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      Motor- and cognition-related safety of pimavanserin in patients with Parkinson's disease psychosis

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          Abstract

          Background

          Pimavanserin, a selective 5-HT 2A inverse agonist/antagonist, is the only treatment approved by the US Food and Drug Administration for hallucinations and delusions associated with Parkinson's disease (PD) psychosis.

          Aim

          We aimed to evaluate motor- and cognition-related safety in pimavanserin-treated patients with PD psychosis.

          Methods

          This analysis included patients with PD psychosis treated with pimavanserin 34 mg from a pooled analysis of 3 randomized, double-blind, placebo-controlled, 6-week studies [NCT00477672 (study ACP-103-012), NCT00658567 (study ACP-103-014), and NCT01174004 (study ACP-103-020)] and a subgroup of patients with PD dementia with psychosis from HARMONY (NCT03325556), a randomized discontinuation study that included a 12-week open-label period followed by a randomized double-blind period of up to 26 weeks. Motor- and cognition-related safety were examined.

          Results

          The pooled analysis included 433 randomized patients (pimavanserin, 202; placebo, 231). Least squares mean (standard error [SE]) change from baseline to week 6 Unified Parkinson's Disease Rating Scale (UPDRS) II + III score was similar for pimavanserin [−2.4 (0.69)] and placebo [−2.3 (0.60)] (95% Confidence Interval [CI]:−1.9, 1.6). The change from baseline to week 6 for UPDRS II and UPDRS III scores was similar between groups. In the HARMONY open-label period, 49 patients with PD dementia with psychosis were treated with pimavanserin 34 mg, 36 of whom were randomized in the double-blind period (pimavanserin, 16; placebo, 20). In the open-label period, the mean (SE) change from baseline to week 12 ( n = 39) Extra-Pyramidal Symptom Rating Scale (ESRS-A) score was −1.7 (0.74); in the double-blind period, the results were generally comparable between the pimavanserin and placebo arms. The change from baseline in Mini-Mental State Examination (MMSE) score was also comparable between pimavanserin- and placebo-treated patients in HARMONY [open-label ( n = 37): mean (SE) change from baseline to week 12, 0.3 (0.66)]. Rates of motor- and cognition-related adverse events were similar between pimavanserin and placebo in both analyses.

          Conclusions

          Pimavanserin 34 mg was well tolerated and did not yield a negative impact on motor- or cognition-related function in patients with PD psychosis.

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          Most cited references38

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          Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results.

          We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.
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            Cognitive decline in Parkinson disease

            Dementia is commonly encountered in advanced stages of Parkinson disease (PD), but evidence is accumulating that cognitive decline can manifest much earlier in the disease course. Aarsland and colleagues review current knowledge regarding cognitive impairment in patients with PD, focusing on cerebrospinal fluid and imaging biomarkers as potential predictors of cognitive decline in this population.
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              Predictors of nursing home placement in Parkinson's disease: a population-based, prospective study.

              To examine the rate and predictors of nursing home placement in patients with Parkinson's disease. Four-year prospective study. A population-based study in western Norway 178 community-dwelling subjects with Parkinson's disease. Main outcome measure was the time from baseline to nursing home admission. Baseline evaluation of motor symptoms (Unified Parkinson's Disease Rating Scale, UPDRS), cognition (clinical dementia interview, Gottfries, Brane & Steen dementia scale, and Mini-Mental State Examination), depression (clinical interview and the Montgomery & Asberg Depression Rating Scale), and psychotic symptoms (UPDRS Thought Disorder item) were performed. Forty-seven patients (26.4%) were admitted to a nursing home during the 4-year study period. Institutionalized patients were older, had more advanced Parkinson's disease with more severe motor symptoms and impairment of activities of daily living, were cognitively more impaired, were more often living alone, and had more hallucinations than those who continued to live at home. Duration of disease, levodopa dose, and gender distribution did not differ between the two groups. A Cox proportional hazards linear regression analysis showed that old age, functional impairment, dementia, and hallucinations were independent predictors of nursing home admission. Both motor and neuropsychiatric symptoms contributed to institutionalization, but the presence of hallucinations was the strongest predictor. This finding indicates it is possible that effective treatment of hallucinations may reduce the need for institutionalization in patients with Parkinson's disease.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                05 October 2022
                2022
                : 13
                : 919778
                Affiliations
                [1] 1Acadia Pharmaceuticals Inc , San Diego, CA, United States
                [2] 2University of Exeter Medical School , Exeter, United Kingdom
                [3] 3Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati , Cincinnati, OH, United States
                Author notes

                Edited by: Steven Frucht, Grossman School of Medicine, New York University, United States

                Reviewed by: Joseph Harold Friedman, Butler Hospital, United States; Artur Francisco Schumacher-Schuh, Federal University of Rio Grande do Sul, Brazil

                *Correspondence: Alberto J. Espay alberto.espay@ 123456uc.edu

                This article was submitted to Dementia and Neurodegenerative Diseases, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2022.919778
                9580496
                36277907
                eee4daac-4d5b-49b0-b052-80ae6db7a46c
                Copyright © 2022 Abler, Brain, Ballard, Berrio, Coate and Espay.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 April 2022
                : 07 September 2022
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 39, Pages: 10, Words: 6206
                Categories
                Neurology
                Original Research

                Neurology
                parkinson's disease,pimavanserin,cognition,motor function,psychosis
                Neurology
                parkinson's disease, pimavanserin, cognition, motor function, psychosis

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