AzTrials
AzTrials

DepressionPhase 1/2NCT00088699

Rapid Antidepressant Effects of Ketamine in Major Depression

A Phase 1/2 study testing Ketamine in people with Depression and Mood Disorders, run by National Institute of Mental Health (NIMH) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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. Read more about this study

Who is it for?
Ages 18 to 65 yearsHealthy volunteers can take part
Conditions the study is for
Depression, Mood Disorders, Major Depresssion
What is being tested?
Ketamine
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
67 participants
Where
1 siteUnited States
Study dates
26 Jul 2004to 31 Jul 2017
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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 Major Depressive Disorder (MDD) 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
Show all 15Show fewer
  • Current depressive episode of at least 4 weeks duration.
  • Additional inclusion criteria for substudy 4 (patients with MDD)
  • 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).
  • 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.

Who cannot join

  • 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.
Show all 29Show fewer
  • 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)
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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

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.

Read more

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.

Read the detailed 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).

Being tested
Ketamine, Placebo
Keywords
Depression, NMDA Antagonist, Treatment Resistant, Glutamatergic System, Major Depression
Medical subject headings
Depression, Mood Disorders, Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00088699
Study groupRoleWhat they receive
Ketamine, Then PlaceboExperimentalKetamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg.
Receives: Drug: Ketamine; Drug: Placebo
Placebo, Then KetamineExperimentalPlacebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg
Receives: Drug: Ketamine; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline

  2. 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.

    Measured: Day 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Aug 2004 (estimated)
  2. Study start26 Jul 2004
  3. Primary completion31 Jul 2017
  4. Study completion31 Jul 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Other
Allocation
Randomised
Intervention model
Crossover
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
67 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00088699
Sponsor's protocol ID
040222
Other IDs
04-M-0222
Status last verified
31 Jul 2017
First submitted
30 Jul 2004
Last updated
12 Oct 2018
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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. 2019 Jul;24(7):1040-1052. doi: 10.1038/s41380-018-0028-2. Epub 2018 Feb 27.

    PubMed 29487402

  • Evans JW, Lally N, An L, Li N, Nugent AC, Banerjee D, Snider SL, Shen J, Roiser JP, Zarate CA Jr. 7T 1H-MRS in major depressive disorder: a Ketamine Treatment Study. Neuropsychopharmacology. 2018 Aug;43(9):1908-1914. doi: 10.1038/s41386-018-0057-1. Epub 2018 Apr 5.

    PubMed 29748628

  • Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA. Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling. Int J Neuropsychopharmacol. 2018 Aug 1;21(8):740-747. doi: 10.1093/ijnp/pyy041.

    PubMed 29668918

  • Evans JW, Szczepanik J, Brutsche 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.2018.01.027. Epub 2018 Feb 15.

    PubMed 29580569

  • 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. No abstract available.

    PubMed 29560906

  • 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. 2018 Jul;23(7):1626-1631. doi: 10.1038/mp.2017.109. Epub 2017 May 30.

    PubMed 28555075

  • Jones GH, Gilbert JR, Johnston JN, Akula N, Schulmann A, Arakelian M, Peng S, Yuan P, Winful EA, Yavi M, Quintanilla B, Elkahloun A, Moaddel R, Henter ID, Greenstein D, Machado-Vieira R, Bartley CM, Kadriu B, Amit M, Rezvani K, Kvarta MD, McMahon FJ, Zarate CA Jr. Convergent neuroimmune signaling underlying rapid antidepressant response to ketamine and psychedelics. Mol Psychiatry. 2026 Jul 28. doi: 10.1038/s41380-026-03777-z. Online ahead of print.

    PubMed 42521762

  • Hejazi N, Kheirkhah M, Riedner B, Yuan Q, Chholak R, Momenan R, Jones G, Goldman D, Zarate CA Jr. Modulation of early non-rapid eye movement slow wave activity by ketamine in treatment-resistant depression. Neuropsychopharmacology. 2026 Jun 16. doi: 10.1038/s41386-026-02465-4. Online ahead of print.

    PubMed 42304135

  • Kheirkhah M, Hejazi NS, Nugent AC, Gilbert JR, Leistritz L, Walter M, Duncan WC Jr, Goldman D, Zarate CA Jr. Exploring the link between waking gamma and sleep delta power in healthy volunteers and individuals with treatment-resistant depression. J Affect Disord. 2025 Sep 15;385:119448. doi: 10.1016/j.jad.2025.119448. Epub 2025 May 19.

    PubMed 40398609

  • Kheirkhah M, Duncan WC Jr, Yuan Q, Wang PR, Jamalabadi H, Leistritz L, Walter M, Goldman D, Zarate CA Jr, Hejazi NS. REM density predicts rapid antidepressant response to ketamine in individuals with treatment-resistant depression. Neuropsychopharmacology. 2025 May;50(6):941-946. doi: 10.1038/s41386-025-02066-7. Epub 2025 Feb 15.

    PubMed 39955416

  • Ballard ED, Greenstein D, Reiss PT, Crainiceanu CM, Cui E, Duncan WC Jr, Hejazi NS, Zarate CA Jr. Functional changes in sleep-related arousal after ketamine administration in individuals with treatment-resistant depression. Transl Psychiatry. 2024 Jun 4;14(1):238. doi: 10.1038/s41398-024-02956-2.

    PubMed 38834540

  • Alexander L, Hawkins PCT, Evans JW, Mehta MA, Zarate CA Jr. Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals. Transl Psychiatry. 2023 Dec 1;13(1):371. doi: 10.1038/s41398-023-02674-1.

    PubMed 38040678

  • Punturieri C, Duncan WC Jr, Greenstein D, Shandler G, Zarate CA Jr, Evans JW. An exploration of actigraphy in the context of ketamine and treatment-resistant depression. Int J Methods Psychiatr Res. 2023 Sep 5;33(1):e1984. doi: 10.1002/mpr.1984. Online ahead of print.

    PubMed 37668277

  • Quintanilla B, Medeiros GC, Greenstein D, Yuan P, Johnston JN, Park LT, Goes FS, Gould TD, Zarate CA Jr. kappa-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine. J Clin Psychopharmacol. 2023 Mar-Apr 01;43(2):89-96. doi: 10.1097/JCP.0000000000001663.

    PubMed 36821406

  • Hejazi NS, Farmer CA, Oppenheimer M, Falodun TB, Park LT, Duncan WC Jr, Zarate CA Jr. The relationship between the HDRS insomnia items and polysomnographic (PSG) measures in individuals with treatment-resistant depression. J Psychiatr Res. 2022 Apr;148:27-33. doi: 10.1016/j.jpsychires.2022.01.022. Epub 2022 Jan 11.

    PubMed 35092868

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Ketamine in people with Depression and Mood Disorders, run by National Institute of Mental Health (NIMH) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

MADRS Score - Baseline (time frame: Baseline). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00088699, which also lists 52 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Oct 2018.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in