Completed

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

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What is being tested

Ketamine

+ Placebo

Drug
Who is being recruted

Mental Disorders+2

+ Behavioral Symptoms

+ Depression

From 18 to 65 Years
See all eligibility criteria
How is the trial designed

Other Study

Phase 1 & 2
Interventional
Study Start: July 2004
See protocol details

Summary

Principal SponsorNational Institute of Mental Health (NIMH)
Last updated: December 11, 2025
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Study start date: July 26, 2004

Actual date on which the first participant was enrolled.

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).

Official TitleInvestigation of the Rapid (Next Day) Antidepressant Effects of an NMDA Antagonist 
NCT00088699
Principal SponsorNational Institute of Mental Health (NIMH)
Last updated: December 11, 2025
Sourced from a government-validated database.Claim as a partner

Protocol

This section provides details of the study plan, including how the study is designed and what the study is measuring.
Design Details

67 patients to be enrolled

Total number of participants that the clinical trial aims to recruit.

Other Study

Some studies explore topics that don't fall into a specific category. These might include innovative research, new technologies, or emerging healthcare areas.



Eligibility

Researchers look for people who fit a certain description, called eligibility criteria: person's general health condition or prior treatments.
Conditions
Criteria

Any sex

Biological sex of participants that are eligible to enroll.

From 18 to 65 Years

Range of ages for which participants are eligible to join.

Healthy volunteers allowed

If individuals who are healthy and do not have the condition being studied can participate.

Conditions

Pathology

Mental DisordersBehavioral SymptomsDepressionDepressive DisorderMood Disorders

Criteria

* 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.

Study Plan

Find out more about all the medication administered in this study, their detailed description and what they involve.
Treatment Groups
Study Objectives

2 intervention groups are designated in this study

This study does not include a placebo group 

Treatment Groups

Group I

Experimental
Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg.

Group II

Experimental
Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg

Study Objectives

Primary Objectives

Study Centers

These are the hospitals, clinics, or research facilities where the trial is being conducted. You can find the location closest to you and its status.

This study has 1 location

Suspended

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, United StatesSee the location
CompletedOne Study Center