Memantine Plus Es-citalopram in Elderly Depressed Patients With Cognitive Impairment

Overview

Alzheimer's disease (AD), the most common dementing disorder of later life, is a major cause of disability and death in the elderly. Although a number of theoretical causes exist, the etiology of AD is still unknown. Consequently, the focus of treatments has been palliative, designed to ameliorate AD symptoms. Recent efforts, however, have revealed some surprising data suggesting that cholinesterase inhibitors (AchEIs), used over the last decade, and recently released memantine (an N-methyl-D-aspartate (NMDA) receptor antagonist), may confer protection to neurons. Thus, they may offer a slowing of cognitive decline and/or improvement in behavioral symptoms associated with memory impairment. Over the last decade, it has been well documented that mild cognitive impairment (MCI) increases the risk of conversion to AD and that coincident depression and MCI (Dep-MCI) further increases the risk 2 to 3 fold. The primary focus of this line of investigation is to treat the very high risk to dement patient population with Dep-MCI, before they develop AD, in the hopes of delaying AD onset. Memantine had not been studied in DEP-MCI patients. Since treatment of these patients with combined antidepressant and AChEIs has been associated with cognitive improvement in pilot studies, we explore whether treatment of DEP-MCI with memantine in addition to antidepressant treatment would benefit cognitive performance and lead to a low rate of conversion to dementia. We evaluate the cognitive and antidepressant benefit of combined open-label es-citalopram and memantine treatment over 48 weeks in a DEP-CI sample.

The study is conducted in a sample of 35 elderly (50-90 years old) outpatients who meet study inclusion criteria for depression (DEP) (DSM-IV criteria for major depression, dysthymic disorder, or depression NOS) and mild cognitive impairment (MCI; e.g. operationally defined as between "normal" and "dementia"), i.e., Dep-MCI. The research plan includes: i) Obtaining a baseline psychiatric and neuropsychological test profile, ii) If currently on an ineffective antidepressant, having a one week washout (3 weeks for fluoxetine), iii) A treatment trial beginning with a two-week es-citalopram lead-in period. At two weeks, memantine (Namenda) is added starting at 5 mg/day and increased until the maximum dose of 20 mg/day is reached by six weeks. The study psychiatrist administers: the 24-item Hamilton Depression Rating Scale (HAM-D); the Clinical Global Impression (CGI, 1-7 scale) initial severity and subsequent change ratings separately for depression, cognition, and overall clinical status; the Treatment Emergent Symptom Scale (TESS) for somatic side effects. A trained technician administers the neuropsychological battery at baseline, 12, 24 and 48 weeks. If the patient is an antidepressant non-responder during the first 12-weeks, the es-citalopram is changed to an alternative antidepressant, as clinically indicated by the treating psychiatrist. The patient remains on the memantine for the entire 48-weeks, irrespective of antidepressant response. This will tell us about the efficacy and tolerability of es-citalopram+memantine on both cognitive and depressive symptoms in Dep-MCI patients and will potentially have broader public health implications because Dep-MCI is a wide-spread clinical problem where management needs to be improved.