Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

Abstract

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).

Conflict of interest statement

AKT is a co-inventor on a patent for antipsychotic-induced weight gain at the time of this study (U.S. patent no. 10,662,475). CCZ had a patent on antipsychotic-induced weight gain markers at the time of this study. CAA had ownership/partnership in Splice Therapeutics at the time of this study, and also serves on the advisory board for AxoSim Inc. and the board of directors for ASENT. JAT, PED, PT, JL, MTK, and AG were employed by Myriad Neuroscience/Assurex Health at the time of this study. MTK and ESC were employed by Myriad Genetics at the time of this study. DJM was a co-inventor on two patents assessing risk for antipsychotic-induced weight gain at the time of this study and was also a co-investigator on two pharmacogenetic studies where genetic test kits were provided as in-kind contribution by Myriad Neuroscience but did not receive any salary, equity, stocks, or options from any pharmacogenetic companies. SK received research support from the University of Toronto, Department of Psychiatry Academic Scholar Award, the Labatt Family Innovation Fund in Brain Health, and the Canadian Institutes of Health Research (CIHR) at the time of this study, and received honorarium from Empowerpharm for past consultation. JMB and JET received funding and payment from Myriad Neuroscience to conduct the GAPP-MDD trial until the contract was terminated by Myriad Neuroscience. BMD was employed by Myriad Genetics at the time of this study and received salary and stock options. JLK is an unpaid member of the Myriad Neuroscience Scientific Advisory Board. All other authors declare no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1. HAM-D17 clinical outcomes at 8 weeks by treatment arm in the GAPP-MDD clinical trial and the previous GUIDED trial [14].

A Per-protocol (PP) cohort. GAPP-MDD trial: Guided care arm N = 127, TAU arm N = 69; GUIDED trial: Guided care arm N = 560, TAU arm N = 607. B Intent-to-treat (ITT) cohort. GAPP-MDD trial: Guided care arm N = 211, TAU arm N = 97); GUIDED trial: Guided care arm N = 621, TAU arm N = 677.

Fig. 2. Medication congruency by week in the Per-Protocol cohort of the GAPP-MDD clinical trial and the previous GUIDED trial [14].

The proportion of patients taking genetically congruent medications from the GAPP-MDD and GUIDED trials are shown in blue and orange, respectively. Squares represent Guided-Care treatment arms, and circles represent TAU treatment arms.

Fig. 3. Meta-analysis of randomized-controlled trials evaluating combinatorial pharmacogenomic testing.

A Meta-analysis of symptom improvement. B Meta-analysis of response. C Meta-analysis of remission.