Nitrous TRD Bipolar Depression

Investigators will study approximately 64 patients with Treatment-Resistant Bipolar
Depressive Disorder, defined as a failure of at least 1 antidepressants in the current
depressive episode and 2 lifetime medication failures. The study will last approximately 6 to
8 weeks, involving randomization into one of two treatment groups receiving 3 one hour long
inhalation treatments over a week. Post-treatment assessments follow each inhalation
treatment and are conducted 1 week and 2 weeks following the final inhalation treatment.
Patients are then randomized again into the Second Stage of the study, involving the same
treatment and post-treatment schedule as the First Stage detailed above.

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