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Rapid Antidepressant Effects of Ketamine in Major Depression

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier:
NCT00088699
First received: July 30, 2004
Last updated: November 23, 2016
Last verified: July 2016

July 30, 2004
November 23, 2016
July 2004
April 2017   (final data collection date for primary outcome measure)
Efficacy (reduction from baseline in Montgomery Asberg Depression Rating Scale scores between groups); 2) putative biomarkers of response (task-dependent and resting-state activity in the anterior cingulate cortex (ACC) and the amygdala; [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
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Complete list of historical versions of study NCT00088699 on ClinicalTrials.gov Archive Site
  • 3) GABA and Glx/Glutamate ratio; 4) gray matter volume and integrity of white matter fibers connecting the ACC and the amygdala; 4) fMRI task-dependent and resting-state activity changes in the ACC and the amygdala; [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
  • 5) Correlations between fMRI task-dependent and resting-state activity changes in the ACC and the amygdala; and 6) differential neural effects of ketamine vs. placebo in patients with MDD, BD, and healthy control subjects. [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
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Rapid Antidepressant Effects of Ketamine in Major Depression
Investigation of the Rapid (Next Day) Antidepressant Effects of an NMDA Antagonist

This study examines whether Ketamine can cause a rapid-next day antidepressant effect in patients with Major Depression/Bipolar Disorder .

Purpose: 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.

Bipolar affective disorder (manic-depressive illness) and unipolar depression are common,

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. In two separate trials, we tested riluzole (an inhibitor of glutamate release) and found it to have antidepressant properties in patients with unipolar and bipolar depression (Zarate et al. 2004, 2005). In another study, we found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and last approximately 1 week (Zarate et al in 2006). The current protocol consists of 6 studies designed to address 6 major questions. Two of these studies (1 and 5) have met their enrollment quota and sufficient analyzable data has been obtained.

Study 1 (Rapid improvement research in unipolar depression)

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant major depression? 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 (Study completed).

Study 2 (Rapid improvement research in bipolar depression)

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? Patients, ages 18 to 65 years with treatment-resistant

bipolar depression will in a double-blind crossover study receive either intravenous ketamine or saline solution added to a mood stabilizer (lithium or valproate).

Study 3 (Rapid and sustained improvement research in unipolar depression)

Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine? Patients, ages 18 to 65 years, with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine will in a double-blind study receive either riluzole or placebo to determine if the rapid response obtained can be sustained.

Substudy 4 (Predictors and neural correlates of antidepressant response to ketamine)

What are the predictors and neural correlates of antidepressant response to ketamine? Patients, ages 18 to 65 years with treatment-resistant MDD and BD will, in a double-blind crossover study, receive either intravenous ketamine or saline solution and multimodal MRI, MEG and polysomnography.

Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be

achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression, and 4) predictors and neural correlates of antidepressant response to ketamine can be identified.

Substudy 5 (Neurophysiological Mechanisms of Rapid Antidepressant Response to Ketamine)

Will activity of glutamatergic circuits within the brain change following the onset of ketamine-induced antidepressant effects help predict response to ketamine? Drug-free bipolar and unipolar patients participating in Substudies 2 and 3 will undergo PET scans before and 2-hours following drug infusion (consistent with the timing of onset of antidepressant effects). (Study completed)

Substudy 6 (Role of Glutamatergic and GABAergic systems in treatment response to ketamine/riluzole)

Will subjects with treatment-resistant major depression who receive ketamine followed by riluzole show a greater increase in the concentration of GABA, glutamate, glutamine and NAA compared to subjects randomized to placebo? Unipolar patients participating in Substudy 3 will have 1H-MRS scans immediately before both infusions (ketamine, placebo) and at the end of each experimental phase.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
  • Depression
  • Mood Disorders
  • Bipolar Depression
  • Major Depresssion
  • Drug: Ketamine
  • Drug: Riluzole
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
324
April 2017
April 2017   (final data collection date for primary outcome measure)
  • 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 Bipolar I or II depressed 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 2 (patients with MDD)

1. Subjects must take VPA or lithium (valproate 50-125 g/ml or lithium 0.6-1.2 mEq/L) for at least 4 weeks prior to Visit 2 and for the entire duration of the study. If the subject is not taking lithium or VPA, the research physician may start them on lithium or VPA at the NIH.

Additional inclusion criteria for substudy 4 (patients with MDD or BD)

  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. Subjects with bipolar disorder must have a YMRS of 12 or less at baseline for Phase I.
  4. A failed adequate trial of ECT would count as an adequate antidepressant trial.
  5. 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 or BD)

  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.

Both
18 Years to 65 Years   (Adult)
Yes
Contact: Libby Jolkovsky (877) 646-3644 libby_jolkovsky@nih.gov
Contact: Carlos A Zarate, M.D. (301) 451-0861 zaratec@mail.nih.gov
United States
 
NCT00088699
040222, 04-M-0222
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National Institute of Mental Health (NIMH)
National Institute of Mental Health (NIMH)
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Principal Investigator: Carlos A Zarate, M.D. National Institute of Mental Health (NIMH)
National Institutes of Health Clinical Center (CC)
July 2016

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