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A New Perspective in the Treatment of Parkinson’s Disease Psychosis

US Neurology, 2016;12(2):93–7 DOI: https://doi.org/10.17925/USN.2016.12.02.93

Abstract:

Neuropsychiatric symptoms, such as psychosis, are well described in Parkinson’s disease (PD); most appear to be due to disease pathology with exacerbation caused by dopaminergic treatment. More than 50% of patients with PD develop psychosis at some point throughout their disease course. Clinicians need to routinely assess patients with PD for psychotic symptoms, particularly hallucinations. Treatment of psychotic symptoms in PD is an unmet need as there are currently no US Food and Drug Administration (FDA) approved medications specifically for PD psychosis (PDP). Current treatments for PDP have been adapted from dopamine antagonists used to treat psychosis in other conditions, such as schizophrenia. Typical antipsychotics, as well as some atypical antipsychotics, worsen PD motor symptoms due to blockade of dopamine D2 receptors. Quetiapine and clozapine have been studied in PDP and are the most commonly used treatments for PDP. Clozapine has been shown to be effective; however, regular bloodwork is required, while data for quetiapine are inconsistent. Pimavanserin, a highly selective serotonin (5HT2A subtype) receptor inverse agonist, is not associated with motor worsening in PDP patients due to the absence of dopamine blockade. In a double-blind, placebo-controlled study, pimavanserin showed significant improvement in moderate to severe psychosis compared to placebo, with good tolerability and without worsening of PD motor symptoms. These data suggest that pimavanserin is a safe and efficacious treatment for PDP psychosis and could be a potential new treatment option for PDP.
Keywords: Parkinson’s disease psychosis (PDP), atypical antipsychotics, pimavanserin, non-pharmacologic treatments
Disclosure: Rajesh Pahwa has served as a consultant, speaker or advisor for AbbVie, Acadia, Acorda, Adamas, Cynapsus, Impax, Lundbeck, Medtronic, Neurocrine, Pfizer, Sage, St Jude Medical, Teva, UCB, and US WorldMeds. He has received research funds awarded to the University of Kansas Medical Center from AbbVie, Acorda, Adamas, Avid, Biotie, Boston Scientific, Cala Health, Civitas, Cynapsus, Kyowa, National Parkinson Foundation, NIH/NINDS, Parkinson Study Group, and US World Meds. Kelly E Lyons has served as a consultant for Adamas, Medtronic, St Jude Medical and US WorldMeds. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
Received: February 17, 2016 Accepted: March 29, 2016
Correspondence: Rajesh Pahwa, University of Kansas Medical Center, Parkinson’s Disease and Movement Disorder Center, 3599 Rainbow Blvd, MS 3042, Kansas City, KS 66160, US. E: rpahwa@kumc.edu
Support: The publication of this article was supported by Acadia Pharmaceuticals. The views and opinions expressed are those of the authors and do not necessarily reflect those of Acadia Pharmaceuticals.

Parkinson’s disease (PD) has been traditionally defined by the motor symptoms of bradykinesia, resting tremor, rigidity and postural instability;1 however, more recently, it has been recognized that neuropsychiatric symptoms such as psychosis, anxiety, depression, apathy, impulse control disorders and dementia are also often present in PD and can significantly impact quality of life of patients with PD.2 The American Academy of Neurology (AAN) quality improvement guidelines recommend that neuropsychiatric symptoms should be assessed annually in all patients with PD.3 When neuropsychiatric symptoms are observed, it is important to attempt to uncover the cause of these symptoms as they may be situational, medication related, the result of other medical conditions, intrinsic to PD or a combination of these factors.

The recognition and treatment of PD psychosis (PDP) is a significant unmet need. It has been estimated that over 50% of patients with PD develop psychosis at some point during their disease course.4 However, this estimate may be low as many patients do not realize that these symptoms are associated with PD or they may be hesitant to report these symptoms,5 and often physicians do not ask the patients about psychosis. In addition, reported studies have used inconsistent methodologies, assessment tools, and definitions of psychosis.6

Visual hallucinations are the most common symptom in PDP with prevalence rates increasing throughout the disease course. When accounting for dementia there is a five-fold increase in prevalence of PDP over time compared with non-demented patients.7 Less frequently, patients with PDP experience auditory, tactile and somatic hallucinations.7 The development of PDP often begins with vivid dreams and nightmares. This can be followed by the development of illusions in which a person misinterprets an existing object, such as seeing insects in a carpet pattern; presence hallucinations in which there is a feeling that someone is in the room; and passage hallucinations where a shadow, person or animal is seen briefly passing in the periphery.6,7 Initially, visual hallucinations often involve nonthreatening people or animals; however, they can still be disruptive to patients and family members and should not be ignored or go untreated. As the disease progresses, the patient often loses insight and may develop more disturbing hallucinations as well as paranoia and delusions.7–9 Risk factors for PDP include cognitive impairment/ dementia, older age, older age at diagnosis, longer disease duration, higher dosages of dopaminergic medications, more severe motor symptoms, sleep disorders, ocular disorders, and depression.5

In addition to having a significant impact on the patients' quality of life,10 PDP significantly increases caregiver burden11 and mortality.12 PDP is also one of the strongest predictors of longterm care placement.13,14 It was shown in one study that patients with PDP placed in long-term care facilities tend to stay there permanently and have a greater mortality rate when compared to patients with PD without psychosis and older individuals in long-term care facilities from the general population.15 Additional analyses examining all aspects of care demonstrated that annual costs for PDP were $67,251 compared to patients with PD without psychosis which were $38,742.16 These data highlight the importance of early recognition of PDP and the need for effective treatment.

Treatment of Parkinson’s disease psychosis
Screening tools for PDP have been evaluated by the AAN,17 the Movement Disorder Society,18 and a more recent review evaluating the literature through 201519 and each concluded that there are no currently available scales to accurately screen for PDP and each recommended that it should be a priority to develop a PD-specific psychosis scale. Therefore, during the clinical examination, healthcare professionals should routinely ask the patient and caregiver about PDP symptoms to reduce the impact of undetected PDP. When PDP is detected, initial practices should include assurance of healthy sleep-wake cycles and good sleep hygiene. Assuring normal sensory input levels such as assessing hearing or vision deficits and applying appropriate aids if needed can also be helpful. Finally, it should be confirmed that appropriate lighting is available, and if applicable, a familiar and comfortable environment should be maintained.8 Medical conditions such as infection and dehydration can lead to psychotic symptoms and therefore, these must be considered as potential contributors and, if present, should be treated.20

PDP is thought to be a result of intrinsic factors related to PD, but can also be caused or enhanced by various medications.6 Therefore, all psychoactive non-PD medications, including anti-depressants, anticholinergics, benzodiazepines, opioids and anticholinergics should be reviewed and when possible, these agents should be reduced or discontinued.21 Once non-PD medications are at a minimum, PD medications may need to be reduced, although this may result in reduced motor function. Typically, PD medications would be slowly reduced or eliminated in the following

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Keywords: Parkinson’s disease psychosis (PDP), atypical antipsychotics, pimavanserin, non-pharmacologic treatments