Changing the treatment paradigm for Parkinson’s disease psychosis with pimavanserin

ABSTRACT

Introduction: Parkinson’s disease psychosis (PDP) may affect up to 60% of patients with Parkinson’s disease over the course of their disease, and is associated with poor prognosis, including increased risks of mortality and nursing home placement. PDP treatments have been limited to off-label use of atypical antipsychotics, most of which pose risks of worsened motor symptoms and other potential adverse events (AEs) due to their dopamine receptor blockade and additional off-target receptor affinities. Pimavanserin is a highly selective 5-HT_2A inverse agonist and poses no known risks for worsening of parkinsonism or other off-target receptor AEs. Pimavanserin is the first and only medication approved for PDP treatment.

Areas covered: This review covers estimated prevalence, clinical characteristics, diagnostic criteria, and risk factors for PDP; the hypothetical progression of PDP; management of PDP including use of antipsychotics; pharmacology and clinical trial data on pimavanserin; and expert opinion on PDP treatment. The NLM/PubMed database was searched for papers using the search terms of "PDP" AND "treatment" AND "pimavanserin" for the last 10 years.

Expert opinion: The recent insights into PDP pathophysiology and approval of the only medication specifically to treat PDP are key advances that should improve the recognition, diagnosis, and management of PDP.

KEYWORDS:

• Diagnostic criteria
• Parkinson’s disease psychosis (PDP)
• progression
• risk factors
• symptoms
• treatment

Article Highlights

• Parkinson’s disease psychosis (PDP) may affect up to 60% of patients over their lifetime. PDP is associated with poor prognosis, including increased risks of mortality and nursing home placement, and greater caregiver burden.

• Symptoms of PDP include hallucinations that may occur with all five senses (most commonly visual and least frequently gustatory), illusions, and delusions; definitions and formal criteria for PDP as a distinct disease entity have been established.

• The symptoms of PDP are believed to progress such that symptoms that are not bothersome at an early stage will most likely progress to be more severe, varied, and troublesome.

• Management of PDP has traditionally included use of atypical antipsychotics that all have inverse agonism of serotonergic type 2A (5-HT_2A) receptors; however, actions of these agents on other receptors may cause adverse events such as worsened motor symptoms, orthostatic hypotension, daytime sedation, etc.

• Pimavanserin is the most highly selective 5-HT_2A inverse agonist with lower affinity for 5-HT_2C and other off-target receptors, and these attributes make it unlikely to block postsynaptic dopaminergic and other off-target receptors. It is the only medication approved by the United States Food and Drug Administration for the treatment of PDP; clozapine is approved for PDP in the European Union.

• Pimavanserin is the preferred option for most patients with PDP based on its regulatory approval and demonstrated clinical efficacy and safety.

Acknowledgments

The authors thank Larry Deblinger and Robin Smith, PhD, of The Curry Rockefeller Group, LLC for editorial support in the preparation of this manuscript.

Declaration of interest

KE Lyons: Speaker for Acadia. Consultant for Abbott and the Parkinson Foundation.

R Pahwa: Compensated advisory services, consulting, research grant support, or speaker honoraria: Abbott, AbbVie, Acadia, Acorda, Adamas, Biogen, Boston Scientific, CalaHealth, Cavion, Global Kinetics, Intec, Kyowa, Lilly, Lundbeck, Neurocrine, NIH/NINDS, Parkinson Foundation, Photopharmics, Prilenia, Sunovion, Teva Neuroscience, Theranexus, Theravance, US WorldMeds, Voyager.N Hermanowicz: Clinical trials/funding support: AbbVie, Eli Lilly, Fort, Global Kinetics Corporation, Parkinson Study Group, Revance, Sunovion, Voyager. Honoraria for speaking or consulting: AbbVie, Acadia, Adamas, Allergan, Teva, US WorldMeds.

T Davis: Investigator/co-investigator in studies funded by AbbVie, Inc., The Parkinson Foundation, The Peterson for Parkinson Foundation. Consultant since 2017: AbbVie and Acadia Pharmaceuticals.F Pagan: Research grants: US WorldMeds. Educational Grant: Medtronic. Consulting/Speaker: AbbVie, Acadia, Acorda, Adamas, Merz, Sunovion, Teva, US WorldMeds.

SH Isaacson: Honoraria for CME, consultant, research grants, and/or promotional speaker on behalf of AbbVie, Acadia, Acorda, Adamas Pharmaceuticals, Addex, Allergan, Amarantus, Auspex, Avid, Axovant, AZ Therapies, Biogen, Biotie, Britannia, Cynapsus, Eisai, Eli Lilly, GE Healthcare, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Medtronics, Merz, The Michael J. Fox Foundation, Neurocrine, Neuroderm, NINDS/NIH, Parkinson Study Group, Pfizer, Pharma2B, Prothena, Roche, Sanofi, Shire, Sunovion, Teva, UCB, US WorldMeds, and XenoPort. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Initial author roundtable and editorial assistance for the manuscript were funded by Acadia Pharmaceuticals. Authors received no payment for writing the paper.