Antidepressant Effects of NR2B in Major Depression
Condition: Major Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Intervention: MK-0657; Placebo
Intervention description: Daily double-blind administration of the NR2B antagonist MK-0657 (4-8 mg/day); Daily double-blind administration of placebo
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: NMDA Receptor; Depression Treatment; Unipolar Depression; Treatment Resistant; Glutamatergic; Depression; Major Depression

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.
    

Eligibility 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.