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

Abstract

BackgroundA 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.MethodsPatients 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.ResultsTwo 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]).ConclusionsPGx-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 registrationEuropean Clinical Trials Database 2013-002228-18, registration date September 16, 2013; ClinicalTrials.gov NCT02529462, retrospectively registered: August 19, 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-017-1412-1) contains supplementary material, which is available to authorized users.

Value of Supportive Care Pharmacogenomics in Oncology Practice

“…Multiple studies have recently been published illustrating the clinical value of multigene pharmacogenetic panels when treating patients with depression. At least four rigorous studies have shown significantly better treatment outcomes for major depressive disorder with pharmacogenomic guidance compared with the standard clinical approach .…”

Pharmacogenetic testing for the guidance of psychiatric treatment of a schizoaffective patient with haltlose personality disorder

“…1 It was the second article 2 on this topic within a month, coming from the same country, confirming for us how useful pharmacogenetic testing can be in our daily practice. Reading these articles reminded us of a third, where we had the pleasure to revisit the process of clinical equipoise, 3 something that we believe should be an essential part of the modern model of psychiatric practice for treatment resistance.…”

Development of the PGx‐Passport: A Panel of Actionable Germline Genetic Variants for Pre‐Emptive Pharmacogenetic Testing

“…47 To appeal to the request for evidence demonstrating clinical utility, the collective clinical utility for a subset of genes in the PGx-Passport (Table S1) is being assessed in a cluster randomized controlled trial including 8,100 patients across healthcare institutions in 7 European countries. 21 Several promising studies indicate the (cost-)effectiveness of PGx panel-based testing on healthcare utilization in psychiatry and polypharmacy, [22][23][24]26 where observed cost savings ranged from $218 23 to $2,778 48 per patient. Others have modeled the cost-effectiveness of one-time genetic testing to minimize a lifetime of adverse drug reactions, and concluded an incremental cost-effectiveness ratio of $43,165 per additional life year and $53,680 per additional quality-adjusted life year, and, therefore, cost-effective.…”

“…Logistics and cost‐effectiveness are, therefore, optimized when delivered in a pre‐emptive panel‐based approach; pharmacotherapy does not have to be delayed, awaiting single‐gene testing results and costs for genotyping are minimized, as marginal acquisition costs of testing and interpreting additional pharmacogenes is near‐zero . Although a sufficiently powered and well‐designed study assessing the (cost‐)effectiveness of pre‐emptive PGx testing is yet to be concluded, a number of small randomized observational studies indicate promising clinical utility of PGx panel testing . Another important challenge hampering adoption of pre‐emptive panel testing is the lack of standardization regarding variants included in such panels.…”

“…20 Although a sufficiently powered and well-designed study assessing the (cost-)effectiveness of pre-emptive PGx testing is yet to be concluded, 21 a number of small randomized observational studies indicate promising clinical utility of PGx panel testing. [22][23][24][25][26] Another important challenge hampering adoption of pre-emptive panel testing is the lack of standardization regarding variants included in such panels. Additionally, recommendations on which variants to test differ strikingly across the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labels and also CPIC and DPWG recommendations.…”