Abstract

PIMAVANSERIN (NUPLAZID): A SELECTIVE 5-HT2A INVERSE AGONIST FOR PARKINSON’S DISEASE PSYCHOSIS

M. Mani Chandana*, Tagore Tanniru, Erothi Balakoti, Routhu Pratyusha, K. Eswar Kumar, B. Lakshman

ABSTRACT

Psychosis is among the most disabling non-motor complications of Parkinson’s disease (PD), affecting up to 60% of patients over the course of illness and increasing the risks of institutionalisation and death. Treatment has long been constrained by the dopamine D2-receptor antagonism shared by most antipsychotics, which can worsen parkinsonism, by the haematological monitoring required for clozapine, and by the inconsistent evidence for quetiapine. Pimavanserin (NUPLAZID), a selective serotonin 5-HT2A receptor inverse agonist and antagonist with lesser 5-HT2C activity and no appreciable dopaminergic, muscarinic, histaminergic or adrenergic affinity, was approved by the US Food and Drug Administration in 2016 as the first therapy indicated for hallucinations and delusions associated with PD psychosis (PDP). This review integrates the discovery, physicochemical and pharmacological profile, pharmacokinetics, clinicalevidence, comparative position, safety, use in special populations and regulatory status of pimavanserin. In the pivotal six-week trial, pimavanserin 34 mg daily reduced psychosis scores more than placebo (difference −3.06 points on the SAPS-H+D) without worsening motor function, and a relapse-prevention trial in dementia-related psychosis reduced the hazard of relapse by about two-thirds. A network meta-analysis found pimavanserin and clozapine to be the only agents that significantly improved psychosis in PDP, although no completed peer-reviewed head-to-head trial is available. Principal concerns are QT-interval prolongation, the class warning of increased mortality in elderly patients with dementia-related psychosis, peripheral oedema and confusion, and absent data in severe renal and hepatic impairment. Key gaps include direct comparison with clozapine and quetiapine, long-term cognitive and cardiovascular outcomes, and access in low- and middle-income countries.

Keywords: pimavanserin; Parkinson’s disease psychosis; 5-HT2A inverse agonist; non-dopaminergic antipsychotic; NUPLAZID; QT prolongation.