Brain Aging and Treatment Response in Geriatric Depression

This study is designed to conduct a double-blind placebo-controlled trial of Namenda
(Memantine) as an augmentation to Lexapro (Escitalopram) in depressed older adults 60 years
of age and older. Throughout the course of the study, the investigators anticipate screening
about 400 subjects to recruit 134 participants in the first four years. This study will
require that the subjects complete up to 20 (twenty) visits in 12 (twelve) months to the
study site during their participation. The purpose of this study is to determine whether
Namenda (memantine) when taken in combination with Lexapro (escitalopram), may improve the
quality of treatment response by making it faster and more complete, and also by improving
thinking and memory in comparison to Lexapro taken with a placebo. Enrolled subjects will be
provided with 10-20 mg of escitalopram for 12 months, and concurrently randomly assigned to
either memantine or placebo groups. The investigators will also examine the safety and
tolerability (how well the treatment works and the side effects) of a combination of Namenda
and Lexapro as compared to placebo and Lexapro in subjects with major depressive disorder and
mild cognitive impairment who are at least 60 years of age. Memantine is likely to accelerate
and enhance antidepressant response to escitalopram and improve cognitive performance.
Subjects with amnestic mild cognitive impairment or biomarkers of brain aging at baseline are
likely to have preferential response to the combination of memantine and escitalopram
compared to escitalopram and placebo, thus identifying a more personalized treatment approach
in the high-risk subgroups for poor clinical outcomes.

Inclusion Criteria:

- Meets DSM 5 criteria for major depressive disorder (recurrent and nonrecurrent course
will be identified)

- Score of 16 or higher on the 24-item Hamilton Rating Scale for Depression (HDRS) at
study entry

- Score of 24 or higher on the Mini-Mental State Exam (MMSE)

- Age 60 years old or older

Exclusion Criteria:

- History of psychiatric illness or a substance abuse disorder other than unipolar
depression, diagnosed prior to the onset of the first depressive episode

- Presence of psychotic symptoms

- Severe or acute medical illness (e.g., major surgery, metastatic cancer, stroke, heart
attack) 6 months prior to study entry

- Acute suicidal or violent behavior or history of suicide attempt within the year prior
to study entry

- Presence of delirium, neurodegenerative dementia, Parkinson's disease, or any other
central nervous system (CNS) diseases

- Toxic or metabolic abnormalities on laboratory examination

- Medications taken or medical illnesses present that could account for depression

- Active heart failure categorized as Class III or greater according to New York Heart
Association criteria

- Heart attack or crescendo angina within the 3 months prior to study entry

- Symptomatic cardiac arrhythmias or symptomatic, hemodynamically significant mitral or
aortic valvular disease

- Resting heart rate less than 50 beats per minute and a corrected QT (QTc) interval
greater than 0.45 seconds

- Second or third degree atrioventricular block

- Systolic blood pressure greater than 180 mmHg or less than 90 mmHg and diastolic blood
pressure greater than 105 mmHg or less than 50 mmHg at study entry

- Treated with depot neuroleptic therapy within 6 months prior to study entry

- Treated with any neuroleptic, antidepressant, anxiolytic medication (other than
lorazepam), or over-the-counter CNS-active medications used for treatment of
depression (e.g, St. John's Wort, kava-kava, melatonin) within 2 weeks (4 weeks for
fluoxetine or monoamine-oxidase inhibitors [MAOIs]) prior to the first administration
of study medication

- Known allergy to escitalopram or memantine or history of ineffective treatment with
escitalopram or memantine for current depressive episode

- Requires concomitant therapy with any prescription or over-the-counter medications
that have potentially dangerous interactions with either escitalopram or memantine

- Requires electroconvulsive therapy (ECT) or received ECT within 3 months prior to
study entry

- Initiated psychotherapy within 3 months prior to study entry or will be initiating or
terminating psychotherapy during the study