Depression, Mild Cognitive Impairment (MCI)
Conditions
Keywords
Major Depression, Geriatric Major Depression, Executive Cognitive Dysfunction, Mild Cognitive Impairment, Older Adults, Geriatric, Executive Cognitive Impairment, Quality of Life, Disability, Comorbidity, Medical Burden, Safety, Candidate Genes
Brief summary
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.
Detailed description
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.
Interventions
DRUGEscitalopram
All subjects will receive 10 to 20mg of escitalopram open-label throughout the trial. Participants will begin taking one 10mg capsule once per day, and this dosage may be increased or decreased depending on the participant's response to the medication. Participants will continue on their assigned dosage of escitalopram until treatment completion.
DRUGMemantine
Memantine dosage will be 5 to 20mg a day. Participants will initially take one 5mg capsule once a day, which will be gradually increased to a maximum of 10mg capsules twice per day.
DRUGPlacebo
Placebo pills will be taken in combination with the active Namenda (Memantine) pills. Participants will initially take 1 capsule per day, which will be increased to a maximum of 1 capsule twice per day.
Sponsors
National Institute of Mental Health (NIMH)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hamilton Depression Rating Scale | Measured at 3 months; 6 months and 12 months | Clinician administered scale measures severity of depressive symptoms. This measure includes 24 items. Response options vary item to item and include the following ranges: \[0-2\], \[0-3\], and \[0-4\]. A score of 0 suggests absence of symptoms and/or difficulties and higher scores represent more severe difficulties. Possible overall score range \[0-74\], higher scores representing more severe difficulties. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Montgomery Asberg Depression Rating Scale | Measured at 3 months; 6 months and 12 months | Clinician administered item scale measures severity of depressive symptoms. The 10 items are measured on a 7-point scale ranging from 0 to 6; creating a total range of 0-60. A score of 0 suggests absence of symptoms and higher scores represent greater severity of depression.Severity gradations for the MADRS have been proposed (9-17 = mild, 18-34 = moderate, and ≥ 35 = severe). Treatment remission is defined as an endpoint total score ≤ 10. |
| Change in Cognitive Domain Scores | Measured at 6 months and 12 months | Neuropsychological battery of tests which included the following domains: learning, delayed recall, and executive functioning. Raw scores were transformed to z-scores for each test score of interest for each participant, and then averaged. These z-scores were averaged within each neuropsychological domain to produce composite scores and then averaged over all tests to calculate a global performance score. Higher scores are indicative of better performance. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Measured at 3, 6 months and 12 months | The UKU (Udvalg for Kliniske Undersogelser) Side Effect Rating Scale organizes symptoms into 4 categories (i.e., Psychic, Neurologic, Autonomic, Other) containing 8-19 symptoms each. Each symptom receives a score for degree and causal relationship. Degree is scored between 0-3 with higher scores being more severe. Causal relationship is scored as improbable, possible, or probable. |
Countries
United States
Participant flow
Pre-assignment details
A total of 20 participants were excluded after being consented and prior to randomization. 5 were determined to be ineligible after completing the in-person screen visit in which they were consented. 15 withdrew consent before being randomized.
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram and Memantine Participants will take a combination of Escitalopram and Memantine for 12 months
Escitalopram: All subjects will receive 10 to 20mg of escitalopram open-label throughout the trial. Participants will begin taking one 10mg capsule once per day, and this dosage may be increased or decreased depending on the participant's response to the medication. Participants will continue on their assigned dosage of escitalopram until treatment completion.
Memantine: Memantine dosage will be 5 to 20mg a day. Participants will initially take one 5mg capsule once a day, which will be gradually increased to a maximum of 10mg capsules twice per day. | 48 |
| Escitalopram and Placebo Participants will take a combination of Escitalopram and placebo for 12 months
Escitalopram: All subjects will receive 10 to 20mg of escitalopram open-label throughout the trial. Participants will begin taking one 10mg capsule once per day, and this dosage may be increased or decreased depending on the participant's response to the medication. Participants will continue on their assigned dosage of escitalopram until treatment completion.
Placebo: Placebo pills will be taken in combination with the active Namenda (Memantine) pills. Participants will initially take 1 capsule per day, which will be increased to a maximum of 1 capsule twice per day. | 47 |
| Total | 95 |
Baseline characteristics
| Characteristic | Escitalopram and Memantine | Escitalopram and Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 34 Participants | 39 Participants | 73 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 8 Participants | 22 Participants |
| Age, Continuous | 71 years STANDARD_DEVIATION 6.9 | 72.8 years STANDARD_DEVIATION 6.8 | 71.9 years STANDARD_DEVIATION 6.8 |
| Hamilton Depression Rating Scale Score | 17.8 units on a scale STANDARD_DEVIATION 2.3 | 17.7 units on a scale STANDARD_DEVIATION 2.4 | 17.8 units on a scale STANDARD_DEVIATION 2.3 |
| Race/Ethnicity, Customized African American | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Caucasian | 37 Participants | 33 Participants | 70 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants | 8 Participants | 11 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United States | 48 participants | 47 participants | 95 participants |
| Sex: Female, Male Female | 26 Participants | 25 Participants | 51 Participants |
| Sex: Female, Male Male | 22 Participants | 22 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 47 |
| other Total, other adverse events | 41 / 48 | 41 / 47 |
| serious Total, serious adverse events | 0 / 48 | 0 / 47 |
Outcome results
Primary
Change in Hamilton Depression Rating Scale
Clinician administered scale measures severity of depressive symptoms. This measure includes 24 items. Response options vary item to item and include the following ranges: \[0-2\], \[0-3\], and \[0-4\]. A score of 0 suggests absence of symptoms and/or difficulties and higher scores represent more severe difficulties. Possible overall score range \[0-74\], higher scores representing more severe difficulties.
Time frame: Measured at 3 months; 6 months and 12 months
Population: The number of participants with available data at each time point differs due to participant dropout over the course of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram and Memantine | Change in Hamilton Depression Rating Scale | Baseline | 17.8 units on a scale | Standard Deviation 2.3 |
| Escitalopram and Memantine | Change in Hamilton Depression Rating Scale | 3 Months | 6.0 units on a scale | Standard Deviation 4.5 |
| Escitalopram and Memantine | Change in Hamilton Depression Rating Scale | 6 Months | 5.9 units on a scale | Standard Deviation 5.2 |
| Escitalopram and Memantine | Change in Hamilton Depression Rating Scale | 12 Months | 7.2 units on a scale | Standard Deviation 5.8 |
| Escitalopram and Placebo | Change in Hamilton Depression Rating Scale | 12 Months | 5.4 units on a scale | Standard Deviation 5.3 |
| Escitalopram and Placebo | Change in Hamilton Depression Rating Scale | Baseline | 17.7 units on a scale | Standard Deviation 2.4 |
| Escitalopram and Placebo | Change in Hamilton Depression Rating Scale | 6 Months | 6.9 units on a scale | Standard Deviation 5.1 |
| Escitalopram and Placebo | Change in Hamilton Depression Rating Scale | 3 Months | 6.7 units on a scale | Standard Deviation 4.7 |
Secondary
Change in Cognitive Domain Scores
Neuropsychological battery of tests which included the following domains: learning, delayed recall, and executive functioning. Raw scores were transformed to z-scores for each test score of interest for each participant, and then averaged. These z-scores were averaged within each neuropsychological domain to produce composite scores and then averaged over all tests to calculate a global performance score. Higher scores are indicative of better performance.
Time frame: Measured at 6 months and 12 months
Population: The number of participants with available data at each time point differs due to participant dropout over the course of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram and Memantine | Change in Cognitive Domain Scores | Baseline | .02 z score | Standard Deviation 0.62 |
| Escitalopram and Memantine | Change in Cognitive Domain Scores | 6 Months | 0.03 z score | Standard Deviation 0.53 |
| Escitalopram and Memantine | Change in Cognitive Domain Scores | 12 Months | .15 z score | Standard Deviation 0.67 |
| Escitalopram and Placebo | Change in Cognitive Domain Scores | Baseline | -.04 z score | Standard Deviation 0.7 |
| Escitalopram and Placebo | Change in Cognitive Domain Scores | 6 Months | -.1 z score | Standard Deviation 0.67 |
| Escitalopram and Placebo | Change in Cognitive Domain Scores | 12 Months | -.26 z score | Standard Deviation 0.71 |
Secondary
Change in Montgomery Asberg Depression Rating Scale
Clinician administered item scale measures severity of depressive symptoms. The 10 items are measured on a 7-point scale ranging from 0 to 6; creating a total range of 0-60. A score of 0 suggests absence of symptoms and higher scores represent greater severity of depression.Severity gradations for the MADRS have been proposed (9-17 = mild, 18-34 = moderate, and ≥ 35 = severe). Treatment remission is defined as an endpoint total score ≤ 10.
Time frame: Measured at 3 months; 6 months and 12 months
Population: The number of participants with available data at each time point differs due to participant dropout over the course of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram and Memantine | Change in Montgomery Asberg Depression Rating Scale | Baseline | 16.7 units on a scale | Standard Deviation 3.2 |
| Escitalopram and Memantine | Change in Montgomery Asberg Depression Rating Scale | 3 Months | 7.1 units on a scale | Standard Deviation 5.9 |
| Escitalopram and Memantine | Change in Montgomery Asberg Depression Rating Scale | 6 Months | 6.0 units on a scale | Standard Deviation 5.5 |
| Escitalopram and Memantine | Change in Montgomery Asberg Depression Rating Scale | 12 Months | 8.8 units on a scale | Standard Deviation 7.3 |
| Escitalopram and Placebo | Change in Montgomery Asberg Depression Rating Scale | 12 Months | 8.0 units on a scale | Standard Deviation 6.5 |
| Escitalopram and Placebo | Change in Montgomery Asberg Depression Rating Scale | Baseline | 14.8 units on a scale | Standard Deviation 3.5 |
| Escitalopram and Placebo | Change in Montgomery Asberg Depression Rating Scale | 6 Months | 8.6 units on a scale | Standard Deviation 4.5 |
| Escitalopram and Placebo | Change in Montgomery Asberg Depression Rating Scale | 3 Months | 8.7 units on a scale | Standard Deviation 5.5 |
Other Pre-specified
Number of Participants With Adverse Events
The UKU (Udvalg for Kliniske Undersogelser) Side Effect Rating Scale organizes symptoms into 4 categories (i.e., Psychic, Neurologic, Autonomic, Other) containing 8-19 symptoms each. Each symptom receives a score for degree and causal relationship. Degree is scored between 0-3 with higher scores being more severe. Causal relationship is scored as improbable, possible, or probable.
Time frame: Measured at 3, 6 months and 12 months
Population: The number of participants with available data at each time point differs due to participant dropout over the course of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Escitalopram and Memantine | Number of Participants With Adverse Events | 6 Months | 3 Participants |
| Escitalopram and Memantine | Number of Participants With Adverse Events | 3 Months | 3 Participants |
| Escitalopram and Memantine | Number of Participants With Adverse Events | 12 Months | 1 Participants |
| Escitalopram and Placebo | Number of Participants With Adverse Events | 3 Months | 2 Participants |
| Escitalopram and Placebo | Number of Participants With Adverse Events | 6 Months | 5 Participants |
| Escitalopram and Placebo | Number of Participants With Adverse Events | 12 Months | 0 Participants |