Treatment resistant depression (TRD) is a major public health problem. Current therapeutic options for this patient population remain limited. With all available treatments, only a sub-set of those patients who achieve an antidepressant response are likely to achieve treatment-induced remission. The need for antidepressant medication that can provide both rapid and long lasting relief of TRD symptoms is widely recognized. There is new evidence that drugs that block NMDA glutamate receptors (NMDA antagonists) are promising candidates for meeting this need. Existing studies in TRD have used only a low-dose, brief infusion of ketamine that would not be expected to re-sensitize the NMDA receptor; in agreement with this theory, these prior studies have found only temporary improvements of depression. Our key hypothesis is that a higher-dose, longer-term ketamine infusion, such as that used in chronic pain studies, would provide a more robust and lasting improvement from depression.

Accordingly, we will test whether a 100-hour ketamine infusion would be more effective than the standard 40-minute ketamine infusion currently used in other TRD studies. We will randomize subjects to one of 2 arms: (1) 100-hour (+/- 4 hours) ketamine infusion plus clonidine for the entire infusion (2) 40-minute ketamine infusion (plus clonidine) following a 100+/- hour saline infusion. All subjects will receive clonidine, an alpha-2 agonist, to minimize side effects of ketamine (namely, brief/mild psychotic and cognitive symptoms).

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.

1. a. Controlled up to 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. up to 100-hour(+/-)IV placebo (saline) infusion
3. a. Controlled up to 100-hour IV ketamine infusion b. clonidine safener PO prior to infusion
4. a.Controlled up to 100-hour IV ketamine infusion b. clonidine safener PO prior to infusion

In both conditions, 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.

Symptoms were measured 4 times daily over the course of the 4-day infusion using the Brief Psychiatric Rating Scale and the Clinical and Adverse Events Checklist. For symptoms that occurred on more than one assessment, the highest severity rating is reported.

A pilot and feasibility study with limited statistical power due to a small sample size. Another limitation was the lack of a scale specifically measuring dissociative symptoms. In addition, the allowance of co-occurring antidepressant use could result in increased heterogeneity of responses unrelated to the study medication. Finally, the sample was ethnically homogeneous.