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

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ClinicalTrials.gov Identifier: NCT01876823
Recruitment Status : Completed
First Posted : June 13, 2013
Results First Posted : October 24, 2014
Last Update Posted : October 24, 2014
Sponsor:
Information provided by (Responsible Party):
New York State Psychiatric Institute

Tracking Information
First Submitted Date  ICMJE June 5, 2013
First Posted Date  ICMJE June 13, 2013
Results First Submitted Date  ICMJE September 23, 2013
Results First Posted Date  ICMJE October 24, 2014
Last Update Posted Date October 24, 2014
Study Start Date  ICMJE April 2006
Actual Primary Completion Date March 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2014)
Change in Selective Reminding Test - Total Immediate Recall (SRT-IR) [ Time Frame: baseline, 48 weeks ]
Change in Selective Reminding Test-Total Immediate Recall (SRT-IR) scores from baseline to Week 48: Measures word recall (maximum 12 words per trial, across 6 trials). Maximum total recall score across 6 trials is 72; minimum recall is 0 across 6 trials. The higher the raw score, the better the patient did at recalling the target words. The unit of measure is the raw score, or the sum of the number of words recalled across all 6 trials.
Original Primary Outcome Measures  ICMJE
 (submitted: June 10, 2013)
Change in Selective Reminding Test - Total Immediate Recall (SRT-IR) [ Time Frame: baseline, 12 weeks, 24 weeks, 48 weeks ]
Change from baseline SRT-IR
Change History Complete list of historical versions of study NCT01876823 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2014)
  • Change in Wechsler Memory Scale-III (WMS-III) [ Time Frame: Baseline, Week 48 ]
    Change in Wechsler Memory Scale-III scores from baseline to Week 48: The WMS-III Visual Reproduction sub-test was used to measure visual working memory and delayed memory. Patients were shown pictures of four drawings and were asked to reproduce them from memory immediately after seeing them, and 25 minutes after seeing them. The four scores are summed and the greater the total raw score, the better the patient did on the assessment. The maximum raw score for this test is a 41 on both the immediate and delayed portions (the overall range is 0-82 points). The change score is calculated using the total scores of both the immediate and delayed portions.
  • Change in Selective Reminding Test - Delayed Recall (SRT-DR) [ Time Frame: Baseline, Week 48 ]
    Change in Selective Reminding Test-Delayed Recall scores from baseline to Week 48: SRT Delay is administered 15 minutes after the immediate recall portion. Patients are asked to remember as many of the words as they can from the 6 trials. Maximum raw score is a 12 for free recall. If a patient is unable to recall a word, they are given a chance to recognize it among three incorrect word choices. Maximum raw score for recognition is 12. The greater the score on the delayed recall portion, the better the patient does on the assessment.
  • Change in Trails B [ Time Frame: Baseline, Week 48 ]
    Change from baseline to Week 48 on Trails B: Measures attention and executive function. It asks patients to connect numbers and letters in numerical to alphabetical order from (1-13 and A-L) as fast as they can. Patients are timed; the longer it takes for the patient to connect the numbers and letters, the worse their score. Unit of measure is in seconds. The amount of errors that the patient makes during trails is also recorded.
  • Change in Trails A [ Time Frame: Baseline, Week 48 ]
    Change in Trails A scores from baseline to Week 48: Measures attention and executive function. It asks patients to connect numbers from 1-25 in numerical order as fast as they can. Patients are timed; the longer it takes for the patient to connect the numbers, the worse their score. Unit of measure is in seconds. The amount of errors that the patient makes during trails is also recorded.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2013)
  • Change in Wechsler Adult Intelligence Scale-III (WAIS-III) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline WAIS-III
  • Change in Wechsler Memory Scale-III (WMS-III) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline WMS-III
  • Change in Selective Reminding Test - Delayed Recall (SRT-DR) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline SRT-DR
  • Change in Visuospatial (Benton) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline Benton
  • Change in Boston Naming Test (BNT) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline BNT
  • Category Fluency Test (CFT) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
  • Change in Trails B [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline Trails B
  • Change in Go-No-Go [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline Go-No-Go
  • Change in Simple and Complex Reaction Time [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline Simple and Complex Reaction Time
  • Change in Trails A [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline Trails A
  • Change in Continuous Performance Task (CPT) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline CPT
  • Change in University of Pennsylvania Smell Identification Test (UPSIT) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline UPSIT
Current Other Pre-specified Outcome Measures
 (submitted: October 23, 2014)
  • Change in 24-item HAMD [ Time Frame: Baseline, Week 48 ]
    Change in 24-item Hamilton Rating Scale for Depression (HAMD) scores from baseline to Week 48: HAMD measures depression severity based on a series of 24 items items. The range of HAMD total score is 0-74; 0 indicates no depressive symptoms and a maximum HAMD score is a 74, where the greater the score indicates more significant psychopathology. In this study, moderate to severe depression is considered a HAMD-24 greater than 14.
  • Change in Treatment Emergent Side Effects (TESS) [ Time Frame: Baseline, Week 48 ]
    Somatic side effect rating scale which includes 26 common somatic side effects associated with previous medication clinical trials; rated by the study physician. Factors were dichotomized to "yes" or "no" responses on this scale, which equated to the symptom being either present or not present. "Yes" and "no" responses were given a value of 0 (no) or 1 (yes). Responses from the entire group were calculated and the mean at baseline and the last visit is reported below.
  • Change in Clinical Global Impression - Depression Change [ Time Frame: Baseline, Week 48 ]
    The CGI Depression Change follows a seven-point likert scale. Compared to the patient's condition at baseline in the study [prior to medication initiation], the patient's condition is rated as: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment. Responses were calculated for the entire group. Mean at final visit has been reported below. Higher mean at baseline indicates a decrease in depression scores.
  • Change in Clinical Global Impression - Cognitive Change [ Time Frame: Baseline, Week 48 ]
    The CGI Cognitive Change follows a seven-point likert scale. Compared to the patient's condition at baseline in the study [prior to medication initiation], the patient's condition is rated as: 1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment. Responses from the entire group were calculated. Mean at final visit and baseline is reported below.
  • Conversion to Dementia Using Clinical Dementia Rating (CDR) [ Time Frame: Baseline, Week 48 ]
    The CDR is a numeric rating scale that is used to quantify the severity of one's cognitive function. The scale goes from 0=normal; 0.5=mild cognitive impairment; 1 to 3=mild to moderate/severe dementia. CDR was used a dichotomous outcome measure (no=0; yes=1).
Original Other Pre-specified Outcome Measures
 (submitted: June 10, 2013)
  • Change in 24-item HAMD [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
    Change from baseline 24-item HAMD
  • Treatment Emergent Side Effects (TESS) [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
  • Clinical Global Impression - Depression Change [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
  • Clinical global Impression - Cognitive Change [ Time Frame: Baseline, Week 12, Week 24, Week 48 ]
  • Change in Clinical Dementia Rating (CDR) [ Time Frame: Baseline, Week 24, Week 48 ]
    Change from baseline CDR
 
Descriptive Information
Brief Title  ICMJE Memantine Plus Es-citalopram in Elderly Depressed Patients With Cognitive Impairment
Official Title  ICMJE Effects of Combined Memantine (Namenda) Plus Escitalopram (Lexapro) Treatment in Elderly Depressed Patients With Cognitive Impairment
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Mild Cognitive Impairment
  • Major Depressive Disorder
  • Alzheimer's Disease
Intervention  ICMJE
  • Drug: es-citalopram
    es-citalopram 10mg/day will be given for the first week, and 20mg/day starting at week 2.
    Other Name: Lexapro
  • Drug: Memantine
    After two weeks on Lexapro, Memantine 5mg will be added. The dose will increase to 10mg for the second week and will be increased at a rate of 5mg per week. Memantine dosage will not exceed 20mg.
    Other Name: Namenda
Study Arms  ICMJE Experimental: es-citalopram and Memantine Treatment
concurrent es-citalopram plus memantine were administered for 48 weeks.
Interventions:
  • Drug: es-citalopram
  • Drug: Memantine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 10, 2013)
60
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE March 2010
Actual Primary Completion Date March 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Of either sex, age greater than 49 years old
  2. Meets criteria for both "depression" and "cognitive impairment".
  3. 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)

  4. 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:

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

  5. Willing and capable of giving informed consent

Exclusion Criteria:

  1. 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)
  2. Meets criteria for:

    1. schizophrenia
    2. alcohol or substance dependence or abuse within the last 6 months.
  3. Suicidal attempt in last 6 months or current suicidal intent.
  4. Patients currently on an effective antidepressant medication
  5. Use of cholinesterase inhibitors in the last year.
  6. Neurological disease including stroke, epilepsy, or other neurodegenerative disorders.
  7. An acute, severe or unstable medical condition such as metastatic or active cancer, hepatic disease, or primary renal disease requiring dialysis.
  8. 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.
  9. Patient with a history of non-response to Citalopram or es-citalopram
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01876823
Other Study ID Numbers  ICMJE 6277R
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party New York State Psychiatric Institute
Study Sponsor  ICMJE New York State Psychiatric Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Gregory Pelton, M.D. New York State Psychiatric Institute
Study Chair: Davangere Devanand, M.D. New York State Psychiatric Institute
PRS Account New York State Psychiatric Institute
Verification Date September 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP