Treatment Resistant Depression
Conditions
Brief summary
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
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.
Interventions
GENETICGenotyping assays
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.
Sponsors
Massachusetts General Hospital
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinician's Report That AGT Modified His/Her Decision Regarding Which Antidepressant to Prescribe. | Measured: +/- 24 hours of baseline assessments and +/- 24 hours of receiving assay results | 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. |
| 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) | Measures at discharge, 1 month, 3 months, and 6 months | To determine the impact of AGT versus TAU on total number of side effects determined by using the Udvalg for Kliniske Undersogelser (UKU). 1. 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) 2. 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) |
Countries
United States
Participant flow
Pre-assignment details
Although clinicians were randomized to either receive or not receive the AGT results, they were not considered enrolled. Only the patients were enrolled in the study. Also, each participating clinician covered only one subject.
Participants by arm
| Arm | Count |
|---|---|
| Treatment as Usual Subjects in the Treatment as Usual group will proceed with treatment as usual, but have their blood samples for genotyping stored for future analysis.
Patients will receive questionnaires to measure their mood, side effects, and symptoms.
Subjects will be asked to provide saliva samples for GWAS analysis at a later date (note: GWAS analysis and genotyping for the Treatment as Usual group was not performed due to early termination of the study)
Patients will be asked to participate in 3 follow-up phone calls to measure their mood. | 2 |
| Assay Guided Treatment This group will receive a genotyping test to determine the specific levels of gene activity. This test was used to guide clinicians decision making for which antidepressants to prescribe and/or at what doses.
Subjects will receive questionnaires to measure their mood, side effects, and symptoms.
Subjects will be asked to provide saliva samples for GWAS analysis at a later date (note; GWAS analysis was not performed in the AGT group due to early termination of the study.
Subjects will be asked to participate in 3 follow-up phone calls to measure their mood. | 2 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
Baseline characteristics
| Characteristic | Assay Guided Treatment | Treatment as Usual | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Continuous | 43.5 years | 59 years | 51.25 years |
| Region of Enrollment United States | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 2 / 2 | 1 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
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.
Time frame: 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)
Population: Quick Inventory of Depression symptom-16 (QIDS-SR 16) Baseline. Data was not collected for all time points for all participants.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment as Usual | Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | QIDS-SR 16 Baseline | 18 Score on QIDS-SR |
| Treatment as Usual | Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | QIDS 16 Discharge | 7.5 Score on QIDS-SR |
| Treatment as Usual | Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | QIDS 16 at 1 month | 6 Score on QIDS-SR |
| Treatment as Usual | Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | QIDS 16 at 3 months | 4 Score on QIDS-SR |
| Assay Guided Treatment | Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | QIDS-SR 16 Baseline | 22.5 Score on QIDS-SR |
Secondary
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). 1. 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) 2. 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)
Time frame: Measures at discharge, 1 month, 3 months, and 6 months
Population: Missing data on one AGT subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment as Usual | Adverse Events (Side Effects) | Number of side effects at discharge | 7 Number of side effects |
| Treatment as Usual | Adverse Events (Side Effects) | Number of side effects at 1 month | 1 Number of side effects |
| Treatment as Usual | Adverse Events (Side Effects) | Number of side effects at 3 months | 1 Number of side effects |
| Treatment as Usual | Adverse Events (Side Effects) | Number of side effects at 6 months | 2 Number of side effects |
| Assay Guided Treatment | Adverse Events (Side Effects) | Number of side effects at discharge | 4 Number of side effects |
Secondary
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.
Time frame: Measured: +/- 24 hours of baseline assessments and +/- 24 hours of receiving assay results
Population: 2 of 4 clinicians received AGT results for antidepressant decision making. One of two clinicians randomized to receive AGT results reported that his choice of antidepressant was definitely influenced by AGT results; the other clinician randomized to receive AGT results did not receive the AGT information within the defined time limit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Assay Guided Treatment | Clinician's Report That AGT Modified His/Her Decision Regarding Which Antidepressant to Prescribe. | AGT beneficial in decision making | 1 participants |
| Assay Guided Treatment | Clinician's Report That AGT Modified His/Her Decision Regarding Which Antidepressant to Prescribe. | AGT not beneficial in decision making | 0 participants |
Secondary
Treatment Adherence
To determine the impact on adherence of AGT versus TAU at 7-10 days after admission
Time frame: To determine the impact on adherence of AGT versus TAU at 7-10 days after admission
Population: Number of subjects adherent to antidepressant medications
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment as Usual | Treatment Adherence | Number adherent at discharge | 2 Participants |
| Treatment as Usual | Treatment Adherence | Number adherent at 1 month | 1 Participants |
| Treatment as Usual | Treatment Adherence | Number adherent at 3 months | 1 Participants |
| Treatment as Usual | Treatment Adherence | Number adherent at 6 months | 1 Participants |
| Assay Guided Treatment | Treatment Adherence | Number adherent at discharge | 2 Participants |