Pimavanserin: novel pharmacotherapy for Parkinson’s disease psychosis

ABSTRACT

Introduction: Pimavanserin is the first FDA-approved atypical antipsychotic drug indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP).

Areas covered: This review focuses on the preclinical discovery of pimavanserin. It analyzes the pharmacological, behavioral and molecular mechanisms of pimavanserin and their contribution to the therapeutic advantages of the drug as reported in published preclinical and clinical studies, press releases and product labels.

Expert opinion: Pimavanserin exhibits a unique pharmacological profile with nanomolar affinity at serotonin 5-HT_2A and 5-HT_2C receptors. Functionally, it acts as a potent inverse agonist at 5-HT_2A receptors, with selectivity over 5-HT_2C receptors and no appreciable activity at other neurotransmitter receptors. Behavioral studies found that pimavanserin reversed impaired behaviors in animal models predictive of antipsychotic activity, and with no impairment of motor functions. The drug exhibits long plasma half-life (57 hours), which support its once/day administration. A pivotal phase III clinical trial demonstrated significant improvement in PDP symptoms in patients receiving pimavanserin compared to placebo-treated patients. The drug also displayed relatively benign safety and tolerability profiles. Pimavanserin’s mechanism of action might contribute to its unique psychopharmacological properties in the improved treatment of PDP, and perhaps psychosis in other diseases including schizophrenia and dementia-related psychosis.

KEYWORDS:

• Clinical trials
• inverse agonist
• motor symptoms
• serotonin receptors
• Parkinson’s disease
• psychosis

Article highlights

• Parkinson’s disease psychosis (PDP) impairs the functional activities of Parkinson’s disease (PD) patients, places a heavy burden on families and caregivers, and is one of leading causes for placement of patients in nursing homes and long-term care facilities.

• Management of PDP was limited due to the absence of effective medications with acceptable safety and tolerability profiles and without strict blood test monitoring.

• Preclinical studies reported that pimavanserin, a potent serotonin 5-HT_2A inverse agonist, reversed psychotic-like behaviors in animal models predictive of antipsychotic activity. It did not worsen motor symptoms in animal models predictive of extrapyramidal side effects.

• Phase III clinical trial demonstrated that pimavanserin improved hallucinations and delusions in PDP patients without worsening of motor symptoms, a major adverse event associated with treatment with dissimilar antipsychotic drugs other than quetiapine and clozapine.

• FDA approval of pimavanserin in April 2016 as the first atypical antipsychotic drug indicated for the treatment of hallucinations and delusions associated with PDP is considered a step forward in the improved management of PDP. The unique pharmacological profile of pimavanserin encourages its evaluation in other psychotic disorders including schizophrenia and Alzheimer’s disease psychosis.

• This box summarizes key points contained in the article

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. A reviewer on this manuscript has disclosed being a paid consultant to Acadia Pharmaceuticals.

Additional information

Funding

This manuscript has not been funded.