Antidepressant Effects of NR2B in Major Depression

NCT00472576 | Completed Phase 1 Results

• 2 other identifiers: 07015207-M-0152
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Major Depression

Keywords

NMDA Receptor; Depression Treatment; Unipolar Depression; Treatment Resistant; Glutamatergic; Depression; Major Depression

Outcome Measures

Primary Outcomes (1)

• Montgomery-Asberg Depression Rating Scale (MADRS)

  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.

  Measured daily for 12 days, where the endpoint is the primary outcome

Secondary Outcomes (1)

• Hamilton Depression Rating Scale (HDRS)

  Measured daily for 12 days, where the endpoint is primary

Study Arms (2)

Placebo then MK-0657

EXPERIMENTAL

Double-blind crossover administration of placebo then MK-0657 (4-8 mg/day)

Drug: MK-0657; Drug: Placebo

MK-0657 then Placebo

EXPERIMENTAL

Double-blind crossover administration of MK-0657 (4-8 mg/day) then placebo

Drug: MK-0657; Drug: Placebo

Interventions

MK-0657 DRUG

Daily double-blind administration of the NR2B antagonist MK-0657 (4-8 mg/day)

Also known as: NR2B antagonist

MK-0657 then Placebo; Placebo then MK-0657

Placebo DRUG

Daily double-blind administration of placebo

Also known as: Inactive drug

MK-0657 then Placebo; Placebo then MK-0657

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.
• 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.
• Subjects must have an initial score of at least 22 on the MADRS at screen and at baseline of study phase II.
• 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).
• Current major depressive episode of at least 4 weeks duration.

You may not qualify if:

• 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.
• Subjects with a history of DSM-IV drug or alcohol dependency or abuse (including for nicotine and caffeine) within the preceding 3 months.
• Subjects with a diagnosis of Obsessive Compulsive Disorder or Posttraumatic Stress Disorder as defined in the DSM-IV.
• Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.
• 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.
• 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).
• Clinically significant abnormal laboratory test or electrocardiogram.
• Subjects with uncorrected hypothyroidism or hyperthyroidism.
• Subjects with one or more seizures without a clear and resolved etiology.
• Previous lack of antidepressant response to ketamine or hypersensitivity to ketamine or amantadine.
• Treatment with fluoxetine within 5 weeks prior to study phase I.
• Treatment with any other concomitant medication not allowed 7 days (14 days for MAOIs) prior to study phase II.
• Treatment with clozapine or ECT within 2 months prior to study phase II.
• MADRS greater than 4 on item 10 (suicidal ideation).
• No structured psychotherapy will be permitted during the study.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med. 1969 Oct;62(10):989-93. doi: 10.1177/003591576906201005. No abstract available.

  PMID: 4899510 BACKGROUND

• 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. doi: 10.1016/s0031-9384(98)00225-x.

  PMID: 10073475 BACKGROUND

• 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. doi: 10.1016/s0163-1047(05)80010-x.

  PMID: 8067982 BACKGROUND

• Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ, Potter WZ, Zarate CA Jr. A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol. 2012 Aug;32(4):551-7. doi: 10.1097/JCP.0b013e31825d70d6.

  PMID: 22722512 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Depressive Disorder; Depression

Interventions

4-methylbenzyl 3-fluoro-4-((pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Limitations and Caveats

The study was ended early due to recruitment problems.

Results Point of Contact

• Title: Dr. Carlos Zarate
• Organization: Experimental Therapeutics and Pathophysiology Branch, DIRP, NIMH

zaratec@mail.nih.gov

301-451-0861

Study Officials

• Carlos A Zarate, MD

  Experimental Therapeutics and Pathophysiology Branch, DIRP, NIMH

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief of Experimental Therapeutics and Pathophysiology Branch of NIMH, DIRP

Study Record Dates

• First Submitted: May 10, 2007
• First Posted: May 11, 2007
• Study Start: May 1, 2007
• Primary Completion: August 1, 2009
• Study Completion: August 1, 2009
• Last Updated: August 3, 2012
• Results First Posted: April 7, 2011

Record last verified: 2012-07

Locations

US (1)