Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Study type: Interventional
Phase: Phase 2

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)
    

Intervention name(s): Sertraline; Placebo; BupropionXL
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 50-200mg/day; 1-4 pills per day; 150-450 mg/day
Other intervention name(s): Zoloft; WelbutrinXL
Intervention MeSH terms: Sertraline
Allocation: Randomized
Intervention model: Sequential Assignment
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).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Depression, Major Depressive Disorder, Mood Disorder