Alzheimer's Disease, Apathy, Dementia
Conditions
Keywords
Alzheimer's Disease, Apathy, Dementia, Methylphenidate
Brief summary
The purpose of the study is to determine the efficacy of methylphenidate over placebo in treating apathy in patients with Alzheimer's dementia. Apathy is one of the earliest and most profound disturbances that occur in Alzheimer's dementia (AD). Hypotheses: 1. Methylphenidate (MPH) will improve apathy significantly more than placebo in AD. 2\. Successful treatment of apathy will improve Instrumental Activities of Daily Living (IADLs), and caregiver burden.
Detailed description
Objective: Apathy is one of the earliest and most profound disturbances that occur in Alzheimer's dementia (AD). Based on promising preliminary data from our open-label pilot study we propose a double blind, placebo-controlled randomized clinical trial of methylphenidate for treatment of apathy in AD. Research Design: Randomized double blind, placebo-controlled study which will evaluate the effect of methylphenidate on apathy and also the impact of improvement of apathy on caregiver burden and functional status. Hypotheses: 1. Methylphenidate will improve apathy significantly more than placebo in AD. 2\. Successful treatment of apathy will improve Instrumental Activities of Daily Living (IADLs), and caregiver burden. Methodology: 60 patients with apathy in the context of AD will be recruited over the next three years. In our proposed study patients will be recruited from relevant clinics at the Omaha Veterans Affairs Medical Center (VAMC) including clinics in Geriatric Psychiatry, Neurology, Primary Care and Geriatric Medicine. 30 patients each with AD and apathy will be randomly assigned to placebo or MPH. All patients in the methylphenidate arm will be started at 5mg twice daily and titrated to 10mg twice daily at two weeks. Patients will be continued in this arm for 12 weeks followed by a 2-week discontinuation phase. Patients will be assessed on regular intervals using the Apathy Evaluation Scale, Instrumental Activities of Daily Living, Zarit Burden Scale and Mini Mental State Examination. Findings: None, the study is not complete. Clinical Relationships: While memory is the key cognitive problem in AD, apathy is the key behavioral problem. Apathy is characterized by indifference, disengagement, passivity, and lack of enthusiasm, interest, empathy and interpersonal involvement. Apathy is the most common, one of the earliest and probably the most persistent of behavioral problems in AD. Apathy is the most disturbing behavior to caregivers and has the greatest impact on functional status and caregiver burden. Despite this, apathy as a behavioral problem has largely been neglected. Most of the research directed towards behavioral problems in dementia is targeted towards more visible behaviors such as agitation, and psychosis. Remarkably, there are no published randomized, double blind, placebo controlled studies in the treatment of apathy associated with AD. Impact/Significance: Around 1.4 million veterans suffer from apathy in association with AD. Apathy is a strong predictor for functional decline and caregiver burden. Treatment of apathy is remarkably understudied and is absolutely critical to allow veterans to maximize their functional status, social engagement and quality of life, and thus delaying placement in assisted living or nursing home settings.
Interventions
DRUGMethylphenidate
Subject will receive 5mg twice a day for two weeks then 10mg twice a day until week 12 of the study.
OTHERPlacebo
Standard inactive pill.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of dementia of the Alzheimer type (DSM-IV Text Revision (TR) criteria) 2. Mini-mental state examination (MMSE) \>18, but \<29 3. Apathy Evaluation Scale (AES) score of more than 40 4. Ability to provide informed consent by either the patient or caregiver. 5. If subjects are being treated with antidepressants, they should be on a stable dose of antidepressants for at least two months prior to the enrollment into the study. 6. If subjects are being treated with cholinesterase inhibitors and memantine, they should be on stable dose of those medications at least four months prior to the enrollment into the study.
Exclusion criteria
1. Patient currently taking methylphenidate or hypersensitivity or prior significant adverse events with methylphenidate. 2. Patients currently taking Adderall (amphetamine mixed salts) or Dexedrine (dextroamphetamine sulphate) or any other amphetamine product. 3. Uncontrolled hypertension (BP \> 140/90) or tachycardia (100) at screening visit 4. Patients with frontotemporal dementia 5. Patients meeting criteria for Major Depressive Disorder on the Mini International Neuropsychiatric Inventory (MINI) 6. Patients with active psychosis as determined by MINI 7. Patients currently being treated with antipsychotics 8. History of uncontrolled seizure disorder 9. History of malignant hypertension, symptomatic cardiovascular disease, cardiomyopathy, known structural cardiac defect or medically unstable arrhythmias. 10. History of Tourette's syndrome or presence of motor tics 11. Patients with glaucoma 12. Patients taking monoamine oxidase inhibitors (MAOIs) 13. Patient taking clonidine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apathy Evaluation Scale Score at 12 Weeks | At 12 weeks | The Apathy Evaluation Scale (AES) has been specifically developed to assess apathy and discriminate it from depression. This 18 item scale with score ranging from 18 to 72, assesses apathy in behavioral, cognitive and emotional domains over the previous four weeks. Higher scores indicate worsening apathy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mini-mental State Examination (MMSE) at 12 Weeks | At 12 weeks | Mini-mental State Examination (MMSE) is a commonly used screening measure for cognition with questions pertaining to orientation, registration, recall, visuo-spatial construction, attention span etc. Score on MMSE ranges from 0-30, higher scores indicating improving cognition |
| Clinical Global Impression | At 12 weeks | The Clinical Global Impression scale is an observational scale of global evaluation, which assesses the change in degree of illness in relation to the original assessment. The severity sub-scale reported below ranges from 1-7 wherein higher scores indicate worsening severity of illness. |
Countries
United States
Participant flow
Recruitment details
60 subjects meeting the inclusion and exclusion criteria were recruited from outpatient clinics at the Nebraska Western Iowa Health Care System between 2006-2009.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 Methylphenidate
Methylphenidate: Subject will receive 5mg BID for two weeks then 10mg BID until week 12 of the study. | 30 |
| Arm 2 Placebo
Placebo: Standard inactive pill. | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
Baseline characteristics
| Characteristic | Arm 1 | Total | Arm 2 |
|---|---|---|---|
| Activities of Daily Living | 21.3 units on a scale STANDARD_DEVIATION 2.7 | 22 units on a scale STANDARD_DEVIATION 2.6 | 22.9 units on a scale STANDARD_DEVIATION 2.2 |
| Age, Continuous | 77.5 years STANDARD_DEVIATION 7.9 | 76.6 years STANDARD_DEVIATION 7.9 | 76.1 years STANDARD_DEVIATION 8.4 |
| Apathy Evaluation Scale | 51.9 units on a scale STANDARD_DEVIATION 7.1 | 49.7 units on a scale STANDARD_DEVIATION 6.8 | 47.6 units on a scale STANDARD_DEVIATION 5.8 |
| Clinical Global Impression-severity (CGI-S) | 5.5 units on a scale STANDARD_DEVIATION 0.6 | 5.3 units on a scale STANDARD_DEVIATION 0.6 | 5.1 units on a scale STANDARD_DEVIATION 0.6 |
| Mini-mental State Examination (MMSE) | 23.7 units on a scale STANDARD_DEVIATION 2.5 | 23.8 units on a scale STANDARD_DEVIATION 2.5 | 24 units on a scale STANDARD_DEVIATION 2.6 |
| Modified Mini-Mental State Examination (3MS) | 80.1 units on a scale STANDARD_DEVIATION 9 | 81.3 units on a scale STANDARD_DEVIATION 9.5 | 82.6 units on a scale STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 30 participants | 60 participants | 30 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 60 Participants | 30 Participants |
| The Executive Interview (EXIT-25) | 16.9 units on a scale STANDARD_DEVIATION 6.3 | 16.8 units on a scale STANDARD_DEVIATION 6.4 | 16.8 units on a scale STANDARD_DEVIATION 6.6 |
| Zarit Burden Scale | 28.1 units on a scale STANDARD_DEVIATION 13 | 26.9 units on a scale STANDARD_DEVIATION 13 | 25.3 units on a scale STANDARD_DEVIATION 13.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 30 | 16 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Apathy Evaluation Scale Score at 12 Weeks
The Apathy Evaluation Scale (AES) has been specifically developed to assess apathy and discriminate it from depression. This 18 item scale with score ranging from 18 to 72, assesses apathy in behavioral, cognitive and emotional domains over the previous four weeks. Higher scores indicate worsening apathy.
Time frame: At 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate Group | Apathy Evaluation Scale Score at 12 Weeks | 38.2 units on a scale | Standard Deviation 9.1 |
| Placebo Group | Apathy Evaluation Scale Score at 12 Weeks | 43.6 units on a scale | Standard Deviation 7.5 |
p-value: <0.05Mixed Models Analysis
Secondary
Clinical Global Impression
The Clinical Global Impression scale is an observational scale of global evaluation, which assesses the change in degree of illness in relation to the original assessment. The severity sub-scale reported below ranges from 1-7 wherein higher scores indicate worsening severity of illness.
Time frame: At 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate Group | Clinical Global Impression | 3.9 units on a scale | Standard Deviation 1.1 |
| Placebo Group | Clinical Global Impression | 4.8 units on a scale | Standard Deviation 0.6 |
Secondary
Mini-mental State Examination (MMSE) at 12 Weeks
Mini-mental State Examination (MMSE) is a commonly used screening measure for cognition with questions pertaining to orientation, registration, recall, visuo-spatial construction, attention span etc. Score on MMSE ranges from 0-30, higher scores indicating improving cognition
Time frame: At 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate Group | Mini-mental State Examination (MMSE) at 12 Weeks | 25.8 units on a scale | Standard Deviation 2.7 |
| Placebo Group | Mini-mental State Examination (MMSE) at 12 Weeks | 23.6 units on a scale | Standard Deviation 4 |
p-value: =0.01Mixed Models Analysis