Pharmacogenomics for Antidepressant Guidance and Education

Study Overview
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Brief Summary
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More than one out of three individuals treated for major depressive disorder (MDD) do not experience a full reduction of symptoms even when treated with adequate antidepressant medication. These individuals may have treatment-resistant depression. This is a condition that contributes to the tremendous costs of MDD, in terms of health care costs, functional impairment (limitation of an individual's functional ability), and diminished quality of life. There is a clear need for personalized medicine, for people at high risk for treatment-resistant depression. If these individuals could be identified early in the course of their depression, they could be recommended for more intensive or specialized interventions. Doing so could improve their likelihood of having a full reduction in their symptoms. Today, there are many treatment options for MDD. Individuals can spend months or years in and out of treatment before receiving one that works for their treatment-resistant depression. The investigators want to study treatment resistant depression by examining specific genes (genotyping) that might influence how your body responds to certain antidepressant medications. This process of examining specific genes is not experimental. To look at your specific genes, the investigators will collect a blood sample. Genes contain the material passed from parent to child that determines the make-up of the body and mind. For example, some genes control the color of your hair or eyes. Genes are contained in your DNA (deoxyribonucleic acid). There are many differences in DNA, from one person to another. These differences may affect a person's chances of having a particular disease.

Detailed Description
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This will be a 6-month, randomized, controlled study of assay-guided treatment (AGT) versus treatment as usual (TAU) in adult inpatients with major depressive disorder. Two hundred subjects will be randomized to receive AGT or TAU. After subjects are screened, determined to be eligible, and complete baseline assessments, blood samples for genotyping will be obtained from all subjects as well as saliva samples for future GWAS analysis from all subjects. Only those subjects that are randomized to the AGT arm will have their blood samples immediately analyzed. Subjects in the TAU arm will have their blood samples stored for future analysis.. Once the blood samples are obtained, the attending psychiatrists will be asked to indicate their top three choices of antidepressants and at what doses they will initiate treatment. In order to prevent delays in providing treatments, the first choice antidepressants will be started prior to receiving assay results. Upon receiving the assay reports (AGT arm), the attending psychiatrists will be asked whether the reports influenced their choice of antidepressant treatments and doses of antidepressants, as well as their confidence in their choices. The attending psychiatrists will then document any switches in antidepressant treatments or changes in doses of current antidepressant medications on a structured form. The assay reports will be available between 3 to 5 days after the blood samples are taken. The attending psychiatrists who are randomized to be provided the results of CYP genotyping will also be provided a phone number for consultation with Genomind Labs regarding the interpretation of the results. Trough antidepressant blood samples for the AGT arm (10-12 hours after last dose) for therapeutic drug monitoring (TDM) will be obtained within 24 hours of discharge. Blood samples will also be obtained from the TAU arm, but they will be stored for future analysis of CYP genotyping and biomarker analysis of treatment resistant MDD. Clinical follow-up will proceed as felt to be clinically indicated. For subjects who have been discharged before the assay results are received, the attending psychiatrists will complete the from indicating changes in treatments as if patients were still in hospital. Results and recommendations will be forwarded to the identified outpatient psychiatrists. (note: blood levels of antidepressants were not analyzed) The AGT arm is not standard care for patients with depression. The addition of assay-results and questionnaires makes the AGT arm different than standard care. Only the questionnaires make the TAU arm different than standard care. Note: Within 24 hours after you are admitted to the Inpatient Psychiatric Unit, the baseline assessment will occur. If you stay in the Inpatient Psychiatric Unit for more than one week, the weekly assessment will occur every 7 days. Typically, patients spend an average of 8-10 days in the Inpatient Psychiatric Unit. The day before or the day of your discharge from the Inpatient Psychiatric Unit, your discharge assessment will occur. One, 3, and 6 months after you are discharged, you will be asked to complete follow-up assessments.

Official Title
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Pharmacogenomics for Antidepressant Guidance and Education

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Genetic: Genotyping assays


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 Written informed consent Meets DSM-IV criteria in the Structured Clinical Interview for DSM-IV-TR (SCID-I/P)17 and the MINI for current major depressive disorder, without psychotic features QIDS-SR score of at least 10 (i.e., moderate depression) at initial visit Failure of at least 1 prior adequate trial of a standard antidepressant (i.e., 6 weeks at adequate dose), assessed by the Antidepressant Treatment History Questionnaire (ATRQ)18 criteria Inpatient and expected to remain so for 5 or more days Hospitalized within past 72 hours Exclusion Criteria: Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (to include oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy). Immediately after the pregnancy test, women with positive pregnancy tests will be unable to enroll in the study Women who are breastfeeding Patients who have taken an investigational psychotropic drug within the last 3 months Section 12 status (involuntary admission)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Treatment as Usual (TAU)<br>This group will provide blood samples to be analyzed at a later date for genotyping to determine the activity of CYP-450 enzymes that are important in metabolizing antidepressant medications.Treatment will be initiated based on the attending clinicians decision making absent genotyping results. All subjects in the group will receive the following assessment instruments for diagnosis: SCID-I/P and the Mini International Neuropsychiatric Interview (MINI) All subjects in the group will have the severity of their depression measured by the HAM D-17 (physician rating scale), the QIDS-SR-16 (patient rating). Clinical status will be measured by the CGI-S scale (1-7 with 7 being high functioning). Side effects ratings will be measured by the UKU. ATRQ will be used to assess the degree of treatment resistance by measuring the number of prior antidepressant trials. Patients in the TAU group will provide saliva samples for future GWAS analysis. | |
| Assay Guided Treatment (AGT)<br>This group will provide blood samples for genotyping test to determine the activity of CYP-450 enzymes that are important in metabolizing antidepressant medications . This test result will be available within 3-5 days available to guide clinicians in their choice and dosing of antidepressant medications. All subjects in the group will have the severity of their depression measured by the Hamilton Depression Rating Scale-17 (physician rating scale), the QIDS-SR-16 (patient rating scale). Clinical status will be measured by the CGI-S scale (1-7 with 7 being high functioning). Side effects ratings will be measured by the Udvalg for Kliniske Undersogelser (UKU). ATRQ will be used to assess the degree of treatment resistance by measuring the number of prior antidepressant trials. Patients in the AGT group will provide saliva samples for future GWAS analysis. | Genetic: Genotyping assays<br>* Patients will provide blood samples at the beginning of the study. If the patient is in the AGT group (as opposed to the TAU group), their blood samples will be sent for genotyping immediately. AGT psychiatrists will be given the results of genotyping within 3-5 days in order to decide which antidepressants to use long-term and at what doses. Patients in the Treatment as Usual group will have their blood samples stored for future analysis. Both groups will provide saliva samples for GWAS analysis at a alter date; however, since the study was terminated early, GWAS testing for both groups and genotyping for the TAU group were not performed. Patients will receive questionnaires to measure their mood, side effects, and symptoms. Patients will be asked to participate in 3 follow-up phone calls (1 month, 3 months, and 6 months) to measure their mood.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | To determine the efficacy of assay-guided treatment (AGT) versus treatment-as-usual (TAU), in terms of depression severity as measured by change in the Quick Inventory of Depressive Symptoms (QIDS-SR 16), adjusted for baseline severity, upon discharge, and at 1, 3, and 6 months post discharge from inpatient treatment. The QUIDS-SR 16 is a self rating 16 item multiple-choice questionnaire that measure severity of depression over the past week. The range on the QIDS-SR IS 0-27, with 0-5 indicating no depression; 6-10, mild depression; 11-15; moderate depression; 16-20 severe depression; and greater than or equal to 21, very severe depression. | Measured: Baseline (within 72 hours of admission), once weekly (+/- 24 hours), discharge (7-10 days after admission +/- 24 hours), and 1, 3, 6 months after discharge (+/- 4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinician's Report That AGT Modified His/Her Decision Regarding Which Antidepressant to Prescribe. | Clinicians randomized to receive AGT results were asked to report whether the AGT results impacted their decision making with regards to their choice of antidepressant and/or dosing of the antidepressant. | Measured: +/- 24 hours of baseline assessments and +/- 24 hours of receiving assay results | 
| Treatment Adherence | To determine the impact on adherence of AGT versus TAU at 7-10 days after admission | To determine the impact on adherence of AGT versus TAU at 7-10 days after admission | 
| Adverse Events (Side Effects) | To determine the impact of AGT versus TAU on total number of side effects determined by using the Udvalg for Kliniske Undersogelser (UKU). TAU group reported a total of 8 different side effects, but 11 total events with two subjects over the time frame listed below; the events were expected. (see itemized adverse events) AGT group reported a total of four different side effects and 4 events with one subject over the time frame listed; the events were expected.(see itemized adverse events) | Measures at discharge, 1 month, 3 months, and 6 months |