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Parkinson's Disease and Parkinson's Disease Psychosis: A Perspective on the Challenges,Treatments, and Economic Burden
Doral Fredericks, PharmD, MBA; James C. Norton, PhD; Carolyn Atchison, MSc; Robert Schoenhaus, PharmD; and Michael W. Pill, PharmD

Parkinson's Disease and Parkinson's Disease Psychosis: A Perspective on the Challenges,Treatments, and Economic Burden

Doral Fredericks, PharmD, MBA; James C. Norton, PhD; Carolyn Atchison, MSc; Robert Schoenhaus, PharmD; and Michael W. Pill, PharmD
Economic Burden of PDP

While the economic costs of PD are significant, they are magnified in those patients also diagnosed with PDP. An oft-cited study found that the odds ratio for nursing home placement is 16 times higher for PD patients with psychosis (hallucinations) than for patients with PD remaining in the community.21

Of the total economic burden for PD, Huse and colleagues (2005) attributed almost 70% to indirect costs related to productivity loss and provision of uncompensated care by family members.6 There is evidence that productivity loss is greatest in the later stages of the disease50; however, even in the first year after diagnosis, indirect costs due to loss of patient and caregiver productivity represented 45% of total expenses.51
 
Parkinson’s Disease Psychosis Impact on Long-Term Care Utilization

Symptoms of psychosis are strongly correlated to nursing home placement, regardless of age.21,25 In a 10-year analysis of costs utilizing claims data for commercially insured members with Parkinson’s disease (PD) under age 65 years (n = 1151), patients requiring an ambulatory assistance device and institutionalization incurred 6 to 7 times the direct costs of their matched controls. Among all patients with PD, 24% had diagnosed mental disorders, 11% had neuropsychiatric disorders, and 10% had sleep disorders. Among the institutionalized cohort of patients with PD versus matched controls, 57% versus 10% had mental disorders, and 29% versus 4% had neuropsychiatric disorders.51

Analysis of Medicare claims data from 2000-2010 provides evidence of the heavy burden associated with PDP52:

74.6% of patients with Parkinson’s disease psychosis (PDP) spent time in a long-term care (LTC) facility (average, 179 days) compared with 55.8% of patients with PD without psychosis (average, 83 days).

In LTC specifically, the average annual all-cause cost was $31,178 for patients with PDP compared with $14,461 for PD without psychosis.

Annual all-cause reimbursement across all components of care for patients with PDP averaged $67,251, while that for PD patients without psychosis was $38,742.

Traditional and New Approaches to PDP Management

The pathophysiology of PDP and pharmacological rationale for treatment are associated with 3 main neurotransmitter systems: dopamine, acetylcholine, and serotonin.53,54 Medical management of PDP aims to reduce the frequency and severity of psychotic symptoms with minimal worsening of PD motor symptoms. Traditional management of PDP has been challenged by the lack of effective and safe pharmacological treatment options and the opposing nature of atypical antipsychotics and dopaminergic therapies given to treat motor symptoms. Frequently, an initial step in treating hallucinations and delusions associated with PD is to first reduce anti-PD medications, such as anticholinergics, selegiline, amantadine, dopamine agonists, catechol-O-methyltransferase inhibitors, and lastly, levodopa. Reducing dopaminergic therapies, however, may worsen motor symptoms.54 To treat symptoms of psychosis when reduction of dopaminergic therapies is not a viable option, 2 alternatives exist: use of recently approved pimavanserin55 or off-label use of atypical antipsychotics, particularly clozapine and quetiapine. However, off-label use of some atypical antipsychotics may worsen motor symptoms by antagonizing dopaminergic therapy.53

Atypical Antipsychotics

Atypical antipsychotics, also known as second-generation antipsychotics, have long been used to treat PDP, but they are generally not well tolerated because the doses needed to block limbic  D2 receptors also result in blockage of the dorsal striatal D2 receptors, reducing the therapeutic effects of dopamine treatment on motor symptoms.56 These medications are associated with a higher risk of mortality when used in elderly patients with dementia.54 Only clozapine (Level B evidence),
with monitoring of absolute neutrophil count, or quetiapine (Level C evidence) have been considered as appropriate for use by the American Academy of Neurology. One Class I study and 1 Class II study found that clozapine improved psychosis and, in some cases, motor function. One Class II study demonstrated that quetiapine possibly improves psychosis. However, it is important to note that the American Academy of Neurology guidelines were last updated in 2006,53 prior to the introduction of an FDA-approved agent.55

At this time only 1 atypical antipsychotic, pimavanserin (NUPLAZID®, ACADIA Pharmaceuticals Inc.), is approved by the FDA for the treatment of hallucinations and delusions associated with PDP.55 Pimavanserin acts as an inverse agonist/antagonist at serotonin 5-HT2A receptors with high binding affinity and at serotonin 5-HT2C receptors with lower binding affinity. In vitro, pimavanserin has no appreciable affinity for dopaminergic (including D2) receptors. A clinical study demonstrated the efficacy of pimavanserin as a treatment for hallucinations and delusions associated with PDP and also showed that pimavanserin does not have an effect on motor function compared with placebo, nor does it have appreciable effects on blood cell counts or metabolic parameters. While pimavanserin shares the class warning regarding increased risk of death in elderly patients with dementia, the boxed warning is modified to permit treatment of the hallucinations and delusions associated with PDP in this population.57 Atypical antipsychotics used to treat PDP are listed in Table 2.26,55,57-60



 
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