Pimavanserin for Parkinson's Disease psychosis: Effects stratified by baseline cognition and use of cognitive‐enhancing medications

Abstract

Background : PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective : To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods : Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results : Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 ( P = 0.012) and –5.66 versus –3.15 ( P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions : The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Aberrant resting-state oscillatory brain activity in Parkinson's disease patients with visual hallucinations: An MEG source-space study

“…Alterations in serotonin neurotransmission have also been proposed in the pathophysiology of hallucinations in PD, with a specific role for the serotonin 2 receptor ( Factor et al, 2017 ). Treatment with pimavanserin, a serotonin 2A inverse-agonist, has been shown to alleviate psychosis in both PD patients with normal and impaired cognitive functioning ( Espay et al, 2018 ; Kianirad and Simuni, 2017 ). To date, only one study has examined in vivo changes in serotonin receptor binding in PD with positron emission tomography (PET) and found increased serotonin binding in the ventral visual pathway in PD patients with VH compared to patients without hallucinations ( Ballanger et al, 2010 ).…”

Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy

“…Pimavanserin effectively reduced hallucinations and delusions associated with DRP in multiple clinical studies, which included patients with the major forms of dementia, and was well tolerated by elderly fragile patients in the studies [33][34][35][36][37]149]. The purpose of this review was to identify mechanisms that explain the role of 5-HT 2A Rs in both the etiology and treatment of DRP.…”

“…Although the prespecified primary endpoint of efficacy at 6 weeks was met, the separation between placebo and pimavanserin groups was no longer statistically significant at 12 weeks in the AD trial, due primarily to an increased placebo response at that time point. In both PD and AD trials, further analysis of subgroups revealed that efficacy was greater in PD patients who were cognitively impaired as indicated by lower Mini-Mental State Examination scores [ 35 ] and in AD patients with more severe psychiatric symptoms [ 36 ]. Significantly, pimavanserin was well tolerated in PD and AD patients, did not cause motoric side effects, and did not worsen cognition in AD subjects over 12 weeks of drug administration [ 34 , 36 ], a timeframe in which atypical antipsychotic drugs do worsen cognition [ 19 ].…”

Hallucinations in Parkinson’s disease: new insights into mechanisms and treatments

“…The 5HT2A inverse agonist, Pimavanserin, was recently shown in a large randomised controlled trial to improve psychosis and visual hallucinations in Parkinson’s disease, 25 with greatest improvement observed in patients with poorer cognition. 26 Initial concerns of higher rates of mortality were shown to be no higher than those in this already frail patient group. 27 …”