Treatment Resistant Depression (Pilot)

Not Applicable

Completed

Conditions: Depressive Disorder, Treatment-Resistant

Interventions: Drug: Ketamine
Drug: Clonidine
Drug: placebo

Registration Number: NCT01179009

Lead Sponsor: Washington University School of Medicine

Brief Summary: 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).

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

Inclusion Criteria

Not provided

Exclusion Criteria

confirmed bipolar disorder, schizophrenia, or schizoaffective disorder;
current or recent substance abuse/dependence (or any lifetime recreational ketamine or PCP use);
any severe Axis II personality disorder or schizophrenia spectrum disorder that, in the PI's judgment, could confound diagnosis or adherence to treatment;
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;
current treatment with any medication contraindicated with ketamine or clonidine;
lifetime illegal use of PCP or ketamine; no clinical use of ketamine for past 3 months
meets DSM-IV criteria for Mental Retardation;
currently hospitalized;
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;
is pregnant or breast-feeding; unwilling to use birth control if female of child bearing potential
unable to provide informed consent.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ketamine 40-minute infusion	placebo	40-minute ketamine infusion following a 100-hours +/- placebo (saline) infusion. Participants will also receive a safener (clonidine)
ketamine 100-hour infusion	Ketamine	100-hour infusion of ketamine plus a safener (clonidine)
ketamine 100-hour infusion	Clonidine	100-hour infusion of ketamine plus a safener (clonidine)
ketamine 40-minute infusion	Clonidine	40-minute ketamine infusion following a 100-hours +/- placebo (saline) infusion. Participants will also receive a safener (clonidine)
ketamine 40-minute infusion	Ketamine	40-minute ketamine infusion following a 100-hours +/- placebo (saline) infusion. Participants will also receive a safener (clonidine)

Primary Outcome Measures

Name	Time	Method
Montgomery-Asberg Depression Rating Scale (MADRS) Total Score	8 weeks	The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item scale that measures the severity of depression, with a higher score indicating a higher level of depression. The range of scores is 0 to 60.
Clinical Global Impression (CGI) Global Improvement Score.	8 weeks	The Clinical Global Improvement is a 7-point scale where the anchors range from 1 (very much improved) to 7 (very much worse).

Secondary Outcome Measures