Pimavanserin, a Serotonin2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis

Abstract

Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD). Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP), although quetiapine has never been shown to be effective in a placebo-controlled study. The demonstrated efficacy of clozapine in PDP has been attributed to serotonin (5-HT 2A ) receptor blockade. We postulated that pimavanserin (ACP-103), a highly selective 5-HT 2A inverse agonist, would attenuate psychosis in patients with PDP, but avoid motoric worsening and non-motoric side effects. In this double-blind, randomized multicenter 28-day study, the tolerability and efficacy of pimavanserin was compared with placebo in 60 patients with L-DOPA or dopamine (DA) agonist-induced PDP. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. Antipsychotic efficacy was evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS) and a UPDRS Part I psychosisrelevant item. Pimavanserin did not differentiate from placebo with regard to motor impairment, sedation, hypotension, or other side effects. The principal measures of efficacy of antipsychotic response to pimavanserin, the SAPS total domain score, only showed a trend. However, the pimavanserin-treated patients showed significantly greater improvement in some but not all measures of psychosis, including SAPS global measures of hallucinations and delusions, persecutory delusions, and the UPDRS measure of delusions and hallucinations. Pimavanserin showed significantly greater improvement in psychosis in patients with PDP at a dose which did not impair motor function, or cause sedation or hypotension Thus, pimavanserin may represent a novel treatment for PDP. Furthermore, these results support the hypothesis that attenuation of psychosis secondary to DA receptor stimulation in PDP may be achieved through selective 5-HT 2A receptor antagonism.

Characterization of 3,4-Methylenedioxymethamphetamine (MDMA) EnantiomersIn Vitroand in the MPTP-Lesioned Primate:R-MDMA Reduces Severity of Dyskinesia, WhereasS-MDMA Extends Duration of ON-Time

“…These results support the potential efficacy of 5-HT 2A antagonists against PD dopaminergic psychosis demonstrated previously with ACP-103 (Meltzer et al, 2010). The data are also in accordance with two recent anatomical studies which found increased 5-HT 2A receptor levels in the temporal cortex of PD patients with visual hallucinations (Ballanger et al, 2010;Huot et al, 2010b).…”

Parkinson's disease, visual hallucinations and apomorphine: A review of the available evidence

“…Use of the selective 5-HT2A antagonist pimavanserin has been shown to resolve psychotic behavior in an animal model (6-hydroxydopamine), while in clinical trials use of pimavanserin, previously demonstrated to be well tolerated, has more recently been reported to have a beneficial effect on VH in PD patients [56][57][58].…”

Comparative Utility of Atypical Antipsychotics for the Treatment of Psychosis in Parkinson’s Disease: A Systematic Review and Bayesian Network Meta-analysis

“…When assessing the eligibilities of the full-text articles, 12 articles were excluded. Five of these articles did not use the BPRS or UPDRS-III as the endpoint, [23][24][25][26][27] five were lacked necessary information, 12,[28][29][30][31] one was a study including not patients with PD, 13) and one was an extension of an open-label study of another appropriate study. 32) Therefore, ten articles were potentially appropriate for the present study.…”