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

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.

Inclusion criteria

• Of either sex, age greater than 49 years old
• Meets criteria for both "depression" and "cognitive impairment".
• Study Criteria for "depression":

i. Patients who meet DSM-IV criteria for Major Depression, Dysthymic Disorder, or Dysthymia symptoms criteria of minimum 6 month duration (not the 2 year DSM-IV criteria). ii. 24-item HAM-D greater than 13; and iii. Clinical Global Impression (CGI) for severity of Depression greater than 2 (absolute score at least mild to moderate depression on a 7-point scale)

• Study Criteria for "cognitive deficit":

i. Subjective memory complaint ii.Mini Mental Status Exam (MMSE) greater than 24; and at least one of a, b, or c:

• less than 3 on MMSE 5 min delay on recall
• scores on 2 neuropsychological tests greater than 1 Standard Deviation (SD) below standardized norms, or
• score on 1 neuropsychological tests greater than 2 SD below standardized norms.

Neuropsychological tests for inclusion criteria (subset of larger battery):

Selective Reminding Test with delay Wechsler Memory Scale (WMS): Visual Reproduction - with delay, % savings from immed to delay Controlled Oral Word Association Test Trails B Digit symbol subtest of Wechsler Adult Intelligence Scale (WAIS)-III Continuous Performance Test iii. CGI for severity of Cognitive deficit greater than 2 (absolute score on a 7-point scale:1=no deficit to 7=severe deficit). iv. Clinical Dementia Rating (CDR) = 0 or 0.5

• Willing and capable of giving informed consent

Exclusion criteria

• Meets Criteria for dementia (DSM-IV) or probable Alzheimer's disease by National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria (NINCDS-ADRDA criteria)
• Meets criteria for:

• schizophrenia
• alcohol or substance dependence or abuse within the last 6 months.
• Suicidal attempt in last 6 months or current suicidal intent.
• Patients currently on an effective antidepressant medication
• Use of cholinesterase inhibitors in the last year.
• Neurological disease including stroke, epilepsy, or other neurodegenerative disorders.
• An acute, severe or unstable medical condition such as metastatic or active cancer, hepatic disease, or primary renal disease requiring dialysis.
• Patients who can not tolerate being tapered off antidepressant medication (i.e. greater than a 25% incr. in baseline HAM-D) or has a history indicating patient is unlikely to tolerate psychotropic washout.
• Patient with a history of non-response to Citalopram or es-citalopram