Treatment Resistant Depression (Pilot)

This experiment is a pilot study involving up to 20 healthy males or females between the ages
of 18-65 to test whether a 100-hour ketamine infusion plus clonidine would be more effective,
with longer lasting results, then the standard 40-minute ketamine infusion (plus clonidine).
Each of the 2 arms, will be evaluated using a between subject, double-blind, randomized
design. An additional subset of 20 non-randomized patients, separate from the original
randomized clinical trial (RTC), will receive an MRI pre and post ketamine infusion.

1. a. Controlled 100-hour IV ketamine infusion b. clonidine safener PO prior to infusion

2. a. Controlled 40-minute IV ketamine infusion b. clonidine safener PO prior to infusion
c. 100-hour(+/-)IV placebo (saline) infusion

3. a. Controlled 100-hour IV ketamine infusion b. clonidine safener PO prior to infusion c.
MRI pre and post ketamine infusion

In both conditions and the neuroimaging subset, participants will be admitted to the
Washington University School of Medicine Clinical Research Unit at Barnes-Jewish Hospital for
approximately 108-hours (Monday morning-Friday evening). Pulse, blood pressure,
pulse-oximetry, and an electrocardiogram strip will be routinely monitored. Serial labs and
clinical/safety ratings will be done pre-, during, and post-infusion, with the last
assessments being used to assure that subjects have returned to their "baseline" prior to
discharge from the research unit. Participants will continue to see their primary
psychiatrist throughout the study.

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.

12. For participants in the neuroimaging subset: history of claustrophobia, serious head
injuries, seizures disorder, developmental delays, pacemaker, metal implants,
permanent metal piercings or anything else that would preclude having an MRI.