A Depression and Opioid Pragmatic Trial in Pharmacogenetics (Depression Trial)

Study Overview
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Brief Summary
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This study is comprised of three separate pharmacogenetic trials grouped into a single protocol due to similarities in the intervention, the hypotheses, and the trial design. The three trials are the Acute Pain Trial, the Chronic Pain Trial, and the Depression Trial. Participants can enroll in only one of the three trials. All three trials were registered on ClinicalTrials.gov under NCT04445792. In July 2023 each of the three treatment trials was registered under a separate NCT# and NCT04445792 was converted to a screening record per recent guidance on master protocol research programs (MPRPs). This record is specific to the Depression Trial within the ADOPT-PGx protocol. The Depression Trial is a prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria will be randomly assigned to either immediate pharmacogenetic testing and genotype-guided anti-depressant therapy (Intervention arm) or standard care with 6-month delayed pharmacogenetic testing (Control arm). The investigators will test the hypothesis that pharmacogenetic testing and genotype-guided anti-depressant therapy will reduce depression symptoms in participants who's body processes some anti-depressants faster or slower than normal.

Detailed Description
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Pain and depression are conditions that impact substantial proportions of the US population. Finding safe and effective drug therapies for both conditions is challenging. In the case of treatment for acute and chronic pain, the challenge is finding effective therapy while minimizing adverse effects or opioid addiction (and the ensuing consequences). For depression, there are few clinically relevant predictors of successful treatment leading to multiple trials of inadequate therapy for some patients. Both opioid and antidepressant prescriptions can be guided by pharmacogenetics (PGx) data based on existing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC). This study is designed to evaluate the impact of pharmacogenetic testing and genotype-guided pain or anti-depressant therapy on pain control or depression symptoms in a pragmatic setting. The rationale for examining a genotype-guided approach to acute and chronic pain management is based on the importance of CYP2D6 for the bioactivation of tramadol, codeine, and hydrocodone and data from a pilot study supporting improved pain control in intermediate and poor CYP2D6 metabolizers in the genotype-guided arm who are taking these drugs at baseline. Similarly, the rationale for examining a genotype-guided approach to depression medication therapy is based on the demonstrated role of CYP2D6 in the bio inactivation and CYP2C19 oxidation of select, commonly used SSRIs. Secondly, data from industry sponsored trials support the hypothesis of improved depression symptom control in a genotype-guided arm. Study objectives: Determine if genotype-guided dosing or selection of antidepressants among participants with at least 3 months of depressive symptoms who require new or revised antidepressant therapy leads to improved control of depression, compared to usual care.

Official Title
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A Depression and Opioid Pragmatic Trial in Pharmacogenetics

Conditions
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Depression

Intervention / Treatment
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* Other: Pharmacogenetic testing
* Other: Clinical decisions support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Depression Trial Age ≥ 8 years English speaking or Spanish speaking Patients followed at psychiatry clinics or primary care clinics at an enrolling site (such as, but not limited to, Internal Medicine, Family Medicine, or Pediatrics) Documentation of depression and/or provider report of depression Evidence of depressive symptoms for at least 3 months based on patient interview or documentation in electronic health records Recent initiation of SSRI therapy, recent revised SSRI therapy, or anticipated need for revised or new SSRI therapy per health care provider Exclusion Criteria Trial-wide: Life expectancy less than 12 months Are too cognitively impaired to provide informed consent and/or complete study protocol Are institutionalized or too ill to participate (i.e. mental or nursing home facility or incarcerated) Have a history of allogeneic stem cell transplant or liver transplant People with prior clinical pharmacogenetic test results for genes relevant for the study in which they will enroll (CYP2D6 for the pain studies and CYP2D6 or CYP2C19 for depression) or already enrolled in an ADOPT PGx trial Depression Trial Plan to move out of the area within 6 months of enrollment Have active psychosis or diagnosed psychotic disorders (schizophrenia, schizoaffective disorder, delusional disorder, psychotic depression, substance induced psychosis, schizophreniform disorder) Have dementia or other neurocognitive disorders due to any cause, such as Alzheimer's disease, vascular/subcortical, lewy body disease, frontotemporal lobar degeneration Have cognitive developmental delay and/or cognitive disability, including autism spectrum disorders (Note: ADHD is not an exclusion criteria) Has a seizure disorder Have bipolar disorder

Ages Eligible for Study
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Minimum Age: 8 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Immediate vs. delayed pharmacogenetic testing and genotype-guided pain or depression therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Depression - Immediate PGx Testing<br>Immediate genetic testing of CYP2D6 and CYP2C19 and clinical decisions support for antidepressant prescribing to the healthcare provider | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>Other: Clinical decisions support<br>* Prescribing recommendations to the provider based on the pharmacogenetic testing results<br>|
| Other: Depression - Delayed PGx Testing<br>Delayed genetic testing of CYP2D6 and CYP2C19 and return of results after the conclusion of the 6-month follow-up period | Other: Pharmacogenetic testing<br>* Genetic testing of CYP2D6 and CYP2C19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3 Month Depression Symptom Control Change from Baseline | Depression symptom control, defined as change in PROMIS depression T-scores from baseline to 3-months in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers | Baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3 Month Change in PHQ of Depression Symptomatology Change from Baseline Scores | Change in PHQ-8 scores between baseline and 3 months in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers. Achieve 50% reduction in scores. | baseline and 3 months | 
| 3 Month Medication Side Effect Burden Change from Baseline | Side effect burden is defined as the number of side effects experienced from a specified list of possible side effects, weighted by the severity of each side effect in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers | 3 months | 
| 3 Month Medication Adherence Change from Baseline | Medication adherence score derived from the Voils Medication Adherence survey in genotypic or pheno-converted CYP2D6 ultra-rapid or poor metabolizers or CYP2C19 ultra-rapid, rapid, or poor metabolizers | 3 months | 
| 6 Month Depression Remission Change from Baseline | Remission is defined as whether or not the summed raw responses to the PROMIS emotional distress depression survey is ≤ 16, corresponding to a participant respond rarely or never to most or all questions. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacogenetic, CYP2D6, CYP2C19