Pharmacogenomic Decision Support With GeneSight Psychotropic to Guide the Treatment of Major Depressive Disorder

Evidence exists supporting the ability of genetic variations to influence patient drug response and side effects. Previous studies utilizing an open-label design have shown significant improvement in major depressive disorder (MDD) patient outcomes following use of the GeneSight Psychotropic (GEN) test. The first objective of this trial is to utilize a double-blinded, randomized clinical trial design to replicate previous findings of improvement in clinical outcomes in MDD subjects whose medication therapy was guided by GEN testing. Another objective is to determine the added benefit of Enhanced-GeneSight (E-GEN) compared to GEN for the pharmacogenomic guidance of treatment selections. Furthermore, this trial intends to develop an evidence-based case for the value of GEN and E-GEN to Canadian healthcare payers.

The primary objectives of this study are 1) to compare the efficacy of GEN to treatment as usual (TAU) in improving response to psychotropic treatment in outpatients suffering from a MDD and having had - within the current episode - an inadequate response to at least one psychotropic medication included in GEN; and 2) to validate the utility of the new CAMH markers and demonstrate the superior predictive capabilities and greater clinical utility of E-GEN as compared to GEN.

This study is designed as a three-arm multi-centre, double-blind (participants and raters), randomized controlled trial to compare the clinical and economic outcomes of GEN, E-GEN and TAU for patients suffering from a MDD and having had - within the current episode - an inadequate response to at least one psychotropic medication included in GEN. Participants will be randomized in a 1:1:1 ratio to each of the three treatment arms. Recruitment will be 24 months. Follow-up will be 12 months.

Subjects will complete short diagnostic interviews specific to their clinical diagnosis, basic metabolic measures (eg. blood pressure, weight), and provide buccal swab samples for genetic analysis (the unanalyzed buccal swabs and associated DNA will be biobanked). During the first visit, blood and urine samples will be required for laboratory panel screening and blood biobanking. Subjects will be monitored over a one year period and clinical measures and healthcare resource utilization will be obtained. Treating clinicians in the GEN and E-GEN arms will receive an easy to implement report providing pharmacogenomic guidance for prescribing psychotropic medications to their patients.

The study will recruit subjects from 10 sites, stratified into 2 clusters. Nine study sites altogether will form one of the two stratified clusters. CAMH will constitute the tenth study site and the second stratified cluster.The sample size required for this study was calculated using effect size estimates drawn from a previous study conducted by Hall-Flavin et al \[Pharmacogenetics Genomics 2013; 23(10)\]. Assuming an effect size of 0.30 in HAM-D17 score favoring the treatment group, intra class coefficient between clusters of 20%, statistical power of 90%, an alpha level of 0.05, and an expected 16.7% rate of premature discontinuation by Week 8 (primary endpoint), a total of 570 subjects (i.e., 190 per treatment arm) are required to detect the same effect in this study.

Eligibility Criteria:
Inclusion Criteria:

* 18 years of age or older;
* Suffer from a Major Depressive Episode meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria;
* Have had an inadequate response within the current episode to at least one psychotropic treatment in GEN. Inadequate response is defined as inadequate efficacy after 6 weeks of a psychotropic treatment or discontinuation of a psychotropic treatment due to adverse events (AEs) or intolerability;
* Have each a score on the 16-item Clinician Quick Inventory of Depressive Symptomatology (QIDS-C16) and 16-item Self-Report Quick Inventory of Depressive Symptomatology (QIDS-SR16) rating scales ≥ 11;
* Be able to understand the requirements of the study and provide written informed consent to participate in this study;
* Agree to abide by the study protocol and its restrictions and be able to complete all aspects of the study, including all visits and tests.

Exclusion Criteria:

* Patients posing a serious suicidal risk and/or in need of immediate hospitalization as judged by the Investigator;
* Patients with a diagnosis of Bipolar I or II disorder;
* Patients with a current Axis I diagnosis of:

  * Delirium
  * Dementia
  * Amnestic and/or other cognitive disorder
  * Schizophrenia or other psychotic disorder;
* Patients having experienced hallucinations, delusions, or any psychotic symptomatology within the current depressive episode or during prior depressive episodes;
* Patient is currently in an inpatient facility;
* Patients with a history of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic or euthyroid for at least 6 months;
* Patients who meet DSM-IV-TR criteria for any significant current substance use disorder;
* Patients with:

  * hepatic insufficiency (three times the upper limit of normal (ULN) for aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)); liver transplant recipient; cirrhosis of the liver;
  * malignancy (except basal cell carcinoma) and/or chemotherapy within 1 year prior to screening; malignancy more than 1 year prior to screening must have been local and without metastasis and/or recurrence, and if treated with chemotherapy, without nervous system complications;
  * significant unstable medical condition or life threatening disease with - need for therapies that may obscure the results of treatment and/or of the study;
* Participation in another clinical trial within 30 days of the screening visit;
* Anticipated inability to attend scheduled study visits;
* Patients who in the judgment of the Investigator may be unreliable or uncooperative with the evaluation procedure outlined in this protocol;
* Patients with a history of prior pharmacogenomic testing;
* Any change in psychotropic medication (including change in dosage) between screening and baseline;
* Patients currently receiving electroconvulsive therapy (ECT), deep brain stimulation (DBS) or transcranial magnetic stimulation (TMS) treatments, or currently scheduled to receive maintenance treatments of ECT, DBS, or TMS during the course of the study;
* Patients who self-report to be pregnant or lactating;
* Patients with a history of gastric bypass surgery.