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

Sponsor:	National Institute of Mental Health (NIMH)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00995111

Purpose

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.

Condition	Intervention	Phase
Major Depression	Drug: AZD6765	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double-Blind, Placebo Control, Crossover Assignment, Efficacy Study
Official Title:	An Investigation of the Antidepressant Effects of a Low-Trapping Mixed NR2A/2B Antagonist in Treatment-Resistant Major Depression

Resource links provided by NLM:

MedlinePlus related topics: Antidepressants Depression

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Change from baseline in the MADRS total score. [ Time Frame: 1 week ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Proportion of subjects in remission (defined as MADRS total score less than or equal to 10; proportion of subjects w/response (defined as, greater than or equal to 50% reduction from baseline in MADRS total score); change from baseline in SSI to... [ Time Frame: 1 week ] [ Designated as safety issue: No ]

Estimated Enrollment:	24
Study Start Date:	September 2009
Estimated Study Completion Date:	June 2011
Estimated Primary Completion Date:	June 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Group A: Active Comparator	Drug: AZD6765 N/A

Detailed Description:

Objective: Approximately 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatments and response to these medications often takes weeks to months. In the meantime, patients continue to suffer from their symptoms and be at risk of self-harm as well as harm to their personal and professional lives. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system, specifically on the NMDA receptor complex. A recent study by our group found that a single intravenous dose of the non-competitive NMDA antagonist ketamine produced a rapid, robust and relatively sustained antidepressant effect in patients with treatment-resistant major depression. Because ketamine's psychotomimetic effect challenges our ability to develop it as an antidepressant that can be given chronically, we will study more subunit selective NMDA antagonists. AZD6765 (also known as ARR15896) was found to have antidepressant-like properties in the forced swim test and learned helplessness paradigm. AZD6765 is a low trapping, fast off-rate NMDA antagonist that hits both the NR2A and NR2B subunits. We propose to examine whether AZD6765 produces rapid antidepressant effects in patients with treatment-resistant major depressive disorder but without causing psychotomimetic effects.

Study population: Treatment-resistant major depressive disorder.

Design: Male and female patients, ages 18 to 65 years, with a diagnosis of major depressive disorder, currently in an episode of major depression, will be recruited for this study. This study consists of the double-blind crossover administration of either AZD6765 (150 mg/infusion) or placebo. The specific objective of this study is to assess the efficacy of a single-intravenous infusion of a low trapping mixed NR2A/2B antagonist (AZD6765, 150 mg) compared with placebo in improving overall depressive symptomatology in patients with treatment-resistant major depressive disorder. Other aims: 1. to determine if change in anterior cingulate activation to an emotional (fearful faces presentation) and a cognitive (n-back) task correlates with antidepressant response to AZD6765 in patients with treatment-resistant major depression. 2. To determine if change in brain neurochemicals (glutamate/GABA) changes correlates with antidepressant response (decrease in MADRS total scores) to AZD6765 in patients with treatment resistant major depression.

Outcome measures: Primary: MADRS total score. Secondary outcome measures: Proportion of subjects in remission (MADRS total score less than or equal to 10) and response (greater than or equal to 50% reduction from baseline in MADRS total score); change from baseline in the SSI total score; change from baseline in BDI, CGI-S, HAM-A, HDRS and VAS total scores; MEG and MRS as biomarkers of response.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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:

Current or past history of psychotic features or a diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.
Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for caffeine or nicotine dependence) within the preceding 3 months.
Subjects with a DSM IV Axis II borderline or antisocial personality disorder.
Female subjects who are either pregnant or nursing.
Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
Subjects with uncorrected hypothyroidism or hyperthyroidism.
Subjects with one or more seizures without a clear and resolved etiology.
A current diagnosis of cancer (except basal or squamous cell skin carcinoma), unless in remission for at least 5 years.
QT interval corrected by Fridericia formula (QTcF) on screening ECG of greater than or equal to 450 (msec).
Clinically significant abnormal laboratory tests.
Treatment with a reversible MAOI within 4 weeks prior to study phase II.
Treatment with fluoxetine within 5 weeks prior to study phase II.
Treatment with any other concomitant medication not allowed 14 days prior to study phase II.
Treatment with clozapine or ECT within 3 months prior to study phase II.
Lifetime history of deep brain stimulation.
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00995111

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Institute of Mental Health (NIMH)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Adamec RE, Burton P, Shallow T, Budgell J. Unilateral block of NMDA receptors in the amygdala prevents predator stress-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, Perez L, del Valle R, Gomez 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. No abstract available.

Responsible Party:	National Institutes of Health ( Carlos A. Zarate, M.D./National Institute of Mental Health )
Study ID Numbers:	090240, 09-M-0240
Study First Received:	October 14, 2009
Last Updated:	November 5, 2009
ClinicalTrials.gov Identifier:	NCT00995111 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Acute Antidepressant Effects
Antidepressant
Glutamate
Glutamate Antagonist

NMDA Antagonist
Depression
Major Depression

Additional relevant MeSH terms:

Depression
Mental Disorders
Therapeutic Uses
Psychotropic Drugs
Mood Disorders
Depressive Disorder, Major

Depressive Disorder
Central Nervous System Agents
Pharmacologic Actions
Antidepressive Agents
Behavioral Symptoms

ClinicalTrials.gov processed this record on November 20, 2009