Rapid Antidepressant Effects of Ketamine in Major Depression

Tracking Information
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; (submitted: September 2, 2015)	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; (submitted: September 2, 2015)	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 ]; 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 ]
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	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	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.
Detailed Description	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; 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; Bipolar Depression; Major Depresssion
Intervention ICMJE	Drug: Ketamine; Drug: Riluzole
Study Arms	Not Provided
Publications *	Agnoli A, Ruggieri S, Casacchia M. Restatement and prospectives of ergot alkaloids in clinical neurology and psychiatry. Pharmacology. 1978;16 Suppl 1:174-88.; Agren H, Mefford IN, Rudorfer MV, Linnoila M, Potter WZ. Interacting neurotransmitter systems. A non-experimental approach to the 5HIAA-HVA correlation in human CSF. J Psychiatr Res. 1986;20(3):175-93.; Anderson IM. SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety. 1998;7 Suppl 1:11-7.; Vande Voort JL, Ballard ED, Luckenbaugh DA, Bernert RA, Richards EM, Niciu MJ, Park LT, Machado-Vieira R, Duncan WC Jr, Zarate CA Jr. Antisuicidal Response Following Ketamine Infusion Is Associated With Decreased Nighttime Wakefulness in Major Depressive Disorder and Bipolar Disorder. J Clin Psychiatry. 2017 Sep/Oct;78(8):1068-1074. doi: 10.4088/JCP.15m10440.; Pennybaker SJ, Niciu MJ, Luckenbaugh DA, Zarate CA. Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion. J Affect Disord. 2017 Jan 15;208:560-566. doi: 10.1016/j.jad.2016.10.026. Epub 2016 Oct 26. Review.; Bernert RA, Luckenbaugh DA, Duncan WC, Iwata NG, Ballard ED, Zarate CA. Sleep architecture parameters as a putative biomarker of suicidal ideation in treatment-resistant depression. J Affect Disord. 2017 Jan 15;208:309-315. doi: 10.1016/j.jad.2016.08.050. Epub 2016 Oct 14.; Park M, Newman LE, Gold PW, Luckenbaugh DA, Yuan P, Machado-Vieira R, Zarate CA Jr. Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression. J Psychiatr Res. 2017 Jan;84:113-118. doi: 10.1016/j.jpsychires.2016.09.025. Epub 2016 Sep 30.; Berg HE, Ballard ED, Luckenbaugh DA, Nugent AC, Ionescu DF, Zarate CA Jr. Recognition of emotional facial expressions in anxious and nonanxious depression. Compr Psychiatry. 2016 Oct;70:1-8. doi: 10.1016/j.comppsych.2016.06.007. Epub 2016 Jun 14.; Ballard ED, Vande Voort JL, Luckenbaugh DA, Machado-Vieira R, Tohen M, Zarate CA. Acute risk factors for suicide attempts and death: prospective findings from the STEP-BD study. Bipolar Disord. 2016 Jun;18(4):363-72. doi: 10.1111/bdi.12397. Epub 2016 May 27.; Ballard ED, Luckenbaugh DA, Richards EM, Walls TL, Brutsché NE, Ameli R, Niciu MJ, Vande Voort JL, Zarate CA Jr. Assessing measures of suicidal ideation in clinical trials with a rapid-acting antidepressant. J Psychiatr Res. 2015 Sep;68:68-73. doi: 10.1016/j.jpsychires.2015.06.003. Epub 2015 Jun 16.; Luckenbaugh DA, Ameli R, Brutsche NE, Zarate CA Jr. Rating depression over brief time intervals with the Hamilton Depression Rating Scale: standard vs. abbreviated scales. J Psychiatr Res. 2015 Feb;61:40-5. doi: 10.1016/j.jpsychires.2014.12.015. Epub 2014 Dec 27.; Ortiz R, Niciu MJ, Lukkahati N, Saligan LN, Nugent AC, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr. Shank3 as a potential biomarker of antidepressant response to ketamine and its neural correlates in bipolar depression. J Affect Disord. 2015 Feb 1;172:307-11. doi: 10.1016/j.jad.2014.09.015. Epub 2014 Oct 16.; Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Zarate CA Jr. A single infusion of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar Disord. 2015 Jun;17(4):438-43. doi: 10.1111/bdi.12277. Epub 2014 Nov 14.; Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Slonena EE, Vande Voort JL, Brutsche NE, Zarate CA Jr. Effect of baseline anxious depression on initial and sustained antidepressant response to ketamine. J Clin Psychiatry. 2014 Sep;75(9):e932-8. doi: 10.4088/JCP.14m09049.; Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, Brutsché NE, Ameli R, Furey ML, Zarate CA Jr. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 2014 Nov;58:161-6. doi: 10.1016/j.jpsychires.2014.07.027. Epub 2014 Aug 12.; Cornwell BR, Salvadore G, Furey M, Marquardt CA, Brutsche NE, Grillon C, Zarate CA Jr. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. 2012 Oct 1;72(7):555-61. doi: 10.1016/j.biopsych.2012.03.029. Epub 2012 Apr 21.; Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012 Jun 1;71(11):939-46. doi: 10.1016/j.biopsych.2011.12.010. Epub 2012 Jan 31.; Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010 Aug;67(8):793-802. doi: 10.1001/archgenpsychiatry.2010.90.; DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010 Dec;71(12):1605-11. doi: 10.4088/JCP.09m05327blu. Epub 2010 Jul 13.; Machado-Vieira R, Yuan P, Brutsche N, DiazGranados N, Luckenbaugh D, Manji HK, Zarate CA Jr. Brain-derived neurotrophic factor and initial antidepressant response to an N-methyl-D-aspartate antagonist. J Clin Psychiatry. 2009 Dec;70(12):1662-6. doi: 10.4088/JCP.08m04659. Epub 2009 Sep 8.; Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA Jr. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. 2009 Jan 15;65(2):181-4. doi: 10.1016/j.biopsych.2008.09.029. Epub 2008 Nov 8.; Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
* 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: August 1, 2017)	233
Original Enrollment ICMJE; (submitted: June 23, 2005)	26
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	INCLUSION CRITERIA: General patient inclusion criteria; Male or female subjects, 18 to 65 years of age.; Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.; 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.; Subjects must have an initial score of at least 20 on the MADRS at screen and at baseline of study phase I.; 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; 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); Age of onset less than 40 years of age.; 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).; Subjects with bipolar disorder must have a YMRS of 12 or less at baseline for Phase I.; A failed adequate trial of ECT would count as an adequate antidepressant trial.; In women of childbearing age, a negative pregnancy test within 24 hours of MRI. Inclusion criteria for healthy control subjects (Substudy 4 only); Age 18-65 years.; Written informed consent completed. EXCLUSION CRITERIA: General patient exclusion criteria; Current or past diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.; Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.; Female subjects who are either pregnant or nursing.; Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.; Subjects with uncorrected hypothyroidism or hyperthyroidism.; Subjects with one or more seizures without a clear and resolved etiology.; Treatment with a reversible MAOI within 4 weeks prior to study phase I.; Treatment with fluoxetine within 5 weeks prior to study phase I.; 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.; No structured psychotherapy will be permitted during the study.; 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); 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.; Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.; Clinically significant abnormal laboratory tests.; For imaging procedures, Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip).; 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); Current or past Axis I diagnosis; Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clips).; Presence of medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.; Treatment with any of the exclusionary medications detailed in Appendix G 14 days prior to Phase 1 of the Substudy 4.; Current or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine).; Presence of psychiatric disorders in first-degree relatives.; Female subjects who are either pregnant or nursing. 7.8.Current NIMH employee/staff or their immediate family member.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 65 Years (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
Administrative Information
NCT Number ICMJE	NCT00088699
Other Study ID Numbers ICMJE	040222; 04-M-0222
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
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