• 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.