NMDA Receptor Antagonist Nitrous Oxide Targets Affective Brain Circuits

Inclusion Criteria: * Adults 18-65 years of age * Right-handed * Controls: Not meet The Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depressive disorder (MDD) by scoring ≤7 on the Hamilton Depression Rating Scale (HDRS), 17-item; Treatment-Resistant Major Depression (TRMD) patients: Must meet a ≥17 score on the HDRS. * Controls: Must not have any history of depression as determined by reported history and medical record review; TRMD: Documented (chart review) failure to respond to ≥3-4 adequate dose/duration antidepressant treatments; ≥1 in the current depressive episode. * Good command of the English language Exclusion Criteria: * Meets criteria for any DSM-IV Axis I diagnosis as documented in medical records and as determined by structured clinical interview (except MDD for the TRMD group) * Known primary neurological disorders or medical disorders including dementia, stroke, encephalopathy Parkinson's Disease, brain tumors, multiple sclerosis, seizure disorder, severe cardiac or pulmonary disease * Any central nervous system active medication as determined by study investigator * Any known disease affecting drug metabolism and excretion (e.g. renal or liver disease) as determined by study investigator * Left-handedness * Not eligible for MRI scans (e.g. history of claustrophobia/implanted metal as per MRI Screening Tool) * Current use of psychotropic medications, antidepressants, or prescription or non-prescription drugs/herbals intended to treat depression or anxiety (control group only) * Any recent (within past 12 months) history of substance dependence or abuse, determined by reported history or urine drug screen * Ability to become pregnant and not using effective contraception * Contraindication against the use of nitrous oxide: 1. Pneumothorax 2. Bowel obstruction 3. Middle ear occlusion 4. Elevated intracranial pressure 5. Chronic cobalamin and/or folate deficiency treated with folic acid or vitamin B12 6. Pregnant patients 7. Breastfeeding women * Inability to provide informed consent * Any other factor that in the investigators' judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from clinic).