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Predictors of Antidepressant Response

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ClinicalTrials.gov Identifier: NCT02178696
Recruitment Status : Completed
First Posted : July 1, 2014
Results First Posted : December 5, 2017
Last Update Posted : December 5, 2017
Sponsor:
Information provided by (Responsible Party):
Jon-Kar Zubieta, University of Michigan

Tracking Information
First Submitted Date  ICMJE June 12, 2014
First Posted Date  ICMJE July 1, 2014
Results First Submitted Date  ICMJE August 4, 2017
Results First Posted Date  ICMJE December 5, 2017
Last Update Posted Date December 5, 2017
Study Start Date  ICMJE January 2011
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 31, 2017)
  • Changes in Mu-opioid Binding Potential During PET [ Time Frame: (90 minute PET scans) assessed at Weeks 1 and 2 ]
    Binding Potential = Bmax/Kd (receptor concentration/affinity). This is the most common measure of in vivo receptor binding with positron emission tomography. Whole brain changes in mu-opioid receptors binding potential during PET from the Inactive to the Active placebo condition. Positive numbers presented here represent reductions in binding potential from the inactive to the active condition.
  • Changes in BOLD Response During Reward fMRI Task (Monetary Incentive Delay, MID) [ Time Frame: (90 minute fMRI scans) assessed at Weeks 1 and 2 ]
    % BOLD signal changes in the nucleus accumbens from the Inactive to the Active Placebo condition.
Original Primary Outcome Measures  ICMJE
 (submitted: June 30, 2014)
  • Changes in mu-opiod and dopamine binding potential during PET [ Time Frame: Week 1 and Week 2 ]
  • Changes in BOLD response during reward and decision making fMRI tasks [ Time Frame: Week 1 and Week 2 ]
Change History Complete list of historical versions of study NCT02178696 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 31, 2017)
  • Changes in Dopamine (D 2/3) Binding Potential During PET. [ Time Frame: (90 minute PET scan) assessed at Weeks 1 and 2 ]
    Binding Potential= Bmax/Kd (receptor concentration/affinity). This is the most common measure of in vivo receptor binding with PET. Striatal changes in D2/3 receptor binding potential during PET from the Inactive to the Active condition. Positive numbers presented here represented reductions in binding potential from the inactive to the active condition.
  • Changes From Baseline in Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) Score [ Time Frame: From Pre to post- active placebo, and from pre to post- inactive placebo (1 week intervention) ]
    This scale is a self-report measure of depression with 16 items. Questions in the QIDS - SR-116 correlate with the nine DSM-IV symptom criterion domains, Including: Sleep disturbance (initial, middle, and late insomnia or hypersomnia) (Q 1 - 4), Sad mood (Q 5), Decrease/increase in appetite/weight (Q 6 - 9), Concentration (Q 10), Self-criticism (Q 11), Suicidal ideation (Q 12), Interest (Q 13), Energy/fatigue (Q 14), Psychomotor agitation/retardation (Q 15 - 16). Severity of depression can be judged based on the total score: 1-5= No depression; 6-10= Mild depression; 11-15= Moderate depression; 16-20= Severe depression; 21-27= Very severe depression. The PHQ-9 and QIDS were used to assess changes in mood during the placebo intervention (first 2 weeks), and therefore results are described as changes from the inactive to the active condition.
  • Changes From Baseline in PHQ-9 Depression Scores. [ Time Frame: From Pre to post- active placebo, and from pre to post- inactive placebo (1 week intervention) ]
    The Patient Health Questionnaire-9, is a multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression, based on participant answers. PHQ-9 scores of 5, 10, 15, and 20 represents mild, moderate, moderately severe and severe depression, respectively. The minimum possible score is 0 and the maximum possible score is 27. The PHQ-9 and QIDS were used to assess changes in mood during the placebo intervention (first 2 weeks), and therefore results are described as changes from the inactive to the active condition.
  • Hamilton Depression Rating Scale Scores [ Time Frame: Screening, week 0, week 2, week 4, week 8 and week 10 ]
    The total score is obtained by summing the score of each item, 0-4 (symptom is absent, mild, moderate, or severe) or 0-2 (absent, slight or trivial, clearly present). For the 17-item version, scores can range from 0 to 54, with 0 meaning no depression, and 54, severe depression. The Hamilton Depression Rating Scale was used to assess symptoms during the open label antidepressant treatment phase, so results are described as mean scores at each bi-weekly visit.
  • Montgomery-Asberg Depression Rating Scale [ Time Frame: Screening, week 0, week 2, week 4, week 8 and week 10 ]
    Designed in 1979 by researchers as an adjunct to the Hamilton Rating Scale for Depression (HAMD) which would be more sensitive to the changes brought on by antidepressants and other forms of treatment than the Hamilton Scale. MADRS was used to assess symptoms during the open label antidepressant treatment phase, so results are described as mean scores at each bi-weekly visit. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60 where 0 is no depression and 60 is most extreme depression. The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts Usual cutoff points are: 0 to 6 - normal[5] /symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression
Original Secondary Outcome Measures  ICMJE
 (submitted: June 30, 2014)
Depression severity assessed with several depressive questionnaires [ Time Frame: At initial screening, Week 0, Week 2, Week 4, Week 8, and Week 10 visits, or until the participants leave the study. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: June 30, 2014)
  • Blood samples [ Time Frame: Week 1 and Week 2 ]
    5mL collected for analysis of genetic information, hormone levels, and cortisol levels
  • Neuropsychological test results [ Time Frame: at baseline and Week 10 ]
    Affect processing: Emotional Words Task and Facial Emotion Perception test. Attention and Inhibitory Control: Parametric Go/NoGo, Trail Making test and the Stroop Color Word test . Inferential Reasoning (including cost-benefit analysis): Delayed Discounting of Money Rewards, Iowa Gambling Task, and the Wisconsin Card Sorting Test. Visual Perception: Benton Visual Discrimination Form.
 
Descriptive Information
Brief Title  ICMJE Predictors of Antidepressant Response
Official Title  ICMJE Predictors of Antidepressant Response
Brief Summary Major depression is a highly prevalent, frequently debilitating illness that too often fails to respond to currently available treatments such as antidepressant medication. Furthermore, randomized controlled trials of antidepressants consistently demonstrate large placebo effects. The investigators hypothesize that individual differences in the function of key brain circuits underlie the observed variability in clinical responses to both placebo and antidepressant medication. This study will test this hypothesis by recruiting treatment-seeking volunteers with major depression, with or without comorbid nicotine dependence. Volunteers will participate in positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans in the context of a treatment trial in which they will receive both placebo and antidepressant medication. A major goal of the study is to improve prediction of individual clinical responses in future treatment trials in which brain imaging may be unavailable, and to study the mechanisms of antidepressant response in Major Depression.
Detailed Description We performed a single-blinded two-week cross-over randomized controlled trial of two identical oral placebos (described as having either potentially "active" fast-acting antidepressant-like effects or to be "inactive") followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor (SSRI) or in some cases, another agent as clinically indicated. The volunteers were studied with PET and the µ-opioid receptor selective radiotracer [11C]carfentanil after each 1-week "inactive" and "active" oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously (i.v.) within sight of the volunteer during PET scanning every 4 min over 20 min only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was utilized to test the individual capacity to acutely activate endogenous opioid neurotransmission under expectations of antidepressant effect.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Other
Condition  ICMJE Depression
Intervention  ICMJE
  • Other: Placebo, identified as placebo to participants
    White tablets
  • Drug: Celexa or other antidepressant as clinically indicated
    Open label s-citalopram, 20 mg start up dose, increasing to 40 mg as clinically indicated; If prior non-response to this medication is noted by the patient, alternative treatments may include another first-line antidepressant:fluoxetine 20 mg; paroxetine up to 60 mg; sertraline up to 200 mg; bupropion up to 300 mg
    Other Name: S-citalopram 20-40 mg orally
  • Other: Placebo, identifed to participants as "Active medication"
    Blue Capsule
Study Arms  ICMJE
  • Experimental: Known Placebo First
    This arm gets a placebo that they know is a placebo (called inactive), then has 2 scans performed (FMRI and PET), then a 2-3 day washout, and then gets a so-called "active medication" (which is also actually a placebo), and another pair of scans. Following these, participants receive 10 weeks of open-label antidepressant administration (Celexa or alternative as explained in intervention description). First line antidepressant will be Celexa unless not clinically indicated.
    Interventions:
    • Other: Placebo, identified as placebo to participants
    • Drug: Celexa or other antidepressant as clinically indicated
    • Other: Placebo, identifed to participants as "Active medication"
  • Experimental: "Active" (blinded) Placebo first group
    This arm gets a placebo that they don't know is a placebo (called Active), then has 2 scans performed (FMRI and PET), then a 2-3 day washout, and then gets a so-called "inactive medication" (which participants know is a placebo), and another pair of scans. Following these, participants receive 10 weeks of open-label antidepressant administration (Celexa as explained in intervention description). First line antidepressant will be Celexa unless not clinically indicated.
    Interventions:
    • Other: Placebo, identified as placebo to participants
    • Drug: Celexa or other antidepressant as clinically indicated
    • Other: Placebo, identifed to participants as "Active medication"
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 21, 2017)
44
Original Estimated Enrollment  ICMJE
 (submitted: June 30, 2014)
80
Actual Study Completion Date  ICMJE October 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria: Inclusion criteria will include:

  • Participants diagnosed with Major Depressive Disorder and will include Hamilton Depressive Rating Scale (HDRS) scores >15

Exclusion Criteria:

  • Comorbid conditions that are medical, neurological or psychiatric, pregnancy, use of hormones (including birth control) or use of psychotropic agents
  • We will only permit certain past anxiety disorder diagnoses, including generalized anxiety, panic, agoraphobia, social phobia
  • We also will exclude left-handed individuals and patients who have used any centrally acting medications or recreational drugs with the past 2 months
  • No history of an implant, pacemaker or pacemaker wires, open heart surgery, artificial heart valve, brain aneurysm surgery, middle ear implant, hearing aid, braces or extensive dental work, cataract surgery or lens implant, implanted mechanical or electrical device, or artificial limb or joint
  • No metallic object in their body (such as braces) or have a history of foreign metallic object in the body such as bullets, BB's, pellets, shrapnel, or other metal fragments
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02178696
Other Study ID Numbers  ICMJE HUM00033328
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jon-Kar Zubieta, University of Michigan
Study Sponsor  ICMJE University of Michigan
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jon-Kar Zubieta, MD, PhD University of Michigan
PRS Account University of Michigan
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP