Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double-Blind, Placebo-Controlled Trial of Valproate to Attenuate the Progression of Alzheimer's Disease (AD)
Brief Summary: The purpose of this trial is to demonstrate whether valproate therapy delays the emergence of agitation and/or psychosis in outpatients with probable Alzheimer's disease (AD) who have not experienced agitation and psychosis in their illness. A secondary aim is to determine whether valproate therapy delays the progression of cognitive and functional measures of the illness. This trial will also assess the tolerability and safety of low-dose, long-term valproate therapy. Valproate, an anticonvulsant drug, was selected because of its possible symptomatic efficacy for agitation in AD, known safety profile in numerous clinical populations, and in view of recent data supporting its neuroprotective potential in AD.


Options:
A: 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
B: Inclusion Criteria:

* Diagnosis of Dementia of the Alzheimer's Type
* Ambulatory, Outpatients who have an informant living/visiting at least 8 hours/week over 3-4 days.
* Presence of delusions, hallucinations, agitation impacting functioning and requiring medication treatment
* Agitation or psychotic symptoms began after signs or symptoms of dementia

Exclusion (prospective participants must not:)

* Be benefiting from psychotropic medication, antidepressants or anticonvulsants
* Be diagnosed with schizophrenia, schizoaffective disorder, delusional disorder or mood disorder with psychotic features.
* Have severe or unstable medical illness requiring active treatment
* Have hypersensitivity or intolerance of any of the study medications
C: Inclusion Criteria:

* Probable AD by National Institute of Neurological Disorders and Stroke (NINDS)-Alzheimer's Disease and Related Disorder Association (ADRDA) criteria.
* Males or females.
* \> 55 and \< 90 years of age.
* Weight \> 40 kg (88.2 lbs.).
* Residing in the community at Screen and Baseline. Participants may reside in assisted living facilities, but not in long-term care nursing facilities or assisted living facilities that provide intensive support for people with dementia nor may they reside in a secure unit necessary for behavioral management.
* Mini Mental State Examination (MMSE) at Screen and Baseline 12-20 inclusive.
* Computed tomography (CT) or magnetic resonance imaging (MRI) since onset of dementia consistent with the diagnosis of probable AD. Single lacunes in non-critical areas and non-specific white matter changes that are interpreted as age-related are not grounds for exclusion. Any ambiguous scan results must be reviewed with the Project Director.
* Fluent in English or Spanish.
* Supervision available for study medication.
* Study partner to accompany subject to all visits.
* Study partner must have in-person contact with the participant \> 2 days/week.
* Able to ingest oral medication.
* Total Neuropsychiatric Inventory (NPI) score for previous 4 weeks \< 8 at Screening, and for the period between Screening and Baseline.
* NPI item score for the items assessing delusions, hallucinations, agitation/aggression all greater than or equal to 1 for 4 weeks prior to Screening (less than once/week and mild severity at most) and for the period between Screening and Baseline.
* Scores of greater than or equal to 1 for items rating delusions, hallucinations, and agitation/aggression taken from the NPI, modified to assess these features since onset of illness. This will be derived from a second interview with the modified NPI. (Agitation/psychosis during episodes of delirium are not considered exclusionary.).

Exclusion Criteria:

Exceptions to these criteria may be considered on a case-by-case basis at the discretion of the Project Director:

* Non-AD dementia.
* Females of child-bearing potential.
* Residence in a long-term care facility or equivalent at Baseline.
* Presence or previous history of agitation or psychosis requiring active psychotropic medication since the illness began.
* History of clinically significant stroke.
* Current evidence or history in past two years of: focal brain lesion, head injury with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse.
* Sensory impairment that would prevent subject from participating in or cooperating with the protocol.
* Medical contraindications to study participation.
* Use of another investigational agent within two months prior to Screening.
* Evidence of any significant clinical disorder or laboratory finding that renders the subject unsuitable for receiving an investigational new drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal, or other systemic disease or laboratory abnormality.
* Clinical contraindication to the use of valproate (e.g., known hypersensitivity or allergic reactions, severe neutropenia, severe hepatic disease, or urea cycle disorder. A urea cycle disorder should be considered in patients with history of unexplained encephalopathy following protein meals, or family history of urea cycle disorder).
* History of seizure within past 5 years prior to Screening.
* Platelet count \< 100,000/mm\^3.
* International Normalized Ratio (INR) \> 1.2 or partial thromboplastin time (PTT) \> 40 seconds.
* Active neoplastic disease. Exceptions: skin tumors other than melanoma are not excluded; patients with stable prostate cancer may be included at the discretion of the Project Director; women who have been treated for breast cancer and have no metastases and whose survival is expected to exceed 2 years may be considered for inclusion on a case-by-case basis in consultation with the Project Director; patients with purely localized bladder wall cancers may be included at the discretion of the Project Director.

Excluded Medications:

* Use of psychotropics for treatment of agitation or psychosis. Antidepressants used in stable doses for 3 months prior to Screening to treat depression or anxiety, but not agitation, will be permitted. Low dose sedatives for sleep, but not agitation, will be permitted. Cholinesterase inhibitors used in stable doses for at least 3 months prior to Screening are permitted.
* Regular use of narcotic analgesics within 3 months of Screening.
* Anti-parkinsonian medications (e.g. levodopa, selegiline, pergolide, bromocriptine, pramipexole) within 2 months of Screening.
* Use of drugs with significant central anticholinergic or antihistaminic effects (eg, benztropine, trihexyphenidyl, dicyclomine, diphenhydramine, cyproheptadine, diphenoxylate, hydroxyzine, meclizine, prochlorperazine, promethazine) within 2 months of Screening.
* Use of other investigational drug studies within two months prior to Screening.
* Use of other anticonvulsants within 5 years prior to Screening.
* Use of zidovudine at any time.
* Use of tricyclic antidepressants within 1 month prior to Screening.
* Regular use of high doses of salicylates at Screening (\> 1,300 mg/d).
* Vitamin E \> 2,100 IU/d within 1 month prior to Screening.
* Warfarin use is permitted when approved by the Project Director and INR and PTT criteria are met.
D: Inclusion Criteria:

* Dementia, either sex, age 50-95 years
* Probable Alzheimer's disease
* Intellectual impairment present for at least 6 months
* Mini Mental State Exam (MMSE) score of 5-26 for outpatients and 2-26 for nursing home patients
* Availability of informant who has had direct contact with the patient for an average of at least once every week during the 3 months prior to study entry
* Meets Neuropsychiatric Inventory (NPI) criteria for either (1) psychosis, or (2) agitation/aggression
* Able to mobilize independently (if wheelchair-bound, the patient must be able to self-propel)
* Free of psychotropic medication (or able to tolerate washout) for at least 1 week prior to study entry. Low dose antidepressants and sedative/hypnotics allowed if they cannot be washed out and the dose remains stable for the study duration
* Expected to complete the study (including all efficacy evaluations) and be without major sensory impairment that would prevent participation in any aspect of the study

Exclusion Criteria:

* Current primary Axis I psychiatric disorder other than AD
* Substance abuse or dependence currently, or within the past year
* Dementia due to head trauma
* History of allergy to risperidone or intolerance to risperidone
* Diffuse Lewy body disease
* History of seizure disorder, infectious encephalitis, Parkinson's disease, central nervous system (CNS) neoplasm, tardive dyskinesia, stroke, transient ischemic attack (TIA) or uncontrolled atrial fibrillation
* Use of monoamine oxidase inhibitors (MAOIs) and unable to undergo 3-week washout; patients also may not take MAOIs for 2 weeks after completing the study
* In treatment with (a) depot antipsychotic within 2 weeks of the screening visit
* Untreated or incompletely treated hypothyroidism
* Active, unstable medical condition that requires active medication adjustment or surgery
* Need for electroconvulsive treatment (ECT)
* Significant risk for harm to themselves or others as a result of randomization to placebo
* History of malignant neoplasm during the last 5 years

Answer: C