Antidepressant Effects of NR2B in Major Depression

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Carlos Zarate, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00472576
First received: May 10, 2007
Last updated: July 19, 2012
Last verified: July 2012
  Purpose

Purpose : This study will determine whether MK-0657, a selective NR2B Antagonist, can quickly improve symptoms of depressed mood, psychomotor retardation, poor motivation and reduced enjoyment of things in patients with major depression.

MK-0657 decreases the activity of a brain receptor called NMDA, which the chemical glutamate binds to, possibly inducing a rapid antidepressant response. People between 18 and 55 years of age who have major depression of at least 4 weeks' duration and have not been helped by two antidepressants approved for major depression may be eligible for this study. Women who are able to have children are excluded. Participants are admitted to the NIH Clinical Center for two study phases, as follows. Phase I (1 to 2 weeks): Patients are tapered off their current medications. Phase II (7 weeks): Patients are randomly assigned to take either MK-0657 or placebo (look-alike capsules with no active ingredient) by mouth for 12 days. At some point during the second part this phase, patients who had been taking MK-0657 are switched over to placebo and those who had been taking placebo are switched to MK-0657. Participants undergo the following procedures during the study:Physical examination twice (at the beginning and at the end of the study) Electrocardiogram (ECG) four times Blood tests about six times Rating scales up to 28 times to assess the effects of MK-0657 on mood and thinking Blood pressure measurements three times a day.

Study examines the effectiveness of a new medication, targeting a system called glutamate, will improve depression when compared with placebo.


Condition Intervention Phase
Major Depression
Drug: MK-0657
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Investigation of the Antidepressant Effects of the Selective NR2B Antagonist MK-0657 in Major Depression

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Montgomery-Asberg Depression Rating Scale (MADRS) [ Time Frame: Measured daily for 12 days, where the endpoint is the primary outcome ] [ Designated as safety issue: No ]
    The Montgomery-Asberg Depression Rating Scale (MADRS) measures the severity of depression where smaller scores indicate less depression and higher scores suggest more severe depression. Possible scores for this 10 item version range from 0 to 60. Generally, a score of 18 or greater is used to indicate a substantial depression level. The measure at the end of the study is the primary outcome.


Secondary Outcome Measures:
  • Hamilton Depression Rating Scale (HDRS) [ Time Frame: Measured daily for 12 days, where the endpoint is primary ] [ Designated as safety issue: No ]
    The Hamilton Depression Rating Scale (HDRS) measures the severity of depression where smaller scores indicate less depression and higher scores suggest more severe depression. Possible scores for this 17 item version range from 0 to 52. Generally, a score of 18 or greater is used to indicate a substantial depression level. The measure at the end of the study is primary.


Enrollment: 5
Study Start Date: May 2007
Study Completion Date: August 2009
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Placebo then MK-0657
Double-blind crossover administration of placebo then MK-0657 (4-8 mg/day)
Drug: MK-0657
Daily double-blind administration of the NR2B antagonist MK-0657 (4-8 mg/day)
Other Name: NR2B antagonist
Drug: Placebo
Daily double-blind administration of placebo
Other Name: Inactive drug
Experimental: MK-0657 then Placebo
Double-blind crossover administration of MK-0657 (4-8 mg/day) then placebo
Drug: MK-0657
Daily double-blind administration of the NR2B antagonist MK-0657 (4-8 mg/day)
Other Name: NR2B antagonist
Drug: Placebo
Daily double-blind administration of placebo
Other Name: Inactive drug

Detailed Description:

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 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, 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. Together, these data suggest that the NMDA receptor may play an important role in the mechanism of antidepressant action. Unfortunately, ketamine's psychotomimetic effects preclude its use as a chronic antidepressant; these side effects probably are a result of ketamine's effects on multiple NMDA subunits. Thus, studying selective NMDA subunit antagonists in depression is a reasonable next step. The NR2B subunit stands as a prime candidate to test in depression. Preclinical data by our group indicates that the NR2B subunit is involved in the mechanism of antidepressant action as indicated by changes in phosphorylation of serine residues in the learned helplessness model of depression and with chronic treatment with imipramine. In addition, we found that the NR2B antagonist R0 25-6981 has antidepressant-like properties in the forced swim test. We propose to examine whether the selective NR2B antagonist (MK-0657) produces rapid antidepressant effects in patients with treatment-resistant major depression but without causing psychotomimetic effects.

Male and female patients, ages 18 to 55 years, 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 the NR2B antagonist MK-0657 (4-8 mg/day) or placebo.

The specific aim of this study is to assess the efficacy of 12 days of a selective NR2B antagonist (MK-0657, 4-8 mg/day given orally) 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 selective NR2B antagonist (MK-0657) will have a more rapid and superior response compared to when they are randomized to placebo. This is a proof of concept and treatment study.

Approximately, 27 subjects will be randomized; the accrual ceiling for this protocol is 60 subjects.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  1. Male or female (not of reproductive potential, unable to conceive) subjects, 18 to 55 years of age. A female patient not of reproductive potential is defined as one who: a) has reached menopause with: i) no menses for the past 3 or more years OR ii) no menses for greater than 1 year but less than 3 years with confirmation of FSH levels elevated into the postmenopausal range; or b) has undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation.
  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 Major Depression (296.3) 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 22 on the MADRS at screen and at baseline of study phase II.
  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). If subjects have only failed to respond to one adequate antidepressant trial by history, they will be permitted to receive a prospective trial of a standard antidepressant. Subjects who fail to respond to this prospective trial will meet criteria for treatment-resistance and be eligible to randomize. Subjects responding to the prospective trial will be ineligible to randomize. (A CORE representative will be present when the subject is informed as to the decision to randomize or not).
  6. Current major depressive episode of at least 4 weeks duration.

EXCLUSION CRITERIA:

  1. Current or past history of bipolar disorder, 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 (including for nicotine and caffeine) within the preceding 3 months.
  3. Subjects with a diagnosis of Obsessive Compulsive Disorder or Posttraumatic Stress Disorder as defined in the DSM-IV.
  4. Subjects with a diagnosis of Borderline or Antisocial Personality disorder. Other Axis II disorders do not qualify one for exclusion from the study.
  5. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
  6. Patient has a history of any cardiovascular disease, including myocardial infarction, cardiac arrhythmias or conduction abnormalities, cerebrovascular accident, transient ischemic attack (TIA), or peripheral vascular disease.
  7. Patient has systolic blood pressure of less than 90 mm Hg or greater than 135 mm Hg at the screen visit or has orthostatic hypotension at the screen visit (greater than or equal to 20 mm Hg decline in systolic blood pressure compared with previous supine systolic blood pressure plus orthostatic symptoms within 3 minutes after standing).
  8. Clinically significant abnormal laboratory test or electrocardiogram.
  9. Subjects with uncorrected hypothyroidism or hyperthyroidism.
  10. Subjects with one or more seizures without a clear and resolved etiology.
  11. Previous lack of antidepressant response to ketamine or hypersensitivity to ketamine or amantadine.
  12. Treatment with fluoxetine within 5 weeks prior to study phase I.
  13. Treatment with any other concomitant medication not allowed 7 days (14 days for MAOIs) prior to study phase II.
  14. Treatment with clozapine or ECT within 2 months prior to study phase II.
  15. MADRS greater than 4 on item 10 (suicidal ideation).

No structured psychotherapy will be permitted during the study.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00472576

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Carlos A Zarate, MD Experimental Therapeutics and Pathophysiology Branch, DIRP, NIMH
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Carlos Zarate, M.D., Chief of Experimental Therapeutics and Pathophysiology Branch of NIMH, DIRP, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00472576     History of Changes
Other Study ID Numbers: 070152, 07-M-0152
Study First Received: May 10, 2007
Results First Received: March 14, 2011
Last Updated: July 19, 2012
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
NMDA Receptor
Depression Treatment
Unipolar Depression
Treatment Resistant
Glutamatergic
Depression
Major Depression

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 01, 2014