Nitrous TRD Bipolar Depression

Inclusion Criteria: * Adults 18-65 years of age * Treatment-resistant bipolar depressive disorder without psychosis and a MADRS baseline score of \>20. All patients must have history of being on a serum-verified (at time of entry into study) mood stabilizer \[lithium at 0.5-1.2mEq/L; or valproic acid, 50-125mcg/ml\] for 4 weeks prior to entry into the study and remain on this mood stabilizer during the course of the trial. Further, subjects will have failed two adequate dose/duration antidepressant courses in their lifetime, including one in the current depressive episode (verified by Antidepressant Treatment History Form). * Good command of the English language Exclusion Criteria: * Schizophrenia * Schizoaffective disorder * Obsessive-compulsive disorder or panic disorder * Active or recent substance abuse or dependence (in remission at least 1 year prior to the study; exception = nicotine use disorders) * A diagnosis of personality disorder that may interfere with the patient's ability to improve on nitrous oxide as determined by study investigator * Acute medical illness that may pose subject at risk during nitrous oxide administration (neurological disorders or medical disorders including dementia, stroke, encephalopathy, Parkinson's Disease, brain tumors, multiple sclerosis, seizure disorder, severe cardiac disease, any disease known to affect drug metabolism and excretion, i.e. renal or liver disease) per P.I. discretion * Active suicidal intention (inability to contract for safety) * Active psychotic symptoms * Patients with significant pulmonary disease and/or requiring supplemental oxygen * Contraindication against the use of nitrous oxide: pneumothorax; bowel obstruction; middle ear occlusion; elevated intracranial pressure; chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12; pregnant patients; breastfeeding women; previous administration of NMDA-receptor antagonists (e.g., ketamine); current electro-convulsive therapy treatment