Innovations In Clinical Neuroscience

JAN-FEB 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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16 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 R E V I E W P Parkinson's disease (PD) is a prevalent disorder that affects approximately 40 to 1,000 persons/100,000, with increased occurrence in older individuals. 1 PD is characterized by progressive neurodegeneration that manifests in the early stages as mild cognitive impairment and moderate motor dysfunction, namely bradykinesia, rigidity, and tremor. 2,3 As PD advances, the severity escalates, culminating in significant motor dysfunction, such as freezing of gait, falls, and choking, and neuropsychiatric complications, including psychosis. PD psychosis (PDP) occurs in up to 75 percent of PD cases and is associated with increased caregiver burden, nursing home admission, and mortality. 2–5 Manifestations of PDP include visual hallucinations (VH), the most common presentation, which is observed in up to 70 percent of patients with PDP. Other presentations of PDP include delusions, illusions, and auditory or presence hallucinations. 6 Despite the need to reduce morbidity and mortality associated with PDP, treatment options are limited. Psychosis development might be partially attributable to medications used to treat PD motor dysfunction. 7 As a result, first-line therapy for treating PDP consists of reducing or discontinuing anticholinergic medications, monoamine oxidase inhibitors (MAOI), levodopa, or dopamine agonists (DA), the cessation of which might worsen motor symptoms. 6,8 However, these medications are likely not the sole factor in the development of PDP, as symptoms tend not to directly correlate with medication usage, and patients might continue to experience PDP after these drugs are discontinued. 9 If medication adjustment is not appropriate or fails to resolve symptoms, second- generation antipsychotics may be prescribed for PDP. 10–11 These medications are not approved by the United States Food and Drug Administration (FDA) for the treatment of PDP, and among the antipsychotics, only clozapine has compelling evidence to support its effectiveness in PDP. Given the morbidity, mortality, and societal costs associated with PDP and dearth of effective, well-tolerated medications, new treatment options are needed. 10,11 Pimavanserin (Nuplazid TM , Acadia Pharmaceuticals®, San Diego, California) is an antipsychotic with a unique mechanism of action that functions as a highly selective, partial inverse agonist at 5-HT 2A receptors. 12,13 Pimavanserin shows promise as a safe, A B S T R A C T Objective: Pimavanserin is the first United States Food and Drug Administration (FDA)-approved treatment for Parkinson's disease psychosis (PDP). This article reviews the safety, efficacy, and pharmacology data for pimavanserin and its role in therapy. Method of Research: Initial literature sources were identified via MEDLINE search (1946–September 2016) of pimavanserin and ACP-103 (original molecular designation). Reference review and search of FDA. gov and clinicaltrials.gov yielded additional studies. English-language studies of pimavanserin for PDP were evaluated. Animal studies were excluded. Randomized, controlled trials (RCTs) were prioritized. Results: Four RCTs were identified. In each, pimavanserin was well-tolerated with few adverse effects and no worsening of motor symptoms. A Phase II trial displayed a nonsignificant trend toward Scale for Assessment of Positive Symptoms (SAPS) improvement (p=0.09), with significant benefits in secondary efficacy markers. However, two Phase III trials, including one that was terminated early, failed to show significant SAPS improvement. A third Phase III trial with an improved research design utilized a nine-item subset of the SAPS, the SAPS-PD, as the primary outcome and demonstrated that pimavanserin 40mg was effective in improving PDP compared to placebo (p=0.0014, effect size=0.50). Secondary outcomes were also significantly improved: Clinical Global Impression of Severity (CGI-S) (p=0.0007, effect size=0.52) and Clinical Global Impression of Improvement (CGI-I) (p=0.0011, effect size=0.51), caregiver burden (p=0.0016, effect size=0.50), nighttime sleep (p=0.0446, effect size=0.31), and daytime wakefulness (p=0.012, effect size=0.39). Conclusion: Evidence suggests pimavanserin attenuates PDP symptoms with few adverse effects and little risk of worsening motor function. With limited treatment options for PDP, pimavanserin represents an important therapeutic innovation. Keywords: Pimavanserin, ACP-103, Parkinson's disease psychosis. Pimavanserin: A Novel Drug Approved to Treat Parkinson's Disease Psychosis by AMANDA K. KITTEN, PharmD; SARAH A. HALLOWELL, PharmD; STEPHEN R. SAKLAD, PharmD, BCPP; and KIRK E. EVOY, PharmD, BCACP, BC-ADM, CTTS Drs. Kitten, Hallowell, Saklad, and Evoy are with the College of Pharmacy, The University of Texas at Austin in Austin, Texas. Innov Clin Neurosci. 2017;15(1–2):16–22 FUNDING: The authors received no funding for the development of this manuscript. DISCLOSURES: Dr. Saklad declares the following: employee of The University of Texas at Austin College of Pharmacy; appointed to the Texas Department of State Health Services, San Antonio State Hospital and the UT Health Science Center San Antonio School of Medicine; speakers bureau for Otsuka / Lundbeck; consultant for NCS Pearson, and Takeda; speaker for several professional organizations; Board of Directors for the College of Psychiatric and Neurologic Pharmacists Foundation; Business Development Council for the College of Psychiatric and Neurologic Pharmacists; expert witness on both defendant and plaintiff sides; no direct stock ownership in pharmaceutical corporations. Drs. Kitten, Hallowell, and Evoy have no conflicts of interest relevant to the content of this article. CORRESPONDENCE: Kirk E. Evoy, PharmD, BCACP, BC-ADM, CTTS; Email: evoy@uthscsa.edu

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