressão/genética , Farmacogenética , Antidepressivos/efeitos adversos , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Depressão/patologia , Feminino , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Receptor 5-HT2A de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Resultado do TratamentoRESUMO
The objective of this study was to evaluate the potential benefit of utilizing a pharmacogenomic testing report to guide the selection and dosing of psychotropic medications in an outpatient psychiatric practice. The non-randomized, open label, prospective cohort study was conducted from September 2009 to July 2010. In the first cohort, depressed patients were treated without the benefit of pharmacogenomic testing (the unguided group). A DNA sample was obtained from patients in the unguided group, but the results were not shared with either the physicians or patients until the end of the 8-week study period. In the second cohort (the guided group), testing results were provided at the beginning of the 8-week treatment period. Depression ratings were collected at baseline and after 2 weeks, 4 weeks and 8 weeks of treatment using the Quick Inventory of Depressive Symptomatology, Clinician Rated (QIDS-C16) and the 17-item Hamilton Rating Scale for Depression (HAM-D17). Clinician and patient satisfaction was also assessed. The reduction in depressive symptoms achieved within the guided treatment group was greater than the reduction of depressive symptoms in the unguided treatment group using either the QIDS-C16 (P=0.002) or HAM-D17 (P=0.04). We concluded that a rapidly available pharmacogenomic interpretive report provided clinical guidance that was associated with improved clinical outcomes for depressed patients treated in an outpatient psychiatric clinic setting.