Rapid Antidepressant Effects of Ketamine in Major Depression
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|ClinicalTrials.gov Identifier: NCT00088699|
Recruitment Status : Completed
First Posted : August 2, 2004
Last Update Posted : March 15, 2018
|First Submitted Date ICMJE||July 30, 2004|
|First Posted Date ICMJE||August 2, 2004|
|Last Update Posted Date||March 15, 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
||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 ]|
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00088699 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|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|
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
|Study Arms||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Enrollment ICMJE
|Actual Study Completion Date||July 31, 2017|
|Actual Primary Completion Date||July 31, 2017 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
General patient inclusion criteria
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)
Inclusion criteria for healthy control subjects (Substudy 4 only)
General patient exclusion criteria
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)
Exclusion Criteria for healthy control subjects (Substudy 4 only)
7.8.Current NIMH employee/staff or their immediate family member.
|Ages||18 Years to 65 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00088699|
|Other Study ID Numbers ICMJE||040222
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||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|
|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