Pharmacogenetic-Guided Antidepressant Prescribing in Adolescents

Study Overview
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Brief Summary
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This is a parallel arm randomized (1:1) controlled trial. Adolescents aged 12-17 years (n=452) that did not respond or tolerate first-line fluoxetine therapy will be randomly allocated to receive 12-weeks of pharmacogenetic-guided antidepressant therapy (experimental intervention) or GLAD-PC guided prescribing (control intervention).

Detailed Description
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Goal: To test the efficacy of pharmacogenetic-guided antidepressant prescribing for adolescents with depression. Background: For an adolescent with moderate to severe depression, antidepressant medication is prescribed, often in combination with psychotherapy. The class of antidepressants recommended for use is selective serotonin reuptake inhibitors (SSRIs) with fluoxetine recommended as the first-line medication, and four other SSRIs recommended for consideration (sertraline, citalopram, escitalopram, fluvoxamine) if the adolescent does not respond or tolerate fluoxetine. For most adolescents, medication prescribing, and monitoring will be managed by a primary care physician or community pediatrician rather than by a mental health care provider, and guidelines exist to support this management (Guidelines for Adolescent Depression in Primary Care, GLAD-PC). However, GLAD-PC does not account for SSRI metabolism phenotypes that could change whether the SSRI selected is efficacious or tolerated. Our team of researchers, clinician scientists, patient partners, and primary care providers has designed a trial to test the impact of accounting for metabolism phenotypes, through pharmacogenetic-guided antidepressant prescribing, on adolescent outcomes, experiences, and health care utilization. Principal Question: Compared to GLAD-PC informed prescribing, does pharmacogenetic-guided prescribing for depressed adolescents who have not responded or tolerated first-line fluoxetine therapy, have superior efficacy following 12-weeks of therapy with an alternative SSRI? The Trial: This is a parallel arm randomized controlled trial. Adolescents aged 12-17 years (n=452) that did not respond or tolerate first-line fluoxetine therapy will be randomly allocated to receive pharmacogenetic-guided antidepressant therapy (experimental intervention) or GLAD-PC guided prescribing (control intervention). Participants and prescribing physicians will be blinded to which intervention was received. The primary outcome is depressive symptom remission at 12 weeks measured using the Quick Inventory of Depressive Symptomatology - Adolescent (17-item) (QIDS-A17). Secondary outcomes include side effects, role functioning, medication adherence, and health-related quality of life measured 4-, 8-, and 12-weeks after intervention initiation as well as cost-effectiveness.

Official Title
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Pharmacogenetic-Guided Antidepressant Prescribing (PGx-GAP) in Adolescents

Conditions
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Depression in Adolescence

Intervention / Treatment
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* Other: Pharmacogenetic-guided dosing
* Other: GLAD-PC guided dosing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 12-17 Depression as the primary concern, confirmed by the treating physician QIDS-A17 score greater than or equal to 11 indicating moderate-to-severe symptoms Prior failure of fluoxetine therapy due to inefficacy or intolerance Intention to start a new SSRI English fluency Exclusion Criteria: Co-occurring psychosis, bipolar disorder, eating disorder, autism spectrum disorder, fetal alcohol spectrum disorder, or intellectual disability A score of 2 or 3 on suicide item 13 of the QIDS-A17 High-risk alcohol or substance use (excluding cannabis and tobacco) as indicated by a score of monthly or more on the S2BI History of non-response to 3 or more antidepressants (including fluoxetine, i.e. failure of fluoxetine and two other agents) as confirmed by the treating physician Psychotherapy or brain stimulation-based therapy initiated within 8 weeks of referral, or plans to initiate/change these therapies during study participation History of liver or hematopoietic cell transplant History of CYP2B6, CYP2C19, or CYP2D6 testing

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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: This is a parallel arm randomized controlled trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pharmacogenetic (PGx)-Guided<br>Participants and their physician will receive a one-time prescribing report after completing baseline for second-line selective serotonin reuptake inhibitors with dosing information based on CYP2B6, CYP2C19, and CYP2D6 genotype data. | Other: Pharmacogenetic-guided dosing<br>* SSRI dosing based on Clinical Pharmacogenetics Implementation Consortium's SSRI dosing guidelines.<br>|
| Active Comparator: Guidelines for Adolescent Depression in Primary Care (GLAD-PC)-Guided<br>Participants and their physician will receive a one-time prescribing report after completing baseline for second-line selective serotonin reuptake inhibitors based on GLAD-PC dosing guidelines. | Other: GLAD-PC guided dosing<br>* SSRI dosing based on GLAD-PC clinical practice guidelines<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with depression remission | Quick Inventory of Depressive Symptomatology - Adolescent - 17-item (QIDS-A17) total score < 6. Scores range from 0-27, with higher scores indicative of more severe depression. | Baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with side effects and adverse drug reactions | Frequency, Intensity, Burden of Side Effects Rating (FIBSER) scale. Total scores range from 0-6 (3 items); cut-points are used to indicate moderate (score of 3) or severe (score of 5) adverse drug reaction/side effect interference with activities. | Baseline to 12 weeks | 
| Percent Change in Role functioning | WHO Disability Assessment Schedule. Scores range from 0 to 48, with higher scores indicative of worse role functioning. | Baseline to 12 weeks | 
| Percent Change in Depressive Symptom Severity | Quick Inventory of Depressive Symptomatology - Adolescent - 17-item (QIDS-A17). Scores range from 0-27, with higher scores indicative of more severe depression. | Baseline to 12 weeks | 
| Percent Change in clinician assessment of depressive symptom severity | Change in Clinical Global Impression Severity (CGI-S) scale. Scores range from 0-7, with higher scores indicative of more severe illness. | Baseline to 12 weeks | 
| Change in self-report health care resource use | Resource use questionnaire that captures number of visits and out-of-pocket costs for various mental health services. | Baseline to 12 weeks | 
| Change in health care utilization | Administrative data will be obtained on medication information (agent, dose, duration) and health care utilization (doctor visits, hospitalizations, emergency room visits). | Baseline to 12 weeks | 
| Change in health-related quality of life | EuroQoL 5 Dimension - Youth (EQ-5D-Y). Five descriptive items code level of perceived problems in health states and a visual analog scale has a score from 0-100, with higher scores indicative of better health. | Baseline to 12 weeks | 
| Change in medication adherence | Medication Adherence Report Scale (MARS-5) scores. Scores range from 5-25 with higher scores indicative of better medication adherence. | 4 to 12 weeks | 
| Change in behavioral activation | Emergence of activation based on Treatment-Emergent Activation and Suicidality Assessment Profile. Total scores range from 0-114 (38 items) with higher scores indicating greater behavioral activation. | Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, Adolescence, SSRI, Antidepressant, Pharmacogenetics