finding balance: new strategies to optimize care for ... · introduction p arkinson’s disease...

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New Strategies to Optimize Care for Patients With Parkinson’s Disease Psychosis

FINDING BALANCE:

FACULTYJennifer G. Goldman, MD, MSMichael S. Okun, MDDaniel Weintraub, MD

RELEASE DATE: August 1, 2016EXPIRATION DATE: August 1, 2017

CME MONOGRAPH

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FACULTY Jennifer G. Goldman, MD, MSAssociate ProfessorSection of Parkinson’s Disease and Movement Disorders Department of Neurological SciencesRush University Medical CenterChicago, Illinois

Michael S. Okun, MDChair, Department of NeurologyAdelaide Lackner ProfessorCo-Director, Movement Disorders CenterUniversity of Florida College of MedicineGainesville, Florida

Daniel Weintraub, MD Associate Professor of Psychiatry and NeurologyPerelman School of Medicine at the University of PennsylvaniaParkinson’s Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC)Corporal Michael J. Crescenz Department of Veterans Affairs Medical CenterPhiladelphia Veterans Affairs Medical CenterPhiladelphia, Pennsylvania

Estimated Time to Complete Activity: 1 hour

TARGET AUDIENCEThis activity has been designed to meet the educational needs of neurolo-gists and psychiatrists involved in the care of patients with Parkinson’s dis-ease psychosis (PDP).

LEARNING OBJECTIVESUpon completion of this activity, participants will have improved their ability to:1. Discuss the clinical features and risk factors for PDP 2. Develop individualized pharmacologic treatment plans for patients

with PDP that consider motor and nonmotor symptoms3. Evaluate the mechanism of action, tolerability, safety, and efficacy of

pharmacologic treatment options for PDP4. Employ multidisciplinary communication strategies to improve quality

of life in patients with PDP

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CREDIT DESIGNATION The Postgraduate Institute for Medicine designates this enduring mate-rial for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

Jennifer G. Goldman, MD, MS, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Contracted Research: ACADIA Pharmaceuticals Inc; and Biotie Therapies; Consulting Fees (eg, advisory boards): ACADIA Pharmaceuticals Inc; and Pfizer Inc.

Michael S. Okun, MD, has no real or apparent conflicts of interest to report.

Daniel Weintraub, MD, had a financial agreement or affiliation dur-ing the past year with the following commercial interests in the form of Consulting Fees (eg, advisory boards): ACADIA Pharmaceuticals Inc.

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:

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DISCLOSURE OF UNLABELED USEThis educational activity might contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational ac-tivity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired in-formation to enhance patient outcomes and their own professional devel-opment. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this ac-tivity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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Introduction

Parkinson’s disease (PD) psychosis (PDP) is a common neuropsychiatric manifestation of PD. It is associated

with increased patient morbidity and mortality, worsened quality of life, as well as heightened burden on caregivers. Additionally, PDP is associated with an increased rate of nursing home placement and hospitalization.1,2 Making a timely diagnosis of PDP for patients who frequently have multiple psychiatric comorbidities can be challenging, espe-cially given the lack of validated assessment tools specific to PDP.3 The exact etiology of PDP remains elusive, but there have been recent advancements in the understanding of the neurobiology of this disease. Even with these advance-ments, many patients with PDP are still not diagnosed in a timely fashion.4

There are, however, opportunities to improve the management of these patients. Historically, treatment of PDP has relied on adjustments (typically, reductions) of dopaminergic or other PD pharmacotherapy, or ini-tiation of off-label antipsychotic therapy. Such strategies carry their own degree of risk, such as worsening par-kinsonism. Increased understanding of the neurobiol-ogy of PDP has also led to the development of new thera-peutic options that may improve patient safety while maintaining a balance between control of PDP and control of motor symptoms. The US Food and Drug Administra-tion (FDA) has recently approved one of these new thera-pies, pimavanserin, for the treatment of PDP.5 This review summarizes new approaches for the diagnosis and treatment of PDP.

Complexities of Parkinson’s Disease PsychosisEpidemiologyRecent evidence suggests that the prevalence of PDP may be higher than previously thought, with up to 60% of patients experiencing psychotic symptoms for at least a month at some point during the course of their illness.6 The revision in this esti-mation has been influenced by the incorporation of broader diagnostic criteria from the National Institute of Neurologi-cal Disorders and Stroke and the National Institute of Mental Health, which include the presence of illusions or a false sense of presence or passage in addition to the historical criteria of delusions or hallucinations.6,7

Clinical PresentationPatients with PDP may present with a wide range of psychotic symptoms, ranging from misperception of external stimuli to frank hallucinations to disruptive delusional behavior (Table 1).8 Identifying clinical manifestations that distin-guish PDP from other reasons for acute confusion, delirium, or cognitive changes can be challenging, and facilitating timely management or referral is important. Although PDP has historically been thought of as a manifestation of well- established PD,5 a chronology of psychotic manifestations over the course of illness remains an area of active investigation.9,10

Hallucinations occur in 10% to 48% of patients with PD.11 Visual hallucinations are the most common manifestation of PDP, occurring in up to one-third of patients who have received chronic dopaminergic therapy.12 Hallucinations in nonvisual sensory domains (ie, auditory, gustatory, olfactory, and tac-tile) may also occur, typically in conjunction with visual hal-lucinations.13 Visual hallucinations are the dominant type in the early stages of hallucination development, and, as some studies indicate, the co-occurrence of nonvisual hallucina-tions may occur as PD progresses.13 For some patients, visual hallucinations can be perceived as either neutral or pleasant; for others, PDP symptoms can be frightening and disruptive. Some patients may not be inclined to report their hallucina-tions. However, hallucinations should not be ignored, and it is important for health care providers to ask patients with PD about hallucinations. Although patients who experience hallu-cinations may retain insight regarding these experiences, this insight may be potentially lost as PD progresses.

Delusions most commonly present as psychosis progresses and in the setting of cognitive impairment. Delusions affect approximately 5% to 10% of patients with PD,14 and typically are associated with a loss of insight. These delusions also tend to be thematic (eg, spousal infidelity or abandonment).7

Parkinson’s disease psychosis does have its own cluster of clinical features, which helps to differentiate it from other forms of psychosis, particularly those associated with schizophrenia, psychotic depression, or delirium. These include the following:

• Possible presentation with a clear sensorium and retained insight, distinguishing it from delirium12

• Lower incidence of delusions of grandiosity and bizarre beliefs and disorganized thinking than that seen with schizophrenia12

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Finding Balance: New Strategies to Optimize Care for Patients With Parkinson’s Disease Psychosis



• Hallucinations that are more likely to be visual or to be occurring in nonauditory modalities compared with those encountered with schizophrenia8

• Auditory hallucinations that are typically vague and less threatening than those experienced by patients with schizophrenia8

• Lower incidence of delusions of grandiosity or nihilism/self-deprecation than that seen with psychotic bipolar dis-order or psychotic depression, respectively.15

Risk Factors or Correlates of Parkinson’s Disease PsychosisSuccessful identification of risk factors or correlates may help to facilitate a timely diagnosis of PDP. Several risk factors or cor-relates have been identified for the emergence of PDP, including the following:

• Dopaminergic medications for PD2 • Polypharmacy with psychoactive drugs6

• Severity and duration of PD11

• Comorbid sleep disturbances, such as rapid eye move-ment sleep behavior disorder (RBD) and excessive daytime sleepiness11,16

• Advancing patient age11 • Cognitive impairment11

• Alterations in vision or the visual pathways8,11

• Alterations in neurotransmitter systems, including cholin-ergic17 and serotonergic systems18,19

• Axial parkinsonism11

• Family history of dementia11

Of note, genetic risk factors may influence the emergence of PDP, and there have been several attempts to identify these elements. Historical examinations have addressed dopamine transporter gene polymorphisms,

catechol-O-methyltransferase, serotonin 2A (5-hydroxy-tryptamine [HT]

2A) receptor genes, apolipoprotein ε4 or

ε2, cholecystokinin promoter polymorphisms, and angiotensin-converting enzyme II genotype, with inconclusive results.20 Another study failed to show any association between psychotic symptoms and polymorphisms in apolipoprotein-, α-synuclein–, or microtubule-associated protein tau genes.20

Comorbid DisordersDepression and RBD symptoms have been associated with PDP, as has cognitive impairment. One recent study found that the odds of patients with PD experiencing psychotic symptoms were 5 times greater in patients with both depressive disorder and sleep-wakefulness disorder.16 Previous investigations have explored the possibility that patients with PD who hallucinate while awake are experiencing rapid eye movement intrusions, with changes in their sleep-wake cycles.21,22 There may also be a common neural substrate for these comorbidities, and the presence of comorbid psychiatric and other nonmotor symptoms may be a sign of future cognitive deterioration and worsening psychiatric symptoms.16 Parkinson’s disease dementia and PDP are commonly comorbid occurrences, which presents additional treatment challenges, given the safety concerns surrounding use of antipsychotic agents in elderly patients with dementia-related psychosis.23

Etiology of Parkinson’s Disease PsychosisAlthough the exact etiology of psychosis in PD has not been pinpointed, there have been recent advancements in the understanding of the various mechanisms that may drive its emergence, including neurotransmitter and structural, func-tional, or metabolic brain abnormalities, as well as visual

Table 1. Spectrum of Psychotic Symptoms Experienced by Patients With Parkinson’s Disease8

Symptom Characterization

Illusions Misperception or misinterpretation of external objects/stimuli

Presence hallucinations Perception of a shadow, person, or animal in close proximity

Passage hallucinations Fleeting, passing, or moving images in peripheral vision

Simple hallucinations Flashes of light, geometric patterns, and colors

Complex hallucinations Formed or more elaborate false sensory perceptions that can occur in different modalities; association with visual impairment that is not correctable through surgery, pharmaceutical treatment, glasses, or contact lenses (may have partial sight, but legal blindness is also encompassed by this association)

Multimodal hallucinations Hallucinations in multiple domains, including visual, auditory, gustatory, tactile, and olfactory

Misidentification syndromes

Capgras Belief that a spouse, family member, or other close contact has been replaced by an impostor

Fregoli Belief that a person (usually a stranger) is actually another known person in disguise

Delusions Fixed, false beliefs



processing pathway alterations and sleep disorders. The use of dopamine replacement therapy and other PD medica-tions has been linked with the development of psychotic symptoms, in part on the basis of experience with dopa-minergic treatments and data from randomized placebo- controlled studies.2,7 Indeed, all dopaminergic drug classes (ie, levodopa, dopamine agonists, monoamine oxidase inhibi-tors, and catechol-O-methyltransferase inhibitors added to levodopa) have been associated with psychosis induction or its exacerbation in PD.8 Furthermore, there is evidence of dopa-mine contributions to PDP because decreasing the dose or discontinuation of dopaminergic replacement therapies may improve PDP symptoms.8

However, the dopamine hypothesis is insufficient to fully explain the whole story of PDP because other neurotransmit-ters may contribute (eg, cholinergic and serotonergic systems) and other clinical and pathologic factors may play a role. In addition, given the fact that some patients with PD and most patients with the related disorder, dementia with Lewy bodies (DLB), experience hallucinations in the absence of dopamine replacement therapy, other possible factors in the emergence

of PDP have been examined.7 The development of PDP is likely attributable to a combination of extrinsic and intrinsic factors, including complex interactions among multiple neurotrans-mitters, such as dopamine, acetylcholine, and serotonin.24

Evidence also suggests that the emergence of psychotic symptoms in PD may involve alteration of the visual system, including cortical visual processing pathways. Patients with PDP have been noted to have greater problems with visual acu-ity and color-and-contrast recognition and a greater incidence of ocular disease compared with patients with PD who do not hallucinate.25-28

Studies have provided evidence that serotonin 5-HT2A

receptors may be associated with the development of halluci-nations. An autopsy study that used autoradiographic binding as a means of defining 5-HT

2A receptors found a 45.6% increase

in binding in the inferolateral temporal cortex (a key compo-nent of the visual pathway) of patients with PD and hallucina-tions relative to those with PD who did not experience hallu-cinations.17 Positron emission tomography brain imaging has shown that 5-HT

2A receptor binding in the ventral visual path-

way and other regions is greater in patients with PD who have visual hallucinations than in those with PD who do not experi-ence visual hallucinations (Figure 1).18

Parkinson’s disease dementia has been linked with Lewy body deposition, and dementia is a risk factor for the emer-gence of psychosis.28 In fact, there is a great deal of clinical and neurobiologic overlap between PD dementia and DLB. Temporal lobe distribution of Lewy bodies has been linked with well-formed visual hallucinations in both patients with PD dementia and those with DLB.

Evaluation StrategiesFor patients with PD who present with psychotic symptoms, it is imperative to establish the etiology of the psychosis in a timely manner. There are numerous challenges in assessing these patients, and the PSYCHOSIS acronym may be helpful in establishing a differential diagnosis framework (Table 2).33

Figure 1. Areas of serotonin 2A binding potential increases18

Reproduced with permission from Archives of Neurology. 2010;67(4):416-421. Copyright © 2010 American Medical Association. All rights reserved.

Overlap Between Parkinson’s Disease Dementia and Dementia With Lewy Bodies

Historically, it has been difficult to clinically differentiate between PD dementia and DLB, with expert consensus

establishing a key distinction on the basis of the temporal rela-tionship between onset of dementia and motor dysfunction.29 Previous criteria required the patient to have had parkinsonism for more than a year before the onset of dementia to establish the diagnosis of PD dementia,30 but recently proposed, revised criteria for clinical PD allow a diagnosis of PD dementia to be made without this 1-year waiting period.31 Under current DLB diagnostic criteria, dementia that occurs at the time of parkin-sonism or within 1 year of onset of parkinsonism is diagnosed as DLB.32



Diagnostic criteria for PDP, according to the National Institute of Neurological Disorders and Stroke and National Institute of Mental Health–sponsored working group, include the presence of 1 or more of the following: visual illusions, false sense of presence, hallucinations, and delusions.6 Although assessment tools for rating PDP have been developed, many lack basic content and metrics necessary to adequately cap-ture the phenomena of PDP and to follow the phenomena over time.34 Clinicians should be vigilant and regularly ask their patients with PD whether they are experiencing any psychotic symptoms.

The International Parkinson and Movement Disorder Soci-ety Task Force has evaluated and recommended 4 rating scales for the assessment of PDP: the Brief Psychiatric Rating Scale, the Neuropsychiatric Inventory, the Positive and Negative Syn-drome Scale, and the Scale for Assessment of Positive Symptoms (SAPS). A recent clinical trial created a modified version of the SAPS for use in PD, the SAPS-PD.35 The development of a vali-dated screening instrument specific to PDP remains a need for patients and practicing clinicians.36

Management of Parkinson’s Disease PsychosisInitial Management StepsManagement strategies for PDP are complex and predicated on the etiology of the psychosis. Expert opinion has helped to inform initial management in the absence of formal guidelines to address patients with newly presenting PDP.37 The initia-tion of new medications or adjustment of current medications can have a profound effect on motor and nonmotor symptoms for patients with PD, so it is important to rule out reversible or treatable causes of psychotic symptoms, such as infection, delirium, or metabolic abnormalities.12 Reversible conditions, such as dehydration and medication-associated effects, should be addressed. Any medications that may be contributing to the

psychosis, which are not essential and are not being used to manage the underlying PD, should be reduced. Anticholinergics are leading candidates for withdrawal, as are tricyclic antide-pressants, opioid analgesics, and benzodiazepines.12 After this step, the reduction of medications used to treat PD may be considered.37,38

Nonpharmacologic MeasuresNonpharmacologic measures may be helpful in the management of patients who present with PDP, par-ticularly if their symptoms are mild and if caregiv-ers are involved. Visual techniques, such as trying to focus on the perceived object or looking away from the hallucinations, may be helpful. Cognitive techniques, such as turning on lights or making a conscious notation of the false nature of the hallucinations, as well as interactive techniques, such as discussing the hallucination with a caregiver/family member and obtaining reassurance from others, may also be helpful.39 One study found that 78% of patients with PD and visual hallucinations used visual techniques (33%), cognitive techniques (69%), and interactive techniques (62%) as a means of coping with their hallucinations.39

Historical Use of AntipsychoticsSelection of pharmacotherapy to treat psychotic symptoms of patients with PD is extremely challenging for clinicians for a vari-ety of reasons, including maintenance of safety while preserving the balance between motor and nonmotor symptoms. Histori-cally used antipsychotics have not been specifically approved for PDP. Many antipsychotics, particularly typical antipsychot-ics such as haloperidol, can potentially worsen parkinsonism through the blockade of dopamine D2 receptors.40 When used at doses that are efficacious, atypical antipsychotics provide greater blockade of 5-HT

2A receptors, with a lesser effect on

reducing dopamine D2 receptor activity.40 If more conservative measures are unable to provide satisfactory control of PDP, then the use of antipsychotic therapy may be considered.

Approximately half of patients with PDP are prescribed an antipsychotic,23 and it is important to understand the safety and efficacy data behind each choice to optimize patient outcomes. Practice parameters from the American Academy of Neurology and an evidence-based review from the International Parkinson and Movement Disorder Society have provided some guidance regarding commonly used medications that are not indicated specifically for PDP.3,41 There have been relatively few large ran-domized controlled trials assessing antipsychotic therapy for PD. In addition, safety concerns regarding the use of antipsy-chotics for elderly patients with dementia, such as an increased risk of cerebrovascular adverse events and mortality, have been established.41,42 These findings prompted the generation of black

Table 2. Evaluation of Psychosis in Patients With Parkinson’s Disease: Differential Diagnosis33

P Parkinson’s disease medications

SY Systemic illness

C Centrally acting medication

H Hepatic, renal, or other metabolic dysfunction

O Overdose of medications or intoxication

S Sensory deprivation (eg, hearing and visual impairment)

I Infection (eg, urinary tract infection and pneumonia)

S Structural lesions (eg, stroke, subdural hematoma, intracranial hemorrhage, and trauma)

Republished with permission of Humana Press, from Movement Disorder Emergencies, Steven J. Frucht, ed, 2nd ed, 2013; permission conveyed through Copyright Clearance Center, Inc.



box warnings for both typical and atypical antipsychotics.41,43 Other adverse events associated with atypical antipsychotic use include orthostatic hypotension, dry mouth, sedation, dizziness, and constipation.12 Despite these concerns, many patients con-tinue to be treated with pharmacologic options that have limited to no evidence for efficacy or that carry a risk for the deteriora-tion of motor symptoms.23

In a recent case-control study of 7877 matched pairs of patients with PD (Table 3), those who received antipsychotic therapy had a higher hazard ratio of death over 6 months (intention-to-treat analysis hazard ratio, 2.35; 95% confidence interval, 2.08–2.66; P < .001) than those who did not receive an antipsychotic.44 The risk was greater with use of both typical and atypical antipsychotics, but higher for those patients who received typical antipsychotics (intention-to-treat analysis

hazard ratio, 1.54; 95% confidence interval, 1.24–1.91; P < .001). Fewer than 10% of the patients included in this study carried a diag-nosis of dementia, so the findings are not specific to patients with PD and comorbid dementia. This study addresses the risks asso-ciated with the use of antipsychotics; how-ever, some atypical antipsychotics have the potential to improve outcomes for patients, with control of both motor and nonmotor symptoms.45

Clozapine is an atypical antipsychotic that has evidence (level B) supporting its efficacy in the treatment of PDP on the basis of two 4-week, double-blind, placebo-controlled, randomized clinical trials with 12-week open-label extensions.3,41 It is still

off-label for the treatment of PDP in the United States. There is a 0.38% risk of agranulocytosis with clozapine, thus necessitating serial blood count monitoring.12 Clozapine has a greater affin-ity for serotonin 5-HT

2 receptors than for D2 and D3 receptors

(Table 4), which explains its efficacy without exacerbation of parkinsonism.40 Patients in the United States are required to have their blood drawn weekly for the first 6 months of therapy, biweekly for the next 6 months, and then monthly after the first year of therapy as part of the Clozapine Risk Evaluation and Mitigation Strategy program.46 Other side effects that may be of concern include sedation, drooling, and orthostatic hypoten-sion.2,41 Although clozapine appears to be well tolerated with respect to motor symptoms, it is rarely prescribed, with one large Veterans Affairs study showing its use in fewer than 2% of treated cases.23 The need for frequent blood examination is a

Table 3. Increased Mortality in Patients With Parkinson’s Disease With Antipsychotic Use44

Antipsychotic

Intention-to-Treat Analysis Exposure-Only Analysis

Hazard Ratio (95% CI)

P ValueHazard Ratio

(95% CI)P Value

Haloperidol 5.08 (3.16–8.16) < .001 4.80 (2.41–9.57) < .001

Other typical antipsychotic

1.82 (0.94–3.50) .07 0.82 (0.35–1.88) .63

Olanzapine 2.79 (1.97–3.96) < .001 2.76 (1.58–4.84) < .001

Quetiapine 2.16 (1.88–2.48) < .001 1.93 (1.59–2.33) < .001

Risperidone 2.46 (1.94–3.12) < .001 2.62 (1.83–3.76) < .001

Other atypical antipsychotic

1.19 (0.60–2.37) .62 1.14 (0.41–3.18) .80

Abbreviation: CI, confidence interval.

Table 4. Receptor Selectivity* of Antipsychotic Drugs Used in the Treatment of Parkinson’s Disease Psychosis40

Receptor Class Clozapine Haloperidol Olanzapine Pimavanserin Quetiapine Risperidone

Serotonin

5-HT2A 7 50 2.5 0.4 250 0.2

5-HT2B 40 NR 80 NR 1100 12

5-HT2C 40 NR 80 16 NR 100

5-HT1A NR NR NR NR NR NR

Dopamine

D1 NR 100 100 NR NP 60

D2 50 0.1 4 NR 30 0.5

D3 NR 0.2 25 NR 9 13

Abbreviations: HT, hydroxytryptamine; NP, not performed; NR, no response.

*Data are dissociation equilibrium constant values in nanomoles. Smaller dissociation equilibrium constant values correspond with greater receptor binding affinity.



significant barrier to the use of clozapine.47 Dosing in patients with PD typically begins at 6.25 mg at night and increases as tolerated and needed.12

Quetiapine is an atypical antipsychotic that is similar in structure to clozapine. Although quetiapine is commonly used in clinical practice as an off-label means of treating PDP, practice parameters state that there is “insufficient evidence to conclude on the efficacy of quetiapine for the treatment of psychosis in PD.”41 It has been designated as investigational for the treatment of PDP, without the need for specialized monitoring, with level C evidence.3 Although studies com-paring quetiapine and clozapine have suggested they have similar efficacy, the efficacy data from clinical trials have been inconsistent when quetiapine has been compared with placebo, with only 1 of 5 randomized trials showing posi-tive PDP outcomes.41,48 One study demonstrated improve-ment on the Clinical Global Impression (CGI) Scale (P = .03) and on the hallucination item of the Brief Psychiatric Rating Scale (P = .02).49

Like clozapine, quetiapine appears to be well toler-ated with respect to motor symptoms, and possible side effects include orthostatic hypotension and sedation.2,41 Quetiapine dosing in patients with PD typically begins at 12.5 mg every night, with a gradual increase to a range of 50 to 150 mg at night.12

Olanzapine has been studied as an off-label means of treating PDP. It has affinity for serotonin receptors and a great affinity for D2 receptors.40 It has been asso-ciated with the deterioration of motor symptoms in patients with PD, without any demonstrated efficacy in the treatment of hallucinations.41 American Academy of Neurology practice parameters state that olanzapine should not be considered for the treatment of PDP.3 Other off-label treatments include risperidone and aripiprazole, both of which have been linked with the dete-rioration of motor symptoms.50-52

Cholinesterase InhibitorsCholinesterase inhibitors, such as galantamine, rivastigmine, and donepezil, have also been explored as potential therapeutic options for PDP. Hallucinations may be due to a lack of balance in the cholinergic and dopaminergic systems (both anticho-linergic and dopaminergic treatment may precipitate hallu-cinations). The evidence supporting the use of cholinesterase inhibitors comes largely from smaller studies, includ-ing case series and open-label trials. These smaller investigations set the stage for a planned subanaly-sis from the Exelon in Parkinson’s Disease Demen-tia Study (EXPRESS) Group, which assessed the role of rivastigmine in the treatment of dementia associated with PD

for both hallucinating and nonhallucinating patients.53,54 Patients in the EXPRESS study who were treated with rivastigmine reported a lower incidence of hallucinations than those treated with placebo (4.7% vs 9.5%; P = .04).53 Patients with hallucinations at baseline had a greater improve-ment in cognitive scores relative to placebo (change in Alzheimer’s Disease Assessment Scale cognitive subscale, 4.27; P = .002) than nonhallucinating patients (change in Alzheimer’s Disease Assessment Scale cognitive subscale, 2.09; P = .015).54 Neuropsychiatric Inventory-10 scores also showed greater improvements (rivastigmine vs placebo) in hallucinating patients than in nonhallucinating patients.54

The Cholinesterase Inhibitors to Slow Progression of Visual Hallucinations in Parkinson’s Disease (CHEVAL) study is currently recruiting patients to explore the effi-cacy of early initiation of rivastigmine therapy on delaying hallucination progression in patients with PD and experienc-ing minor hallucinations.55 It is a randomized, double-blind, placebo-controlled study, with a primary outcome of median time until patients with PD and minor visual hallucinations progress to major hallucinations without insight.

Serotonin Receptor Inverse AgonistPimavanserin is a 5-HT

2A inverse agonist, and to a lesser extent

antagonist, that has recently gained FDA approval specifi-cally for the treatment of PDP.5 It is an atypical antipsychotic, and as with other antipsychotics, it carries a black box warning regarding the increased risk of mortality in elderly patients with dementia-related psychosis.56 It is not approved for the treat-ment of patients “with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.”56

Pimavanserin binds to the 5-HT2A

receptor in the absence (inverse agonist activity) or presence (antagonist activ-ity) of serotonin. When serotonin is present, pimavanserin competes for the receptor, thus antagonizing receptor activation by serotonin. In the absence of serotonin, pimavanserin binds to the receptor and decreases constitu-tive activity. Pimavanserin has a high affinity for the 5-HT

2A

receptor, with very little affinity for other receptors, includ-ing the D2 receptor.40 Historically used medications in the treatment of PDP may have activity at multiple receptors, including D2 and D3, resulting in more pronounced side effects, such as parkinsonism.

In a double-blind, placebo-controlled, phase 2 study of 60 patients with PDP by Meltzer and colleagues, pima-vanserin did not produce a significant change in the SAPS total domain score.57 However, its use did result in sig-nificant improvement in several measures specific to psy-chosis, including the SAPS global scores and the Unified



Parkinson’s Disease Rating Scale measures of hallucinations and delusions.

This phase 2 study was followed by a randomized, double-blind, placebo- controlled, phase 3 study, in which patients received 1 of 2 doses (10 or 40 mg) of pimavanserin tartrate or placebo.40 Efficacy was not demonstrated, but safety was again demonstrated, with a suggestion for improve-ments in nighttime sleep and caregiver bur-den at the 40-mg dose.

A second phase 3 study by Cummings and colleagues involved 1:1 randomiza-tion of 199 patients to placebo or 40 mg of pimavanserin tartrate.58 A 2-week lead-in of brief psychosocial therapy was offered prior to randomization, and patients with a significant response to brief psychosocial therapy were excluded from the medication phase of the study.58 A new primary out-comes scale was also used, the SAPS-PD. This was a 9-item scale designed to capture items from the complete 20-item SAPS Hallucina-tions Plus Delusions Scale that were most relevant to PD, specifically, hallucinations and delusions58,59:

• Hallucinations:- H1 Auditory hallucinations- H3 Voices conversing- H4 Somatic or tactile hallucinations- H6 Visual hallucinations- H7 Global rating of severity of hallucinations

• Delusions:- D1 Persecutory delusions- D2 Delusions of jealousy- D7 Delusions of reference- D13 Global rating of severity of delusions

Other secondary outcomes included CGI (both CGI-improvement and CGI-severity), Unified Parkinson’s Dis-ease Rating Scale motor scores, caregiver burden, night-time sleep, and daytime wakefulness.58 SAPS-PD scores decreased (Figure 2A) by 5.79 with pimavanserin vs 2.73 with placebo (P = .0014), a significant improvement in psy-chosis. In addition, there were significant improvements in CGI-severity (P = .0007) and CGI-improvement (P = .0011) assessments (Figures 2B and 2C, respectively), as well as caregiver burden scores (P = .002), nighttime sleep scores (P = .045), and daytime wakefulness scores (P = .012) at the end of the study period. No significant changes in motor symp-toms were noted with pimavanserin. After the initiation of

these studies, the FDA changed the definition of dosage to include only the active agent; therefore, the 40-mg dose of pimavanserin tartrate translates to 34 mg when excluding the tartrate salt.59

The onset of action for pimavanserin is approxi-mately 2 to 4 weeks (Figure 2).58 Dosing for pimavanserin is 34 mg once daily, without the need for drug titration or adjustment of concomitant carbidopa/levodopa.56 Because pimavanserin has been shown to prolong the QTc interval, patients who are at risk for prolonged QT interval or who take other medications that increase the QT interval should avoid taking pimavanserin.56 Those patients who are taking strong cytochrome P450 3A4 inhibitors, for example, ketoconazole or nefazodone, should take 17 mg once daily instead of 34 mg of pimavanserin because these medications will increase pimavanserin plasma levels.56 Commonly reported side effects (≥ 5% and twice the rate of placebo) are peripheral edema and confusional state.56

Investigational TreatmentsThe exploration of serotonergic compounds as a means of treating PDP is ongoing. Two phase 2 clinical trials assess-ing the safety and efficacy of nelotanserin, another 5-HT

2A

receptor inverse agonist, are currently recruiting patients.60,61 One study is examining the safety and efficacy of this

Abbreviations: CGI, Clinical Global Impression; SAPS-PD, Scale for Assessment of Positive Symptoms for Use in Parkinson’s Disease.

Reprinted from Lancet, 383, Cummings J, et al, Pimavanserin for patients with Parkinson’s disease psy-chosis: a randomised, placebo-controlled phase 3 trial, 533-540, 2014, with permission from Elsevier.

Figure 2. Scale for Assessment of Positive Symptoms for Use in Parkinson’s Disease and Clinical Global Impression end point data58



compound in the treatment of visual hallucinations in patients who have DLB or PD dementia,60 whereas the other is assess-ing safety and efficacy in the treatment of RBD in patients who have DLB.61

Another phase 2 study is currently being planned to explore the efficacy of continuous apomorphine infusion in the treatment of patients with PD and visual hallucinations whose symptoms are not adequately controlled with clozapine or cholinesterase inhibitors.62

Multidisciplinary ManagementGiven the significant challenges of PDP, both neurologists and psychiatrists should have the clinical skills to recognize and man-age this complex entity appropriately. Nonmotor features of PD may often carry more of a burden than motor symptoms, and may even be present before the physical manifestation of classic motor signs. To optimize patient care, psychiatrists and neurologists may benefit from participation in joint case conferences and teaching programs as well as training in each other’s field of expertise.63 Such communication could help to develop customized man-agement strategies for individual patients, including those with advanced PD.64

Continuum of CareAs with other chronic illnesses, PD places a significant amount of stress on not only the patient, but also on family members and other caregivers. This becomes more evident as the level of disability increases over time, with prospective longitudi-nal studies revealing worsened severity and prevalence over time.6 Parkinson’s disease psychosis and its associated hal-lucinations and delusions are leading predictors of caregiver stress, more so than other neuropsychiatric or motor symp-toms of PD.65 Parkinson’s disease psychosis is also a principal reason cited in the placement of patients with PD into long-term care facilities and nursing homes.65 Even when initial hallucinations are not threatening, there is a strong likelihood that there will be progression to more serious hallucinations and loss of insight. A study by Goetz and colleagues of patients with “benign hallucinations” at baseline noted deterioration in thought disorder in most patients (81%).66 Only 2 patients who did not receive some form of intervention for their hallucinations were still classified as being “benign” after a period of 3 years, and most patients whose hallucina-tions were stable had their PD treatment reduced to achieve this outcome.66

Hospitalization and nursing home placement may also present challenges to the continuation of therapies that have demonstrated efficacy for patients. There is a risk of recurrence of hallucinations when patients whose symptoms have been controlled are taken off atypical

antipsychotic medications that previously helped their symp-toms.67 Education of nursing home facility clinicians and staff regarding the safety and efficacy of various pharmacologic options for patients with PD is important to improve outcomes and to overcome logistical challenges of medication adminis-tration and monitoring.47

ConclusionsGiven the complexity of PDP and the need to simultaneously manage motor and nonmotor symptoms, clinicians should remain vigilant for the possibility of PDP, regularly asking their patients with PD and their caregivers about the presence of psychotic symptoms. Parkinson’s disease psychosis is frequently underrecognized, and may be a harbinger of clinical deteriora-tion and nursing home placement. A variety of options can be used to help control symptoms once they emerge. Antipsychotic use should be considered with caution, with safety and efficacy weighed for each individual patient. Medications, including his-torical and new treatment, that primarily target serotonin recep-tors with minimal influence on dopamine receptors may help clinicians maintain the balance of control of motor and nonmo-tor symptoms. Collaboration among psychiatrists, neurologists, and patients and their caregivers can help to optimize outcomes for patients who are struggling with PDP. n

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1. What percentage of patients with PD will likely experience psychotic symptoms during the course of their illness?

A. 10%

B. 20%

C. 40%

D. 60%

2. What is the predominant form of hallucination experienced by patients with PDP in the early stages of psychosis?

A. Auditory

B. Tactile

C. Visual

D. Olfactory

3. All the following have been established as risk factors for the development of PDP, EXCEPT:

A. Apolipoprotein ε polymorphisms

B. Patient age

C. Severity of underlying PD

D. Dementia

4. How does the presence of RBD affect the likelihood of psychotic symptoms in patients with PD?

A. Risk is lower

B. Risk is twice as high

C. Risk is 3 times as high

D. Risk is 5 times as high

5. Which of the following medications may contribute to the emergence of psychotic symptoms in patients with PD?

A. Anticholinergics

B. Opioid analgesics

C. Benzodiazepines

D. All the above

6. Which of the following pharmacologic options has level B evidence supporting its use in the treatment of PDP?

A. Clozapine

B. Haloperidol

C. Olanzapine

D. Quetiapine

7. Pimavanserin has a _________ affinity for 5-HT2A receptors and a __________ affinity for D2 receptors.

A. High, high

B. High, low

C. Low, low

D. Low, high

8. A 75-year-old male with a history of PD develops hallucinations, and his neurologist places him on clozapine. His psychotic symptoms remain well controlled for a period of 6 months, and his caregiver asks how frequently he needs to continue to have his blood drawn. His neurologist accurately replies that for the next 6 months, he should have it drawn:

A. Every week

B. Every 2 weeks

C. Every month

D. He no longer has to have his blood drawn

9. Which of the following strategies might help psychiatrists and neurologists optimize their care for patients with PDP?

A. Participation in joint case conferences

B. Participation in academic teaching programs

C. Training in each other’s field of expertise

D. All the above

10. Although not specifically validated for PDP, all the following rating scales have been classified as “recommended” for clinical trials on PDP therapy, EXCEPT:

A. Brief Psychiatric Rating Scale

B. Neuropsychiatric Inventory

C. Positive and Negative Syndrome Scale

D. Unified Parkinson’s Disease Rating Scale Part I

CME Posttest Questions Worksheet

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