Treatment Resistant Depression (Pilot)

Inclusion criteria: 1. males and females aged 18-65 years; 2. Diagnostic and Statistical Manual (DSM) IV diagnosis of Major Depressive Disorder, recurrent, severe; 3. depression must be considered treatment refractory as defined by Montgomery Asberg Depression Rating Scale (MADRS) score of 22 or above which is consistent with other studies; 4. on a stable dose of permitted antidepressant medication or no medication pre-infusion; 5. not currently psychotic and no history of psychosis within the previous 12 months; psychosis reported in the distant past may not be exclusionary if brief, per PI's judgment; 6. no history of significant clinical or intolerable side effects or complications from clonidine; 7. if a female of child-bearing potential: not pregnant or breast feeding and agrees to use birth control during the time of pre-dosing and infusions; and 8. able to give informed consent. Exclusion Criteria: 1. confirmed bipolar disorder, schizophrenia, or schizoaffective disorder; 2. current or recent substance abuse/dependence (or any lifetime recreational ketamine or PCP use); 3. any severe Axis II personality disorder or schizophrenia spectrum disorder that, in the PI's judgment, could confound diagnosis or adherence to treatment; 4. the presence of any abnormal laboratory findings or serious medical disorder or condition that may, in the judgment of the PI, confound the assessment of relevant biologic measures or diagnoses including: clinically significant organ system dysfunction; significant and uncontrolled endocrine disease, including diabetes mellitus; hypothyroidism; cardiovascular disease; coagulopathy; significant anemia; significant acute infection; glaucoma; dehydration; epilepsy; any diagnosed cardiac condition causing documented hemodynamic compromise or dysfunction of the SA or AV node; any diagnosed respiratory condition causing documented or clinically recognized hypoxia (e.g., chronic obstructive or restrictive pulmonary disease); after evaluation, anyone determined to have a potentially compromised airway that could be difficult to intubate; fever; BMI less than 14.5; or any medical condition known to interfere with cognitive performance; medication-related exclusions include memantine, or any medication that could be considered contraindicated ketamine; 5. current treatment with any medication contraindicated with ketamine or clonidine; 6. lifetime illegal use of PCP or ketamine; no clinical use of ketamine for past 3 months 7. meets DSM-IV criteria for Mental Retardation; 8. currently hospitalized; 9. acutely suicidal or homicidal (i.e., in imminent danger with plan, urges and intent to harm oneself or others) including any prior serious attempts (e.g., those requiring hospitalization) at the PI's discretion; 10. is pregnant or breast-feeding; unwilling to use birth control if female of child bearing potential 11. unable to provide informed consent.