PET and MRI Brain Imaging of Bipolar Disorder

PET and MRI imaging will be used to investigate the aims described above in patients who
have bipolar disorder or unipolar depression and are currently experiencing a depressive
episode. Both healthy controls and depressed participants with bipolar disorder or unipolar
depression will be recruited. Patients who are on medication before enrolling in the study
will have a three week washout. At baseline, healthy controls and patients will have an MRI
consisting of both structural and functional sequences. Psychological measures will also be
obtained at baseline. Within one week of the MRI, both patients and healthy controls will
have one CUMI and one DASB PET scan.

Following the baseline PET scans, patient participants will begin medication treatment with
either lithium or lamotrigine, based on the clinical judgement of the treating psychiatrist.
Psychological measures will be obtained every 2 weeks. After 6 weeks of medication treatment
at a therapeutic dose, patients will be assessed for remission (defined as a 50% decrease in
the HDRS score from baseline). If this criteria is met, patient participants will then have
follow-up PET scans (one CUMI and one DASB). If this criteria is not met, the patient will
be switched to the other medication under study and will be reevaluated after an additional
4 weeks of medication treatment. Patients who still do not demonstrate a 50% decrease in
their HDRS will be considered non-responders and will have repeat CUMI and DASB scans.

PATIENTS

BIPOLAR

Inclusion Criteria:

- Bipolar patients suffering from a major depressive episode currently or recently (in
the month prior to scanning). Patients on psychiatric medication will have failed
their current regimen for the treatment of their depression: they will meet criteria
for depression, be seeking treatment for it, and have been on an adequate dose of
antidepressant or mood stabilizer (as defined by the Antidepressant Treatment
Form—see Oquendo et al., 2003) for 4 weeks or more.

- Of sufficient severity to score at least 15 on the first 17 items of the Hamilton
Depression Rating Scale or a score of 10 to 14 on the first 17 items of the Hamilton
Depression Scale in conjunction with a score of at least 29 on the Beck Depression
Inventory.

- Age range 18-65 years.

- Off all psychotropic and other types of drugs likely to interact with serotonin
transporters and 5-HT1A receptors for at least 21 days. Allowed short-acting
benzodiazepines for distressing anxiety or insomnia (up to 24 hours prior to each PET
scan). Patients will be off neuroleptics for 3 weeks and off fluoxetine for 6 weeks
prior to study. Off serotonin depleting drugs such as reserpine for 3 months. Patient
will also be off anti-coagulant/anti-platelet treatment such as coumadin, with the
exception of aspirin for 10 days.

- Willing to travel for PET scanning

Exclusion Criteria:

- Other major psychiatric disorders such as schizophrenia, schizoaffective illness;
current drug or alcohol abuse (within past 2 months), or drug or alcohol dependence
<6mos ago; anorexia nervosa or bulimia nervosa in the past year; IV drug use or
ecstasy use more than two times.

- A first-degree family history of schizophrenia if the subject is less than 33 years
old (mean age of onset for schizophrenia plus two standard deviations).

- Significant active physical illness particularly those that may affect the brain or
serotonergic system including blood dyscrasias lymphomas, hypersplenism,
endocrinopathies, renal failure or chronic obstructive lung disease, autonomic
neuropathies, peripheral vascular disease, diabetes, low hemoglobin and malignancy,
significant anemic disease or blood loss and the lab parameters platelet count <
80,000.

- Lacks capacity to consent.

- Actively suicidal-begins expressing a plan for suicide during the washout phase or
develop suicidal ideation that warrants admission or requires medication or treatment
intervention.

- Electroconvulsive therapy (ECT) within the past 6 months.

- Pregnancy, currently lactating; planning to conceive during the course of study
participation or abortion in the past two months.

- Metal implants, pacemaker or metal prostheses or orthodontic appliances, the presence
of shrapnel

- Current, past or anticipated exposure to radiation, that may include: being badged
for radiation exposure in the workplace, participation in nuclear medicine
procedures, including research protocols in the last year.

- A neurological disease or loss of consciousness for more than a few minutes

- Medicinal Patch (participants will be asked to remove before MRI)

- Patients who are responding satisfactorily to psychiatric medications, because they
will not be washed-out for purposes of this study

- A documented history of a lack of response to a trial of adequate dose and duration
of both lithium and lamotrigine defined as minimal clinical response to lamotrigine
200 mgs for at least 4 weeks or lithium serum levels of at least 0.8 (or dose >= 900
mgs) for at least 4 weeks.

- Patient is unlikely to be able to tolerate medication washout

- Claustrophobia

- Blood donation within 8 weeks of the start of the study.

- History of bleeding disorder or are currently taking anticoagulants.

UNIPOLAR

Inclusion:

- Unipolar patients suffering from a major depressive episode currently or recently (in
the month prior to scanning). Patients on psychiatric medication will have failed
their current regimen for the treatment of their depression: they will meet criteria
for depression, be seeking treatment for it, and have been on an adequate dose of
antidepressant or mood stabilizer (as defined by the Antidepressant Treatment
Form—see Oquendo et al., 2003) for 4 weeks or more.

- Of sufficient severity to score at least 15 on the first 17 items of the Hamilton
Depression Rating Scale or a score of 10 to 14 on the first 17 items of the Hamilton
Depression Scale in conjunction with a score of at least 29 on the Beck Depression
Inventory.

- Age range 18-65 years.

- Off all psychotropic and other types of drugs likely to interact with serotonin
transporters and 5-HT1A receptors for at least 21 days. Allowed short-acting
benzodiazepines for distressing anxiety or insomnia (up to 24 hours prior to each PET
scan). Patients will be off neuroleptics for 3 weeks and off fluoxetine for 6 weeks
prior to study. Off serotonin depleting drugs such as reserpine for 3 months. Patient
will also be off anti-coagulant/anti-platelet treatment such as coumadin, with the
exception of aspirin for 10 days.

- Willing to travel for PET scanning

Exclusion:

- Other major psychiatric disorders such as schizophrenia, schizoaffective illness;
current drug or alcohol abuse (within past 2 months), or drug or alcohol dependence
<6mos ago; anorexia nervosa or bulimia nervosa in the past year; IV drug use or
ecstasy use more than two times.

- A first-degree family history of schizophrenia if the subject is less than 33 years
old (mean age of onset for schizophrenia plus two standard deviations).

- Significant active physical illness particularly those that may affect the brain or
serotonergic system including blood dyscrasias lymphomas, hypersplenism,
endocrinopathies, renal failure or chronic obstructive lung disease, autonomic
neuropathies, peripheral vascular disease, diabetes, low hemoglobin and malignancy,
significant anemic disease or blood loss and the lab parameters platelet count <
80,000.

- Lacks capacity to consent.

- Actively suicidal-begins expressing a plan for suicide during the washout phase or
develop suicidal ideation that warrants admission or requires medication or treatment
intervention.

- Electroconvulsive therapy (ECT) within the past 6 months.

- Pregnancy, currently lactating; planning to conceive during the course of study
participation or abortion in the past two months.

- Metal implants, pacemaker or metal prostheses or orthodontic appliances, the presence
of shrapnel

- Current, past or anticipated exposure to radiation, that may include: being badged
for radiation exposure in the workplace, participation in nuclear medicine
procedures, including research protocols in the last year.

- A neurological disease or loss of consciousness for more than a few minutes

- Medicinal Patch (participants will be asked to remove before MRI)

- Patients who are responding satisfactorily to psychiatric medications, because they
will not be washed-out for purposes of this study

- A documented history of a lack of response to a trial of adequate dose and duration
of both lithium and lamotrigine defined as minimal clinical response to lamotrigine
200 mgs for at least 4 weeks or lithium serum levels of at least 0.8 (or dose >= 900
mgs) for at least 4 weeks.

- Patient is unlikely to be able to tolerate medication washout

- Claustrophobia

- Blood donation within 8 weeks of the start of the study.

- History of bleeding disorder or are currently taking anticoagulants.

- Past unsuccessful treatment of Lithium of adequate dose and duration.

HEALTHY CONTROLS

Inclusion:

- No lifetime history of Axis I disorders

- Age range 18-65 years.

- Willing to travel for PET scanning.

Exclusion:

- Past or present alcohol/substance abuse or dependence; IV drug use or ecstasy use
more than two times.

- A first-degree relative with history of major depression, schizophrenia,
schizoaffective disorder, or suicide attempt; two or more first degree relatives with
a history of substance dependence.

- Significant active physical illness particularly those that may affect the brain or
serotonergic system including blood dyscrasias lymphomas, hypersplenism,
endocrinopathies, renal failure or chronic obstructive lung disease, autonomic
neuropathies, peripheral vascular disease, diabetes, low hemoglobin and malignancy,
significant anemic disease or blood loss, and the following lab parameters: platelet
count < 80,000

- Lacks capacity to consent

- Pregnancy, currently lactating; planning to conceive during the course of study
participation or abortion in the past two months

- Metal implants, pacemaker or metal prostheses or orthodontic appliances, the presence
of shrapnel

- Current, past or anticipated exposure to radiation, that may include: being badged
for radiation exposure in the workplace, participation in nuclear medicine
procedures, including research protocols in the last year.

- A neurological disease or loss of consciousness for more than a few minutes

- Medicinal Patch (participants will be asked to remove before MRI)

- Subjects on drugs or medication that affect the serotonin system

- Claustrophobia

- Blood donation within 8 weeks of the start of the study.

- History of bleeding disorder or are currently taking anticoagulants.