Brain Aging and Treatment Response in Geriatric Depression

The proposed project will evaluate the role of neuroimaging biomarkers of brain aging (i.e., neurodegenerative and vascular brain changes) and mild cognitive impairment in the patterns of treatment response to memantine combined with escitalopram compared to escitalopram and placebo.

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.

Eligibility Criteria:
Inclusion Criteria:

* Meets the Diagnostic and Statistical Manual of Mental Disorders (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