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.

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Bipolar affective disorder (manic-depressive illness) and unipolar depression are common, 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. In two separate trials, we tested riluzole (an inhibitor of glutamate release) and found it to have antidepressant properties in patients with unipolar and bipolar depression (Zarate et al. 2004, 2005). In another study, we found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and last approximately 1 week (Zarate et al in press). The current protocol consists of 3 studies designed to address 3 major questions:

Study 1 (Rapid improvement research in unipolar depression):

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant major depression? 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.

Study 2 (Rapid improvement research in bipolar depression):

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? Patients, ages 18 to 65 years with treatment-resistant bipolar depression will in a double-blind crossover study receive either intravenous ketamine or saline solution added to a mood stabilizer (lithium or valproate).

Study 3 (Rapid and sustained improvement research in unipolar depression):

Does riluzole (an inhibitor of glutamate release) promote and maintain response in patients with treatment-resistant major depression who have received a single intravenous dose of ketamine? Patients, ages 18 to 65 years, with treatment-resistant major (unipolar) depression who have received a single intravenous dose of ketamine will in a double-blind study receive either riluzole or placebo to determine if the rapid response obtained can be sustained.

Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, and 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression.

• Depression
• Major Depression/Bipolar Disorder

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

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• INCLUSION CRITERIA - STUDY 1:

  1. Male or female subjects, 18 to 60 years of age.
  2. Female subjects of childbearing potential must be using a medically accepted means of contraception.
  3. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
  4. Subjects must fulfill DSM-IV criteria for Major Depression (296.3) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
  5. Subjects must have an initial score of at least 18 on the 21-item HDRS at screen and at baseline of study phase I.
  6. Current or past history of lack of response to two adequate antidepressant trials (may be from the same chemical class) operationally defined using the Antidepressant Treatment History Form (ATHF).

  7. Current major depressive episode of at least 4 weeks duration.

     EXCLUSION CRITERIA - STUDY 1:

  8. Current or past history of psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
  9. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (including for nicotine) within the preceding 3 months.
  10. Female subjects who are either pregnant or nursing.
  11. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
  12. Subjects with uncorrected hypothyroidism or hyperthyroidism.
  13. Subjects with one or more seizures without a clear and resolved etiology.
  14. Previous treatment with ketamine or hypersensitivity to amantadine.
  15. Treatment with a reversible MAOI within 4 weeks prior to study phase I.
  16. Treatment with fluoxetine within 5 weeks prior to study phase I.
  17. Treatment with any other concomitant medication not allowed 14 days prior to study phase I.
  18. Treatment with clozapine or ECT within 3 months prior to study phase I.
  19. Judged clinically to be at serious suicidal risk.

No structured psychotherapy will be permitted during the study.

INCLUSION CRITERIA - STUDY 2:

1. Male or female subjects, 18 to 65 years of age.
2. Female subjects of childbearing potential must be using a medically accepted means of contraception.
3. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
4. Subjects must fulfill DSM-IV criteria for Bipolar I or II depressed without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
5. Subjects must have an initial score of at least 20 on the MADRS at screen and at baseline of study phase I.
6. 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 (as defined in Thase et al., 2000).
7. Current depressive episode of at least 4 weeks duration.

8. Subjects must take VPA or lithium (valproate 50-125 mg/ml or lithium 0.6-1.2 mEq/L) for at least 4 weeks prior to Visit 2. If the subject is not taking lithium or VPA, the research physician may start them on lithium or VPA at the NIH.

   EXCLUSION CRITERIA - STUDY 2:

9. Current or past diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
10. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.
11. Female subjects who are either pregnant or nursing.
12. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
13. Subjects with uncorrected hypothyroidism or hyperthyroidism.
14. Subjects with one or more seizures without a clear and resolved etiology.
15. Previous treatment with ketamine or hypersensitivity to amantadine.
16. Treatment with a reversible MAOI within 4 weeks prior to study phase I.
17. Treatment with fluoxetine within 5 weeks prior to study phase I.
18. Treatment with any other concomitant medication not allowed 14 days prior to study phase I.

No structured psychotherapy will be permitted during the study.

INCLUSION CRITERIA - STUDY 3:

1. Male or female subjects, 18 to 65 years of age.
2. Female subjects of childbearing potential must be using a medically accepted means of contraception.
3. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
4. Subjects must fulfill DSM-IV criteria for Major Depression (296.3) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.
5. Subjects must have an initial score of at least 22 on the MADRS at screen and at baseline of study phase I.
6. Subjects with a greater than a 25% decrease in the MADRS total scores between screen and baseline of study phase I will be dropped from the study.
7. Current or past history of lack of response to two adequate antidepressant trials (may be from the same chemical class) operationally defined using the Antidepressant Treatment History Form (ATHF).

8. Current major depressive episode of at least 4 weeks duration.

   EXCLUSION CRITERIA - STUDY 3:

9. Presence of psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
10. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (excluding nicotine or caffeine) within the preceding 3 months.
11. Female subjects who are either pregnant or nursing.
12. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
13. Subjects with uncorrected hypothyroidism or hyperthyroidism.
14. Subjects with one or more seizures without a clear and resolved etiology.
15. Previous treatment with riluzole or hypersensitivity to it or to amantadine.
16. Previous lack of response to ketamine or riluzole for depression.
17. Treatment with a reversible MAOI within 2 weeks prior to study phase I.
18. Treatment with fluoxetine within 5 weeks prior to study phase I.
19. Treatment with any other concomitant medication not allowed 14 days prior to study phase I.
20. No structured psychotherapy will be permitted during the study.