Methylphenidate for Apathy in Alzheimer's Dementia: A Controlled Study

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.

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