The primary aims of this study are to:

1. Quantify serotonin transporter (5-HTT) binding potential (BP) in vivo in bipolar disorder patients (BPD) during a major depressive episode (MDE).
2. Assess the effect of lithium treatment of bipolar disorder on 5-HTT.
3. Assess the effect of lithium treatment of bipolar disorder on 5-HT1A BP.
4. Assess the effect of lamotrigine treatment of bipolar disorder on 5-HTT and 5-HT1A BP.
5. Assess the effect of lithium treatment of unipolar depression on 5-HTT BP.

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.

The number of participants reflected in each group are those that were available for both PET and HDRS-24 baseline measures that also met quality control standards for the imaging data. This number differs slightly from total participants enrolled.

Full study duration for participants: enrollment through final data collection (approximately 6 months)

Definitions for adverse event and/or serious adverse event used to collect adverse event information matches clinicaltrials.gov.

Limitations include: 1. a small sample size, which precludes investigation into interaction factors (e.g. sex/BPD subtype); 2. a short washout duration (3 weeks for ethical reasons), which may not be sufficient to abate treatment effects; 3. scans for both patients and controls conducted across multiple sites, though, importantly, all pre- and post-treatment scans within-participant were conducted at the same site.