We propose to study the efficacy and tolerability of lamotrigine in the treatment of older adults with bipolar depression and to compare measures of brain energy metabolism between older subjects with bipolar depression and healthy age-matched controls in order to better understand treatment response in geriatric bipolar depression.

We will use MRI techniques and neuropsychological testing to investigate potential markers of treatment response in elderly bipolar depressed patients receiving lamotrigine and age-matched, non-depressed controls.

We intend to test these hypotheses:

1. At least 50% of older subjects with bipolar depression will respond treatment with lamotrigine as evidenced by a 50% reduction on the Montgomery Asberg Rating Scale (MADRS). In addition, treatment with lamotrigine will be safe and well tolerated as evidenced by a drop-out rate of less than 10% due to adverse effects.
2. Compared with healthy age-matched, non-demented, non-depressed controls, subjects with geriatric bipolar depression will demonstrate abnormalities in cerebral energy metabolism as assessed by elevated levels of glutamate and lactate, and decreased levels of NAA, using 1H MRS at 4T.
3. Successful treatment with lamotrigine in geriatric bipolar depression will result in decreases in lactate and glutamate, and elevations in NAA.
4. Baseline measures of executive functioning and information processing speed (measured by performance on the Wisconsin Card Sorting Test (WCST), Trails A and B and Stroop tests) will be impaired in subjects with geriatric bipolar depression compared with healthy controls. These measures will improve with successful treatment with lamotrigine and correlate with improvements in markers of cerebral energy metabolism (lactate, glutamate, NAA).

Inclusion Criteria (for Bipolar Subjects):

• 60 years or older
• Meet DSM-IV diagnostic criteria for Bipolar Disorder, Current Episode Depressed
• First episode of mania before the age of 50 (early-onset bipolar disorder)
• Montgomery-Asberg Depression Rating Scale (MADRS) Score of greater or equal to 20.
• Young Mania Rating Scale (YMRS) of less than or equal to 6.
• Able to provide informed consent
• Must speak English
• Must be able to visit McLean Hospital for the screening visit and six study visits during the 8-week duration of the study.
• Subjects may be taking other medications for bipolar depression including antidepressants, mood stabilizers and antipsychotic mediations prior to lamotrigine therapy, but may not have any dosage adjustments of these medications in the week before lamotrigine is added.

Exclusion Criteria (for Bipolar Subjects):

• Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease.
• History of seizure disorder
• History or current diagnosis of the following psychiatric illnesses: any organic mental disorder (including dementia), schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorder not otherwise specified, unipolar major depressive disorder, patients with substance dependence disorders, including alcohol, active within the last 12 months.
• First episode of mania after the age of 50 (to exclude late-onset bipolar disorder)
• History of multiple adverse drug reactions or allergy to the study drugs.
• Use of medications that are excluded in this study (benzodiazepines, barbiturates; however, the use of non-benzodiazepine sedative hypnotics (such as zolpidem (Ambien)) may be used as needed except within 48 hours of the MRI scan)
• Any of the exclusion criteria mentioned in the MRI risks section below

Inclusion Criteria (for Controls):

• 60 years or older
• Able to provide informed consent
• Must speak English
• Women entering this study must be post-menopausal

Exclusion Criteria (for Controls):

- Same criteria for the Bipolar Depressed group with the exception of the "first episode of mania" which is not applicable.