Rapid Antidepressant Effects of Ketamine in Major Depression
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
|Official Title:||Investigation of the Rapid (Next Day) Antidepressant Effects of an NMDA Antagonist|
- 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 ]
- 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 ]
|Study Start Date:||July 2004|
|Estimated Study Completion Date:||April 2017|
|Estimated Primary Completion Date:||April 2017 (Final data collection date for primary outcome measure)|
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00088699
|Contact: Libby Jolkovsky||(877) firstname.lastname@example.org|
|Contact: Carlos A Zarate, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Carlos A Zarate, M.D.||National Institute of Mental Health (NIMH)|