Rapid Antidepressant Effects of Ketamine in Major Depression

Depression Clinical Trial

Official title:

Investigation of the Rapid (Next Day) Antidepressant Effects of an NMDA Antagonist

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00088699
• Other study ID #: 040222
• Secondary ID: 04-M-0222
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 26, 2004
• Est. completion date: July 31, 2017

Study information

• Verified date: July 31, 2017
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 67
• Est. completion date: July 31, 2017
• Est. primary completion date: July 31, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

• 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.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Major Depresssion
• Mood Disorders

Intervention

Drug:
• Ketamine

• Placebo

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Mental Health (NIMH)

Country where clinical trial is conducted

United States, 

References & Publications (6)

Evans JW, Lally N, An L, Li N, Nugent AC, Banerjee D, Snider SL, Shen J, Roiser JP, Zarate CA Jr. 7T (1)H-MRS in major depressive disorder: a Ketamine Treatment Study. Neuropsychopharmacology. 2018 Apr 5. doi: 10.1038/s41386-018-0057-1. [Epub ahead of pri — View Citation

Evans JW, Szczepanik J, Brutsché N, Park LT, Nugent AC, Zarate CA Jr. Default Mode Connectivity in Major Depressive Disorder Measured Up to 10 Days After Ketamine Administration. Biol Psychiatry. 2018 Oct 15;84(8):582-590. doi: 10.1016/j.biopsych.2018.01. — View Citation

Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA Jr. Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling. Int J Neuropsychopharmacol. 2018 Apr 13. doi: 10.1093/ijnp/pyy041. [Epub ahead of — View Citation

Kadriu B, Gold PW, Luckenbaugh DA, Lener MS, Ballard ED, Niciu MJ, Henter ID, Park LT, De Sousa RT, Yuan P, Machado-Vieira R, Zarate CA. Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder. Mol Psychiatry — View Citation

Nugent AC, Ballard ED, Gould TD, Park LT, Moaddel R, Brutsche NE, Zarate CA Jr. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry. 2018 Feb 27. doi: 10.1038/s41380-018-0028-2. [Epub ahead o — View Citation

Nugent AC, Zarate CA Jr. Using Neuroimaging to Decipher the Mechanism of Action of Ketamine: A Pathway to Novel Therapeutics? Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Oct;2(7):549-551. doi: 10.1016/j.bpsc.2017.08.006. Epub 2017 Oct 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MADRS Score - 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.	Baseline
Primary	MADRS Score - Day 1 Following Intervention	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.	Day 1