Depression
Conditions
Keywords
Depression, Major Depressive Disorder, Mood Disorder
Brief summary
This study will examine multiple carefully selected clinical and biological markers, using both existing state-of-the-art technologies as well as pioneering, innovative approaches. The study is designed to identify moderators and mediators of treatment response for depression in order to specify a biosignature of treatment response for depression. Evaluation of the usefulness of these markers in a carefully conducted clinical trial comparing an antidepressant to placebo will assist in developing a Depression Treatment Response Index (DTRI) to help clinicians match treatments to patients with MDD, resulting in timely selection of treatments best suited for individual patients and thus approaching personalized treatment. The resulting index provides a truly novel means of synthesizing the contribution of key clinical and biological parameters in an easy to use tool for clinical care.
Detailed description
The current study is designed to identify biomarkers for the prediction of differential treatment outcomes between the SSRI antidepressant sertraline (SERT) and placebo (PBO) in a randomized trial for patients with MDD. In addition, a second stage will collect data to explore moderators and mediators of treatment outcomes between pharmacologically distinct active treatment arms: sertraline (SERT), a serotonergic antidepressant or bupropion (BUP), a nonserotonergic antidepressant. To reduce biologic heterogeneity, we will only enroll patients with early onset of DSM IV MDD (before age 30) because these criteria in probands have been shown to be associated with increased familial loading in families. Patients will also have recurrent MDD with 2 or more recurrences (including current episode). Additionally, patients will be required to have a current symptom severity score of 14 or more on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR), both at study screening and at the randomization (baseline) visit. In the first stage, patients will receive an 8-week course of treatment in one of the two study arms. As part of the Sequential Multiple Assignment Randomized Trial (SMART) design patients that have not achieved a response at the end of 8 weeks to their stage one treatment, defined by \< 50% improvement on the Clinical Global Improvement scale (CGI), will be switched to Stage 2 treatment (8 weeks). Patients who have achieved satisfactory response (\>= 50% improvement on the CGI) will be continued on treatment for an additional 8 weeks. Specific Aims Moderator Aims (Aim 1): To identify baseline clinical, neuroimaging, neurophysiological, and behavioral moderators of differential treatment outcome (mean symptom change and tolerability) for sertraline (SERT, a serotonergic antidepressant) versus placebo (PBO) for the treatment of MDD. Symptom change will be measured using the mean change from baseline in the 17-item Hamilton Rating Scale for Depression (HRSD17). Tolerability will be measured using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) and the Treatment Emergent Symptom Scale (TESS). Mediator Aims (Aim 2): To identify early phase (week 1) changes in neuroimaging, neurophysiological, and behavioral tasks as mediators of differential treatment outcomes (symptom change, tolerability) to SERT and PBO. Main Treatment Effects Aim (Aim 3): To compare the 8-week outcomes of SERT vs. PBO using mixed model regression analysis to maximize power to discriminate treatment efficacy differences. Primary Outcomes: \- 17-item Hamilton Rating Scale for Depression (HRSD17) Secondary Outcomes: \- the Frequency, Intensity, and Burden Side Effects Rating (FIBSER)
Interventions
DRUGSertraline
50-200mg/day
DRUGPlacebo
1-4 pills per day
DRUGBupropionXL
150-450 mg/day
Sponsors
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Patients were entered into Stage 1, treated with sertraline (Treatment A) or placebo (Treatment B), and used for the primary analysis which included the identification of potential mediators and moderators of response for these two treatments. In stage two, responders to Treatment A remained on sertraline, and non-responders were switched to bupropion (Treatment C). Responders to Treatment B remained on placebo, and non-responders were switched to sertraline (Treatment D).
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Adults, age 18-65 * Written informed consent obtained * Outpatients with a current primary diagnosis of nonpsychotic recurrent or chronic MDD per the SCID-I * QIDS-SR score of ≥ 14 at Screening Visit and Randomization (Baseline) Visit * No failed antidepressant trials of adequate dose and duration, as defined by the MGH-ATRQ, in the current episode * Agrees to, and is eligible for, all biomarkers procedures (EEG/psychological testing, MRI, and blood draws)
Exclusion criteria
* History of inadequate response (to trials at adequate dose for adequate duration) or poor tolerability to sertraline (SERT) or bupropion (BUP) * Pregnant or breastfeeding * Plan to become pregnant over the ensuing 12 months following study entry or are sexually active and not using adequate contraception * History (lifetime) of psychotic depression, schizophrenia, bipolar (I, II, or NOS) disorder, schizoaffective disorder, or other Axis I psychotic disorder * Current primary anxiety disorder diagnosis * Meeting DSM-IV criteria for substance abuse in the last 2 months or substance dependence in the last 6 months (except for nicotine) * Require immediate hospitalization for psychiatric disorder * Have an unstable general medical condition (GMC) that will likely require hospitalization or to be deemed terminal (life expectancy \< 6 months after study entry) * Require medications for their GMCs that contraindicate any study medication * Have epilepsy or other conditions requiring an anticonvulsant * Receiving or have received during the index episode vagus nerve stimulation, ECT, or rTMS, or other somatic antidepressant treatments * Currently taking any of the following exclusionary medications: antipsychotic medications, anticonvulsant medications, mood stabilizers, central nervous system stimulants, daily use of benzodiazepines or hypnotics, or antidepressant medication used for the treatment of depression or other purposes such as smoking cessation, since these agents may interfere with the testing of the major hypotheses under study. Nonexcluded concomitant medications are acceptable as long as their clinician determines that antidepressant treatment is safe and appropriate. * Significant liver disease that would contraindicate any study medication * Taking thyroid medication for hypothyroidism may be included only if they have been stable on the thyroid medication for 3 months * Using agents that are potential augmenting agents (e.g., T3 in the absence of thyroid disease, SAMe, St. John's Wort, lithium, buspirone, Omega 3 fatty acids) * Therapy that is depression specific, such as CBT or Interpersonal Psychotherapy of Depression (IPT) is not allowed during participation (participants can participate if they are receiving psychotherapy that is not targeting the symptoms of depression, such as supportive therapy, marital therapy). * Subjects must be fluent in English and have the capacity to understand the nature of the study and sign the written informed consent since non-English speaking personnel are not available for this study, and the research instruments are not yet translated and validated in other languages. * Currently actively suicidal or considered a high suicide risk * Are currently enrolled in another study, and participation in that study contraindicates participation in the EMBARC study. * Any reason not listed herein yet, determined by the site PI, medical personnel, or designee that constitutes good clinical practice and that would in the opinion of the site PI, medical personnel, or designee make participation in the study hazardous.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Rating Scale for Depression | Week 8 | The Hamilton Rating Scale for depression is a measure of depressive severity (HAM-D17; HDRS) * Scores range from 0-52 * Lower scores indicate less depressive symptomatology, and so are the more desirable. |
Countries
United States
Participant flow
Pre-assignment details
Final enrollment Stage 1: 296 (146 SERT, 150 PBO). Individuals who responded to their Stage 1 treatment remained on that treatment in Stage 2. Individuals who did not respond to their Stage 1 treatment were switched to a different treatment in Stage 2.
Participants by arm
| Arm | Count |
|---|---|
| Sertraline SSRI monotherapy
Sertraline: 50-200mg/day | 146 |
| Placebo Placebo control
Placebo: 1-4 pills per day | 150 |
| BupropionXL BupropionXL
150-450mg/day | 0 |
| Total | 296 |
Baseline characteristics
| Characteristic | Placebo | Sertraline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 6 Participants | 10 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 145 Participants | 139 Participants | 284 Participants |
| Age, Continuous | 36.9 years STANDARD_DEVIATION 12.8 | 37.2 years STANDARD_DEVIATION 13.8 | 37.05 years STANDARD_DEVIATION 13.3 |
| Region of Enrollment United States | 150 participants | 146 participants | 296 participants |
| Sex: Female, Male Female | 92 Participants | 102 Participants | 194 Participants |
| Sex: Female, Male Male | 58 Participants | 44 Participants | 102 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 233 / 283 | 89 / 196 | 27 / 53 |
| serious Total, serious adverse events | 10 / 283 | 7 / 196 | 1 / 53 |
Outcome results
Primary
Hamilton Rating Scale for Depression
The Hamilton Rating Scale for depression is a measure of depressive severity (HAM-D17; HDRS) * Scores range from 0-52 * Lower scores indicate less depressive symptomatology, and so are the more desirable.
Time frame: Week 8
Population: Note subjects in the efficacy trial were those that completed 8 weeks of treatment, 115 in the sertraline group, and 123 in the placebo group. SERT had 34 wash-outs, PBO had 27.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sertraline | Hamilton Rating Scale for Depression | 11.06 units on a scale | Standard Deviation 6.71 |
| Placebo | Hamilton Rating Scale for Depression | 12.52 units on a scale | Standard Deviation 7.68 |