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Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes

The Pharmacogenomics Journal volume 15, pages 443–451 (2015)Cite this article

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Abstract

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.

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Acknowledgements

The preparation of figures 3, 4 and 5 by Stephen Pestian is greatly appreciated.

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Authors and Affiliations

  1. Assurex Health, Inc., Mason, OH, USA

    C A Altar, J M Carhart, J D Allen, B M Dechairo & J G Winner

  2. Departments of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    D K Hall-Flavin

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  1. C A Altar
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Correspondence to C A Altar.

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Competing interests

The La Crosse and Hamm Clinic antidepressant studies were funded by the Mayo Clinic Discovery Translation Grant, an internal grant from the Mayo Clinic (Rochester, MN, USA). Assurex Health provided in-kind services consisting of shipping of buccal samples, genotyping all patients DNA and providing the GeneSight report. The Pine Rest prospective and UHS retrospective studies were funded by Assurex Health. Data analysis personnel were provided by Assurex Health. CAA, BMD, JGW, JMC and JDA are employees and potential equity holders of Assurex Health. DH-F has declared no conflict of interest.

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Altar, C., Carhart, J., Allen, J. et al. Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes. Pharmacogenomics J 15, 443–451 (2015). https://doi.org/10.1038/tpj.2014.85

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