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.

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.

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

Small number of subjects