Francis M. Siri, PhD, Medical Writer, Paradigm LTC (email@example.com)
Dr Schneider reports serving as or having served as a paid speaker for Acadia. Dr Stefanacci reports serving as or having served as a paid consultant or advisory board member for Paradigm LTC. Dr Beier reports serving as or having served as a paid speaker for Sunovion and serving as or having served as a paid consultant or advisory board member for Sun Pharma. Dr Resnick reports no relevant financial disclosures. Dr Small reports serving as or having served as a paid consultant or advisory board member for AARP, Acadia, Actavis, Allergan, Avanir, Forum, Genentech, Gerontological Society of America, Handok, Herbalife Nutrition, Janssen, Lilly, Lundbeck, Novartis, Otsuka, Pfizer, Roche, RB Health, Theravalues, and Workman Publishing; owning or having owned stock in Ceremark Pharma LLC; and having received research grants from the Wonderful Company. Dr Warner-Maron reports serving as or having served as a paid consultant or advisory board member for Acadia. Dr Saffel reports serving as or having served as a paid speaker for Acadia, serving as or having served as a paid consultant or advisory board member for Acadia, and owning or having owned stock in Acadia. Direct financial support of this project was provided to the authors by Paradigm LTC.
1Associate Professor, Department of Neurology and Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
2EVERSANA, Berkeley Heights, New Jersey; AtlantiCare/Geisinger, Atlantic City, New Jersey; Thomas Jefferson University College of Population Health, Philadelphia, Pennsylvania
3Senior Partner, Geriatric Consultant Resources LLC; Adjunct Associate Professor of Pharmacy, University of Michigan, Ann Arbor, Michigan
4Professor, Sonya Ziporkin Gershowitz Endowed Chair in Gerontology, and Codirector of the ANP/GNP Nurse Practitioner Program, Department of Organizational Systems and Adult Health, University of Maryland School of Nursing, Baltimore, Maryland; Clinical/Faculty, Roland Park Place, Baltimore, Maryland
5Parlow-Solomon Professor on Aging, Professor of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA; Director, UCLA Longevity Center; Director, Geriatric Psychiatry Division, Semel Institute for Neuroscience and Human Behavior; Stewart and Lynda Resnick Neuropsychiatric Hospital, Los Angeles, California
6Clinical Assistant Professor, Department of Geriatrics, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania
The authors acknowledge Dana Saffel, PharmD, BCGP, CPh, who participated in reviews and editing of the manuscript.
When evaluating patients with psychosis, one must consider underlying conditions such as Parkinson disease (PD), since in addition to the hallmark motor abnormalities, psychosis (eg, hallucinations, illusions, etc) appears in up to 40% of patients with PD. It is critical to diagnose and treat PD psychosis (PDP), since it imposes a major burden on the patient, caregivers, and health care system. Although the etiology of PDP is not fully understood, it is believed to arise from neuron damage in multiple transmitter systems by Lewy body deposition. PDP is associated with age, dementia, depression, daytime somnolence, levodopa therapy, and multidrug therapy; it is progressive; and it can precipitate nursing home placement. Diagnosis requires distinguishing PDP from other psychiatric disorders, infections, metabolic diseases, environmental factors, and medication effects. Treatment is particularly difficult because pharmacotherapy for the motor symptoms tends to exacerbate the psychosis, and conversely, antipsychotic medications tend to worsen the motor symptoms. The 2019 American Geriatrics Society Beers Panel recommendations are to generally avoid all antipsychotic medications in older patients with PD, with exceptions made for quetiapine, clozapine, and pimavanserin. When these agents are used, the Centers for Medicare and Medicaid Services regulations call for gradual dose reduction except for patients with progressive and enduring symptoms. These overall challenges can best be met through the efforts of a well-coordinated interdisciplinary team of physicians, nurses, consulting pharmacists, psychiatrists, physical, occupational and speech therapists, and social workers.
Key words: Parkinson disease, psychosis, antipsychotics, American Geriatrics Society Beers Panel, levodopa, quetiapine, clozapine, pimavanserin
Parkinson disease psychosis (PDP) is an often underdiagnosed but relatively common condition that occurs in up to 40% of persons with Parkinson disease (PD) (Figure 1).1,2 Diagnosis and treatment of PDP in the long-term care (LTC) setting is especially critical because of its high prevalence in this heavily regulated environment. In fact, the number of patients with PD in LTC will likely rise sharply in the coming decades because of 2 concurrent trends: aging of the population leading to an increased PD prevalence, and improved quality of care enabling prolonged survival in advanced disease stages.3 The prevalence of PD was already 5% of the skilled nursing facility (SNF) population in an evaluation published more than 20 years ago4 and more recently was reported to be 6.57%.5
In their current conceptualization of psychosis, both the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition)6 and the World Health Organization define psychosis narrowly by requiring the presence of hallucinations (without insight into their pathologic nature), delusions, or both hallucinations without insight and delusions. As such, impaired reality testing remains central conceptually to psychosis.6 Although the presence of hallucinations and delusions is emphasized in the diagnosis of PDP, its definition continues to evolve, with some evidence that in patients with PDP, these symptoms are mechanistically linked to a broader set of psychological abnormalities.7,8 Such impairment in a person who is already experiencing the motor dysfunction of PD can contribute to reduced quality of life and increased caregiver burden. For many persons with PD, the development of psychosis can precipitate nursing home placement.9
Identification of PDP
Epidemiology and Symptoms
Of the more than 1 million people in the United States estimated to be living with PD,10,11 as many as 40% report delusions and hallucinations, the hallmarks of PDP.11 These demographics correspond to an estimated prevalence of PD in nursing homes that is currently between 5% and 10% and growing.3,4
Generally, visual hallucinations occur first, followed by the development of persecutory or jealous delusions. A 2010 study found that 60% of 230 patients with PD reported either hallucinations or delusions during a 12-year follow-up,1 and another 2010 study found that 63% of 89 patients with PD experienced hallucinations (visual, auditory, tactile, or olfactory) after 10 years.12 However, some patients may not feel comfortable sharing these experiences with their caregivers due to their fear of being perceived to be insane, and thus reliance on questionnaires of caregivers or informants may underestimate the prevalence of hallucinations in patients with PD.13 While symptoms of PDP are common, identification of PDP in a nursing home resident may be challenging if symptoms are not recognized.
Risk factors for the development of PDP include dementia, advanced age, administration of daily doses of levodopa, depression, hallucinations, delusions, sleep disorders, and low activities of daily living.1,14,15 Moreover, there is evidence that medications used in the treatment of PD, including anticholinergics, amantadine, dopamine agonists, levodopa, and monoamine oxidase (MAO) inhibitors may exacerbate psychosis in these patients.16 However, newer data now suggest that PDP arises from neuron damage caused in multiple transmitter systems by Lewy body deposition.17,18
Mechanism of Disease
Delusions and hallucinations in persons with PD are thought to be linked to abnormalities in dopamine, serotonin, and glutamate neurotransmission that occur due to the deposition of Lewy bodies, and resultant neuron destruction throughout various structures of the brain.19 According to the dopaminergic theory, psychotic symptoms are the result of dopamine hyperactivity in the mesolimbic pathway.17 This has been the focus of traditional antipsychotic drug therapy17,20; however, use of dopamine-blocking antipsychotics in patients with PD is not recommended.21 According to the serotonin theory, hyperactivation of 5-HT2A receptors on glutamate neurons in the cerebral cortex can result in psychotic symptoms.19 All atypical antipsychotics include some degree of 5-HT2A blockade as part of their antipsychotic activity. The glutamate theory suggests that hypofunctional N-methyl-d-aspartate glutamate receptors on γ-aminobutyric acid–mediated interneurons in the cerebral cortex result in disinhibited glutamate neurons, leading to downstream hyperactivity of the mesolimbic pathway.20
Health care costs are higher when caring for patients with PDP compared with caring for patients with PD without psychosis. In a Medicare survey of claims data from 2000 to 2010, patients with PDP had higher all-cause costs and resource use.22 The highest annual cost differentials for PDP vs PD without psychosis were found in LTC costs (approximately 116% higher), nursing facility costs (approximately 219% higher), and inpatient costs (approximately 68% higher). Longer stays in LTC and the use of associated resources were major cost drivers. The presence of psychotic symptoms is not only an independent cost-driving factor, but also an intrusion upon the patient’s daily life and a significant determinant of increased caregiver burden.23 PDP significantly increases caregiver distress, for both informal family caregivers and professional caregivers. One of the guiding principles of health care providers has been the “Triple Aim” of improving population health, enhancing the patient experience, and reducing health care costs.24 However, it has recently become apparent that physical and emotional burnout of caregivers of older adults, particularly caregivers of those with deteriorating cognition and psychoses, needs equal attention. Thus, for care of patients with PDP, a “Quadruple Aim” incorporating caregiver mental and emotional well-being is most appropriate.25
The presence of hallucinations and psychotic symptoms is an independent risk factor for nursing home placement and mortality in patients with PD.1,9 Even the presence of minor phenomena can have a negative clinical impact. In a community-based PD sample of 250 patients, minor psychotic phenomena of PDP were associated with more depressive symptoms and worse quality of life compared with PD without current psychotic symptoms.26 PDP is also a primary reason and predictor for hospitalization (second to motor complications), admission to nursing homes, and increased mortality.1,9,27,28 When patients with PDP are admitted to long-term residential care facilities, the associated behaviors can be disruptive and increase caregiver staff burden.
A diagnosis of PDP requires a diagnosis of PD prior to the onset of 1 or more of the following psychotic symptoms that are regularly present for at least 1 month. Psychotic symptoms include the following29:
False sense of presence
Screening for psychosis in PD is important and can be done quickly during a routine visit by inquiring about perceptual changes, particularly the range of visual disturbances that can occur, and asking staff about unusual behaviors that may indicate the presence of hallucinations or delusions. Patients with PDP may manifest behaviors as a result of perceptual abnormalities or abnormal beliefs, and patients’ level of insight into these symptoms may vary significantly. Perceptual abnormalities can occur in any sensory modality but are most frequently visual and are typically unimodal (ie, only visual and do not include other sensory modalities such as hearing), although auditory, olfactory, tactile, and multimodal phenomena do occur.30,31 These visual symptoms are often differentiated into illusions or hallucinations based on whether the abnormality is a misperception of an external source (illusion) or a perception for which there is no external source (hallucination). For instance, seeing pillows on a bed and thinking it is a person would be an illusion, while seeing mice running through the room without any obvious source to explain the mice is likely a hallucination. Additionally, patients may sometimes describe the “sense of a presence” without actually seeing or hearing someone, and this is considered to be a perceptual disturbance known as “false sense of presence” or “phantom boarder syndrome.”
Delusions, or abnormal beliefs, are fixed beliefs that tend to be resistant to change despite conflicting evidence and are not explained by a patient’s cultural or religious background. For instance, a patient’s belief that their spouse is cheating on them and basing that belief on hallucinations of people in the house, despite evidence to the contrary, is a common delusion. Morbid jealously, sometimes referred to as “Othello syndrome” in reference to the Shakespearean character of that name, connotes a suspicion of spousal infidelity in the absence of proof and is accompanied by socially unacceptable behavior based on that preoccupation.32
Once psychosis has been identified in a patient with PD, it is still important to rule out other causes that could be addressed before treating for PDP. Some of the other possible causes include dementias, depression, delirium, schizophrenia or other psychiatric disorders, infections, metabolic abnormalities (eg, hepatic encephalopathy, dehydration), environmental changes (eg, hospitalizations, room changes), and medications (eg, anticholinergics, opioids) before the etiology is attributed to PDP.16,29,33 An additional clinical challenge is the overwhelming majority of PDP patients who report sleep disturbances.33 Hallucinations commonly occur during the transitions to and from sleep and thus may be difficult to distinguish clinically from nocturnal psychotic symptoms.16 It is important to ask facility staff about the time of the abnormal behaviors that may indicate an underlying hallucination in order to help distinguish sleep disturbances from PDP.
Perhaps the most challenging aspect of diagnosing PDP is the difficulty for clinicians to distinguish between nonpsychotic behavioral problems and behaviors that represent a fear or anger response to a hallucination or delusion (eg, psychosis). Careful observation of the resident, along with asking focused, open-ended questions about the resident’s experience, can help with this determination. Questions might include the following:
- What are you upset or worried about?
- What are you afraid of?
- Who are you talking to?
Once a hallucination or delusion is identified, the diagnosis of PDP can be made and treatment options considered.
Treatment of PDP
Optimizing PD dopaminergic medications and selecting an appropriate antipsychotic medication is critical to the medication management of PDP. A major challenge in treating PDP involves the potential adverse effects of most conventional antipsychotic medications that block dopamine receptors. Treating psychosis with a dopamine-receptor blocking agent, the most common form of antipsychotic, can worsen motor symptoms. Conversely, treating the motor dysfunction of PD with dopaminergic medication may worsen psychosis.
Prior to adjusting PD medication or adding an antipsychotic, a thorough evaluation for medications that might cause or exacerbate psychosis should be undertaken, and offending medications should be reduced or discontinued. Medications with strong anticholinergic properties are a good place to start. A short list of medications suggestive of anticholinergic burden include opioid analgesics, sedative-hypnotics, muscle relaxants, tricyclic antidepressants, first-generation antihistamines, and antimuscarinics for urinary incontinence. A more comprehensive list of medications with medium to strong anticholinergic properties is provided in Table 1.21,34
A risk-benefit calculation may help determine whether these anticholinergic medications are indeed necessary, and if so, whether alternatives with a better profile could be prescribed.35,36
Antiparkinson medications should be optimized. The risk-benefit ratio of each antiparkinson medication should be reviewed, and the dosage reduced or discontinued when possible. Recommendations based on clinical experience include discontinuing many PD medications, if doing so does not make motor symptoms intolerable.37 While there is no set guidance, many practitioners reduce and/or discontinue PD medications starting with anticholinergics (eg, trihexyphenidyl, benztropine), amantadine, MAO type B inhibitors (eg, selegiline, rasagiline), dopamine agonists (eg, pramipexole, ropinirole), and catechol-O-methyltransferase inhibitors (eg, entacapone). Reducing the carbidopa/levodopa dosage is typically reserved for cases in which other medication adjustments have failed.
In conjunction with the steps outlined above, clinical evidence suggests that atypical antipsychotics clozapine, quetiapine, and pimavanserin should be considered for persistent and problematic psychosis. Conventional antipsychotics are not recommended for use in patients with PD, since these medications have been reported to significantly worsen the motor dysfunction of parkinsonism; as such, balancing the benefits against the risks is needed on an individual patient basis.31,35 All randomized placebo-controlled studies of treatment of PDP have tested either dopamine-receptor blocking antipsychotics, pimavanserin, or cholinesterase inhibitors.38
Pharmacologic Treatment-Related Research Findings
Pimavanserin is the first and only treatment for PDP approved by the US Food and Drug Administration (FDA). Four randomized placebo-controlled trials with pimavanserin demonstrated that it was well-tolerated with few adverse effects and no worsening of motor symptoms. In the pivotal phase 3 trial, pimavanserin tartrate, 40 mg (equivalent to pimavanserin, 34 mg, the FDA-approved dosage), demonstrated its effectiveness (P = .0014) in improving the primary outcome using a 9-item subset of the Scale for the Assessment of Positive Symptoms (SAPS) that captures only the hallucinations and delusions experienced in PD (the SAPS-PD). The study also showed benefits on the secondary outcomes of Clinical Global Impressions of Severity (CGI-S), Clinical Global Impressions of Improvement (CGI-I), and the exploratory end points of nighttime sleep, daytime wakefulness and caregiver burden (P = .0007, P = .0011, P = .0446, P = .012, and P = .0016, respectively).39,62
There have been 3 adequately designed placebo-controlled studies of low-dose clozapine for the treatment of PDP.40-42 Clozapine was found to be significantly better than placebo in reducing positive symptoms of psychosis, with no worsening of parkinsonism or global cognition on average.
Results of 3 placebo-controlled studies of olanzapine in PDP indicated no between-groups differences in efficacy, and olanzapine was associated with significant worsening of parkinsonism in all 3 studies,43-45 with a higher dropout rate in one study.44 A fourth study found that olanzapine compared unfavorably to clozapine, further arguing against its routine use for managing hallucinations in patients with PD.46
There are no high-quality randomized controlled trials for the use of quetiapine in the treatment of PDP.47 There have been 4 small double-blind, placebo-controlled trials of quetiapine for PDP.48-51 In 3 of the 4 PDP studies, there was no clear benefit with quetiapine compared to placebo. Only 1 of these double-blind studies51 revealed benefit; however, it only looked at hallucinations and not delusions, which are more difficult to treat. The reason for this discrepancy remains unclear, and various explanations, including questioning the appropriateness of the outcome measures, have been proposed.52 Several open-label studies have shown positive results.52-56
There have been 5 comparative studies of antipsychotic treatment for PDP, all involving clozapine.46,52,56-59 All were designed as superiority studies, but few revealed significant differences between compounds, most likely related to the very small sample sizes in each of the studies. In a small randomized active comparative study of risperidone vs clozapine,57 only the risperidone group demonstrated improvement on the Brief Psychiatric Rating Scale (BPRS) psychosis cluster score, although the between-groups differences were not significant. There was also a notable worsening in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score for risperidone compared with clozapine, but due to the small sample size, the finding did not reach statistical significance. A randomized, double-blind comparison of olanzapine and clozapine was terminated early because of exacerbated parkinsonism in olanzapine-treated patients.46 In a randomized trial of ziprasidone vs clozapine in a very small number of patients,58 improvements were noted in both groups without worsening of motor symptoms. However, the sample size was too small to make further conclusions. Finally, there have been 2 randomized comparative studies with quetiapine and clozapine. In one,52 both groups experienced significant improvement in total BPRS score with treatment, with no between-groups difference, and neither group had a worsening in UPDRS motor score. In the other,56 both groups showed improvement in Clinical Global Impression of Change scores, but the clozapine-treated group showed a significant reduction in hallucinations from baseline on the Neuropsychiatric Inventory (an assessment instrument used to measure psychopathology in dementia patients in 12 domains—agitation, hallucinations, delusions, dysphoria, apathy, irritability, euphoria, aberrant motor behavior, disinhibition, appetite, eating abnormalities, and night-time behavioral disturbances), while the quetiapine-treated group demonstrated no change. In one case series,59 an attempt was made to slowly wean psychiatrically stable (ie, no longer psychotic) patients off clozapine or quetiapine, but the study was terminated early after 83% of patients experienced a recurrence of psychosis, including several whose symptoms were worse during the recurrent episode than in the initial episode.
A recent publication evaluating 13 randomized placebo-controlled trials and 1142 cases was the first to compare pimavanserin, clozapine, olanzapine, and quetiapine in a single systematic review and meta-analysis (Figures 2A-2D).60 Statistical analysis summarized in these forest plots found pimavanserin and clozapine to be significantly more efficacious than control, whereas quetiapine and olanzapine showed slight trends toward less efficacy than control. In terms of safety, pimavanserin did not differ significantly from control, whereas clozapine was significantly safer, and olanzapine was significantly less safe than control. These findings roughly align with the earlier analyses from pairwise comparisons of these agents, as described in the previous paragraph. While clinical decisions must additionally take into account individual patient variations, preferences, and practical aspects of drug administration and monitoring, this meta-analysis nonetheless provides a useful reference for evaluating the relative efficacy and safety these agents for treatment of PDP.
The article continues after the Figures.
Length of therapy of PDP treatment will be driven by patient response to therapy. A recent small study indicated that less than 30% of patients with PDP experienced remission,66,67 so treatment for most is lifelong, but this requires ongoing assessment, especially in the context of SNF-required gradual dose reduction (GDR) for antipsychotic medications. Also, the authors noted in one study that 83% of PDP patients experienced disease recurrence when antipsychotic treatment was discontinued.66,67 PDP is generally progressive, is associated with increased morbidity and mortality risk, and risk of nursing home placement and hospitalizations, with symptoms typically worsening over time and requiring ongoing treatment.9,22,27,68
Although no studies support effective nonpharmacologic management of the hallucinations and delusions of PDP, once contributory visual defects are corrected, some general nonpharmacologic interventions may be helpful. For example, if hallucinations or illusions occur in low-light environments, improving room lighting may help. Referral for an eye examination to identify vision deficits is also recommended, and glasses should be worn throughout the day if possible. Situations such as Charles Bonnet syndrome (a condition in which visual hallucinations occur as a result of vision loss) and sleep-related hallucinations are treated behaviorally by improving lighting or decreasing distracting noise and by using assistive devices such as glasses or hearing aids. Other examples of behavioral treatment include person-centered care; optimization of sensory, communication, and physical function (eg, occupational or activities programs, music and sensory therapies), optimization of the environment (eg, bright lights), and behavioral/psychosocial strategies (eg, brief psychosocial therapy, reorientation to place and time).69-72
Movement Disorder Society Update on Treatment of Nonmotor Symptoms of PD
In 2018, the International Parkinson and Movement Disorder Society updated its evidence-based medicine recommendations for treating nonmotor symptoms in PD.47 In this update, the panel reviewed 3 level 1 studies evaluating pimavanserin and determined that pimavanserin is considered “efﬁcacious” for the treatment of psychosis in PD. Although there were no safety concerns, there was a lack of controlled safety data beyond 6 weeks of treatment. Nevertheless, a September 2019 FDA analysis found no new or unexpected safety risks associated with pimavanserin.73 Therefore, pimavanserin is considered “clinically useful” for the treatment of psychosis in PD.47 As a result, the panel updated its overall recommendations for the treatment of psychosis in PD. It found olanzapine to be nonefficacious, with an unacceptable safety risk and no clinical usefulness. Quetiapine was found to have insufficient evidence of efficacy with an acceptable safety risk without requiring any specialized monitoring. Despite the insufficient evidence of efficacy in clinical trials, the panel determined that low-dose quetiapine may be possibly used and can be considered a pragmatic ﬁrst choice in countries where pimavanserin is not available, because of its improved safety proﬁle compared with clozapine.47 Clozapine is considered efficacious and clinically useful with an acceptable safety profile. However, it does require specialized monitoring and is generally considered a second-line therapy after treatment failure with quetiapine or pimavanserin. In countries where pimavanserin is available, such as the United States, it may be preferable for the treatment of PDP since it is the only antipsychotic considered “efﬁcacious” and “clinically useful” without requiring any specialized monitoring.47 The International Parkinson and Movement Disorder Society guidelines also mention that the FDA-approved labels for all antipsychotics contain a boxed warning stating that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.47 However, pimavanserin does have a modified boxed warning that recognizes that pimavanserin may be used to treat PDP, even if the patient has dementia, as long as the dementia is related to the PD.74
American Geriatrics Society (AGS) Beers Panel Recommendations
The AGS 2019 updated Beers Criteria deleted aripiprazole as an option for management of PDP and added pimavanserin as a result of pimavanserin becoming available and FDA-indicated for PDP. Thus, the 2019 AGS Beers Criteria recognize quetiapine, clozapine, and pimavanserin as exceptions to the general recommendation to avoid all antipsychotics in older adults with PD.21 Pimavanserin is also recognized in the criteria as the sole FDA-approved treatment for PDP. The document goes on to state that quetiapine has been studied only in low-quality trials, with efficacy equal to placebo in 5 trials and comparable with clozapine in 2 trials.21
Nursing Facility Regulations Regarding Antipsychotics
The Centers for Medicare and Medicaid Services (CMS) promulgates regulations, commonly referred to as F-tags, on how antipsychotics should be used in nursing facilities. The Unnecessary Medication regulation, F757, requires that all drugs, including antipsychotics, must have a supporting and appropriate diagnosis to support their use documented in the clinical record. Furthermore, all drugs must be dosed properly, administered for the appropriate length of time, and monitored for both therapeutic effect and adverse effects. Psychotropic drugs are addressed in their own regulation, F758. CMS defines a psychotropic drug as any drug that affects brain activities associated with mental processes and behavior. Example drug classes that are considered psychotropic are provided, which include but are not limited to antipsychotics, antidepressants, anxiolytics, and hypnotics. Residents who use psychotropic drugs, including antipsychotics, must undergo a GDR twice in the first year of treatment and then annually thereafter in an attempt to reduce or eliminate the antipsychotic, unless such reduction is clinically contraindicated. However, CMS specifically notes that residents with specific progressive and enduring conditions (such as PDP) may need psychotropic medications indefinitely. GDR of a psychotropic medication may be clinically contraindicated if continued use is in accordance with relevant current standards and the physician has documented that a GDR is not appropriate.75 LTC team members must help ensure the appropriate use of antipsychotic medications in nursing facilities and stay in line with all applicable clinical and regulatory guidelines.
Roles and Responsibilities of the Interdisciplinary Team (IDT)
Optimal identification and management of PDP in LTC facilities (SNFs and assisted-living communities) requires that each member of the IDT fulfill his or her unique role and responsibilities. To get to the proper PDP identification, each member of the IDT needs to be well-versed on identification of PD and recognition of hallucinations and delusions often associated with PD. Helping staff to understand the underlying etiology and presentation of PDP will facilitate staff willingness to provide innovative care approaches to treat the symptoms of this disease. This is best accomplished using this article as a foundation.
The SNF medical director is responsible for assisting with educating the clinical team, including attending physicians, nurse practitioners, and physician assistants, as well as calling on the consultant pharmacist to lead face-to-face discussions.
The consultant pharmacist can provide education on appropriate treatment for PD and PDP and assist in identifying residents who may need focused attention during their monthly medication regimen review of nursing facility residents. The consultant pharmacist can also assist in securing a list of all facility residents receiving a psychotropic agent. Included on this list could be those residents with a PD diagnosis who are on both a psychotropic agent and a PD medication. Residents on this combination would be the first group to be reviewed for consideration of the appropriateness of PDP pharmacotherapy. Based on this evaluation, the consultant pharmacist may recommend adding or modifying appropriate agents for PDP treatment in some cases, and in other cases safely discontinuing inappropriate agents.
Nursing leadership also plays a critical role in alerting attending physicians and prescribers of signs and symptoms of both PD and PDP. While the psychosis diagnosis can be reported via identification (as noted in the Minimum Data Set [MDS] Section E – Psychosis: specifically, the description of psychosis behavior disturbance), the PD diagnosis occasionally goes unrecognized. In fact, one study suggests that even among patients who are clinically evaluated, a diagnosis of PD may be missed in approximately 20% of them.76 Beyond identifying PDP signs and symptoms, nurses can lead team evaluations of residents taking psychotropics to evaluate for adverse events.
Falls are a common adverse effect of many antipsychotics, but falls also can occur as a consequence of PD and may indicate a situation in which PD has gone unrecognized or untreated. Increasing awareness and recognition of PD and psychosis can place a resident on the course to appropriate treatment. A summary of the IDT members and some key aspects of their roles and responsibilities specific to the identification and care of patients with PDP in nursing facilities, along with how they can contribute to improved outcomes for the patient with PDP, are listed in Table 2.
Figure 3 is an algorithm for the diagnosis, treatment and monitoring of PDP in long-term care patients, incorporating the principles and guidelines discussed thus far.
Specialists and Extended IDT Members
Specialists and the extended IDT members are also very important to the identification and optimal management of patients with PDP in nursing facilities. Geriatric psychiatrists have training and expertise that may contribute to a more accurate diagnosis of PDP and an effective treatment plan. Those skills include understanding of age-related changes in neurotransmitter function and sensitivity, drug–drug and drug–disease interactions, adverse effects more likely in older populations, and geriatric psychopharmacologic and nonpharmacologic therapies. Geriatric psychiatrists can be particularly helpful to families that are struggling to cope with and adapt to these challenging clinical situations.
Therapeutic activities staff can be instrumental in implementing appropriate activities for individuals with PDP. Specifically, these individuals can provide appropriate distractions, facilitate environmental changes that optimize function in individuals with PDP, and provide important feedback to primary care providers when there are changes noted in the resident’s behavior.
In summary, the optimal identification and management of patients with PDP who reside in nursing facilities clearly hinges on all members of the IDT fulfilling their respective roles. These include medical directors educating staff on current regulations, policies, and procedures for care of these patients; consultant pharmacists conducting medication regimen review with regard to psychotropic use, recommending appropriate treatment options, and providing education to NF staff regarding medication management for PD and PDP; and nursing leadership raising awareness of signs and symptoms of PDP and psychosis. Effective coordination of these efforts can promote better outcomes for residents, their families, and nursing facility staff.
1. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol. 2010;67(8):996-1001. doi:10.1001/archneurol.2010.166
2. Marras C, Beck JC, Bower JH, et al; Parkinson’s Foundation P4 Group. Prevalence of Parkinson’s disease across North America. NPJ Parkinsons Dis. 2018;4:21. doi:10.1038/s41531-018-0058-0
3. Weerkamp NJ, Tissingh G, Poels PJ, et al. Parkinson disease in long term care facilities: a review of the literature. J Am Med Dir Assoc. 2014;15(2):90-94. doi:10.1016/j.jamda.2013.10.007
4. Lapane KL, Fernandez HH, Friedman JH; SAGE Study Group. Prevalence, clinical characteristics, and pharmacologic treatment of Parkinson’s disease in residents in long-term care facilities. Pharmacotherapy. 1999;19(11):1321-1327. doi:10.1592/phco.19.16.1321.30877
5. Chekani F, Bali V, Aparasu RR. Functional status of elderly nursing home residents with Parkinson’s disease. J Parkinsons Dis. 2016;6(3):617-624. doi:10.3233/JPD-160822
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013.
7. Onofrj M, Carrozzino D, D’Amico A, et al. Psychosis in parkinsonism: an unorthodox approach. Neuropsychiatr Dis Treat. 2017;13:1313-1330. doi:10.2147/NDT.S116116
8. Lee AH, Weintraub D. Psychosis in Parkinson’s disease without dementia: common and comorbid with other non-motor symptoms. Mov Disord. 2012;27(7):858-863. doi:10.1002/mds.25003
9. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc. 2000;48(8):938-942. doi:10.1111/j.1532-5415.2000.tb06891.x
10. Yang W, Hamilton JL, Kopil C, et al. Current and projected future economic burden of Parkinson’s disease in the U.S. NPJ Parkinsons Dis. 2020;6:15. doi:10.1038/s41531-020-0117-1
11. Parkinson’s Foundation. Prevalence Project. Accessed July 27, 2020. https://www.parkinson.org/understanding-parkinsons/statistics/Prevalence-Project
12. Goetz CG, Ouyang B, Negron A, Stebbins GT. Hallucinations and sleep disorders in PD: ten-year prospective longitudinal study. Neurology. 2010;75(20):1773-1779. doi:10.1212/WNL.0b013e3181fd6158
13. Urwyler P, Nef T, Müri RM, et al. Patient and informant views on visual hallucinations in Parkinson disease. Am J Geriatr Psychiatry. 2015;23(9):970-976. doi:10.1016/j.jagp.2014.12.190
14. Friedman JH. Parkinson disease psychosis: update. Behav Neurol. 2013;27(4):469-477. doi:10.3233/BEN-129016
15. Chang A, Fox SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. 2016;76(11):1093-1118. doi:10.1007/s40265-016-0600-5
16. Weintraub D, Hurtig HI. Presentation and management of psychosis in Parkinson’s disease and dementia with Lewy bodies. Am J Psychiatry. 2007;164(10):1491-1498. doi:10.1176/appi.ajp.2007.07040715
17. Taddei RN, Cankaya S, Dhaliwal S, Chaudhuri KR. Management of psychosis in Parkinson’s disease: emphasizing clinical subtypes and pathophysiological mechanisms of the condition. Parkinsons Dis. 2017;2017:3256542. doi:10.1155/2017/3256542
18. Power JH, Barnes OL, Chegini F. Lewy bodies and the mechanisms of neuronal cell death in Parkinson’s disease and dementia with Lewy bodies. Brain Pathol. 2017;27(1):3-12. doi:10.1111/bpa.12344
19. Stahl SM. Parkinson’s disease psychosis as a serotonin-dopamine imbalance syndrome. CNS Spectr. 2016;21(5):355-359. doi:10.1017/S1092852916000602
20. Mahoney JJ III, Kalechstein AD, De La Garza R II, Newton TF. Presence and persistence of psychotic symptoms in cocaine- versus methamphetamine-dependent participants. Am J Addict. 2008;17(2):83-98. doi:10.1080/10550490701861201
21. 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767
22. Hermanowicz N, Edwards K. Parkinson’s disease psychosis: symptoms, management, and economic burden. Am J Manag Care. 2015;21(10 suppl):s199-s206.
23. Martinez-Martin P, Rodriguez-Blazquez C, Forjaz MJ, et al. Neuropsychiatric symptoms and caregiver’s burden in Parkinson’s disease. Parkinsonism Relat Disord. 2015;21(6):629-634. doi:10.1016/j.parkreldis.2015.03.024
24. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff (Millwood). 2008;27(3):759-769. doi:10.1377/hlthaff.27.3.759
25. Bodenheimer T, Sinsky C. From triple to quadruple aim: care of the patient requires care of the provider. Ann Fam Med. 2014;12(6):573-576. doi:10.1370/afm.1713
26. Mack J, Rabins P, Anderson K, et al. Prevalence of psychotic symptoms in a community-based Parkinson disease sample. Am J Geriatr Psychiatry. 2012;20(2):123-132. doi:10.1097/JGP.0b013e31821f1b41
27. Klein C, Prokhorov T, Miniovitz A, Dobronevsky E, Rabey JM. Admission of Parkinsonian patients to a neurological ward in a community hospital. J Neural Transm (Vienna). 2009;116(11):1509-1512. doi:10.1007/s00702-009-0302-1
28. Goetz CG, Stebbins GT. Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology. 1993;43(11):2227-2229. doi:10.1212/wnl.43.11.2227
29. Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria for psychosis in Parkinson’s disease: report of an NINDS, NIMH work group. Mov Disord. 2007;22(8):1061-1068. doi:10.1002/mds.21382
30. Fénelon G, Mahieux F, Huon R, Ziégler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain. 2000;123(4):733-745. doi:10.1093/brain/123.4.733
31. Henderson M, Mellers JDC. Psychosis in Parkinson’s disease: “between a rock and a hard place.” Int Rev Psychiatry. 2000;12(4):319-334. doi:10.1080/09540260020002541
32. Kingham M, Gordon H. Aspects of morbid jealousy. Adv Psychiatr Treat. 2004;10(3):207-215. doi:10.1192/apt.10.3.207
33. Pappert EJ, Goetz CG, Niederman FG, Raman R, Leurgans S. Hallucinations, sleep fragmentation, and altered dream phenomena in Parkinson’s disease. Mov Disord. 1999;14(1):117-121. doi:10.1002/1531-8257(199901)14:1<117::aid-mds1019>3.0.co;2-0
34. Cupp M. Drugs with anticholinergic activity. Pharmacists Lett. August 2019.
35. De Germay S, Montastruc J-L, Rousseau V, et al. Atropinic (anticholinergic) burden in Parkinson’s disease. Mov Disord. 2016;31(5):632-636. doi:10.1002/mds.26595
36. Chen JJ. Treatment of psychotic symptoms in patients with Parkinson disease. Ment Health Clin. 2018;7(6):262-270. doi:10.9740/mhc.2017.11.262
37. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology. 2001;56(suppl 5):S1-S88. doi:10.1212/wnl.56.suppl_5.s1
38. Schneider RB, Iourinets J, Richard IH. Parkinson’s disease psychosis: presentation, diagnosis and management. Neurodegener Dis Manag. 2017;7(6):365-376. doi:10.2217/nmt-2017-0028
39. Kitten AK, Hallowell SA, Saklad SR, Evoy KE. Pimavanserin: a novel drug approved to treat Parkinson’s disease psychosis. Innov Clin Neurosci. 2018;15(1-2):16-22.
40. French Clozapine Parkinson Study Group. Clozapine in drug-induced psychosis in Parkinson’s disease. Lancet. 1999;353(9169):2041-2042. doi:10.1016/S0140-6736(99)00860-0
41. Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med. 1999;340(10):757-763. doi:10.1056/NEJM199903113401003
42. Wolters EC, Hurwitz TA, Mak E, et al. Clozapine in the treatment of parkinsonian patients with dopaminomimetic psychosis. Neurology. 1990;40(5):832-834. doi:10.1212/wnl.40.5.832
43. Breier A, Sutton VK, Feldman PD, et al. Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson’s disease. Biol Psychiatry. 2002;52(5):438-445. doi:10.1016/s0006-3223(02)01392-6
44. Ondo WG, Levy JK, Vuong KD, Hunter C, Jankovic J. Olanzapine treatment for dopaminergic-induced hallucinations. Mov Disord. 2002;17(5):1031-1035. doi:10.1002/mds.10217
45. Nichols MJ, Hartlein JM, Eicken MG, Racette BA, Black KJ. A fixed-dose randomized controlled trial of olanzapine for psychosis in Parkinson disease. F1000Res. 2013;2:150. doi:10.12688/f1000research.2-150.v1
46. Goetz CG, Blasucci LM, Leurgans S, Pappert EJ. Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients. Neurology. 2000;55(6):789-794. doi:10.1212/wnl.55.6.789
47. Seppi K, Ray Chaudhuri K, Coelho M, et al; collaborators of the Parkinson’s Disease Update on Non‐Motor Symptoms Study Group on behalf of the Movement Disorders Society Evidence‐Based Medicine Committee. Update on treatments for nonmotor symptoms of Parkinson’s disease—an evidence-based medicine review [published correction appears in Mov Disord. 2019;34(5):765]. Mov Disord. 2019;34(2):180-198. doi:10.1002/mds.27602
48. Ondo WG, Tintner R, Voung KD, Lai D, Ringholz G. Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson’s disease. Mov Disord. 2005;20(8):958-963. doi:10.1002/mds.20474
49. Rabey JM, Prokhorov T, Miniovitz A, Dobronevsky E, Klein C. Effect of quetiapine in psychotic Parkinson’s disease patients: a double-blind labeled study of 3 months’ duration. Mov Disord. 2007;22(3):313-318. doi:10.1002/mds.21116
50. Shotbolt P, Samuel M, Fox C, David AS. A randomized controlled trial of quetiapine for psychosis in Parkinson’s disease. Neuropsychiatr Dis Treat. 2009;5:327-332. doi:10.2147/ndt.s5335
51. Fernandez HH, Okun MS, Rodriguez RL, et al. Quetiapine improves visual hallucinations in Parkinson disease but not through normalization of sleep architecture: results from a double-blind clinical-polysomnography study. Int J Neurosci. 2009;119(12):2196-2205. doi:10.3109/00207450903222758
52. Morgante L, Epifanio A, Spina E, et al. Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis [published correction appears in Clin Neuropharmacol. 2004;27(5):256]. Clin Neuropharmacol. 2004;27(4):153-156. doi:10.1097/01.wnf.0000136891.17006.ec
53. Fernandez HH, Trieschmann ME, Burke MA, Jacques C, Friedman JH. Long-term outcome of quetiapine use for psychosis among Parkinsonian patients. Mov Disord. 2003;18(5):510-514. doi:10.1002/mds.10374
54. Prohorov T, Klein C, Miniovitz A, Dobronevsky E, Rabey JM. The effect of quetiapine in psychotic Parkinsonian patients with and without dementia: an open-labeled study utilizing a structured interview. J Neurol. 2006;253(2):171-175. doi:10.1007/s00415-005-0943-4
55. López del Val LJ, Santos-Lasaosa S. Quetiapine and ziprasidone in the treatment of the psychotic disorders in Parkinson’s disease. Rev Neurol. 2004;39(7):661-667. doi:10.33588/rn.3907.2004328
56. Merims D, Balas M, Peretz C, Shabtai H, Giladi N. Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson’s disease psychosis. Clin Neuropharmacol. 2006;29(6):331-337. doi:10.1097/01.WNF.0000236769.31279.19
57. Ellis T, Cudkowicz ME, Sexton PM, Growdon JH. Clozapine and risperidone treatment of psychosis in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2000;12(3):364-369. doi:10.1176/jnp.12.3.364
58. Pintor L, Valldeoriola F, Baillés E, Martí MJ, Muñiz A, Tolosa E. Ziprasidone versus clozapine in the treatment of psychotic symptoms in Parkinson disease: a randomized open clinical trial. Clin Neuropharmacol. 2012;35(2):61-66. doi:10.1097/WNF.0b013e31824d5115
59. Fernandez HH, Trieschmann ME, Okun MS. Rebound psychosis: effect of discontinuation of antipsychotics in Parkinson’s disease. Mov Disord. 2005;20(1):104-105. doi:10.1002/mds.20260
60. Zhang H, Wang L, Fan Y, et al. Atypical antipsychotics for Parkinson’s disease psychosis: a systematic review and meta-analysis. Neuropsychiatr Dis Treat. 2019;15:2137-2149. doi:10.2147/NDT.S201029
61. Pollak P, Tison F, Rascol O, et al. Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry. 2004;75(5):689-695. doi:10.1136/jnnp.2003.029868
62. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540. doi:10.1016/S0140-6736(13)62106-6
63. Meltzer HY, Mills R, Revell S, et al. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson’s disease psychosis. Neuropsychopharmacology. 2010;35(4):881-892. doi:10.1038/npp.2009.176
64. A study of safety and efficacy of pimavanserin (ACP-103) in patients with Parkinson’s disease psychosis.ClinicalTrials.gov identifier: NCT00658567. Updated May 19, 2017. Accessed July 31, 2020. https://clinicaltrials.gov/ct2/show/NCT00658567
65. A study of the safety and efﬁcacy of pimavanserin (ACP-103) in patients with Parkinson’s disease psychosis. ClinicalTrials.gov identifier: NCT00477672. Updated May 17, 2017. Accessed July 31, 2020. https://clinicaltrials.gov/ct2/show/NCT00477672
66. Hinkle JT, Perepezko K, Bakker CC, et al. Onset and remission of psychosis in Parkinson’s disease: pharmacologic and motoric markers. Mov Disord Clin Pract. 2018;5(1):31-38. doi:10.1002/mdc3.12550
67. Fernandez HH. Treating psychosis in PD and use of antipsychotics. Brain Support Network. January 31, 2010. Accessed July 27, 2020. https://www.brainsupportnetwork.org/treating-psychosis-in-pd-and-use-of-antipsychotics/
68. Goetz CG, Fan W, Leurgans S, Bernard B, Stebbins GT. The malignant course of “benign hallucinations” in Parkinson disease. Arch Neurol. 2006;63(5):713-716. doi:10.1001/archneur.63.5.713
69. Chen R-C, Liu C-L, Lin M-H, et al. Non-pharmacological treatment reducing not only behavioral symptoms, but also psychotic symptoms of older adults with dementia: a prospective cohort study in Taiwan. Geriatr Gerontol Int. 2014;14(2):440-446. doi:10.1111/ggi.12126
70. Livingston G, Kelly L, Lewis-Holmes E, et al. A systematic review of the clinical effectiveness and cost-effectiveness of sensory, psychological and behavioural interventions for managing agitation in older adults with dementia. Health Technol Assess. 2014;18(39):1-226. doi:10.3310/hta18390
71. de Oliveira AM, Radanovic M, de Mello PCH, et al. Nonpharmacological interventions to reduce behavioral and psychological symptoms of dementia: a systematic review. Biomed Res Int. 2015;2015:218980. doi:10.1155/2015/218980
72. Ballard C, Brown R, Fossey J, et al. Brief psychosocial therapy for the treatment of agitation in Alzheimer disease (the CALM-AD trial). Am J Geriatr Psychiatry. 2009;17(9):726-733. doi:10.1097/JGP.0b013e3181b0f8c0
73. FDA analysis ﬁnds no new or unexpected safety risks associated with Nuplazid (pimavanserin), a medication to treat the hallucinations and delusions of Parkinson’s disease psychosis. News release. US Food and Drug Administration. September 20, 2018. Accessed July 9, 2020. https://www.fda.gov/Drugs/DrugSafety/ucm621160.htm
74. Nuplazid. Prescribing information. Acadia Pharmaceuticals; 2019. Accessed July 9, 2020.
75. Centers for Medicare and Medicaid Services, Center for Clinical Standards and Quality/Survey & Certification Group. State Operations Manual (SOM) surveyor guidance revisions related to psychosocial harm in nursing homes. March 25, 2016. Accessed July 27, 2020. https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Downloads/Survey-and-Cert-Letter-16-15.pdf
76. Schrag A, Ben-Shlomo Y, Quinn N. How valid is the clinical diagnosis of Parkinson’s disease in the community? J Neurol Neurosurg Psychiatry. 2002;73(5):529-534. doi:10.1136/jnnp.73.5.529