Clinical validation of a combinatorial PharmAcogeNomic approach in major Depressive disorder: an Observational prospective RAndomized, participant and rater-blinded, controlled trial (PANDORA trial)

Abstract

Background Major depressive disorder (MDD) is a common, chronic, debilitating mood disorder that causes serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment option; however, only approximately one third of patients respond to the first treatment because of the ineffectiveness or side effects of antidepressants. Precision medicine in psychiatry might offer clinicians the possibility to tailor treatment according to the best possible evidence of efficacy and tolerability for each subject. In this context, our study aims to carry out a clinical validation of a combinatorial pharmacogenomics (PGx) test in an Italian MDD patient cohort with advocacy license independence. Methods Our study is a prospective participant- and rater-blinded, randomized, controlled clinical observational trial enrolling 300 MDD patients who are referred to psychiatric services to receive a new antidepressant due to the failure of their current treatment and/or the onset of adverse effects. Eligible participants are randomized to the TGTG group (Treated with Genetic Test Guide) or TAU group (Treated as Usual). For all subjects, DNA is collected with a buccal brush. The primary outcome is the reduction in depressive symptomatology. The secondary outcomes involve a range of scales that assess MDD symptoms and social functioning outcomes. The assessment is performed at four timepoints: baseline and 4, 8, and 12 weeks. Discussion This project represents the first randomized controlled clinical trial to investigate whether a non-commercial PGx test improves outcomes in an MDD naturalistic cohort. Moreover, the identification of new genetic variants associated with non-response or side effects will improve the efficacy of the test, leading to further cost-saving. Trial registration number ClinicalTrials.gov NCT04615234. Registered on November 4, 2020.

The role of pharmacogenetics in the treatment of major depressive disorder: a critical review

“…Regarding demographic characteristics, most of the studies included individuals of Caucasian origin, an aspect that severely limits the generalizability of the results (2,4,39).…”

“…Major Depressive Disorder (MDD) is a common psychiatric disorder, affecting more than 300 million people globally and representing an important cause of disability worldwide (1)(2)(3).…”

“…Symptomatic remission and maintenance of therapeutic effects over time are the primary goals of MDD treatment and the most common first-line therapeutic strategy for moderate to severe MDD is pharmacological: although different classes of antidepressants are currently available, the pharmacological approach to this disorder is commonly a process of trial and error, thus, it may (and often does) take several attempts to identify the optimal treatment for an individual patient (2)(3)(4). Approximately one third of patients achieve remission after the first therapeutic trial, whereas about another third develop a treatment-resistant form of depression (2,5,6).…”

“…The inherent biological and environmental heterogeneity among patients with this disorder could be one of the causes of the high non-response and incomplete remission rates, suggesting the potential usefulness of identifying specific biomarkers able to predict the response to antidepressants and allowing to individually tailor the treatment for each subject (2,(7)(8)(9).…”

“…Although several randomized controlled trials (RCTs) have yielded interesting results regarding the impact of pharmacogenetic tests on the efficacy outcome of MDD patients' treatment, conflicting opinions remain regarding their usefulness in everyday clinical practice (2)(3)(4)(23)(24)(25).…”