Clinical Utility of Combinatorial Pharmacogenomics-Guided Antidepressant Therapy: Evidence from Three Clinical Studies

Abstract

DNA of 258 patients with treatment-resistant depression was collected in three 8-10 week, two-arm, prospective clinical trials. Forty-four allelic variations were measured in genes for the cytochrome P450 (CYP) enzymes CYP2D6, CYPC19, and CYP1A2, the serotonin transporter (SLC6A4), and the 5-HT2A receptor (HTR2A). The combinatorial pharmacogenomic (CPGx™) GeneSight test results were provided to clinicians to support medication changes from baseline (guided arm), or they were provided at the end of each study to clinicians of unguided patients who were treated as usual (TAU). TAU subjects who at baseline were prescribed medications genetically discordant for them showed only a 12% symptom improvement, far less than the 32.5% or 28.5% improvements of the TAU subjects on yellow-category ('use with caution'; p = 0.002) or green-category medications ('use as recommended'; p = 0.02), respectively. The odds of a clinical response were increased 2.3-fold among all GeneSight-guided compared to all TAU subjects (p = 0.004), and overall, the guided group had a 53% greater improvement in depressive symptoms (p = 0.0002), a 1.7-fold relative improvement in response (p = 0.01), and a number needed to treat for one clinical response above that seen in the TAU group of 6.07.

Keywords: Allele; Anxiety; Combinatorial pharmacogenomics; Depression; Genomics; Polymorphism; Psychiatry; Translational medicine.

Figures

Fig. 1

a The proportion of the 99 subjects in the GeneSight-guided group exceeded that of the 117 subjects in the TAU group who experienced an addition, removal, or change in dose of any panel medication during the clinical trial (p = 0.002, d.f. = 1, χ2 = 9.32). b No difference in antidepressant efficacy, as measured by change in HAM-D17 score, was found between the 122 subjects with and the 94 subjects without a change in a panel drug or dose during each study.

Fig. 2

Proportion of all subjects in the TAU and GeneSight-guided groups (numbers of subjects at the bottom of each bar) who experienced an addition, removal, or change in dose of any panel medication during the clinical trial, as a function of the most severe category (green, yellow, or red) of the medications they were prescribed at baseline. The proportion of subjects on 1 or more red-category medications who experienced a change was higher for the guided subjects than the TAU subjects (p = 0.003, d.f. = 1, χ2 = 8.66).

Fig. 3

GeneSight guidance amplifies the tendency of clinicians of unguided patients to shift patients to genetically appropriate medications. From baseline to the end of the 8- or 10-week studies, 36.4% of the 99 GeneSight-guided patients switched to medications whose most severe category status was green, while 39.1% were switched off of medications whose most severe category status was red. Far smaller proportions (6.7 and 7.1%, respectively) of the 117 TAU subjects were switched in the same directions.

Fig. 4

a The percent decrease in HAM-D17 depression scores (positive y-axis values) from baseline to the study end of GeneSight-guided subjects (green bar, n = 119) exceeded that of TAU subjects (gray bar, n = 139; p = 0.0002). b The greater decreases over 8 weeks in HAM-D17 depression score for the GeneSight as compared to the TAU group are a function of medication category status. The y-axis shows the greater improvement for the GeneSight-guided subjects by subtracting the mean value for that group from the value for the TAU subjects. Results are plotted for groups whose subjects' most cautionary drug status at baseline was in the green (n = 31, TAU; n = 36, GeneSight), yellow (n = 59; n = 47), and red (n = 29; n = 25) category. c Clinical improvement as a function of the most severely categorized baseline medication for each subject in the TAU and GeneSight-guided groups. p values are derived via independent t tests for all subgroup comparisons within the TAU group.