Pimavanserin in the Management of Parkinson Disease Psychosis

Educational Objectives

The goal of this program is to improve diagnosis and management of Parkinson disease psychosis (PDP). After hearing and assimilating this program, the clinician will be better able to:

1. Identify common presentations of PDP.

2. Optimize management of PDP.

3. Provide consultation about a patient who develops psychosis while on multiple agents for treatment of Parkinson disease.

Summary

Epidemiology of Parkinson disease psychosis (PDP): affects nearly half of patients with Parkinson disease (PD); prevalence increases with aging and cognitive impairment

Diagnosis: diagnostic criteria require established PD; parkinsonism that appears after psychosis may be caused by dementia with Lewy body dementia (LBD) rather than PD (however, overlap between PDP and LBD exists); patient must exhibit hallucinations, delusions, illusions, or false sense of presence; alternative diagnoses such as infection and metabolic changes must be excluded; most common presentation visual hallucinations; delusions less common and may herald more severe dementia

Management: involves decreasing dopaminergic tone by reducing therapies that provide motor benefits; one-third of patients receive neuroleptic agents; psychosis accounts for one-fourth of admissions in such patients, so treatment may prevent hospitalization even if it does not alter prognosis

Assessing context of behavior: sudden onset of psychosis uncommon; sense of presence may be present for months or years before patient develops benign hallucinations with preservation of insight; however, sudden onset of frank psychosis more likely to be caused by extrinsic factor such as anticholinergic medication or urinary tract infection

Pathophysiology: disease process involves interplay among dopamine, glutamate, and serotonin; psychosis worsened by increased dopaminergic tone; however, in PDP, serotonergic system overactive, especially 5-hydroxytryptamine-2 (5-HT2) receptors; change in dopaminergic pathway affects serotonergic pathway, and vice versa, via changes seen in brainstem, ventral tegmental area, pars compacta of substantia nigra, nucleus accumbens, and striatum; PD typified by reduction in synaptic reuptake of serotonin, flooding with serotonin, and upregulation of 5-HT2A receptors; this change in binding potential seen throughout brain, especially associative visual areas; differential diagnosis of PDP includes metabolic changes and drug interactions

Approach to treatment: clinician should consider simplifying medication regimen and eliminating anticholinergic drugs; next step reducing antiparkinsonian (dopaminergic) medications; antipsychotics often impair dopaminergic function and thereby improve psychosis, but worsen motor features; when stopping medications, clinician should first eliminate anticholinergic agents, then amantadine; dopamine agonists such as pramipexole and ropinirole probably have little effect in advanced PD, and stopping these drugs may be sufficient to treat psychotic symptoms

Guidelines: Movement Disorder Society recognizes 2 drugs (clozapine and pimavanserin) as clinically useful for PDP; clozapine more efficacious than pimavanserin but requires weekly monitoring; quetiapine considered possibly useful but not supported by high level of evidence; however, quetiapine commonly used, easy to administer, and helps patients sleep; clozapine supported by best evidence including placebo-controlled trials and study showing superiority over quetiapine; pimavanserin supported by randomized controlled trial (RCT) and approved by FDA for treatment of PDP; although two RCTs supported quetiapine, 4 placebo-controlled trials reported failure of drug; ziprasidone used in acute setting but not for long-term management

Properties of pimavanserin: mechanism of action — highly selective for 5-HT2A receptors; drug has no measurable affinity for muscarinic, histaminergic, or adrenergic receptors; pimavanserin inverse agonist that suppresses receptor and abolishes basal activity; pharmacokinetics — half-life long; time to maximum concentration 6 hr; absorption not affected by high-fat meals; single 34-mg dose used without titration; drug eliminated via cytochrome P450 CYP3A4 system and may interact with other drugs

Evidence for pimavanserin: in pivotal trial, patients randomized to placebo or 34 mg pimavanserin; primary endpoint change at 6 wk on Scale for Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD); secondary endpoint change in motor scale; although some patients in trial may have had early dementia, study designed to exclude those with significant cognitive impairment (patient required to score >21 on Mini-Mental State Examination); change of 2.33 points on SAPS-PD considered clinically meaningful; in clinical trial, 6-wk change in score on SAPS-PD 2.73 points in placebo group and 5.79 points in pimavanserin group; however, no differences between groups seen until 4 wk; sensitivity analyses supported benefit of pimavanserin; ≈14% of patients experienced remission of psychosis; findings on motor scale similar in both arms; pimavanserin reduced delusions and hallucinations

Safety of pimavanserin: no safety concerns identified; peripheral edema and nausea more common in pimavanserin group but incidence <10%; in some patients, adverse events led to discontinuation of drug, suggesting that in small group of patients, pimavanserin worsens hallucinations; in future, pharmacodynamic studies may be able to identify patients likely to worsen

Dosing: single 34-mg tablet taken daily, with or without food; no adjustments needed for renal or liver disease; however, if patient on inhibitor of CYP3A4 such as ketoconazole, dose should be reduced

Electrocardiographic (ECG) effects: pimavanserin may lengthen QT interval and should be used with caution in patients already on other agents that prolong QT interval; monitoring with ECG recommended in patients with significant cardiac disease

Pimavanserin and drugs for PDP: several patients in studies on cholinesterase inhibitors or memantine (Namenda); when patients in trial stratified by presence of cognitive impairment, drug appeared most effective in patients with cognitive impairment; administration with rivastigmine, donepezil, galantamine, or memantine may magnify effect of pimavanserin, suggesting opportunity for synergism, but additional studies needed

Readings

Cummings J et al: Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 2014 Feb 8;383(9916):533-40. Erratum in: Lancet 2014 Jul 5;384(9937):28; Espay AJ et al: Pimavanserin for Parkinson’s disease psychosis: Effects stratified by baseline cognition and use of cognitive-enhancing medications. Mov Disord 2018 Nov;33(11):1769-1776; Goldman JG, Holden S: Treatment of psychosis and dementia in Parkinson’s disease. Curr Treat Options Neurol 2014 Mar;16(3):281; Hawkins T, Berman BD: Pimavanserin: A novel therapeutic option for Parkinson disease psychosis. Neurol Clin Pract 2017 Apr;7(2):157-162. Erratum in: Neurol Clin Pract 2017 Aug;7(4):282; Seppi K et al: Update on treatments for nonmotor symptoms of Parkinson’s disease-an evidence-based medicine review. Mov Disord 2019 Feb;34(2):180-198. Erratum in: Mov Disord 2019 May;34(5):765.

Disclosures

For this program, the following has been disclosed: Dr. Espay is on the advisory board for AbbVie, ACADIA Pharmaceuticals, Accorda Therapeutics, Cyanpsus Therapeutics/Sunovion Pharmaceuticals, H. Lundbeck A/S, Impax Laboratories, Teva Pharmaceutical USA, and US WorldMeds; receives honoraria from AbbVie, ACADIA Pharmaceuticals, H. Lundbeck A/S, UCB SA, and US WorldMeds, and has received grants from Great Lakes NeuroTechnologies. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Espay was recorded at the 18th Annual Psychopharmacology Update, presented by the University of Cincinnati and the Global Academy for Medical Education, and held October 26, 2019, in Cincinnati, OH. For information on the 19th Annual Psychopharmacology Update, scheduled for October 2020, in Cincinnati, OH, please visit globalacademycme.com. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PS490602

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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