A Neuroimaging Investigation of Brain Activity in Major Depressive Disorder and Bipolar Disorder

Neural Correlates of Emotional Processing in Depressed and Remitted Bipolar and Unipolar Depressed Subjects: An fMRI Investigation

This study employs functional magnetic resonance imaging to compare brain activation patterns during a depressive episode in patients diagnosed with bipolar disorder, major depressive disorder, and a group of healthy control subjects. Depressed patients will be treated with a combination of fluoxetine and olanzapine and undergo MRI scans before, during, and after pharmacotherapy.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Olanzapine; Drug: Fluoxetine+Olanzapine; Procedure: Functional Magnetic Resonance Imaging

Detailed Description

The purpose of this study is to further characterize the neural correlates of affective processing in BD and MDD subjects using fMRI. Subjects who meet criteria for a major depressive episode in the context of BD (n=15); MDD (n=15) and a group of psychiatrically unaffected control subjects (CS, n=15) will undergo four fMRI scans while experiencing a temporary mood induction through the presentation of affective imagery from the International Affective Picture System (IAPS). Both BD and MDD subjects will receive the same combination pharmacotherapy to treat the depression, with fMRI data acquired before, and 1, 3, 6 weeks following pharmacotherapy initiation. Positive, negative, and neutral affective visual stimuli will be presented in a blocked design.

Comparison(s): The effects of time and group will be analyzed in factorial models. Regions of interest that demonstrate significant group-by-time interactions will be further correlated with self-report and clinician-rated psychometric indices.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G2C4
      • University Health Network - Toronto General Division
    • Toronto, Ontario, Canada, M5T2S8
      • University Health Network - Toronto Western Division

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria: (All three groups)

• age 18-55 years
• satisfactory physical health
• education level and a degree of understanding to communicate effectively with the investigator c
• capable of providing informed consent
• female subjects of childbearing potential, a medically accepted means of contraception.

Additional inclusion criteria for the patient groups include

• DSM-IV-TR criteria for a diagnosis of BD or MDD
• currently meeting criteria for an MDE and
• a Hamilton Depression Rating Scale 17 Item (HDRS-17) score of > 17
• blood indices within normal clinical ranges.

Exclusion Criteria: (All three groups)

• DSM-IV-TR criteria for substance abuse or dependence (except nicotine or caffeine) within the past 6 months
• comorbid neurological or other major psychiatric disorders as defined in the DSM-IV-TR;
• history of neurological trauma resulting in loss of consciousness;
• uncorrected hypothyroidism or hyperthyroidism, including elevated thyroid stimulating hormone (TSH);
• other unstable medical condition;
• female subjects who are pregnant or nursing;

Additional exclusion criteria for the BD and MDD group include:

• prior failure to respond to fluoxetine and olanzapine in combination at adequate dose and duration;
• evidence of serious risk of suicide based on clinician assessment and/or HRSD suicide item > 3;
• course of ECT (electroconvulsive therapy) in the preceding 6 months;
• Young Mania Rating Scale (YMRS) > 7;
• administration of fluoxetine within previous 4 weeks;
• treatment resistance as defined by the failure of two antidepressant trials from dissimilar classes
• Hyperglycemia or diabetes mellitus as defined by a fasting blood glucose value of > 125 mg/dl.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Fluoxetine + Olanzapine	Drug: Olanzapine; Drug: Fluoxetine+Olanzapine; Procedure: Functional Magnetic Resonance Imaging

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MRI Data - Acquired before and 1- 3- and 6- weeks after beginning pharmacotherapy.	6 weeks
17 Item - Hamilton Depression Rating Scale - Weekly	6 weeks
Clinical Global Impression - Improvement/Severity - Weekly	6 weeks
Young Mania Rating Scale - Weekly	6 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Positive Affect Negative Affect Scale	6 weeks
Beck Depression Inventory	6 weeks
State Trait Anxiety Index	6 weeks
Behavioural Activation/Inhibition Scale	6 weeks
SexFX Scale	6 weeks
AMDP-5 Symptom Questionnaire	6 weeks

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: Eli Lilly and Company
• Investigators: Principal Investigator: Sidney H. Kennedy, MD, FRCPC, University Health Network, Department of Psychiatry, University of Toronto

Publications and helpful links

General Publications

• Kumari V, Mitterschiffthaler MT, Teasdale JD, Malhi GS, Brown RG, Giampietro V, Brammer MJ, Poon L, Simmons A, Williams SC, Checkley SA, Sharma T. Neural abnormalities during cognitive generation of affect in treatment-resistant depression. Biol Psychiatry. 2003 Oct 15;54(8):777-91. doi: 10.1016/s0006-3223(02)01785-7.
• Malhi GS, Lagopoulos J, Ward PB, Kumari V, Mitchell PB, Parker GB, Ivanovski B, Sachdev P. Cognitive generation of affect in bipolar depression: an fMRI study. Eur J Neurosci. 2004 Feb;19(3):741-54. doi: 10.1111/j.0953-816x.2003.03159.x.
• Davidson RJ, Irwin W, Anderle MJ, Kalin NH. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry. 2003 Jan;160(1):64-75. doi: 10.1176/appi.ajp.160.1.64.

Study record dates

Study Major Dates

• Study Start: February 1, 2005
• Primary Completion (ACTUAL): June 1, 2009
• Study Completion (ACTUAL): June 1, 2009

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (ESTIMATE): September 16, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): February 8, 2013
• Last Update Submitted That Met QC Criteria: February 6, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: Mood Disorders; Magnetic Resonance Imaging; Major Depressive Disorder; Antipsychotic; Fluoxetine; Olanzapine; Diagnostic Imaging
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Depression; Depressive Disorder; Disease; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Olanzapine; Fluoxetine
• Other Study ID Numbers: UHN REB 04-0204-B; CTA Control #095694