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Rapid Antidepressant Effects of Ketamine in Major Depression

Sponsored by National Institutes of Health Clinical Center (CC)

Phase Quota
Phase 1

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 Start Date: July 2004

Estimated Completion Date: April 2017

Specialties: Psychiatry: Mood Disorders,Neuro/Psych Pharmacol Pharmacy: Drug Trials,Neuro/Psych pharmacology

Interventions

  • Drug: Riluzole
  • Drug: Ketamine
  • Drug: FDG

Inclusion criteria

STUDY POPULATION (FOR SUBSTUDY 4)

  • Male and female patients, ages 18 to 55 years with a diagnosis of MDD, currently depressed or in a current major depressive episode of BD without psychotic features will be recruited into this substudy. In addition, healthy volunteers will also be recruited into this substudy.
  • The proportion of ethnic minorities (vs. Caucasian) in the total sample will be consistent with the ethnic/racial proportions of the Washington D.C. and Montgomery county areas. We appreciate that minority groups tend to be underrepresented in research samples for mood disorders. Therefore, we make every effort to recruit minority patients, in order to ensure that the subject sample represents the community. Although it is not known whether racial differences will affect responses to pharmacotherapy, Substudy 4 will assess such effects; however, the size of the racial subsamples may be too small to identify statistically meaningful differences.

INCLUSION CRITERIA FOR PATIENTS WITH MDD OR BD:

  • Male or female subjects, 18 to 55 years of age.
  • Age of onset less than 40 years of age.
  • Female subjects of childbearing age must be using a medically accepted method of contraception.
  • 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 Depression single episode or recurrent without psychotic features, or Bipolar Disorder (296.5 for Bipolar I Disorder or 296.89 for Bipolar II Disorder) without psychotic symptoms based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P).
  • Subjects must have an initial score on the MADRS of at least 20 at screening, and at baseline for Phase I of Substudy 4.
  • Current or past history of lack of response to one adequate antidepressant trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial.
  • Current major depressive episode of at least 4 weeks duration.
  • In women of childbearing age, a negative pregnancy test within 24 hours of MRI.

INCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS:

  • Age 18-55 years.
  • Written informed consent completed.
  • In women of childbearing age, a negative pregnancy test within 24 hours of MRI.

Exclusion criteria

EXCLUSION CRITERIA FOR PATIENTS WITH MDD OR BD:

  • Current psychotic features or a 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 caffeine or nicotine dependence) within the preceding 3 months. In addition, 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.

  • 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.

  • 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.

  • Subjects with clinical hypothyroidism or hyperthyroidism.

  • Subjects with one or more seizures without a clear and resolved etiology.

  • Treatment with a reversible MAOI within two weeks prior to Phase I of Substudy 4.

  • Treatment with fluoxetine within five weeks or aripiprazole within three weeks before Phase I of Substudy 4.

  • Treatment with any other concomitant medication (Appendix 3) 14 days prior to Phase I of Substudy 4.

  • 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.

  • No structured psychotherapy will be permitted during Substudy 4.

EXCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS:

  • 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 3 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.

Study Locations And Contact Information

  • National Institutes of Health Clinical Center 9000 Rockville Pike, Bethesda Maryland
    Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office PRPL 800-411-1222 prpl@mail.cc.nih.gov
  • National Institutes of Health Clinical Center 9000 Rockville Pike, Bethesda Maryland
  • National Institutes of Health Clinical Center 9000 Rockville Pike, Bethesda Maryland

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