Treatment Resistant Geriatric Depression in Primary Care
Condition: Major Depressive Disorder
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

Summary: 
      This study involves collaboration between McLean Hospital, Geriatric Medicine at the
      Cambridge Health Alliance (CHA) and other sites within the Partners and Harvard Medical
      School network. The investigators plan to recruit individuals 55 to 89 years old with
      treatment resistant depression. Someone with "treatment resistant" depression for this study
      may be someone who still has sad or low feelings and thoughts even though he/she is taking an
      antidepressant medication for at least 8 weeks to help relieve his/her depression. During the
      study, subjects will gradually add memantine hydrochloride in dosages up to 20 mg/day for 8
      weeks to their standard antidepressant treatment.

      The investigators are doing this research study to help answer 3 questions:

        1. Do older adults with treatment resistant Major Depression have lower levels of a
           chemical in the brain called NAAG than older adults without Major Depression?

        2. Do older adults with naturally low NAAG levels do better on memantine hydrochloride
           treatment than older adults with higher amounts of this chemical on memantine
           hydrochloride treatment?

        3. Do older adults with treatment resistant depression have more problems with memory and
           concentration than older adults without depression?

      The investigators are also interested in looking at electrical and neuronal activity of the
      brain, spiritual beliefs, and fatigue in relationship to depression.

      The investigators hypothesize that:

        1. Older individuals with treatment resistant Major Depression will have lower levels of
           NAAG compared with age-matched older control subjects.

        2. Older adults with treatment resistant depression and low NAAG levels will do better on
           treatment with memantine hydrochloride than older adults on memantine with higher NAAG
           levels.

        3. Older adults with depression will do better on tests of attention and executive
           functioning after treatment with memantine hydrochloride.

        4. Healthy controls will do better on tests of attention and executive functioning than
           older adults with depression.
    

Detailed description: 
      RESEARCH DESIGN AND METHODS

      We will enroll up to 20 subjects with major depression, ages 55-89, and up to 20 healthy
      control subjects, ages 55-89 matched with depression group for age, sex, and ethnicity. We
      require 10 subjects in each group to have completed the study protocol with clinical and MRI
      scan data suitable for analysis.

      Subjects in both groups will be recruited from:

        -  Cambridge Health Alliance (CHA) geriatric medicine group practice.

        -  Mount Auburn Outpatient programs and affiliates

        -  Beth Israel Deaconess Medical Center Outpatient programs and affiliates

        -  McLean Hospital Geriatric Psychiatry Outpatient, Inpatient, and Partial (SAGE - Seniors
           Aging Gracefully Everyday) programs

        -  Other inpatient, partial, and outpatient psychiatry programs at McLean Hospital

        -  Outpatient programs affiliated with Partners Healthcare and/or Harvard Medical School,
           such as:

        -  Partners Community Health Care primary care physicians (PCPs),

        -  Massachusetts General Hospital and Brigham and Women's PCP network

        -  Local geriatricians and community psychiatrists

        -  General public and community (through IRB-approved local advertisements), such as:

        -  Public areas (gyms, super markets, etc)

        -  Retirement communities

        -  The Harvard Division on Aging

        -  Newspaper

        -  Radio

        -  Internet

        -  McLean Hospital Geriatric Psychiatry Research Program's research studies, including:

        -  Subjects who have completed participation in treatment or non-treatment studies

        -  Subjects who are actively participating in non-treatment research studies

      One site (McLean Hospital) is engaged in this protocol. CHA and other sites only refer
      subjects to McLean and do not consent subjects or complete any study protocol procedures.
      Subjects must meet all selection criteria in order to participate in the study protocol.

      All subjects will complete a brief pre-screening interview over the phone or in person in
      order to assess their preliminary eligibility for study inclusion.

      Screening Period:

      After signing consent, all study subjects will follow the same screening period (with the
      exceptions for control subjects mentioned below). Screening procedures include a clinical
      diagnostic interview, medical monitoring, physical exam, collecting information regarding
      prior and concomitant medication and adverse events, blood draw, vital signs, height, and
      weight, demographic and clinical history information, as well as assessments of daily
      functioning, mood, anxiety, and cognition.

      Visit 2 / Baseline (Week 0):

      Depression subjects will return to the office after the completion of screening procedures
      (within 14 days of signing consent) to complete baseline procedures which include assessments
      of daily functioning, fatigue, mood, anxiety, medical monitoring, psychiatric interview,
      concomitant medications, adverse events, vitals, 3T scan, EEG with resting state and Flanker
      Task procedures (prior to receiving study medication), spirituality questionnaire, and urine
      pregnancy test (if applicable). Neuropsychological tests will also be completed at this
      visit.

      No changes in psychotropic drugs will be allowed for depression subjects during this the
      screening period before study drug is administered. The subjects with depression will be
      administered (before leaving the office) memantine HCl 5 mg tablets. All depression subjects
      will start at a dose of 5 mg once per day in the morning.

      Visit 3 (Week 1) and Visit 4 (Week 2):

      Following the completion of Visit 2, the subject will return to the office for 2 visits in 2
      consecutive weeks. A psychiatric interview, review concomitant medications and AEs (if any),
      mood and anxiety scales, monitoring of medication tolerability and compliance, vital sign
      collection will be completed at these visits. Study medication will be dispensed and
      depression subjects will be instructed according to the dosing schedule.

      Visit 5 (Week 4) and 6 (Week 6):

      After completing Visit 4, subjects will return to the office 2 weeks later for Visit 5 (Week
      4) and then 2 weeks after that for Visit 6 (Week 6). The same visit procedures will be
      completed at these visits as Visits 3 and 4, except the subject will not meet with the study
      psychiatrist at Visit 6 (Week 6). Subjects may complete Visit 6 in person or over the phone.

      Visit 7 (Week 8) Final Study Visit:

      After completing 8 weeks on study medication, the subject will return to the office for the
      final study visit. This visit will complete the same procedures as Visits 3 through 6 with
      the addition of another 3T scan (with a negative urine pregnancy test, if applicable), EEG
      (with resting state and Flanker Task) and neuropsychological tests. Participants will also
      repeat spirituality and fatigue questionnaires with assistance from study staff.

      Subjects will be asked to return all study medication for the final visit. At this time
      subjects will have the option of staying on the medication or tapering off study medication
      and being referred to the McLean Hospital Geriatric Outpatient Clinic for follow up or to an
      appropriate physician of their choice. We will share information regarding study
      participation and results with the subjects' primary care physician and/or other entities
      only if the subject has completed an "Authorization for Release of Medical Records" form. If
      the subjects chose to discontinue treatment with memantine HCl, the psychiatrist (BPF) will
      instruct subjects how to safely taper off study medication.

      Control Subject Visits:

      Following screening, control subjects will return to the office for 3 visits. Unlike the
      depression group, the control group will NOT receive the study drug memantine HCl. Control
      subjects are not scheduled to meet with the study psychiatrist at the Baseline Week 0 and
      Week 8 visits and complete blood draw and one of the neuropsychological tests during
      participation. Other than the exceptions previously mentioned, control subjects will follow
      the same protocol as the depression subjects for the screening period, Baseline (Week 0), and
      Week 8 Visit. Study staff will monitor adverse events (if any occur), use of concomitant
      medication (if any), and subject safety throughout study participation. Vital signs will also
      be collected at every visit. Mood measures, spirituality and fatigue questionnaires, and
      neuropsychological tests identical to those administered to the depression group will be
      completed during the Week 8 final visit. Controls will also complete the same 3T MRI scanning
      protocol as depression subjects. Controls also have the opportunity to participate in EEG
      acquisition at baseline and study endpoint.

      Follow-up:

      We plan to contact enrolled subjects after the last subject completes the study per protocol
      and the data has been analyzed. This follow-up correspondence will consist of at least 3
      attempts to contact subjects' by phone and 1 certified letter sharing our research findings
      with subjects.
    

Intervention name(s): Memantine
Intervention type(s): Drug
Intervention description(s): Dosing Form: Tablet
Dosage: 5mg, 10 mg
Description:
Memantine hydrochloride (Namenda®), a low to moderate affinity uncompetitive (open-channel) NMDA antagonist, is manufactured and supplied by Forest Laboratories, Incorporated. Only the subjects in the depression group will receive the study drug memantine HCl. Per psychiatrist's instructions, subjects may remain on the maximum dosage of memantine HCl allowed by the study protocol for a given week, or reduce the dosage if concerns regarding tolerability arise. The dosage of memantine HCl cannot be increased more rapidly than the dosing schedule listed below.
Memantine HCl Dosing Schedule:
5 mg qAM week 1 5 mg qAM and 5 mg qHS for week 2 10 mg qAM and 5 mg qHS for week 3 10 mg BID for week 4, 5, 6, 7, and 8
Other intervention name(s): Namenda (NDA # 021487)
Intervention MeSH terms: Memantine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Geriatric; Older adults; Major Depressive Disorder; Magnetic Resonance Spectroscopy; memantine hydrochloride; N-Acetylaspartylglutamate; NAAG; Cognitive impairment