The purpose of this study is to test whether ketamine and D-cycloserine can be safely and effectively used for the treatment of depression. The investigators hypothesize that ketamine will serve as a rapid acting and safe antidepressant in patients with bipolar depression, and furthermore, that D-cycloserine will serve as an effective therapy following ketamine treatment.

Bipolar disorder affects 2% of the population in the United States and the depressive phase contributes disproportionally to morbidity and mortality. At present, few approved treatments for bipolar depression are available, and have primarily depended on manipulations of brain monoaminergic systems. In contrast, recent studies suggest that the N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonist, ketamine, may provide near-immediate relief for treatment resistant depression. Its utility during long-term treatment, however, is limited by its psychotomimetic potency and the need for repeated IV infusions. D-cycloserine (DCS) is an approved oral antibiotic for tuberculosis drug and a well-studied mixed agonist/antagonist at the NMDAR/glycine binding site. DCS showed preliminary evidence of efficacy in a pilot study. DCS would thus be practical from both a safety and route of administration perspective. The present study will explore the feasibility and safety of DCS for maintenance treatments, as measured by magnetic resonance spectroscopy (MRS).

Inclusion Criteria:

• Male and female patients with Diagnostic and Statistical Manual, Version 4 (DSM-IV) diagnosis of bipolar disorder I or II, current major depressive episode without psychotic features, 18-60
• Insufficient therapeutic response during the current episode
• Medically stable for study participation
• Judged clinically not to be at significant suicide or violence risk
• Subject is off all psychotropic and other types of drugs likely to interact with glutamate for at least 14 days before starting the study. One exception is chloral hydrate or short acting benzodiazepines for distressing anxiety or insomnia (up to 72 hours prior to each MRI scan). In addition, subjects will be off antipsychotics for 1 month and off fluoxetine for 6 weeks prior to the study.
• Subject is likely to be able to tolerate a medication washout. Only subjects who have failed their current medication regiment will be washed off medications.

Exclusion Criteria:

• History of chronic psychosis or drug induced psychosis of any kind
• Current DSM-IV diagnosis of drug abuse/dependence in the last six months. Subjects must have a negative drug screen at baseline.
• Women will be excluded if they are pregnant lactating, or not either surgically-sterile or using appropriate methods of birth control. Women must agree to continue using applicable birth control throughout the trial. All women of child-bearing potential must have a negative urine pregnancy test
• Taking any medication contraindicated with ketamine or DCS (ethionamide, isoniazid)
• History of seizures, renal insufficiency or congestive heart failure
• History of clinically significant violence
• History of ketamine abuse/dependence or prior clinically significant adverse reaction to ketamine
• Current alcohol abuse or dependence
• Untreated hypertension
• Clinically abnormal liver function tests (LFTs), thyroid, renal function or anemia
• Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or paramagnetic objects contained within the body which may present a risk to the subject or interfere with the MR scan.
• Medicinal patch, unless removed prior to the MR scan

Limitations include the small-sample and a non-placebo controlled, open-label design.