Protocol Number: 09-M-0240

Title:

An Investigation of the Antidepressant Effects of a Low-Trapping Mixed NR2A/2B Antagonist in Treatment-Resistant Major Depression

Number:

09-M-0240

Summary:

Background:

- Several different kinds of medications have been shown to be effective treatments for depression; however, they often take several weeks to reduce symptoms. A fast-acting medication would be a helpful treatment for many people with depression.

- Previous studies have shown that the drug ketamine, which works on brain cells called NMDA receptors, had a rapid effect on depressive symptoms, but several unpleasant side effects were associated with its use. Another drug that acts on the NMDA receptor, AZD6765, may help alleviate symptoms without the side effects of ketamine.

Objectives:

- To determine whether a single dose of AZD6765 administered intravenously can rapidly improve the symptoms of depression when compared with placebo.

Eligibility:

- Individuals between 18 and 65 years of age who have been diagnosed with major depression without psychotic features and who have not responded to treatment with two antidepressants.

- Participants must have a current episode of major depression of at least 4 weeks' duration.

Design:

- The 6- to 7-week study requires that participants be hospital inpatients for the duration of the study.

- Phase 1 of the study will include psychiatric and physical examinations, including blood and urine testing. Participants taking antidepressant medications will need to taper off and stop their use before Phase 2 of the study begins.

- In Phase 2 of the study, participants will receive a dose of either AZD6765 or placebo (an inactive substance) over 60 minutes. Participants and study doctors will not know which substance the participants receive. After drug or placebo administration, participants will be observed for 7 days, including evaluating symptoms and side effects, monitoring mood and thinking, and conducting physical examinations and blood tests.

- After 1 week, if participants have had a good response to the treatment, they will be observed for another week. If the participants have not had a good response, they will receive a second treatment in which those who received placebo first will now receive AZD6765 and those who received AZD6765 first will now receive the placebo. Observations will then be repeated.

- Participants have the option of having three magnetic resonance imaging (MRI) and three magnetoencephalography (MEG) studies.

- Participants will be provided with follow-up care and treatment with standard medications for up to 3 months following the study.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1. Male or female subjects, 18 to 65 years of age. Women of child bearing potential must have a negative serum pregnancy test and confirmed (by the investigator) use of a highly effective form of birth control.

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 296.2x Major Depressive Disorder, Single Episode or 296.3x Major Depressive Disorder recurrent 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. 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).

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

EXCLUSION CRITERIA:

1. Current or past history of psychotic features or a 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 caffeine or nicotine dependence) within the preceding 3 months.

3. Subjects with a DSM IV Axis II borderline or antisocial personality disorder.

4. Female subjects who are either pregnant or nursing.

5. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

6. Subjects with uncorrected hypothyroidism or hyperthyroidism.

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

8. A current diagnosis of cancer (except basal or squamous cell skin carcinoma), unless in remission for at least 5 years.

9. QT interval corrected by Fridericia formula (QTcF) on screening ECG of greater than or equal to 450 (msec).

10. Clinically significant abnormal laboratory tests.

11. Treatment with a reversible MAOI within 4 weeks prior to study phase II.

12. Treatment with fluoxetine within 5 weeks prior to study phase II.

13. Treatment with any other concomitant medication not allowed 14 days prior to study phase II.

14. Treatment with clozapine or ECT within 3 months prior to study phase II.

15. Lifetime history of deep brain stimulation.

16. Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, have a HDRS item 3 score of greater than or equal to 3 or have made a suicide attempt within the past 6 months.

No structured psychotherapy will be permitted during the study.

Special Instructions:

Currently Not Provided

Keywords:

Acute Antidepressant Effects

Antidepressant

Glutamate

Glutamate Antagonist

NMDA Antagonist

Recruitment Keyword(s):

Depression

Major Depression

Condition(s):

Major Depression

Investigational Drug(s):

AZD6765

Investigational Device(s):

None

Intervention(s):

Drug: AZD6765

Supporting Site:

National Institute of Mental Health

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Adamec RE, Burton P, Shallow T, Budgell J. Unilateral block of NMDA receptors in the amygdala prevents predatorstress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior. Physiol Behav. 1999 Jan 1-15;65(4-5):739-51.

Aguado L, San Antonio A, PŽrez L, del Valle R, G—mez J.Effects of the NMDA receptor antagonist ketamine on flavor memory: conditioned aversion, latent inhibition, and habituation of neophobia. Behav Neural Biol. 1994 May;61(3):271-81.

Beck AT, Kovacs M, Weissman A.Assessment of suicidal intention: the Scale for Suicide Ideation. J Consult Clin Psychol. 1979 Apr;47(2):343-52.

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