Efficacy of prospective pharmacogenetic testing in the treatment of major depressive disorder: results of a randomized, double-blind clinical trial

Abstract

Background: A 12-week, double-blind, parallel, multi-center randomized controlled trial in 316 adult patients with major depressive disorder (MDD) was conducted to evaluate the effectiveness of pharmacogenetic (PGx) testing for drug therapy guidance.

Methods: Patients with a CGI-S ≥ 4 and requiring antidepressant medication de novo or changes in their medication regime were recruited at 18 Spanish public hospitals, genotyped with a commercial PGx panel (Neuropharmagen®), and randomized to PGx-guided treatment (n = 155) or treatment as usual (TAU, control group, n = 161), using a computer-generated random list that locked or unlocked psychiatrist access to the results of the PGx panel depending on group allocation. The primary endpoint was the proportion of patients achieving a sustained response (Patient Global Impression of Improvement, PGI-I ≤ 2) within the 12-week follow-up. Patients and interviewers collecting the PGI-I ratings were blinded to group allocation. Between-group differences were evaluated using χ2-test or t-test, as per data type.

Results: Two hundred eighty patients were available for analysis at the end of the 12-week follow-up (PGx n = 136, TAU n = 144). A difference in sustained response within the study period (primary outcome) was not observed (38.5% vs 34.4%, p = 0.4735; OR = 1.19 [95%CI 0.74-1.92]), but the PGx-guided treatment group had a higher responder rate compared to TAU at 12 weeks (47.8% vs 36.1%, p = 0.0476; OR = 1.62 [95%CI 1.00-2.61]), and this difference increased after removing subjects in the PGx-guided group when clinicians explicitly reported not to follow the test recommendations (51.3% vs 36.1%, p = 0.0135; OR = 1.86 [95%CI 1.13-3.05]). Effects were more consistent in patients with 1-3 failed drug trials. In subjects reporting side effects burden at baseline, odds of achieving a better tolerability (Frequency, Intensity and Burden of Side Effects Rating Burden subscore ≤2) were higher in the PGx-guided group than in controls at 6 weeks and maintained at 12 weeks (68.5% vs 51.4%, p = 0.0260; OR = 2.06 [95%CI 1.09-3.89]).

Conclusions: PGx-guided treatment resulted in significant improvement of MDD patient's response at 12 weeks, dependent on the number of previously failed medication trials, but not on sustained response during the study period. Burden of side effects was also significantly reduced.

Trial registration: European Clinical Trials Database 2013-002228-18 , registration date September 16, 2013; ClinicalTrials.gov NCT02529462 , retrospectively registered: August 19, 2015.

Keywords: Antidepressant response; Depression; Pharmacogenetics; Precision medicine; Randomized clinical trial.

Fig. 1

Schematic of the AB-GEN study procedures. TC: telephone controls; V: follow-up visits; DB: double-blind evaluation; SB: single-blind evaluation

Fig. 2

a Sustained response rate (PGI-I score ≤ 2 on two consecutive evaluations by phone interview). b Response rate based on subjects reporting a PGI-I score ≤ 2 and c change in HDRS-17 score in the total ITT population. TC: telephone controls; ^# p < 0.1; *p < 0.05

Fig. 3

a Response rate based on subjects reporting a PGI-I score ≤ 2 and b change in HDRS-17 score in patients having received 1 to 3 previous treatments for the current depressive episode. *p < 0.05; **p < 0.01

Fig. 4

Differences in medication tolerability according to the FIBSER Burden of side effects subscore. The percentage of patients with scores ≤2 in the tolerability subpopulation are shown at 6 weeks (visit 2) and 12 weeks (visit 3) for the study and control groups. *p < 0.05