CME Monograph SERIES

Parkinson’s Disease Psychosis

FINDING BALANCE:

New Strategies to Optimize Care for Patients With Parkinson’s

Disease Psychosis

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

Visit http://tinyurl.com/FindingBalancePDPpsych for online testing and instant CME certificate FACULTY

JENNIFER G. GOLDMAN, MD, MS This activity is jointly provided by Postgraduate Institute for Medicine and MedEdicus LLC.

MICHAEL S. OKUN, MD

This activity is supported by an independent educational grant from ACADIA Pharmaceuticals Inc.

DANIEL WEINTRAUB, MD

Distributed with

You may also access this monograph online!

http://www.PsychiatricTimes.com/CME/Finding-Balance-PDP

Estimated Time to Complete Activity: 1 hour

TARGET AUDIENCE

This 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 OBJECTIVES

Upon 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 symptoms 3. Evaluate the mechanism of action, tolerability, safety, and efficacy of pharmacologic treatment options for PDP 4. Employ multidisciplinary communication strategies to improve quality of life in patients with PDP

ACCREDITATION STATEMENT

This 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 INTEREST

Postgraduate 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 apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. 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 (e.g., 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 during the past year with the following commercial interest in the form of Consulting Fees (e.g., advisory boards): ACADIA Pharmaceuticals Inc.

2

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: The following PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi SmelkerMitchek, RN, BSN, and Jan Schultz, RN, MSN, CHCP, hereby state that they or their spouse/life partner do not have any financial relationships 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, have no real or apparent conflicts of interest to report.

METHOD OF PARTICIPATION AND REQUEST FOR CREDIT

There 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 and the activity evaluation, a certificate will be made available immediately.

DISCLOSURE OF UNLABELED USE

This 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 official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER

Participants 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.

MEDIA

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Instant CME Certificate Available With Online Testing and Course Evaluation at http://tinyurl.com/FindingBalancePDPpsych FACULTY

JENNIFER G. GOLDMAN, MD, MS

Associate Professor Section of Parkinson’s Disease and Movement Disorders Department of Neurological Sciences Rush University Medical Center Chicago, Illinois

MICHAEL S. OKUN, MD

Chair, Department of Neurology Adelaide Lackner Professor Co-Director, Movement Disorders Center University of Florida College of Medicine Gainesville, Florida

DANIEL WEINTRAUB, MD

Associate Professor of Psychiatry and Neurology Perelman School of Medicine at the University of Pennsylvania Parkinson’s Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC) Corporal Michael J. Crescenz Department of Veterans Affairs Medical Center Philadelphia Veterans Affairs Medical Center Philadelphia, Pennsylvania

FINDING BALANCE:

New Strategies to Optimize Care for Patients With Parkinson’s

Disease Psychosis

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, especially 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 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 Epidemiology

Recent 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 estimation has been influenced by the 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 Presentation

Patients 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 3

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.

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 • 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 disorder or psychotic depression, respectively15

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

Risk Factors or Correlates of Parkinson’s Disease Psychosis

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 4

Fixed, false beliefs

Successful identification of risk factors or correlates may help to facilitate a timely diagnosis of PDP. Several risk factors or correlates 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 movement 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 cholinergic17 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, catecholO-methyltransferase, serotonin 2A (5-hydroxytryptamine [HT]2A) receptor genes, apolipoprotein ε4 or ε2, cholecystokinin promoter polymorphisms, and angiotensinconverting 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 Disorders

Depression 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

Instant CME Certificate Available With Online Testing and Course Evaluation at http://tinyurl.com/FindingBalancePDPpsych 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

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

Etiology of Parkinson’s Disease Psychosis

Although 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-Omethyltransferase 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, the dopamine hypothesis is insufficient to fully 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 binding as a means of defining 5-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.

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 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 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 Strategies

For 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 (Table 2)33 may be helpful in establishing a differential diagnosis framework. 5

P

Parkinson’s disease medications

SY

Systemic illness

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

C

Centrally acting medication

H

Hepatic, renal, or other metabolic dysfunction

Nonpharmacologic Measures

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)

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

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

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 trial created a modified version of the SAPS for use in PD, the SAPS-PD.35 The development of a validated screening instrument specific to PDP remains a need for patients and practicing clinicians.36

MANAGEMENT OF PARKINSON’S DISEASE PSYCHOSIS Initial Management Steps

Management 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 6

Nonpharmacologic 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.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 Antipsychotics

Selection 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 have not been specifically approved for PDP. Many antipsychotics, particularly typical antipsychotics 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-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 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 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.41,42 These findings prompted the generation of black 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 continue to be treated with pharmacologic options that have limited to no evidence for efficacy or that carry a risk for the deterioration of motor symptoms.23

Instant CME Certificate Available With Online Testing and Course Evaluation at http://tinyurl.com/FindingBalancePDPpsych Table 3. Increased Mortality in Patients With Parkinson’s Disease With Antipsychotic Use44 Intention-to-Treat Analysis

Antipsychotic

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)

< .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)

.8

Abbreviation: CI, confidence interval.

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