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Treatment Resistant Depression (Pilot)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Washington University School of Medicine
Sponsor:
Collaborator:
Florida Atlantic University
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01179009
First received: August 2, 2010
Last updated: March 12, 2014
Last verified: March 2014
  Purpose

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 be 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 99+/- 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).

A subset of 18 patients with TRD will receive a 100-hour (+/- 4-hours)ketamine infusion with a head MRI pre and post infusion. Little research has been done on the mechanism of ketamine's putative antidepressant action. There is now a consensus that, in early stages of the novel treatment development for depression, clinical studies should be paired with mechanistic studies (neuroimaging) to understand the underlying mechanism and validate this as a treatment target. Ketamine is thought to have an antidepressant effect by increasing synaptic connections and therefore increasing connectivity in critical cognitive/emotional circuits.


Condition Intervention
Treatment Refractory Depression
Drug: Ketamine
Drug: Clonidine
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Safe Ketamine-Based Therapy for Treatment Resistant Depression

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • reduction in Hamilton Depression Rating Scale (HDRS) scores by >50% [ Time Frame: approximately 5 years ] [ Designated as safety issue: Yes ]

    Primary Aim 1: To evaluate the efficacy and tolerability of a single safener for the prevention of ketamine-induced psychotomimetic effects in healthy humans.

    Primary Aim 2: To evaluate the effect of a standardized IV ketamine plus optimal safener combination treatment on change in the severity of depression in patients with TRD.



Estimated Enrollment: 20
Study Start Date: April 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ketamine 100-hour infusion
100-hour infusion of ketamine plus a safener (clonidine)
Drug: Ketamine
Controlled IV ketamine infusion (0.00225mg/kg-min. [18% (0.0125 mg/kg-min.)
Drug: Clonidine
Participants will receive an approximately 2-day pretreatment of clonidine (max. dose 1mg/day divided doses) prior to and throughout the ketamine infusion.
Other Name: Catapares
Experimental: ketamine 40-minute infusion
40-minute ketamine infusion following a 99 hours +/- placebo (saline) infusion. Participants will also receive a safener (clonidine)
Drug: Ketamine
Controlled IV ketamine infusion (0.00225mg/kg-min. [18% (0.0125 mg/kg-min.)
Drug: Clonidine
Participants will receive an approximately 2-day pretreatment of clonidine (max. dose 1mg/day divided doses) prior to and throughout the ketamine infusion.
Other Name: Catapares
Drug: placebo
IV saline (i.e. placebo ketamine)

Detailed Description:

This experiment is a pilot study involving up to 20 healthy males or females between the ages of 21-65 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 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. 99-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 and the PI will request follow-up office reports from the treating psychiatrist for the remaining 44 weeks of the year post study completion.

  Eligibility

Ages Eligible for Study:   21 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. males and females aged 21-65 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, unchanged dose of permitted antidepressant medication for at least 30 days 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01179009

Contacts
Contact: Julie Schweiger, CCRC 314-362-3153 schweigj@psychiatry.wustl.edu
Contact: Angela Stevens 314-362-6291 stevensa@psychiatry.wustl.edu

Locations
United States, Florida
Florida Atlantic University Active, not recruiting
Boca Raton, Florida, United States, 33431-0991
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: Julie Schweiger, CCRC    314-362-3153    schweigj@psychiatry.wustl.edu   
Contact: Angela Stevens    314-362-6291    stevensa@psychiatry.wustl.edu   
Principal Investigator: Eric Lenze, MD         
Sub-Investigator: Nuri B Farber, MD         
Sponsors and Collaborators
Washington University School of Medicine
Florida Atlantic University
Investigators
Principal Investigator: Eric Lenze, MD Washington University School of Medicine
Principal Investigator: John W Newcomer, MD Washington University School of Medicine and Florida Atlantic University
Principal Investigator: Nuri B Farber, MD Washington University School of Medicine
  More Information

No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01179009     History of Changes
Other Study ID Numbers: 10-0000
Study First Received: August 2, 2010
Last Updated: March 12, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:
depression

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Mental Disorders
Mood Disorders
Clonidine
Ketamine
Adrenergic Agents
Adrenergic Agonists
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Analgesics
Anesthetics
Anesthetics, Dissociative
Anesthetics, General
Anesthetics, Intravenous
Antihypertensive Agents
Autonomic Agents
Cardiovascular Agents
Central Nervous System Agents
Central Nervous System Depressants
Excitatory Amino Acid Agents
Excitatory Amino Acid Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents

ClinicalTrials.gov processed this record on November 25, 2014