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Predictors of Antidepressant Response

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02178696
First Posted: July 1, 2014
Last Update Posted: December 5, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Jon-Kar Zubieta, University of Michigan
  Purpose
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.

Condition Intervention Phase
Depression Other: Placebo, identified as placebo to participants Drug: Celexa or other antidepressant as clinically indicated Other: Placebo, identifed to participants as "Active medication" Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Other
Official Title: Predictors of Antidepressant Response

Resource links provided by NLM:


Further study details as provided by Jon-Kar Zubieta, University of Michigan:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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



Enrollment: 44
Study Start Date: January 2011
Study Completion Date: October 2015
Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.
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

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.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02178696


Locations
United States, Michigan
Department of Psychiatry
Ann Arbor, Michigan, United States, 48108
Sponsors and Collaborators
University of Michigan
Investigators
Principal Investigator: Jon-Kar Zubieta, MD, PhD University of Michigan
  More Information

Publications:
Responsible Party: Jon-Kar Zubieta, MD PhD, University of Michigan
ClinicalTrials.gov Identifier: NCT02178696     History of Changes
Other Study ID Numbers: HUM00033328
First Submitted: June 12, 2014
First Posted: July 1, 2014
Results First Submitted: August 4, 2017
Results First Posted: December 5, 2017
Last Update Posted: December 5, 2017
Last Verified: October 2017

Additional relevant MeSH terms:
Antidepressive Agents
Citalopram
Dexetimide
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents