Apathy is one of the most common behavioral symptoms of Parkinson's disease. Patients with apathy show diminution in motivation and goal-directed behaviors, which is a fundamental aspect of human functioning, affecting dependency and quality of life. Although apathy is thought to be potentially treatable currently there are no effective treatments for apathy. Given the higher incidence of medical and psychiatric comorbidities, the Veterans Affairs health system represents a unique population for which medication response may be different from the general population. This study aims to evaluate if a medication that has already been proven to be useful in Alzheimer's disease patients with apathy, could be helpful in Parkinson's disease as well as decreasing its debilitating consequences and reducing patients' dependency on caregivers, providing well-deserved relief to patients and their loved ones.
Apathy in Parkinson's disease (PD) is a significant public health problem with serious adverse consequences for patients and caregivers. Apathy is present in up to 70% of people with PD. Patients suffering from apathy experience decreased motivation, relying heavily on caregivers to initiate daily activities. The presence of apathy is associated with worse quality of life for patients and caregivers. Moreover, patients with apathy have a faster disease progression and increased likelihood of development of cognitive impairment. Despite the high prevalence of apathy in PD and its serious consequences, there are no proven treatments for this condition. Dopaminergic enhancement appears as a potential mechanism as there is evidence that degeneration of the frontostriatal circuits involving the prefrontal cortex is one of the main mechanisms for the presence of apathy in PD as well as other neurodegenerative disorders, such as Alzheimer's disease (AD). This degeneration is associated with deficits in dopaminergic and noradrenergic input fibers to the prefrontal cortex. Methylphenidate, a dopamine and noradrenaline reuptake inhibitor, has been shown to be safe and effective in PD in the treatment of motor and cognitive symptoms, and several small trials and case series reported improvement in motivation and mood. Recently, methylphenidate was shown to be safe and improve apathy in AD in a series of well-controlled studies conducted by members of our team. This represents a relevant result as similar pathophysiology for apathy has been suggested in both AD and PD. Given the common biological pathways in the onset of apathy in both disorders, we propose that, as is the case in AD, methylphenidate will be a safe and effective treatment for apathy in PD. The goal of the proposed study of Methylphenidate for Apathy in Veterans with Parkinson's Disease (MAV-PD) is to expand upon this encouraging preliminary work by evaluating methylphenidate for the treatment of apathy in PD Veteran patients. It is our strong belief that a trial designed specifically in Veteran population should be conducted, as reliance on data from civilian populations who differ in their level of medical and psychiatric comorbidity, which influence drug response, may not be applicable to Veterans with PD. This study will employ a single-site, parallel, randomized, double-blind, placebo-controlled design conducted on 60 Veterans with apathy and PD. MAV-PD is designed specifically for PD patients with apathy, and as such it employs a concise battery of neuropsychological tests that have been chosen for this patient group. This project is of great importance because it will explore the efficacy and safety of a promising dopamine agonist for treating apathy in PD, where there are no proven treatment options. Should methylphenidate be found effective, it will likely become the first-line therapy for apathy in PD.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
60
The counseling session, in which a trained study clinician will counsel the primary caregiver, will take place at each study visit and after the randomization visit. It will last approximately 20-30 minutes. Each counseling session will consist of the following elements: * Review and adjustment of the patient and caregiver supportive care plans * Emotional support and the opportunity to ventilate feelings * Counseling regarding specific caregiving skills * Assistance with problem-solving of specific issues that the caregiver brings to the sessions * Answers to questions regarding the educational materials The educational materials will consist of a copy of the book "The 36-Hour Day" by Nancy L. Mace and Peter V. Rabins. The caregiver also will be provided with 24-hour phone access to the study nurse or physician for assistance with crises that may arise after hours.
norepinephrine and dopamine reuptake inhibitor
Apathy Evaluation Scale (AES)
This measure is an 18-item scale initially developed as a method for measuring apathy resulting from brain-related pathology.
Time frame: 6 weeks
Clinical Global Impression of Change (CGIC)
The CGIC is a systematic method, developed for the Alzheimer's disease (AD) setting to assess clinically significant change in a clinical trial as viewed by an independent, skilled, and experienced clinician and has been used as an outcome in Parkinson disease trials
Time frame: 6 weeks
Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog)
This scale was developed specifically to assess cognitive functioning in patients with Alzheimer's disease but has also been used in Parkinson disease.65 It is widely used in clinical trials, and its sensitivity in detecting cognitive changes has been demonstrated in a number of studies. Scores are obtained for orientation, word-list recall, and recognition, object naming, ability to follow simple requests, ideational and constructional praxis, and expressive language. Higher scores indicate worse performance.
Time frame: 6 weeks
Continuous Performance Test (CPT)
The CPT was developed to study vigilance or selective attention. In its original form, letters were presented to participants visually one at a time at a fixed rate. The subjects were to press a lever whenever the target letter X appeared and to not press the lever if any other letter was shown. This is called the X-CPT version, and Beck et al found that this version had adequate classification accuracy. Various modifications of the basic X-CPT have been adopted, including changing the target to a number or picture, or a letter series. The CPT version used for this study will be Conner's CPT Version II. The targets are letters and patients do not respond to the letter X (not-X-CPT).
Time frame: 6 weeks
Trail Making Test (TMT)
The TMT is composed of visual search and sequencing tasks that are heavily influenced by executive functioning (concentration, resistance to distraction, and cognitive flexibility/set-shifting) and attention. These easily administered tasks are extremely sensitive to neuropsychological deficits such as frontal lobe deficits, problems with psychomotor speed, visual search, and sequencing deficits. The Test has two parts: A and B. In Part A, subjects connect numbers in order on a piece of paper as quickly as possible. Part A provides a baseline for processing speed for interpretation of the second part, Part B. For Part B, subjects connect numbers and letters alternately in order such that the connections are 1-A-2-B-3-C and so on. Both parts are timed. Lower times are better.
Time frame: 6 weeks
Neuropsychiatric Inventory (NPI)
The NPI assesses the type and severity of behavioral disturbances in dementia. The inventory evaluates 12 domains of neuropsychiatric symptoms (NPS): apathy, agitation, delusions, hallucinations, depression, euphoria, aberrant motor behavior, irritability, disinhibition, anxiety, sleeping, and eating. Frequency (1 = occasionally, less than once/week; 2 = often, about once per week; 3 = frequently, more than once a week; 4 = very frequently, once or more/day or continuously) and severity (1 = mild, 2 = moderate, 3 = severe) scales in each domain are scored based on responses from an informed caregiver involved in the patient's life. The NPI also includes a 5-point rating used to quantify caregiver distress with the patient's NPS symptoms. To obtain an NPI score for each domain, the severity score and the frequency score are multiplied, and the caregiver distress ratings of each domain are added up.
Time frame: 6 weeks
Starkstein Apathy Scale (SAS)
The AS consists of 14 items phrased as questions that are to be answered on a four-point Likert scale. Total score range is 0-42; higher scores indicate more severe apathy.This scale is derived from AES and is tailored to PD. It has been widely validated for the use of Apathy in PD and is recommended by the Movement Disorders Society
Time frame: 6 weeks
Dementia Apathy Interview Rating (DAIR)
The DAIR is a structured interview administered to a caregiver. The rationale to include in the trial is to maintain consistency with the ADMET trial, which will help with comparison between groups. It consists of 29 questions concerning the initiation of behavior, interest, and engagement with the environment. Each interview question consists of two parts. The first part addresses issues of frequency on a four-point scale, with 0 signaling the absence of the behavior and 3 signaling the constant presence of the behavior. The second part of the question asks if the current behavior represents a change from the behavior prior to memory loss. The apathy score is a sum of all items reflecting change, divided by the number of items completed, with higher scores representing greater average apathy. Dividing by the number of items adjusts for the number of behaviors for which there has been a change and expresses the patient's apathy score in terms of the underlying 4-point scale (0-3).
Time frame: 6 weeks
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
This measure is an ADL inventory developed by the ADCS to assess functional performance in patients with AD but has also been used in PD. In a structured interview format that requires less than 15 minutes to administer, informants are queried as to whether subjects attempted each of 24 items in the inventory during the prior 4 weeks and their level of performance. The scale discriminates well the stages of severity of patients, from very mild to severely impaired. It has good test-retest reliability. It includes items from traditional basic ADL scales (e.g., grooming, dressing, walking, bathing, feeding, toileting) as well as instrumental activities of daily living scales (e.g., shopping, preparing meals, using household appliances, keeping an appointment, reading). The ADCS-ADL inventory has been used as an outcome measure in other PD clinical trials.
Time frame: 6 weeks
Questionnaire for Impulsive-Compulsive Disorders in PD (QUIP)
Impulse control disorders (ICDs) are often seen in association with apathy in PD. Dopaminergic medications are considered one of the main mechanisms for the development of impulse control disorders, such as gambling. Given the NPI does not address ICDs another screening tool needs to be added. The QUIP is a widely used questionnaire used for screening of ICDs, The total QUIP-RS score for all ICDs and related disorders combined ranges from 0 to 112 with higher number indicating more severe and/or frequent impulse control disorders.
Time frame: 6 weeks
Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) - Part III and IV
The MDS-UPDRS is one of the most commonly used scales to monitor symptoms related to Parkinson disease. Part III focuses on the primary motor aspects of the condition and part IV focuses on motor fluctuations. Higher scores represent more severe symptoms of parkinsonism. The score range from 0 to 108.
Time frame: 6 weeks
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