Brain Imaging Techniques That Predict Antidepressant Responsiveness (WyethKolden)

Non-Invasive Brain Imaging Techniques That Predict Antidepressant Responsiveness and Provide Insights Into the Mechanism of Action of Venlafaxine ER vs. Fluoxetine

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?

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Venlafaxine ERT; Drug: Fluoxetine

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 In the event of suicidal ideation, subjects will be withdrawn from the study and referred for immediate treatment.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 Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53719
      • University of Wisconsin Madison Psychiatry Department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hamilton Depression (HAM-D) and Anxiety (HAM-A) Rating Scales	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).	Study entry, 2 months, and at end of study (6 mos)
Functional Magnetic Resonance Imaging (fMRI) Response to an Emotional Regulation Task.	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.	At study entry, 2 months and end of study (6 months)

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: 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

Publications and helpful links

General Publications

• Heller AS, Johnstone T, Peterson MJ, Kolden GG, Kalin NH, Davidson RJ. Increased prefrontal cortex activity during negative emotion regulation as a predictor of depression symptom severity trajectory over 6 months. JAMA Psychiatry. 2013 Nov;70(11):1181-9. doi: 10.1001/jamapsychiatry.2013.2430.
• Heller AS, Johnstone T, Light SN, Peterson MJ, Kolden GG, Kalin NH, Davidson RJ. Relationships between changes in sustained fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment. Am J Psychiatry. 2013 Feb;170(2):197-206. doi: 10.1176/appi.ajp.2012.12010014.
• Light SN, Heller AS, Johnstone T, Kolden GG, Peterson MJ, Kalin NH, Davidson RJ. Reduced right ventrolateral prefrontal cortex activity while inhibiting positive affect is associated with improvement in hedonic capacity after 8 weeks of antidepressant treatment in major depressive disorder. Biol Psychiatry. 2011 Nov 15;70(10):962-8. doi: 10.1016/j.biopsych.2011.06.031. Epub 2011 Aug 25.
• Heller AS, Johnstone T, Shackman AJ, Light SN, Peterson MJ, Kolden GG, Kalin NH, Davidson RJ. Reduced capacity to sustain positive emotion in major depression reflects diminished maintenance of fronto-striatal brain activation. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22445-50. doi: 10.1073/pnas.0910651106. Epub 2009 Dec 22.

Study record dates

Study Major Dates

• Study Start: July 1, 2002
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): December 1, 2009

Study Registration Dates

• First Submitted: May 18, 2009
• First Submitted That Met QC Criteria: May 22, 2009
• First Posted (ESTIMATE): May 27, 2009

Study Record Updates

• Last Update Posted (ACTUAL): August 3, 2018
• Last Update Submitted That Met QC Criteria: July 3, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Major Depressive Disorder
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Cytochrome P-450 CYP2D6 Inhibitors; Venlafaxine Hydrochloride; Fluoxetine
• Other Study ID Numbers: 0600B-100953; 2001-294 (OTHER: HS IRB)