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Rapid Antidepressant Effects of Ketamine in Major Depression

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ClinicalTrials.gov Identifier: NCT00088699
Recruitment Status : Completed
First Posted : August 2, 2004
Results First Posted : October 12, 2018
Last Update Posted : October 12, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Tracking Information
First Submitted Date  ICMJE July 30, 2004
First Posted Date  ICMJE August 2, 2004
Results First Submitted Date  ICMJE July 30, 2018
Results First Posted Date  ICMJE October 12, 2018
Last Update Posted Date October 12, 2018
Study Start Date  ICMJE July 26, 2004
Actual Primary Completion Date July 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 12, 2018)
  • MADRS Score - Baseline [ Time Frame: Baseline ]
    Antidepressant effects were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). It is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.
  • MADRS Score - Day 1 Following Intervention [ Time Frame: Day 1 ]
    Antidepressant effects were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). It is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.
Original Primary Outcome Measures  ICMJE Not Provided
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 Rapid Antidepressant Effects of Ketamine in Major Depression
Official Title  ICMJE Investigation of the Rapid (Next Day) Antidepressant Effects of an NMDA Antagonist
Brief Summary

Depressive disorders may be severe, chronic and often life-threatening illnesses. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants.

This study examines whether ketamine can cause a rapid-next day antidepressant effect in patients with Major Depressive Disorder.

This study was designed to address the questions:

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant major depression? What are the neurobiological correlates of antidepressant response (examining multi-modal MRI, MEG, polysomnography and serum markers) Patients, ages 18 to 65 years with treatment-resistant major (unipolar) depression will in a double-blind crossover study receive either intravenous ketamine or saline solution.
Detailed Description

This study will test whether a single dose of ketamine - a drug that blocks a brain receptor called NMDA - can cause a rapid (next day) antidepressant effect in patients with major depression. Several medications are effective for treating depression; however, they take weeks or months to achieve their full effects. A more rapidly acting antidepressant would have a significant impact on the treatment of depression. In a previous study, ketamine produced a rapid antidepressant effect within hours, but the effect lasted less than 1 week. Understanding how ketamine works may lead to a better understanding of the causes of depression and the design of a longer lasting rapidly acting antidepressant.

Patients between 18 and 65 years of age who are currently experiencing an episode of major depression of at least 4 weeks duration and have not responded to two treatment trials may be eligible for this study. Candidates are screened with a medical and psychiatric history, physical examination, and blood and urine tests.

Participants undergo the following tests and procedures:

Medication tapering: Patients who are taking medications for depression are tapered off the drugs over a 1- to 2-week period.

Ketamine/placebo trial: Patients are given a single dose of either ketamine or placebo (an inactive substance), administered intravenously (through a vein) over 40 minutes. After 7 days, patients are given another dose of study drug in crossover fashion; that is, those who previously took ketamine are switched to receive placebo, and those who took placebo are switched to ketamine. Oximetry (measurement of blood oxygen), pulse, and blood pressure are measured continuously for 1 hour before and 4 hours after each ketamine or placebo dose to monitor safety.

Interviews and rating scales: Patients complete a series of psychiatric rating scales to assess the effects of the study drug on mood and thinking. The rating scales are repeated up to 18 times during the study, with each time taking about 15 to 20 minutes.

Physical examination and laboratory tests: Patients have a physical examination, blood tests, weight measure, and electrocardiogram (ECG) at the beginning and end of the study. They will also have multi-modal MRI, MEG, polysomnography and serum marker studies.

The primary endpoint will be the change in clinical ratings of depression. Secondary endpoints will examine neurobiological correlates (i.e., multi-modal MRI, MEG, polysomnography and serum markers) of antidepressant response to ketamine (compared to placebo).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Condition  ICMJE
  • Depression
  • Mood Disorders
  • Major Depresssion
Intervention  ICMJE
  • Drug: Ketamine
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Ketamine, Then Placebo
    Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg.
    Interventions:
    • Drug: Ketamine
    • Drug: Placebo
  • Experimental: Placebo, Then Ketamine
    Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg
    Interventions:
    • Drug: Ketamine
    • Drug: Placebo
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 Completed
Actual Enrollment  ICMJE
 (submitted: September 12, 2018)		 67
Original Enrollment  ICMJE
 (submitted: June 23, 2005)		 101
Actual Study Completion Date  ICMJE July 31, 2017
Actual Primary Completion Date July 31, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

General patient inclusion criteria

  1. Male or female subjects, 18 to 65 years of age.
  2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
  3. Subjects must fulfill DSM-IV criteria for Major Depressive Disorder (MDD) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
  4. Subjects must have an initial score of at least 20 on the MADRS at screen and at baseline of study phase I.
  5. Subjects must have failed to respond in the past to an adequate dose and duration of at least one antidepressant (SSRI, bupropion, or venlafaxine) during a depressive episode
  6. Current depressive episode of at least 4 weeks duration.

Additional inclusion criteria for substudy 4 (patients with MDD)

  1. Age of onset less than 40 years of age.
  2. Subjects with MDD must fulfill DSM-IV criteria for Major Depression single episode or recurrent without psychotic features based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P).
  3. A failed adequate trial of ECT would count as an adequate antidepressant trial.
  4. In women of childbearing age, a negative pregnancy test within 24 hours of MRI.

Inclusion criteria for healthy control subjects (Substudy 4 only)

  1. Age 18-65 years.
  2. Written informed consent completed.

EXCLUSION CRITERIA:

General patient exclusion criteria

  1. Current or past diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
  2. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.
  3. Female subjects who are either pregnant or nursing.
  4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
  5. Subjects with uncorrected hypothyroidism or hyperthyroidism.
  6. Subjects with one or more seizures without a clear and resolved etiology.
  7. Treatment with a reversible MAOI within 4 weeks prior to study phase I.
  8. Treatment with fluoxetine within 5 weeks prior to study phase I.
  9. Treatment with any other concomitant medication not allowed (Appendix A for Substudy 2; Appendix G for Substudy 4) 14 days prior to study phase I.
  10. No structured psychotherapy will be permitted during the study.
  11. Current NIMH employee/staff or their immediate family member.

Additional Exclusion Criteria for substudy 2 (patients with MDD)

1. Previous treatment with ketamine or hypersensitivity to amantadine.

Additional Exclusion Criteria for Substudy 4 (patients with MDD)

  1. Subjects who currently are using drugs (except for caffeine or nicotine), must not have used illicit substances in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines) urine test at screening.
  2. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
  3. Clinically significant abnormal laboratory tests.
  4. For imaging procedures, Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip).
  5. Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of >4.

Exclusion Criteria for healthy control subjects (Substudy 4 only)

  1. Current or past Axis I diagnosis
  2. Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clips).
  3. Presence of medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.
  4. Treatment with any of the exclusionary medications detailed in Appendix G 14 days prior to Phase 1 of the Substudy 4.
  5. Current or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine).
  6. Presence of psychiatric disorders in first-degree relatives.
  7. Female subjects who are either pregnant or nursing.

7.8.Current NIMH employee/staff or their immediate family member.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
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 NCT00088699
Other Study ID Numbers  ICMJE 040222
04-M-0222
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
Study Sponsor  ICMJE National Institute of Mental Health (NIMH)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date July 31, 2017

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