Clinical Validation of a Combinatorial Pharmacogenomic Approach in Major Depressive Disorder

Study Overview
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Brief Summary
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Major depressive disorder (MDD) is a common, chronic, debilitating mood disorder causing serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment choice; however, only about one third of patients respond to the first trial because of antidepressants ineffectiveness or side-effects. This causes suffering for patients and their families and significantly contributes to pushing up costs for healthcare services. Precision medicine in psychiatry might offer to clinicians the possibility to tailor the treatment according to the best possible evidence of effectiveness 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 an advocacy license independence. Our study is a prospective single-blind randomized controlled clinical observational trial enrolling 300 MDD patients. Patients referred to psychiatric services due to the failure and/or the onset of adverse effects of their current treatment for receiving a new antidepressant. Eligible participants with a primary diagnosis of MDD according to DSM-5 criteria and a Hamilton Depression Rating Scale (HAM-D17) with a score > 14 are randomized to TGTG group (Treated with Genetic Test Guide) or TAU group (Treated as Usual). For all subjects, buccal brush for DNA is collected. The primary outcome is the reduction in depressive symptomatology as measured by HAM-D17. 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. This project represents the first randomized controlled clinical trial in which is tested whether a non-commercial PGx test improves outcomes in a 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 a further cost-saving.

Official Title
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Towards Precision Medicine in Psychiatry: Clinical Validation of a Combinatorial Pharmacogenomic Approach.

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: Pharmacogenomics test (PGx)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A current diagnosis of unipolar depression according to Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) An Hamilton Depression Rating Scale (HAMD-17) score >=14 Caucasian ethnicity. Exclusion Criteria: Cognitive impairment (Mini Mental State Examination MMSE <24) Neurological disorders Diagnosis of MDD with psychotic features, bipolar I and II disorders, schizophrenia spectrum and other psychotic disorders, obsessive-compulsive disorder, post-traumatic stress disorder Substance abuse in the last 3 months Comorbidity with personality disorders (cluster A and/or B); pregnancy Comorbidity with other severe medical illness.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treated with Genetic Test Guide (TGTG)<br>Antidepressant monotherapy treatments according to good clinical practice for major depressive disorder guided with the pharmacogenomic test (PGs) | Device: Pharmacogenomics test (PGx)<br>* The clinicians of the TGTG group patients receive the PGx test report within 48 hours and all the participants start the new treatment within 72 hours. According with both Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) guidelines, the PGx report places the most ADs widespread in Italy, into three recommended categories: 1) use as directed (labelled as Green), 2) use with caution (labelled as Yellow), 3) use with extreme caution (labelled as Red)<br>|
| Control: Treated as Usual (TAU)<br>Antidepressant monotherapy treatments according to good clinical practice for major depressive disorder. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | Symptoms improvement as measured by the percent change in Hamilton Depression Rating Scale (HAMD-17). The higher the total score the more severe the depression | Baseline to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response and remission | Response and remission rate at 4-, 8- and 12-weeks according to Hamilton Depression Rating Scale (HAMD-17). 0-7 not depressed; 8-13 mild; 14-18 moderate; 19-22 severe; >23 very severe | Baseline to 4 weeks, to 8 weeks and 12 weeks |