FMRI Study of Brain Response Before and After Lithium Treatment in People With Bipolar Disorder

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00596622
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 46
• Location: 1
• Arms: 3
• Duration (Months): 63
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This study will assess the effects of bipolar disorder on brain activity and will determine if medication changes the brain activity in people with bipolar disorder.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Lithium	Phase 4

Detailed Description

Bipolar disorder (BD) is a chronic brain disorder that causes dramatic changes in a person's mood and energy. People with BD undergo periods of extreme happiness and extreme sadness, known as episodes of mania and depression. A person undergoing an episode of mania often experiences euphoric moods, increased energy, and aggressive behaviors, while a person in a depressed state often experiences low moods, lack of energy, and feelings of sadness. Researchers have recently discovered that abnormalities in certain brain areas that control emotion are often present in those with BD. It is believed that the severe mood shifts in BD may cause alterations in normal brain activity, specifically in corticolimbic activation and connectivity. Current mood stabilizing medications used to treat people with BD may help normalize these brain activity abnormalities. This study will assess the effects of BD on brain activity using functional magnetic resonance imaging (fMRI) and will determine if treatment with lithium changes the brain activity in people with BD.

This 9-week study will include participants who are healthy, have BD, or are siblings of subject with BD. All potential participants will undergo initial testing, which will include a physical examination, blood tests, and an electrocardiogram (EKG). Participants will also be asked to answer questions about their mental health, drug use, personality, family history, and psychological well-being. Eligible participants will then return on a different day to undergo an MRI scan, taking 4 hours to complete. During the scan, participants will be asked to perform tasks designed to show changes in blood flow in specific brain regions. These tasks will include listening to sounds and looking at various letters, words, and pictures. This will mark the completion of the study for healthy participants, first degree relatives, and those participants with BD who do not wish to receive medication treatment.

Following the first MRI scan, participants with BD who wish to undergo medication treatment will begin an 8-week course of lithium. Participants will be asked to come to the clinic at least once a week for medication monitoring visits. During these visits, participants will undergo blood draws and assessments on depression and mania. Participants will return for two repeat MRI scans after Weeks 2 and 8 of lithium treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Dysfunctional Cortico-Limbic Activity and Connectivity in Bipolar Disorder Before and After Lithium Treatment: An fMRI Study
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bipolar Manic Subjects Treated Bipolar mania picture response during fMRI before and after treatment with lithium	Drug: Lithium; Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment.
Experimental: Bipolar Depressed Subjects Treated Bipolar depression picture response during fMRI before and after treatment with lithium	Drug: Lithium; Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment.
Experimental: Bipolar Euthymic Subjects Treated Bipolar euthymia picture response before and after treatment with lithium	Drug: Lithium; Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment.

Outcome Measures

Primary Outcome Measures

1. 17-item Hamilton Depression Rating Scale (HDRS) [Measured at Baseline and after 8 weeks of treatment]

   17-item HDRS is gold standard for measurement of depression with a range from 0 - 52. 10 - 14: mild depression; 14-20 moderate depression; >20: severe and very severe depression.

Secondary Outcome Measures

1. Young Mania Rating Scale [Baseline and 8 weeks]

   Gold standard scale to measure mania, Range 0 - 60; 12 - 15 mild mania; 15 - 20 moderate mania; >20 severe mania

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria for BD participants:

• Meets DSM-IV criteria for bipolar I or II disorder

• Meets criteria to undergo an MRI scan based on MRI screening questionnaire

• Suited for outpatient care during the study as ascertained by a score of less than 5 on the Clinical Global Severity Scale, no significant suicidal or homicidal ideation, and no severe disability

Inclusion criteria for BD depressed participants:

• Meets criteria for DSM-IV depressive episode-current

• Score of greater than 15 but less than 30 on the 17-item HDRS

• Score of less than 12 on the Young Mania Rating Scale

Inclusion criteria for BD (hypo) manic participants:

• Meets criteria for DSM-IV manic episode-current

• Score of less than or equal to 18 on the 17-item HDRS

• Score of greater than 12 but less than 25 on the Young Mania Rating Scale

Inclusion criteria for BD euthymic patients:

• Satisfy criteria for DSM-IV for euthymic state-current for at least 2 weeks.

• 17-item Hamilton Depression Rating Scale < 12; Young Mania Rating Scale score < 10

Exclusion criteria for BD participants:

• Meets DSM-IV criteria for unipolar depression, schizophrenia, schizophreniform disorder, schizoaffective disorder, atypical psychosis, anxiety disorder as a primary diagnosis, mental retardation, or personality disorder

• Received electroconvulsive therapy in the 12 months prior to study entry

• Use of neuroleptics, mood stabilizers, or benzodiazepines in the 2 weeks prior to study entry

• Use of antidepressants in the 2 weeks prior to study entry

• Use of fluoxetine in the 5 weeks prior to study entry

• Use of lithium in the 6 months prior to study entry

• Acutely suicidal or homicidal or requiring inpatient treatment

• Meets DSM-IV criteria for substance/alcohol dependence, excluding caffeine or nicotine, in the 6 months prior to study entry or substance/alcohol abuse in the 3 months prior to study entry

• Use of alcohol in the 1 week prior to study entry and refusal to avoid alcohol use during the course of the study

• Presence of serious acute or chronic medical or neurological illness, including previously known HIV positive status (due to possible CNS involvement) as assessed by history, physical examination, and laboratory examination

• Pregnant or breastfeeding

• Metallic implants or other contraindication to MRI

Inclusion criteria for first degree relatives of bipolar disorder subjects:

• Ages 15-60 years (inclusive) and able to give voluntary informed consent.

• Have never satisfied criteria for DSM-IV BD.

• Satisfy criteria to undergo an MRI scan based on MRI screening questionnaire.

• 17-item Hamilton Depression Rating Scale < 10; Young Mania Rating Scale score < 10

Exclusion criteria for first degree relatives of bipolar disorder subjects:

• Under 15 years of age.

• Meeting DSM-IV criteria for current episode of unipolar depression

• Pregnant or breast feeding.

• Metallic implants or other contraindication to MRI.

• Currently taking any prescription or centrally acting medications.

• Serious acute or chronic medical or neurological illness as assessed by history, physical examination and laboratory examination including CBC and blood chemistry.

• Use of alcohol in the past 1 week and not being able to avoid alcohol use during the course of the study.

Inclusion criteria for healthy subjects:

• Ages 18-60 years (inclusive) and able to give voluntary informed consent.

• No current or past history of psychiatric illness or substance abuse or dependence.

• No current or past history of psychiatric illness or substance abuse or dependence in a first degree relative.

Exclusion criteria for healthy participants:

• Under 18 years of age

• Pregnant or breastfeeding

• Metallic implants or other contraindication to MRI

• Significant family history of psychiatric or neurological illness

• Currently taking any prescription or centrally acting medications

• Serious acute or chronic medical or neurological illness as assessed by history, physical examination, and laboratory examination

• Use of alcohol in the 1 week prior to study entry and refusal to avoid alcohol use during the course of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University Psychiatric Clinic	Indianapolis	Indiana	United States	46222

Sponsors and Collaborators

• Indiana University
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Amit Anand, MD, Indiana University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Indiana University
• ClinicalTrials.gov Identifier: NCT00596622
• Other Study ID Numbers: R01MH075025; 0607-23; DATR A3-NSS; R01MH075025
• First Posted: Jan 17, 2008
• Last Update Posted: Oct 17, 2016
• Last Verified: Aug 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Indiana University: Major Depressive or Manic Episodes; Bipolar; Mania; Depression; Lithium; fMRI; Pictures; Brain Scan
• Additional relevant MeSH terms: Bipolar Disorder; Lithium Carbonate

Study Results

Participant Flow

Arm/Group Title	Bipolar Subjects Who Were Included in Lithium Treatment Arm
Arm/Group Description	Participants with bipolar disorder who undergo fMRI and lithium treatment Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Picture response during fMRI: While undergoing an fMRI scan, participants will be presented with pictures, letters, words, and sounds to evoke emotional responses. There will be a maximum of three MRI scans over 9 weeks.
Period Title: Overall Study
STARTED	46
COMPLETED	33
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Bipolar Depressed Subjects Treated With Lithium	Bipolar Manic Subjects Treated With Lithium	Bipolar Euthymic Subjects Treated With Lithium	Total
Arm/Group Description	Participants with bipolar depression picture response during fMRI before and after treatment with lithium Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Depression and mania scores before and after treatment	Participants with bipolar mania picture response during fMRI before and after treatment with lithium Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Depression and mania scores before and after treatment	Participants with bipolar mania picture response during fMRI before and after treatment with lithium Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Depression and mania scores before and after treatment	Total of all reporting groups
Overall Participants	18	22	6	46
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34 (10)	34 (11)	26 (4)	33 (10)
Sex: Female, Male (Count of Participants)
Female	8 44.4%	15 68.2%	3 50%	26 56.5%
Male	10 55.6%	7 31.8%	3 50%	20 43.5%
Region of Enrollment (participants) [Number]
United States	18 100%	22 100%	6 100%	46 100%

Outcome Measures

1. Primary Outcome

Title	17-item Hamilton Depression Rating Scale (HDRS)
Description	17-item HDRS is gold standard for measurement of depression with a range from 0 - 52. 10 - 14: mild depression; 14-20 moderate depression; >20: severe and very severe depression.
Time Frame	Measured at Baseline and after 8 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bipolar Depressed Participants Treated	Bipolar Manic Subjects Treated	Bipolar Euthymic Subjects Treated
Arm/Group Description	Participants with bipolar depression who undergo fMRI and lithium treatment Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Picture response during fMRI: While undergoing an fMRI scan, participants will be presented with pictures, letters, words, and sounds to evoke emotional responses. There will be a maximum of three MRI scans over 9 weeks.	Participants with bipolar mania who undergo fMRI and lithium treatment Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Picture response during fMRI: While undergoing an fMRI scan, participants will be presented with pictures, letters, words, and sounds to evoke emotional responses. There will be a maximum of three MRI scans over 9 weeks	Participants with bipolar euthymia who undergo fMRI and lithium treatment Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Picture response during fMRI: While undergoing an fMRI scan, participants will be presented with pictures, letters, words, and sounds to evoke emotional responses. There will be a maximum of three MRI scans over 9 weeks
Measure Participants	15	14	4
Baseline 17-item HDRS	20 (4)	6 (3)	6 (4)
After 8 weeks lithium treatment	2 (3)	3 (2)	2 (3)

2. Secondary Outcome

Title	Young Mania Rating Scale
Description	Gold standard scale to measure mania, Range 0 - 60; 12 - 15 mild mania; 15 - 20 moderate mania; >20 severe mania
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bipolar Manic Subjects Treated	Bipolar Depressed Subjects Treated	Bipolar Euthymic Subjects Treated
Arm/Group Description	Bipolar mania picture response during fMRI before and after treatment with lithium Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment.	Bipolar depression picture response during fMRI before and after treatment with lithium Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment.	Bipolar euthymia picture response before and after treatment with lithium Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment.
Measure Participants	14	15	4
Baseline 17-item YMRS	15 (1)	3 (2)	1 (1)
Post 8 week treatment YMRS	3 (2)	2 (3)	2 (3)

Adverse Events

Arm/Group Title	Bipolar Participants Treated
Arm/Group Description	Participants with bipolar disorder who undergo fMRI and lithium treatment Lithium: Dosing will start as one 300-mg capsule per day and will be titrated up to four 300-mg capsules per day for a total of 8 weeks of treatment. Picture response during fMRI: While undergoing an fMRI scan, participants will be presented with pictures, letters, words, and sounds to evoke emotional responses. There will be a maximum of three MRI scans over 9 weeks. Adverse Events information was collected irrespective of the sub-grouping
All Cause Mortality
	Bipolar Participants Treated
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bipolar Participants Treated
	Affected / at Risk (%)	# Events
Total	0/46 (0%)
Other (Not Including Serious) Adverse Events
	Bipolar Participants Treated
	Affected / at Risk (%)	# Events
Total	40/46 (87%)
Cardiac disorders
heart palpitations	5/46 (10.9%)
Eye disorders
blurred vision	3/46 (6.5%)
Gastrointestinal disorders
Increased appetite	5/46 (10.9%)
Drymouth	5/46 (10.9%)
bad taste	3/46 (6.5%)
Nervous system disorders
headaches	15/46 (32.6%)
dizziness	5/46 (10.9%)
forgetfulness	3/46 (6.5%)

Limitations/Caveats

Small number of subjects

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.