Rapid Antidepressant Effects of Ketamine in Major Depression
Rapid Antidepressant Effects of Ketamine in Major Depression
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.
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).
-  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.