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 60 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.

Condition	Treatment or Intervention	Phase
Depression	Drug: Ketamine	Phase II

Further Study Details: 

Expected Total Enrollment:  26

Even though there are many antidepressant drugs for clinical use, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatments, despite adequate dosage, duration, and compliance. Furthermore, these medications may take weeks to months to achieve their full effects and in the meantime, patients continue to suffer from their symptoms and continue to be at risk of self-harm as well as harm to their personal, and professional lives. Thus, there is a clear need to develop novel and improved therapeutics for treatment-resistant major depression that have a rapid onset of action. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. It is thus noteworthy that lamotrigine, which, among other effects reduces glutamate release, has antidepressant effects, and a pilot study has suggested that a single intravenous dose of the non-competitive NMDA antagonist ketamine produced a rapid but only transitory antidepressant effect in patients with treatment-resistant major depression (Berman et al 2000). However, this small pilot with ketamine has not been replicated. Together, these data suggests that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants. We propose to replicate the study by Berman and colleagues to determine whether a rapid antidepressant effect with an NMDA antagonist can be achieved.

Patients, ages 18 years or older, with a diagnosis of major depression (without psychotic features), will be recruited for this study. This study consists of the double-blind crossover administration of either intravenous ketamine (an NMDA antagonist) or saline solution.

The specific aim of this study is to assess the efficacy of a single dose of intravenous ketamine (0.5 mg/kg) compared with placebo in improving overall depressive symptomatology in patients with treatment-resistant major depression.

Our primary hypothesis is that subjects with treatment-resistant major depression who are randomized to a single dose of an NMDA antagonist will have a superior response compared to when they are randomized to placebo. This is a proof of concept and treatment study.

Assuming that 20% will drop out of the study, then a minimum of 26 patients is necessary to in order to obtain a minimum of 22 patients with major depression who will complete the double-blind crossover phase of the study.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
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:
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 (Appendix A) 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.

Maryland
      National Institute of Mental Health (NIMH), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040222; 04-M-0222
Record last reviewed:  June 18, 2004
Last Updated:  November 23, 2004
Record first received:  July 30, 2004
ClinicalTrials.gov Identifier:  NCT00088699
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08