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Treatment Resistant Depression (Pilot)

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ClinicalTrials.gov Identifier: NCT01179009
Recruitment Status : Active, not recruiting
First Posted : August 10, 2010
Last Update Posted : October 6, 2021
Sponsor:
Collaborator:
Florida Atlantic University
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE August 2, 2010
First Posted Date  ICMJE August 10, 2010
Last Update Posted Date October 6, 2021
Actual Study Start Date  ICMJE April 2012
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 23, 2015)
Reduction in (1) Clinical Global Interview (CGI) scores and (2) Montgomery-Asberg Depression Rating Scale (MADRS) scores [ Time Frame: approximately 5 years ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 9, 2010)
reduction in HRSD (depression rating) scores by >50% [ Time Frame: approximately 5 years ]
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.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment Resistant Depression (Pilot)
Official Title  ICMJE A Safe Ketamine-Based Therapy for Treatment Resistant Depression
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 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 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).

A subset of patients with TRD will also receive a 100-hour (+/- 4-hours) ketamine infusion with two head MRIs pre-infusion and one head MRI post-infusion and/or weekly maintenance IM injections of either ketamine or active CNS placebo, lorazepam for up to 16 weeks. Little research has been done on the mechanism of ketamine's putative antidepressant action. There is now a consensus that, in the 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.

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. 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 and/or weekly maintenance IM injections of either ketamine or active CNS placebo, lorazepam for up to 16 weeks.

  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 c. MRI pre and post ketamine infusion
  4. a.Controlled up to 100-hour IV ketamine infusion b. clonidine safener PO prior to infusion c. responders after up to 100-hour IV ketamine infusion receive IM injections of ketamine or lorazepam 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Depressive Disorder, Treatment-Resistant
Intervention  ICMJE
  • Drug: Ketamine
    Controlled IV ketamine infusion (0.00225mg/kg-min. [18% (0.0125 mg/kg-min.). A subset of participants will receive ketamine maintenance injections (0.5-5 mg/kg, IM) for up to 16 weeks after 100-hour infusion.
    Other Names:
    • Ketalar
    • Ketalin
    • Ketalor
  • Drug: Clonidine
    Participants will receive an approximately 5-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)
    Other Name: saline
  • Drug: Scopolamine Transdermal Product
    Some participants will receive a scopolamine transdermal patch prior to and throughout their infusion/injections visits.
    Other Name: Transderm scop, Scopace, Maldemar
  • Drug: lorazepam Injection
    A subset of participants will receive lorazepam IM maintenance injections for up to 16 weeks after 100-hour infusion.
    Other Name: Ativan
Study Arms  ICMJE
  • Experimental: ketamine 100-hour infusion
    100-hour infusion of ketamine plus a safener (clonidine)
    Interventions:
    • Drug: Ketamine
    • Drug: Clonidine
    • Drug: Scopolamine Transdermal Product
  • Experimental: ketamine 40-minute infusion
    40-minute ketamine infusion following a 100-hours +/- placebo (saline) infusion. Participants will also receive a safener (clonidine)
    Interventions:
    • Drug: Ketamine
    • Drug: Clonidine
    • Drug: placebo
  • Experimental: ketamine IM injections
    One-2 weeks after the end of the 96-hour ketamine infusion, subjects assigned to the ketamine maintenance arm will return for ketamine maintenance injections (0.5-5 mg/kg, IM).
    Interventions:
    • Drug: Ketamine
    • Drug: Clonidine
    • Drug: Scopolamine Transdermal Product
  • Experimental: lorazepam IM Injections
    Subjects randomized to the lorazepam control arm will also return for IM lorazepam maintenance injections 2 mg IM (range 0.5 - 4).
    Interventions:
    • Drug: Clonidine
    • Drug: placebo
    • Drug: Scopolamine Transdermal Product
    • Drug: lorazepam Injection
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 30, 2021)
110
Original Estimated Enrollment  ICMJE
 (submitted: August 9, 2010)
164
Estimated Study Completion Date  ICMJE June 2022
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01179009
Other Study ID Numbers  ICMJE 201202157
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE Florida Atlantic University
Investigators  ICMJE
Principal Investigator: Eric Lenze, MD Washington University School of Medicine
Principal Investigator: John W Newcomer, MD Washington University School of Medicine
Principal Investigator: Nuri B Farber, MD Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP