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

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FACULTY JENNIFER G. GOLDMAN, MD, MSMICHAEL S. OKUN, MDDANIEL WEINTRAUB, MD

New Strategies to Optimize Care for Patients

With

CME Monograph

Parkinson’s Disease Psychosis

FINDING BALANCE:

SERIESParkinson’s Disease Psychosis

You may also access this monograph online! http://www.PsychiatricTimes.com/CME/Finding-Balance-PDP

2 © 2016 MedEdicus LLC

Estimated Time to Complete Activity: 1 hour

TARGET AUDIENCEThis activity has been designed to meet the educational needs of neurologists and psychiatrists involved in the care of patients with Parkinson’s disease 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 efficacyofpharmacologictreatmentoptionsforPDP4. Employ multidisciplinary communication strategies to improve quality of life in patients with PDP

ACCREDITATION STATEMENTThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and MedEdicus LLC. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION The Postgraduate Institute for Medicine designates this enduring material 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.

DISCLOSURE OF CONFLICTS OF INTERESTPostgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparentconflictofinterest(COI)theymayhaveasrelatedtothecontentofthisactivity.AllidentifiedCOIarethoroughlyvettedandresolved according to PIM policy. PIM is committed to providing its learners with high-quality CME activities and related materials that promoteimprovementsorqualityinhealthcareandnotaspecificproprietary business interest of a commercial interest.

The faculty reportedthefollowingfinancialrelationshipsorrelationships 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,hadafinancialagreementoraffiliationduringthepastyearwiththefollowingcommercialinterests in the form of Contracted Research: ACADIA Pharmaceuticals Inc; and Biotie Therapies; Consulting Fees (e.g., advisory boards):ACADIAPharmaceuticalsInc;andPfizerInc.

Michael S. Okun, MD,hasnorealorapparentconflictsofinterestto report.

Daniel Weintraub, MD, hadafinancialagreementoraffiliationduring the past year with the following commercial interest in the form of Consulting Fees (e.g., advisory boards): ACADIA Pharmaceuticals Inc.

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

The following PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, RN, BSN, and Jan Schultz, RN, MSN, CHCP, hereby state thattheyortheirspouse/lifepartnerdonothaveanyfinancialrelationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

The following MedEdicus planners and managers, Robert M. Geist IV, MD, Diane McArdle, PhD, and Cynthia Tornallyay, RD, MBA, CHCP,havenorealorapparentconflictsofinteresttoreport.

METHOD OF PARTICIPATION AND REQUEST FOR CREDITThere are no fees for participating in and receiving CME credit for this activity. During the period August 1, 2016, through August 1, 2017, participants must read the learning objectives and faculty disclosures and study the educational activity.

To receive CME credit, participants should read the preamble and the monograph, and complete the posttest and activity evaluation online at http://tinyurl.com/FindingBalancePDPpsych. Upon successfully completing the posttest with a score of 75% or better andtheactivityevaluation,acertificatewillbemadeavailableimmediately.

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 activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the officialprescribinginformationforeachproductfordiscussionofapproved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. 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 activity 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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INTRODUCTIONParkinson’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, especially given the lack of validated assessment tools specifictoPDP.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 advancements, 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 initiation of off-label antipsychotic therapy. Such strategies carry their own degree of risk, such as worsening parkinsonism. Increased understanding of the neurobiology of PDP has also led to the development of new therapeutic options that may improve patient safety while maintaining a balance between control of PDP and control of motor symptoms. The US Food and Drug Administration (FDA) has recently approved one of these new therapies, pimavanserin, for the treatment of PDP.5 This review summarizes new approaches for the diagnosis and treatment of PDP.

COMPLEXITIES OF PARKINSON’S DISEASE PSYCHOSIS

EpidemiologyRecent 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 Therevisioninthisestimationhasbeeninfluencedbythe incorporation of broader diagnostic criteria from the National Institute of Neurological 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 (Table 1),8 ranging from misperception of external stimuli to frank hallucinations to disruptive delusional behavior. Identifying clinical manifestations that distinguish 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

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

New Strategies to Optimize Care for Patients

With Parkinson’s Disease Psychosis

FINDING BALANCE:

4

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 tactile) may also occur, typically in conjunction with visual hallucinations.13 Visual hallucinations are the dominant type in the early stages of hallucination development, and, as some studies indicate, the cooccurrence of nonvisual hallucinations 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 hallucinations. 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 hallucinations 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 delusionsalsotendtobethematic(eg,spousalinfidelityorabandonment).7

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

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:• Possiblepresentationwithaclearsensoriumand retained insight, distinguishing it from delirium12

• Lowerincidenceofdelusionsofgrandiosityandbizarre beliefs and disorganized thinking than that seen with schizophrenia12

• Hallucinationsthataremorelikelytobevisualortobe occurring in nonauditory modalities compared with those encountered with schizophrenia8

• Auditoryhallucinationsthataretypicallyvagueand less threatening than those experienced by patients with schizophrenia8

• Lowerincidenceofdelusionsofgrandiosityornihilism/ self-deprecation than that seen with psychotic bipolar disorder or psychotic depression, respectively15

Risk Factors or Correlates of Parkinson’s Disease PsychosisSuccessfulidentificationofriskfactorsorcorrelatesmay help to facilitate a timely diagnosis of PDP. Several riskfactorsorcorrelateshavebeenidentifiedfortheemergence of PDP, including the following:• DopaminergicmedicationsforPD2

• Polypharmacywithpsychoactivedrugs6

• SeverityanddurationofPD11

• Comorbidsleepdisturbances,suchasrapideye movement sleep behavior disorder (RBD) and excessive daytime sleepiness11,16

• Advancingpatientage11 • Cognitiveimpairment11

• Alterationsinvisionorthevisualpathways8,11

• Alterationsinneurotransmittersystems,including cholinergic17 and serotonergic systems18,19

• Axialparkinsonism11

• Familyhistoryofdementia11

Ofnote,geneticriskfactorsmayinfluencetheemergenceof 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-hydroxytryptamine [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 withPDP,ashascognitiveimpairment.Onerecentstudyfound 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

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

Misidentificationsyndromes 

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

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

Delusions Fixed, false beliefs

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binding in the ventral visual pathway and other regions (Figure 1) is greater in patients with PD who have visual hallucinations than in those with PD who do not experience visual hallucinations.18

Figure 1. Areas of serotonin 2A binding potential increases18

Parkinson’s disease dementia has been linked with Lewy body deposition, and dementia is a risk factor for the emergence 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.

OVERLAP BETWEEN PARKINSON’S DISEASE DEMENTIA AND DEMENTIA WITH LEWY BODIESHistorically,ithasbeendifficulttoclinicallydifferentiatebetween PD dementia and DLB, with expert consensus establishing a key distinction on the basis of the temporal relationship 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 parkinsonism or within 1 year of onset of parkinsonism is diagnosed as DLB.32

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 thesepatients,andthePSYCHOSISacronym(Table 2)33 may be helpful in establishing a differential diagnosis framework.

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, functional, or metabolic brain abnormalities, as well as visual processing pathway alterations and sleep disorders. The use of dopamine replacement therapy and other PD medications has been linked with the development of psychotic symptoms, in part on the basis of experience with dopaminergic treatments and data from randomized placebo-controlled studies.2,7 Indeed, all dopaminergic drug classes (ie, levodopa, dopamine agonists, monoamine oxidase inhibitors, 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 dopamine contributions to PDP because decreasing the dose or discontinuation of dopaminergic replacement therapies may improve PDP symptoms.8

However,thedopaminehypothesisisinsufficienttofully explain the whole story of PDP because other neurotransmitters 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 neurotransmitters, 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 acuity 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 hallucinations. An autopsy study that used autoradiographic bindingasameansofdefining5-HT2A receptors found a 45.6% increase in binding in the inferolateral temporal cortex (a key component of the visual pathway) of patients with PD and hallucinations relative to those with PD who did not experience hallucinations.17 Positron emission tomography brain imaging has shown that 5-HT2A receptor

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

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

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 capture 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 Society 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 Syndrome Scale, and the Scale for Assessment of Positive Symptoms (SAPS). A recent clinical trialcreatedamodifiedversionoftheSAPSforuseinPD,the SAPS-PD.35 The development of a validated screening instrumentspecifictoPDPremainsaneedforpatientsandpracticing clinicians.36

MANAGEMENT OF PARKINSON’S DISEASE PSYCHOSIS

Initial 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 initiation 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 antidepressants, 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, particularly if their symptoms are mild and if caregivers 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.39Onestudyfoundthat78%ofpatientswithPDand 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 variety of reasons, including maintenance of safety while preserving the balance between motor and nonmotor symptoms. Historically used antipsychotics havenotbeenspecificallyapprovedforPDP.Manyantipsychotics, particularly typical antipsychotics such as haloperidol, can potentially worsen parkinsonism through the blockade of dopamine D2 receptors.40 When used at dosesthatareefficacious,atypicalantipsychoticsprovidegreater blockade of 5-HT2A 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 safetyandefficacydatabehindeachchoicetooptimizepatient 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 medicationsthatarenotindicatedspecificallyforPDP.3,41

There have been relatively few large randomized controlled trials assessing antipsychotic therapy for PD. In addition, safety concerns regarding the use of antipsychotics for elderly patients with dementia, such as an increased risk of cerebrovascular adverse events and mortality, have been established.41,42Thesefindingspromptedthegenerationof black box warnings for both typical and atypical antipsychotics.41,43Otheradverseeventsassociatedwithatypical antipsychotic use include orthostatic hypotension, dry mouth, sedation, dizziness, and constipation.12 Despite these concerns, many patients continue to be treated with pharmacologic options that have limited to no evidence forefficacyorthatcarryariskforthedeteriorationofmotorsymptoms.23

P Parkinson’s disease medicationsSY Systemic illnessC Centrally acting medication

H Hepatic, renal, or other metabolic dysfunction

O Overdoseofmedicationsorintoxication

S Sensory deprivation (eg, hearing and visual impairment)

I Infection (eg, urinary tract infection and pneumonia)

SStructural 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.

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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% confidenceinterval,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% confidenceinterval,1.24-1.91;P < .001). Fewer than 10% of the patients included in this study carried a diagnosis ofdementia,sothefindingsarenotspecifictopatientswith PD and comorbid dementia. This study addresses the risks associated with the use of antipsychotics; however, 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 (levelB)supportingitsefficacyinthetreatmentofPDPon 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.12Clozapinehasagreateraffinityfor serotonin 5-HT2 receptors than for D2 and D3 receptors (Table 4), whichexplainsitsefficacywithoutexacerbationof parkinsonism.40 Patients in the United States are required tohavetheirblooddrawnweeklyforthefirst6monthsoftherapy, biweekly for the next 6 months, and then monthly afterthefirstyearoftherapyaspartoftheClozapineRiskEvaluation and Mitigation Strategy program.46Othersideeffects that may be of concern include sedation, drooling, and orthostatic hypotension.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 frequentbloodexaminationisasignificantbarrierto 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,practiceparametersstatethatthereis“insufficientevidencetoconcludeontheefficacyofquetiapineforthetreatment of psychosis in PD.”41 It has been designated as investigational for the treatment of PDP, without the need

AntipsychoticIntention-to-Treat Analysis Exposure-Only Analysis

Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value

Haloperidol 5.08 (3.16-8.16) < .001 4.80 (2.41-9.57) < .001Othertypicalantipsychotic 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) < .001Quetiapine 2.16 (1.88-2.48) < .001 1.93 (1.59-2.33) < .001Risperidone 2.46 (1.94-3.12) < .001 2.62 (1.83-3.76) < .001Otheratypicalantipsychotic 1.19 (0.60-2.37) .62 1.14 (0.41-3.18) .8

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

Abbreviation:CI,confidenceinterval.

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

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 NRDopamine D1 NR 100 100 NR NP 60 D2 50 0.1 4 NR 30 0.5 D3 NR 0.2 25 NR 9 13

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

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for specialized monitoring, with level C evidence.3 Although studies comparing quetiapine and clozapine have suggested theyhavesimilarefficacy,theefficacydatafromclinicaltrials have been inconsistent when quetiapine has been compared with placebo, with only 1 of 5 randomized trials showing positive PDP outcomes.41,48Onestudydemonstratedimprovement 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 tolerated 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

Olanzapinehasbeenstudiedasanoff-labelmeansoftreatingPDP.IthasaffinityforserotoninreceptorsandagreataffinityforD2receptors.40 It has been associated with the deterioration of motor symptoms in patients with PD,withoutanydemonstratedefficacyinthetreatmentofhallucinations.41 American Academy of Neurology practice parameters state that olanzapine should not be considered for the treatment of PDP.3Otheroff-labeltreatmentsincluderisperidone and aripiprazole, both of which have been linked with the deterioration 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 anticholinergic and dopaminergic treatment may precipitate hallucinations). The evidence supporting the use of cholinesterase inhibitors comes largely from smaller studies, including case series and open-label trials. These smaller investigations set the stage for a planned subanalysis from the Exelon in Parkinson’s Disease Dementia 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 improvement 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 currentlyrecruitingpatientstoexploretheefficacyofearlyinitiation of rivastigmine therapy on delaying hallucination progression in patients with PD and experiencing 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-HT2A inverse agonist, and to a lesser extent antagonist, that has recently gained FDA approval specificallyforthetreatmentofPDP.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 treatment 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 activity) 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 constitutiveactivity.Pimavanserinhasahighaffinityfor the 5-HT2Areceptor,withverylittleaffinityforotherreceptors, including 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, pimavanserindidnotproduceasignificantchangeintheSAPS total domain score.57 However, its use did result insignificantimprovementinseveralmeasuresspecificto psychosis, including the SAPS global scores and the UnifiedParkinson’sDiseaseRatingScalemeasuresofhallucinations 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.40Efficacywasnotdemonstrated,butsafety was again demonstrated, with a suggestion for improvements in nighttime sleep and caregiver burden at the 40-mg dose.

A second phase 3 study by Cummings and colleagues involved 1:1 randomization 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,andpatientswithasignificantresponseto brief psychosocial therapy were excluded from the medication phase of the study.58 A new primary outcomes scale was also used, the SAPS-PD. This was a 9-item scale designed to capture items from the complete 20-item SAPS Hallucinations Plus Delusions Scale that were most relevant toPD,specifically,hallucinationsanddelusions58,59: • 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

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OthersecondaryoutcomesincludedCGI(bothCGI-improvementandCGI-severity),UnifiedParkinson’sDisease Rating Scale motor scores, caregiver burden, nighttime sleep, and daytime wakefulness.58 SAPS-PD scores decreased (Figure 2A) by 5.79 with pimavanserin vs 2.73 with placebo (P=.0014),asignificantimprovementinpsychosis. In addition, there weresignificantimprovementsin 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)attheendofthestudyperiod.Nosignificantchanges in motor symptoms were noted with pimavanserin. After the initiation of these studies, the FDA changed thedefinitionofdosagetoincludeonlytheactiveagent;therefore, the 40-mg dose of pimavanserin tartrate translates to 34 mg when excluding the tartrate salt.59

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

The onset of action for pimavanserin is approximately 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. 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 Commonlyreportedsideeffects(≥5%andtwicetherateofplacebo) 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 assessingthesafetyandefficacyofnelotanserin,another

5-HT2A receptor inverse agonist, are currently recruiting patients.60,61Onestudyisexaminingthesafetyandefficacyof this compound in the treatment of visual hallucinations in patients who have DLB or PD dementia,60 whereas the other isassessingsafetyandefficacyinthetreatmentofRBDinpatients who have DLB.61

Another phase 2 study is currently being planned to explore theefficacyofcontinuousapomorphineinfusioninthetreatment of patients with PD and visual hallucinations whose symptoms are not adequately controlled with clozapine or cholinesterase inhibitors.62

MULTIDISCIPLINARY MANAGEMENTGiventhesignificantchallengesofPDP,bothneurologistsand psychiatrists should have the clinical skills to recognize and manage 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 patientcare,psychiatristsandneurologistsmaybenefitfrom participation in joint case conferences and teaching programsaswellastrainingineachother’sfieldofexpertise.63 Such communication could help to develop customized management strategies for individual patients, including those with advanced PD.64

CONTINUUM OF CAREAswithotherchronicillnesses,PDplacesasignificantamount 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 longitudinal studies revealing worsened severity and prevalence over time.6 Parkinson’s disease psychosis and its associated hallucinations and delusions are leading predictors of caregiver stress, more so than other neuropsychiatric or motor symptoms 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%).66Only2patientswhodidnotreceivesome form of intervention for their hallucinations were still classifiedasbeing“benign”afteraperiodof3years,andmost patients whose hallucinations 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 havedemonstratedefficacyforpatients.Thereisariskof recurrence of hallucinations when patients whose symptoms have been controlled are taken off atypical antipsychotic medications that previously helped their symptoms.67 Education of nursing home facility clinicians andstaffregardingthesafetyandefficacyofvariouspharmacologic options for patients with PD is important to improve outcomes and to overcome logistical challenges of medication administration and monitoring.47

Abbreviations: CGI, Clinical Global Impression; SAPS-PD, Scale for Assessment of Positive Symptoms for Use in Parkinson’s Disease.Reprinted from The Lancet, 383, Cummings J, et al, Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial, 533-540, 2014, with permission from Elsevier.

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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 deterioration and nursing home placement. A variety of options can be used to help control

symptoms once they emerge. Antipsychotic use should be consideredwithcaution,withsafetyandefficacyweighedfor each individual patient. Medications, including historical and new treatment that primarily target serotonin receptors withminimalinfluenceondopaminereceptorsmayhelpclinicians maintain the balance of control of motor and nonmotor symptoms. Collaboration among psychiatrists, neurologists, and patients and their caregivers can help to optimize outcomes for patients who are struggling with PDP.

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et al. Minimal hallucinations occur in drug-naive Parkinson’s disease patients, even from the premotor phase. Mov Disord. 2016;31(1):45-52.10. Friedman JH. Editorial on: Pagonabarraga J, Martinez-Hora S, Fernández de Bobadilla R et al. Minimal hallucinations occur in drug-naïve Parkinson’s disease patients even from the premotor phase. Movement Disorders 2015; Available from: DOI:10.1002/mds.26432.Mov Disord. 2016;31(1):9-10.11. Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson’s disease. Neurotherapeutics. 2014;11(1):78-91.12. Goldman JG, Holden S. Treatment of psychosis and dementia in Parkinson’s disease. Curr Treat Options Neurol. 2014;16(3):281.13.GoetzCG,StebbinsGT,OuyangB.Visualplusnonvisual hallucinations in Parkinson’s disease: development and evolution over 10 years. Mov Disord. 2011;26(12):2196-2200.14. Fénelon G, Alves G. Epidemiology of psychosis in Parkinson’s disease. J Neurol Sci. 2010;289(1-2):12-17.

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31. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591-1601.32. McKeith IG, Dickson DW, Lowe J, et al; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872.33. Vaughan CL, Goldman JG. Psychosis and Parkinson’s disease. In: Frucht SJ, ed. Movement Disorder Emergencies: Diagnosis and Treatment. New York, NY: Humana Press; 2013:75-92.34. Fernandez HH, Aarsland D, Fénelon G, et al. Scales to assess psychosis in Parkinson’s disease: critique and recommendations. Mov Disord. 2008;23(4):484-500.35. Voss T, Bahr D, Cummings J, Mills R, Ravina B, Williams H. Performance of a shortened Scale for Assessment of Positive Symptoms for Parkinson’s disease psychosis. Parkinsonism Relat Disord. 2013;19(3):295-299.36. Martinez-Martin P, Leentjens AF, de Pedro-Cuesta J, Chaudhuri KR, Schrag AE, Weintraub D. Accuracy of screening instruments for detection of neuropsychiatric syndromes in Parkinson’s disease. Mov Disord. 2016;31(3):270-279.37.OlanowCW,SternMB,SethiK.Thescientificandclinicalbasis for the treatment of Parkinson disease (2009). Neurology. 2009;72(21)(suppl 4):S1-S136.38. Wishart S, Macphee GJ. Evaluation and management of the non-motor features of Parkinson’s disease. Ther Adv Chronic Dis. 2011;2(2):69-85.39. Diederich NJ, Pieri V, Goetz CG. Coping strategies for visual hallucinations in Parkinson’s disease. Mov Disord. 2003;18(7):831-832.40. Hacksell U, Burstein ES, McFarland K, Mills RG, Williams H. Onthediscoveryanddevelopmentofpimavanserin:anovel drug candidate for Parkinson’s psychosis. Neurochem Res. 2014;39(10):2008-2017.41. Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord. 2011;26(suppl 3):S42-S80.42. U.S. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ ucm053171.htm. Published April 11, 2005. Accessed June 16, 2016.43. Maust DT, Kim MH, Seyfried LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015;72(5):438-445.44. Weintraub D, Chiang C, Kim HM, et al. Association of antipsychotic use with mortality risk in patients with Parkinson disease. JAMA Neurol. 2016;73(5):535-541.45.OkunMS.ShouldwefearantipsychoticsinParkinsondisease patients? NEJM Journal Watch Web site. http://www.jwatch.org/na40940/2016/04/11/should-we-fear- antipsychotics-parkinson-disease-patients. Published April 11, 2016. Accessed June 2, 2016.46. Clozapine REMS. https://www.clozapinerems.com/CpmgClozapineUI/ rems/pdf/resources/ANC_Table.pdf. Published December 23, 2014. Accessed June 16, 2016.47. Hack N, Fayad SM, Monari EH, et al. An eight-year clinic experience with clozapine use in a Parkinson’s disease clinic setting. PLoS One. 2014;9(3):e91545.48. Shotbolt P, Samuel M, David A. Quetiapine in the treatment of psychosis in Parkinson’s disease. Ther Adv Neurol Disord. 2010;3(6):339-350.49.FernandezHH,OkunMS,RodriguezRL,etal.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.

50. Factor SA, Molho ES, Friedman JH. Risperidone and Parkinson’s disease. Mov Disord. 2002;17(1):221-222.51. Fernandez HH, Trieschmann ME, Friedman JH. Aripiprazole for drug-induced psychosis in Parkinson disease: preliminary experience. Clin Neuropharmacol. 2004;27(1):4-5.52.FriedmanJH,BermanRM,GoetzCG,etal.Open-labelflexible- dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson’s disease. Mov Disord. 2006;21(12):2078-2081.53. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med. 2004;351(24):2509-2518.54. Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord. 2006;21(11):1899-1907.55. VU University Medical Center. Cholinesterase inhibitors to slow progression of visual hallucinations in Parkinson’s disease (CHEVAL). ClinicalTrials.gov Web site. https://clinicaltrials.gov/ ct2/show/NCT01856738. Updated December 28, 2015. Accessed May 30, 2016.56. Nuplazid [package insert]. San Diego, CA: ACADIA Pharmaceuticals Inc; 2016.57. 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):881-892.58. 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):533-540.59. Acadia Pharmaceuticals Inc. NUPLAZID™ (pimavanserin): sponsor background information for a meeting of the Psychopharmacologic Drugs Advisory Committee on 29 March 2016. U.S. Food and Drug Administration Web site. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ PsychopharmacologicDrugsAdvisoryCommittee/UCM492453.pdf. Accessed June 16, 2016.60. Axovant Sciences Ltd. Study evaluating nelotanserin for treatment of visual hallucinations in subjects with Lewy body dementia. ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/ NCT02640729. Updated June 13, 2016. Accessed June 24, 2016.61. Axovant Sciences Ltd. Study evaluating nelotanserin for treatment of REM sleep behavior disorder in subjects with dementia with Lewy bodies. ClinicalTrials.gov Web site. https://clinicaltrials.gov/ ct2/show/NCT02708186. Updated June 13, 2016. Accessed June 24, 2016.62. University Medical Center Groningen. Apomorphine in Parkinson’s disease patients with visual hallucinations: a RCT. ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/NCT02702076. Received March 2, 2016. Accessed May 30, 2016.63. Latoo J, Mistry M, Dunne FJ. Diagnosis and management of psychosis in Parkinson’s disease. Progress Neurol Psychiatry. 2012;16(5):7-10.64.GiugniJC,OkunMS.TreatmentofadvancedParkinson’sdisease. Curr Opin Neurol. 2014;27(4):450-460.65. Hermanowicz N, Edwards K. Parkinson’s disease psychosis: symptoms, management, and economic burden. Am J Manag Care. 2015;21(10)(suppl):s199-s206.66. Goetz CG, Fan W, Leurgans S, Bernard B, Stebbins GT. The malignant course of “benign hallucinations” in Parkinson disease. Arch Neurol. 2006;63(5):713-716.67.FernandezHH,TrieschmannME,OkunMS.Reboundpsychosis: effect of discontinuation of antipsychotics in Parkinson’s disease. Mov Disord. 2005;20(1):104-105.

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.Opioidanalgesics 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.Pimavanserinhasa_________affinityfor5-HT2A receptorsanda__________affinityforD2 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.Trainingineachother’sfieldofexpertise D. All the above

10.AlthoughnotspecificallyvalidatedforPDP,allthe followingratingscaleshavebeenclassifiedas “recommended” for clinical trials on PDP therapy, EXCEPT: A. Brief Psychiatric Rating Scale B. Neuropsychiatric Inventory C. Positive and Negative Syndrome Scale D.UnifiedParkinson’sDiseaseRatingScalePartI

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