WyethKolden: Brain Imaging Techniques That Predict Antidepressant Responsiveness

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Completed
• CT.gov ID: NCT00909155
• Collaborator: Wyeth is now a wholly owned subsidiary of Pfizer (Industry)
• Enrollment: 50
• Location: 1
• Arms: 3
• Duration (Months): 89
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Do functional brain changes occur during Venlafaxine ER (extended release) versus Fluoxetine treatment and do changes in selective structures, such as the amygdala, predict treatment response?

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Venlafaxine ERT; Drug: Fluoxetine	N/A

Detailed Description

This is a single site, controlled, double-blind study of outpatients. There are two arms:

1. Forty participants who have a current Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revised (DSM-IV-TR) diagnosis of Major Depression will be recruited. These subjects will be randomized to receive one of two antidepressant medications: Fluoxetine or Venlafaxine ER for the duration of the study. Subjects will gradually be titrated onto the medications and will be seen in the clinic up to 18 times for medication checks, to monitor side effects and depressive symptoms, including suicidal ideation. In the event of suicidal ideation, subjects will be withdrawn from the study and referred for immediate treatment.

2. Twenty normal control subjects with no current or past DSM-IV-TR diagnosis and will receive no medication. Normal control subjects will have up to 5 visits while in the study.

Subjects will contact study staff to complete a phone screen and then eligible subjects will complete a clinic screen. Subjects will then be scheduled to attend the magnetic resonance imaging (MRI) simulation visit and if subjects continue to meet entrance criteria, they will be scheduled for the first MRI. Following the first MRI, subjects in the medication conditions will begin receiving medication.

All subjects will undergo 3 functional magnetic resonance imaging (fMRI)s during the study:

at the beginning of the study, approximately 8 weeks and 26 weeks later. During the MRI, subjects will view slides with positive and negative emotional content. Subjects will complete various clinical interviews or rating scales assessing mood and side effects at each of the visits.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Non-Invasive Brain Imaging Techniques That Predict Antidepressant Responsiveness and Provide Insights Into the Mechanism of Action of Venlafaxine ER vs. Fluoxetine
• Study Start Date: Jul 1, 2002
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Depressed; Venlafaxine treatment Currently depressed subjects; Randomized medication treatment with Venlafaxine extended release tablets (Venlafaxine ERT). Dosage 75-300mg/day for up to 6 months.	Drug: Venlafaxine ERT; Titrated to a minimum dose of 75mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 37.5 mg; Days 7-14: 75 mg; Days 15-180: 75-300mg based on clinician assessment. Titration rate is a maximum of 75mg/7d.; Other Names: Effexor ER
Active Comparator: Depressed; Fluoxetine treatment Currently depressed subjects; Randomized medication treatment with Fluoxetine tablets. Dosage 20-80mg/day for up to 6 months.	Drug: Fluoxetine; Titrated to a minimum dose of 20mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 20mg; Days 7-14: 20mg; Days 15-180: 20-80mg based on clinician assessment. Titration rate is a maximum of 20mg/7d; Other Names: Prozac
No Intervention: Control Non-psychiatric subjects with no past or current history of depression. Subjects will receive no medication

Outcome Measures

Primary Outcome Measures

1. Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales [Study entry, 2 months, and at end of study (6 mos)]

   Hamilton Depression rating scale is a clinician assessment tool to measure severity of depression symptoms. Minimum score is 0 (no symptoms); maximum score is 52 (severe symptoms of depression). Hamilton Anxiety rating scale is a clinician assessment tool to measure severity of anxiety symptoms. Minimum score is 0 (no symptoms); maximum score is 56 (severe symptoms of anxiety).

2. Functional Magnetic Resonance Imaging (fMRI) Response to an Emotional Regulation Task. [At study entry, 2 months and end of study (6 months)]

   Depressed participants were scanned while viewing a sequence of positive and negative images; they were instructed to enhance or supress their emotional response to the image or to continue to attend. To examine brain function when regulating negative affect, we created contrast maps for each participant at all 3 time points by subtracting the attend condition from the suppress condition in response to negative stimuli. Data from all 3 scan sessions were used to assess treatment-induced change in brain activity when regulating emotion. Analyses examining change using difference scores (end vs. starting points), we subtracted initial HAMD score from final HAMD score. For fMRI analyses, in a voxelwise manner, we subtracted initial negative suppress vs attend from final negative suppress vs attend. Control subjects were not depressed, repeat scans to assess change were not completed. Reported results are from BA10, one of our areas of interest.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Intervention Group:

• Right-handed,

• Be able to lie still on their back for about 120 minutes,

• Meet DSM-IV criteria for major depression (single or recurrent),

• Have had depressive symptoms for at least 1 month prior to screen visit,

• Must score an 18 or above on the Hamilton-D at both the initial screening visit and first fMRI scanning session,

• Able to understand and speak English.

• Control Group: same as above with the exception of no diagnosis of psychiatric disorder.

Exclusion Criteria:

• Any history of seizures,

• Current medical disorders that might make interpretation of scan data difficult,

• Diabetes requiring insulin treatment,

• A serious heart disorder or subjects who have had a heart attack within the last 3 months,

• Subjects who meet DSM-IV criteria for alcohol/drug abuse or dependence within the last six months,

• Other current DSM-IV Axis I or Axis II diagnoses,

• A personal or family history of bipolar disorder,

• Current use of medication that affects central nervous system (CNS) function,

• Participation in the last 30 days in a clinical study involving an investigational drug,

• A subject with metallic implants, such as prostheses, shrapnel or aneurysm clip-S, or persons with electronic implants, such as cardiac pacemakers. The magnetic field generated by the MRI machine can cause a displacement or malfunctioning of these devices.

• A subject who is claustrophobic,

• Female subjects who are pregnant,

• A subject at serious risk for suicide,

• Diagnosis of cancer in the past 3 years and/or has active neoplastic disease,

• Nonresponse to 2 adequate trials of antidepressant treatment,

• Nonresponse to 2 adequate trials of an empirically supported psychotherapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Wisconsin Madison Psychiatry Department	Madison	Wisconsin	United States	53719

Sponsors and Collaborators

• University of Wisconsin, Madison
• Wyeth is now a wholly owned subsidiary of Pfizer

Investigators

• Principal Investigator: Gregory Kolden, Ph.D., University of Wisconsin Madison Psychiatry Department
• Principal Investigator: Michael Peterson, MD, Ph.D., University of Wisconsin Madison Psychiatry Department

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT00909155
• Other Study ID Numbers: 0600B-100953; 2001-294
• First Posted: May 27, 2009
• Last Update Posted: Aug 3, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by University of Wisconsin, Madison: Major Depressive Disorder
• Additional relevant MeSH terms: Depressive Disorder; Depression; Depressive Disorder, Major; Fluoxetine; Venlafaxine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Currently Depressed Subjects: Venlafaxine	Currently Depressed Subjects: Fluoxetine	Control (Non-psychiatric Subjects)
Arm/Group Description	Currently depressed subjects; Randomized medication treatment with Venlafaxine extended release tablets (Venlafaxine ERT). Venlafaxine ERT: Titrated to a minimum dose of 75mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 37.5 mg; Days 7-14: 75 mg; Days 15-180: 75-300mg based on clinician assessment. Titration rate is a maximum of 75mg/7d.	Currently depressed subjects; Randomized medication treatment with Fluoxetine Fluoxetine: Titrated to a minimum dose of 20mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 20mg; Days 7-14: 20mg; Days 15-180: 20-80mg based on clinician assessment. Titration rate is a maximum of 20mg/7d	Non-psychiatric subjects with no past or current history of depression. Subjects will receive no medication
Period Title: Overall Study
STARTED	15	14	21
COMPLETED	12	9	14
NOT COMPLETED	3	5	7

Baseline Characteristics

Arm/Group Title	Currently Depressed Subjects: Venlafaxine	Currently Depressed Subjects: Fluoxetine	Control (Non-psychiatric Subjects)	Total
Arm/Group Description	Currently depressed subjects; Randomized medication treatment with Venlafaxine ERT Venlafaxine ERT: Titrated to a minimum dose of 75mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 37.5 mg; Days 7-14: 75 mg; Days 15-180: 75-300mg based on clinician assessment. Titration rate is a maximum of 75mg/7d.	Currently depressed subjects; Randomized medication treatment with Fluoxetine Fluoxetine: Titrated to a minimum dose of 20mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 20mg; Days 7-14: 20mg; Days 15-180: 20-80mg based on clinician assessment. Titration rate is a maximum of 20mg/7d	Non-psychiatric subjects with no past or current history of depression. Subjects will receive no medication	Total of all reporting groups
Overall Participants	15	14	21	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	15 100%	14 100%	21 100%	50 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.74 (11.46)	33.14 (10.71)	31.31 (14.22)	31.65 (12.31)
Sex: Female, Male (Count of Participants)
Female	8 53.3%	8 57.1%	13 61.9%	29 58%
Male	7 46.7%	6 42.9%	8 38.1%	21 42%
Region of Enrollment (participants) [Number]
United States	15 100%	14 100%	21 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales
Description	Hamilton Depression rating scale is a clinician assessment tool to measure severity of depression symptoms. Minimum score is 0 (no symptoms); maximum score is 52 (severe symptoms of depression). Hamilton Anxiety rating scale is a clinician assessment tool to measure severity of anxiety symptoms. Minimum score is 0 (no symptoms); maximum score is 56 (severe symptoms of anxiety).
Time Frame	Study entry, 2 months, and at end of study (6 mos)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Currently Depressed Subjects: Venlafaxine	Currently Depressed Subjects: Fluoxetine	Control (Non-psychiatric Subjects)
Arm/Group Description	Currently depressed subjects; Randomized medication treatment with Venlafaxine ERT Venlafaxine ERT: Titrated to a minimum dose of 75mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 37.5 mg; Days 7-14: 75 mg; Days 15-180: 75-300mg based on clinician assessment. Titration rate is a maximum of 75mg/7d.	Currently depressed subjects; Randomized medication treatment with Fluoxetine Fluoxetine: Titrated to a minimum dose of 20mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 20mg; Days 7-14: 20mg; Days 15-180: 20-80mg based on clinician assessment. Titration rate is a maximum of 20mg/7d	Non-psychiatric subjects with no past or current history of depression. Subjects will receive no medication
Measure Participants	15	14	21
HAMD T0	20.07 (1.94)	21.36 (2.71)	1 (1.55)
HAMA T0	14.07 (3.37)	15.57 (3.82)	NA (NA)
HAMD 2months	8.86 (4.5)	10.15 (4.52)	1.25 (1.34)
HAMA 2months	7.5 (4.55)	8.54 (4.86)	NA (NA)
HAMD 6months	5 (3.67)	7.33 (4.92)	1.64 (1.22)
HAMA 6months	4.25 (3.36)	5.89 (3.86)	NA (NA)

2. Primary Outcome

Title	Functional Magnetic Resonance Imaging (fMRI) Response to an Emotional Regulation Task.
Description	Depressed participants were scanned while viewing a sequence of positive and negative images; they were instructed to enhance or supress their emotional response to the image or to continue to attend. To examine brain function when regulating negative affect, we created contrast maps for each participant at all 3 time points by subtracting the attend condition from the suppress condition in response to negative stimuli. Data from all 3 scan sessions were used to assess treatment-induced change in brain activity when regulating emotion. Analyses examining change using difference scores (end vs. starting points), we subtracted initial HAMD score from final HAMD score. For fMRI analyses, in a voxelwise manner, we subtracted initial negative suppress vs attend from final negative suppress vs attend. Control subjects were not depressed, repeat scans to assess change were not completed. Reported results are from BA10, one of our areas of interest.
Time Frame	At study entry, 2 months and end of study (6 months)

Outcome Measure Data

Analysis Population Description

Depressed subjects were treated with an SSRI or an SNRI, and assessed at 3 time points on an fMRI emotional response task. Differences in depression scores and changes in the fMRI responses were analyzed for changes to better understand the association between emotion regulation, depression, and treatment response.

Arm/Group Title	Depressed; Venlafaxine Treatment	Depressed; Fluoxetine Treatment	Control
Arm/Group Description	Currently depressed subjects; Randomized medication treatment with Venlafaxine extended release tablets (Venlafaxine ERT). Dosage 75-300mg/day for up to 6 months. Venlafaxine ERT: Titrated to a minimum dose of 75mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 37.5 mg; Days 7-14: 75 mg; Days 15-180: 75-300mg based on clinician assessment. Titration rate is a maximum of 75mg/7d. 12 subjects completed the treatment, and both the 2month and 6month fMRI scans.	Currently depressed subjects; Randomized medication treatment with Fluoxetine tablets. Dosage 20-80mg/day for up to 6 months. Fluoxetine: Titrated to a minimum dose of 20mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 20mg; Days 7-14: 20mg; Days 15-180: 20-80mg based on clinician assessment. Titration rate is a maximum of 20mg/7d. 9 subjects completed the treatment, and both the 2month and 6month fMRI scans.	Non-psychiatric subjects with no past or current history of depression. Subjects will receive no medication. Control subjects did not complete the 2month and 6month fMRI scans since no depression was present, no treatment given, and no change in mood state expected. As such, no change in depression score could be calculated to provide a comparable measure in this group analysis. This analysis looked for functional imaging findings that correlated with improvement in depression symptoms.
Measure Participants	12	9	0
Mean (Standard Deviation) [fMRI signal change]	-0.042666667 (0.291892646)	0.0414 (0.332904397)

Adverse Events

Arm/Group Title	Currently Depressed Subjects; Venlafaxine		Currently Depressed Subjects; Fluoxetine		Control (Non-psychiatric Subjects)
Arm/Group Description	Currently depressed subjects; Randomized medication treatment with Venlafaxine ERT. Venlafaxine ERT: Titrated to a minimum dose of 75mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 37.5 mg; Days 7-14: 75 mg; Days 15-180: 75-300mg based on clinician assessment. Titration rate is a maximum of 75mg/7d.		Currently depressed subjects; Randomized medication treatment with Fluoxetine Fluoxetine: Titrated to a minimum dose of 20mg. Further titration based on clinician assessment at followup visits. Intervention to continue through completion of study (180 days). Initial titration: Days 1-7: 20mg; Days 7-14: 20mg; Days 15-180: 20-80mg based on clinician assessment. Titration rate is a maximum of 20mg/7d		Non-psychiatric subjects with no past or current history of depression. Subjects will receive no medication
All Cause Mortality
	Currently Depressed Subjects; Venlafaxine		Currently Depressed Subjects; Fluoxetine		Control (Non-psychiatric Subjects)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Currently Depressed Subjects; Venlafaxine		Currently Depressed Subjects; Fluoxetine		Control (Non-psychiatric Subjects)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/14 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Currently Depressed Subjects; Venlafaxine		Currently Depressed Subjects; Fluoxetine		Control (Non-psychiatric Subjects)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/14 (0%)		0/21 (0%)

Limitations/Caveats

Relatively small number of subjects. Not powered statistically to determine if either treatment arm (fluoxetine or venlafaxine) is superior.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.