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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Single (Participant);   Primary Purpose: Other
Condition Depression
Interventions Other: Placebo, identified as placebo to participants
Drug: Celexa or other antidepressant as clinically indicated
Other: Placebo, identifed to participants as "Active medication"
Enrollment 44
Recruitment Details 4 consented volunteers dropped because of exclusion criteria
Pre-assignment Details Of 44 participants consented, 4 were not assigned to participate due to screen failures.
Arm/Group Title Known Placebo First "Active" (Blinded) Placebo First Group
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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.

Placebo, identified as placebo to participants: White tablets

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

Placebo, identifed to participants as "Active medication": Blue Capsule

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.

Placebo, identified as placebo to participants: White tablets

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

Placebo, identifed to participants as "Active medication": Blue Capsule

Period Title: First Assignment and Washout
Started 20 20
Completed 20 20
Not Completed 0 0
Period Title: Second Assignment After Crossover
Started 20 20
Completed 20 20
Not Completed 0 0
Period Title: Open-label Antidepressant
Started 20 20
Completed 14 13
Not Completed 6 7
Arm/Group Title Total Study Population
Hide Arm/Group Description [Not Specified]
Overall Number of Baseline Participants 40
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Because this is a crossover study, the entire population is represented together for baseline measures
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
19 to 59 years Number Analyzed 40 participants
40
 100.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 40 participants
Female
25
  62.5%
Male
15
  37.5%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 40 participants
40
 100.0%
1.Primary Outcome
Title Changes in Mu-opioid Binding Potential During PET
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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.

Time Frame (90 minute PET scans) assessed at Weeks 1 and 2
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Data in four subjects was missing due to failure in the synthesis of the radio tracer for at least one of the two scans.
Arm/Group Title Changes in Mu-opioid Binding (Inactive -Active Placebo)
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Average regional changes in mu-opioid binding potential from the Inactive to the Active Placebo Condition.
Overall Number of Participants Analyzed 36
Mean (Standard Deviation)
Unit of Measure: Binding potential ratio
0.12  (0.32)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Changes in Mu-opioid Binding (Inactive -Active Placebo)
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments A p<0.001 was established for regions a priori hypothesized (e.g. nucleus accumbens).
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.12
Confidence Interval (2-Sided) 95%
0.016 to 0.23
Parameter Dispersion
Type: Standard Deviation
Value: 0.31
Estimation Comments [Not Specified]
2.Primary Outcome
Title Changes in BOLD Response During Reward fMRI Task (Monetary Incentive Delay, MID)
Hide Description % BOLD signal changes in the nucleus accumbens from the Inactive to the Active Placebo condition.
Time Frame (90 minute fMRI scans) assessed at Weeks 1 and 2
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Hide Analysis Population Description
Data was missing in 11 subjects due to movement artifacts, or incidental findings that made the data not usable.
Arm/Group Title Changes in BOLD Responses During the MID After Placebo
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Changes in BOLD response from the Inactive to the Active condition during the Monetary Incentive Delayed Task in the Nucleus Accumbens.
Overall Number of Participants Analyzed 29
Mean (Standard Deviation)
Unit of Measure: % BOLD changes from Inactive to Active
0.04  (1.13)
3.Secondary Outcome
Title Changes in Dopamine (D 2/3) Binding Potential During PET.
Hide Description

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.

Time Frame (90 minute PET scan) assessed at Weeks 1 and 2
Hide Outcome Measure Data
Hide Analysis Population Description
Data was only collected in 26 subjects as proposed.
Arm/Group Title Average Regional Changes in D2/3 Binding (Inactive-Active Plac
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Average regional changes in D2/3 binding potential from the Inactive to the Active placebo condition.
Overall Number of Participants Analyzed 26
Mean (Standard Deviation)
Unit of Measure: Binding potential ratio
0.08  (0.15)
4.Secondary Outcome
Title Changes From Baseline in Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) Score
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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.

Time Frame From Pre to post- active placebo, and from pre to post- inactive placebo (1 week intervention)
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Changes in QIDS-16SR from screening active/inactive placebo condition to the post scan active/inactive placebo condition.

Approximately 1-2 weeks between the two conditions.

Arm/Group Title Active Placebo Inactive Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 40 40
Mean (Standard Error)
Unit of Measure: Units on a scale
1.7  (3.3) -0.5  (3.2)
5.Secondary Outcome
Title Changes From Baseline in PHQ-9 Depression Scores.
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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.

Time Frame From Pre to post- active placebo, and from pre to post- inactive placebo (1 week intervention)
Hide Outcome Measure Data
Hide Analysis Population Description

Changes in PHQ-9 score from the beginning of the active/inactive placebo and the end of active/inactive PET scan.

Approximately 1-2 weeks between the two conditions.

Arm/Group Title Active Placebo Inactive Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 40 40
Mean (Standard Deviation)
Unit of Measure: Units on a scale
1.6  (3.6) 0.96  (3.9)
6.Secondary Outcome
Title Hamilton Depression Rating Scale Scores
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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.

Time Frame Screening, week 0, week 2, week 4, week 8 and week 10
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[Not Specified]
Arm/Group Title Open-label Antidepressant Treatment After Placebo Experiment
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[Not Specified]
Overall Number of Participants Analyzed 40
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Screening 21  (4.4)
week 0 17.2  (6.5)
week 2 13.3  (7.18)
Week 4 11  (7.73)
week 8 8.65  (6.78)
week 10 5.3  (3.75)
7.Secondary Outcome
Title Montgomery-Asberg Depression Rating Scale
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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

Time Frame Screening, week 0, week 2, week 4, week 8 and week 10
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[Not Specified]
Arm/Group Title MADRS Scores During the Open-label Antidepressant Treatment
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[Not Specified]
Overall Number of Participants Analyzed 40
Mean (Standard Deviation)
Unit of Measure: Units on a scale
Baseline 27  (6.6)
week 0 22  (8.4)
week 2 15  (7)
week 4 13  (10)
week 8 11  (9.7)
week 10 7.7  (5.36)
Time Frame 13 weeks per person
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo (Unknown) Known Placebo
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
Placebo (Unknown) Known Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/20 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo (Unknown) Known Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/20 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Placebo (Unknown) Known Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/20 (0.00%)   0/20 (0.00%) 
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Jon-Kar Zubieta
Organization: University of Michigan
Responsible Party: Jon-Kar Zubieta, 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