NMDA Antagonists in Bipolar Depression

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