Depression
Conditions
Keywords
Pharmacogenetic, CYP2D6, CYP2C19
Brief summary
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
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.
Interventions
Genetic testing of CYP2D6 and CYP2C19
Prescribing recommendations to the provider based on the pharmacogenetic testing results
Sponsors
National Human Genome Research Institute (NHGRI)
University of Florida
Vanderbilt University Medical Center
Indiana University School of Medicine
Icahn School of Medicine at Mount Sinai
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Immediate vs. delayed pharmacogenetic testing and genotype-guided pain or depression therapy
Eligibility
Sex/Gender
ALL
Age
8 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depression Symptom Control as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | Baseline to 3 months | The 8-item PROMIS Emotional Distress Depression 8b and PROMIS Pediatric Depression Symptoms 8a questionnaire assess the extent to which participants experience depression symptoms over the past 7 days using a 5-point Likert scale. The responses to the 8 questions are converted to T-scores using the health measures assessment center scoring service. Pediatric T-scores are cross walked to adult T-scores using the cross walk published in Reeve et al 2016. Cross walked T-scores range from 37.1 to 80.9, higher scores correspond with higher levels of depression symptoms. Changes in T-scores from baseline to 3-months range from -43.8 to 43.8. Negative values of change in T-score correspond to symptom improvement, 0 corresponds to no change in depression T-scores, and positive change in depression T-scores correspond to symptom worsening at 3 months compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Side Effect Burden | 3 months | An 8-item survey was developed to assess the severity of 8 depression medication side effects, using a 4-point scale for rating severity of the side effect: none, mild, moderate, severe. The 8 questions are converted to a side effect burden score ranging from 0 (none for all 8 side effects) to 24 (severe for all 8 side effects). Higher values correspond with more side effects and with higher severity. |
| Medication Non-Adherence as Measured by the Voils Medication Adherence Survey | 3 months | Medication adherence level, non-adherent / adherent, derived from the Voils Medication Adherence survey. Reported as the number of participants who were non-adherent. |
| Number of Participants With Depression Remission as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | 6 months | 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. |
| Change in Depression Symptomatology as Measured by Patient Health Questionnaire (PHQ-8) | Baseline to 3 months | The 8-item PHQ-8 Questionnaire assesses severity of depression over the past 2 weeks using a 4-point scale indicating frequency of depression symptoms: not at all, several days, more than half the days, or nearly every day. The 8 questions are converted to a score ranging from 0 (not at all for all 8 symptoms) to 24 (nearly every day for all 8 symptoms). Changes in PHQ-8 scores from baseline to 3-months range from -24 to 24 and negative values of change in PHQ-8 correspond to improvement in depression at 3 months compared to baseline. |
| Number of Participants With 50% Reduction in Patient Health Questionnaire (PHQ-8) Score | 3 months | — |
| Number of Participants With Drug-gene Concordance | 3 months | Concordance defined as agreement between the PGx phenotype and SSRI medications reported. |
| Number of Participants With Depression Remission as Measured by the Patient Health Questionnaire (PHQ-8) | 6 months | The PHQ-8 scores range from 0 to 24 and remission is defined as having a PHQ-8 score of ≤ 4. |
Countries
United States
Participant flow
Recruitment details
This record is specific to the Depression Trial within the ADOPT PGx protocol. It only contains the participants consented to the Depression Trial.
Pre-assignment details
There were 1572 participants consented into the Depression trial. 112 consented participants were not randomized into the trial and were not assigned to a treatment arm. The 1460 randomized participants will be described moving forward.
Participants by arm
| Arm | Count |
|---|---|
| Depression - Immediate PGx Testing Immediate genetic testing of CYP2D6 and CYP2C19 and clinical decisions support for antidepressant prescribing to the healthcare provider | 727 |
| Depression - Delayed PGx Testing Delayed genetic testing of CYP2D6 and CYP2C19 and return of results after the conclusion of the 6-month follow-up period | 733 |
| Total | 1,460 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
| Overall Study | Enrolled Erroneously | 0 | 1 |
| Overall Study | Follow-up Incorrectly Scheduled | 0 | 1 |
| Overall Study | Lost to Follow-up | 63 | 67 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 9 |
Baseline characteristics
| Characteristic | Depression - Immediate PGx Testing | Depression - Delayed PGx Testing | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 49 Participants | 48 Participants | 97 Participants |
| Age, Categorical >=65 years | 29 Participants | 38 Participants | 67 Participants |
| Age, Categorical Between 18 and 65 years | 550 Participants | 539 Participants | 1089 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 95 Participants | 54 Participants | 191 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 311 Participants | 629 Participants | 1250 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 23 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 121 Participants | 110 Participants | 231 Participants |
| Race (NIH/OMB) More than one race | 16 Participants | 30 Participants | 31 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 32 Participants | 34 Participants | 66 Participants |
| Race (NIH/OMB) White | 235 Participants | 228 Participants | 463 Participants |
| Region of Enrollment United States | 727 Participants | 733 Participants | 1460 Participants |
| Sex: Female, Male Female | 552 Participants | 248 Participants | 1096 Participants |
| Sex: Female, Male Male | 175 Participants | 189 Participants | 364 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 727 | 2 / 733 |
| other Total, other adverse events | 0 / 727 | 0 / 733 |
| serious Total, serious adverse events | 0 / 727 | 0 / 733 |
Outcome results
Primary
Change in Depression Symptom Control as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System)
The 8-item PROMIS Emotional Distress Depression 8b and PROMIS Pediatric Depression Symptoms 8a questionnaire assess the extent to which participants experience depression symptoms over the past 7 days using a 5-point Likert scale. The responses to the 8 questions are converted to T-scores using the health measures assessment center scoring service. Pediatric T-scores are cross walked to adult T-scores using the cross walk published in Reeve et al 2016. Cross walked T-scores range from 37.1 to 80.9, higher scores correspond with higher levels of depression symptoms. Changes in T-scores from baseline to 3-months range from -43.8 to 43.8. Negative values of change in T-score correspond to symptom improvement, 0 corresponds to no change in depression T-scores, and positive change in depression T-scores correspond to symptom worsening at 3 months compared to baseline.
Time frame: Baseline to 3 months
Population: Modified intent to treat (mITT) population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with completed PROMIS Depression surveys at both baseline and 3 months are included. Participants with missing PROMIS depression surveys at either baseline or 3-months are excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Change in Depression Symptom Control as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | -4.3 T-score | Standard Deviation 8.4 |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Change in Depression Symptom Control as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | -4.0 T-score | Standard Deviation 8.1 |
p-value: 0.67795% CI: [-1.54, 1]t-test, 2 sided
Secondary
Change in Depression Symptomatology as Measured by Patient Health Questionnaire (PHQ-8)
The 8-item PHQ-8 Questionnaire assesses severity of depression over the past 2 weeks using a 4-point scale indicating frequency of depression symptoms: not at all, several days, more than half the days, or nearly every day. The 8 questions are converted to a score ranging from 0 (not at all for all 8 symptoms) to 24 (nearly every day for all 8 symptoms). Changes in PHQ-8 scores from baseline to 3-months range from -24 to 24 and negative values of change in PHQ-8 correspond to improvement in depression at 3 months compared to baseline.
Time frame: Baseline to 3 months
Population: Modified ITT population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with completed PHQ-8 surveys at both baseline and 3 months are included. Participants with missing PHQ-8 surveys at either baseline or 3-months are excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Change in Depression Symptomatology as Measured by Patient Health Questionnaire (PHQ-8) | -3.3 score on a scale | Standard Deviation 5.2 |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Change in Depression Symptomatology as Measured by Patient Health Questionnaire (PHQ-8) | -2.7 score on a scale | Standard Deviation 4.8 |
p-value: 0.126495% CI: [-1.4, 0.2]t-test, 2 sided
Secondary
Medication Non-Adherence as Measured by the Voils Medication Adherence Survey
Medication adherence level, non-adherent / adherent, derived from the Voils Medication Adherence survey. Reported as the number of participants who were non-adherent.
Time frame: 3 months
Population: Modified intent to treat (mITT) population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with 2 or more Voils survey questions completed at 3 months are included. Participants with fewer than 2 completed Voils survey questions are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Medication Non-Adherence as Measured by the Voils Medication Adherence Survey | 142 Participants |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Medication Non-Adherence as Measured by the Voils Medication Adherence Survey | 137 Participants |
p-value: 0.8492Chi-squared
Secondary
Number of Participants With 50% Reduction in Patient Health Questionnaire (PHQ-8) Score
Time frame: 3 months
Population: Modified intent to treat (mITT) population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with a completed PHQ-8 survey at baseline and 3 months are included. Participants with an incomplete PHQ-8 survey at either baseline or 3 months are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With 50% Reduction in Patient Health Questionnaire (PHQ-8) Score | 92 Participants |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With 50% Reduction in Patient Health Questionnaire (PHQ-8) Score | 71 Participants |
p-value: 0.0776Chi-squared
Secondary
Number of Participants With Depression Remission as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System)
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.
Time frame: 6 months
Population: Modified intent to treat (mITT) population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with a completed PROMIS depression survey at 6 months are include. Participants with an incomplete PROMIS depression survey are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With Depression Remission as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | 153 Participants |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With Depression Remission as Measured by PROMIS (Patient-Reported Outcomes Measurement Information System) | 122 Participants |
p-value: 0.0246Chi-squared
Secondary
Number of Participants With Depression Remission as Measured by the Patient Health Questionnaire (PHQ-8)
The PHQ-8 scores range from 0 to 24 and remission is defined as having a PHQ-8 score of ≤ 4.
Time frame: 6 months
Population: Modified intent to treat (mITT) population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with a completed PHQ-8 survey at 6 months are include. Participants with an incomplete PHQ-8 survey are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With Depression Remission as Measured by the Patient Health Questionnaire (PHQ-8) | 95 Participants |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With Depression Remission as Measured by the Patient Health Questionnaire (PHQ-8) | 65 Participants |
p-value: 0.0111Chi-squared
Secondary
Number of Participants With Drug-gene Concordance
Concordance defined as agreement between the PGx phenotype and SSRI medications reported.
Time frame: 3 months
Population: Modified intent to treat (mITT) population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with a completed medication review at 3 months are included. Participants without a medication review at 3 months are excluded.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With Drug-gene Concordance | 273 Participants |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Number of Participants With Drug-gene Concordance | 234 Participants |
p-value: 0.0014Chi-squared
Secondary
Side Effect Burden
An 8-item survey was developed to assess the severity of 8 depression medication side effects, using a 4-point scale for rating severity of the side effect: none, mild, moderate, severe. The 8 questions are converted to a side effect burden score ranging from 0 (none for all 8 side effects) to 24 (severe for all 8 side effects). Higher values correspond with more side effects and with higher severity.
Time frame: 3 months
Population: Modified intent to treat (mITT) population consisting of participants with a CYP2C19 poor, rapid, or ultra-rapid metabolizer phenotype or a CYP2D6 poor or ultra-rapid metabolizer phenotype. All mITT participants with completed medication side effect surveys at 3 months are included. Participants with missing side effect surveys at 3-months are excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Depression - Immediate PGx Testing (Modified Intent to Treat, mITT) | Side Effect Burden | 8.2 score on a scale | Standard Deviation 4.3 |
| Depression - Delayed PGx Testing (Modified Intent to Treat, mITT) | Side Effect Burden | 7.8 score on a scale | Standard Deviation 4.5 |
p-value: 0.369295% CI: [-0.4, 1.1]t-test, 2 sided