Alzheimer's Disease, Major Depressive Disorder, Mild Cognitive Impairment
Conditions
Keywords
Memory Decline, Depression, Elderly, Antidepressants, Treatment, memantine
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.
Interventions
DRUGes-citalopram
es-citalopram 10mg/day will be given for the first week, and 20mg/day starting at week 2.
DRUGMemantine
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.
Sponsors
New York State Psychiatric Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 90 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Selective Reminding Test - Total Immediate Recall (SRT-IR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Wechsler Memory Scale-III (WMS-III) | 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) | 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 | 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 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in 24-item HAMD | 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) | 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 | 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 | 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) | 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). |
Countries
United States
Participant flow
Recruitment details
35 depressed and cognitively impaired patients were recruited from the Late Life Depression and Memory Disorders Clinic at Columbia University Medical Center.
Pre-assignment details
Any patients who were diagnosed with schizophrenia, psychoses, bipolar disorder, or alcohol/substance dependence (within the last 6 months) were excluded from participating in the study. Patients already on an effective anti-depressant, non-responders to citalopram/es-citalopram, and those on cholinesterase inhibitors/memantine were also excluded.
Participants by arm
| Arm | Count |
|---|---|
| Es-citalopram and Memantine Treatment concurrent es-citalopram plus memantine were administered for 48 weeks. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Patients moved | 2 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Es-citalopram and Memantine Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 35 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 65.3 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 35 |
| serious Total, serious adverse events | 2 / 35 |
Outcome results
Primary
Change in Selective Reminding Test - Total Immediate Recall (SRT-IR)
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.
Time frame: baseline, 48 weeks
Population: Analysis was intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Selective Reminding Test - Total Immediate Recall (SRT-IR) | 7.5 units on a scale | Standard Deviation 15 |
Secondary
Change in Selective Reminding Test - Delayed Recall (SRT-DR)
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Selective Reminding Test - Delayed Recall (SRT-DR) | 1.2 units on a scale | Standard Deviation 3.9 |
Secondary
Change in Trails A
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Trails A | 1.9 seconds | Standard Deviation 41.2 |
Secondary
Change in Trails B
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Trails B | -36.3 seconds | Standard Deviation 74.5 |
Secondary
Change in Wechsler Memory Scale-III (WMS-III)
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Wechsler Memory Scale-III (WMS-III) | 9.9 units on a scale | Standard Deviation 32.8 |
Other Pre-specified
Change in 24-item HAMD
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in 24-item HAMD | -15.2 scores on a scale | Standard Deviation 4.4 |
Other Pre-specified
Change in Clinical Global Impression - Cognitive Change
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat; ANOVA repeated measures. All values of data collected were included, except for those who exited the study early. In these cases, their last observation was carried forward (LOC).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Clinical Global Impression - Cognitive Change | CGI-Cognitive Change (Baseline) | 3.6 units on a scale | Standard Deviation 0.6 |
| Es-citalopram and Memantine Treatment | Change in Clinical Global Impression - Cognitive Change | Clinical Global Impression-Cogntive Change (WK 48) | 2.7 units on a scale | Standard Deviation 0.9 |
Other Pre-specified
Change in Clinical Global Impression - Depression Change
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat; ANOVA repeated measures. All values of data collected were included, except for those who exited the study early. In these cases, their last observation was carried forward (LOC).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Clinical Global Impression - Depression Change | Cognitive Global Impression at Baseline | 4.1 units on a scale | Standard Deviation 0.5 |
| Es-citalopram and Memantine Treatment | Change in Clinical Global Impression - Depression Change | Cognitive Global Impression at Final Visit (WK 48) | 2.1 units on a scale | Standard Deviation 1.2 |
Other Pre-specified
Change in Treatment Emergent Side Effects (TESS)
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.
Time frame: Baseline, Week 48
Population: Analysis was intent to treat.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Es-citalopram and Memantine Treatment | Change in Treatment Emergent Side Effects (TESS) | Treatment Emergent Side Effects (Baseline) | 6.6 units on a scale | Standard Deviation 4.2 |
| Es-citalopram and Memantine Treatment | Change in Treatment Emergent Side Effects (TESS) | Treatment Emergent Side Effects (WK 48) | 3.2 units on a scale | Standard Deviation 2.9 |
Other Pre-specified
Conversion to Dementia Using Clinical Dementia Rating (CDR)
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).
Time frame: Baseline, Week 48
Population: Analysis was intent to treat; ANOVA repeated measures. All values of data collected were included, except for those who exited the study early. In these cases, their last observation was carried forward (LOC).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Es-citalopram and Memantine Treatment | Conversion to Dementia Using Clinical Dementia Rating (CDR) | 1 participants |