Senior Care South Florida September 16, Manju T. Beier, Pharm D, CGP, FASCP

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1 Parkinson s Disease Psychosis Treatment in Long-Term Care: Clinical and Operational Considerations Manju T. Beier, Pharm D, BCGP, FASCP Senior Partner, GCR LLC Adjunct Clinical Associate Professor of Pharmacy The University of Michigan, Ann Arbor, MI Learning Objectives Delineate neuropsychiatric aspects of Parkinson s disease (PD) and distinguish among different types of dementias on the basis of clinical characteristics Identify the clinical features and risk factors of psychosis and PD psychosis Differentiate the pharmacology, safety, and efficacy of available pharmacologic treatment options Construct a therapeutic plan to manage non-motor symptoms of PD Identify operational strategies to navigate new LTCF requirements and the revised survey process when considering the use of antipsychotic medications Discuss the role of consultant pharmacists and the LTCF care team in managing the neuropsychiatric symptoms of dementia Dr. Beier s Disclosures Sunovion Pharmaceuticals: Honoraria for Consultant and as Speaker 3 1

2 Question 1 What neurological pathology feature is common among Parkinson s disease, Parkinson s dementia and Lewy-body dementia? a. Alpha-synuclein deposits (Lewy-bodies) b. Tremor c. Fluctuating memory impairment d. Beta-amyloid plaques Differentiating the Top Three Dementias Dementia Clinical Features Pathology Neurological Image Alzheimer s dementia Vascular dementia Insidious onset Apathy & depression common Memory deficit Aphasia Apraxia Agnosia Sudden onset Memory deficit Beta-amyloid plaques Tau Tangles Vacuoles Lewy body dementia Memory deficit Fluctuating impairment Psychosis (hallucinations) Extrapyramidal symptoms Alpha-synuclein (Lewy) bodies Alzheimer s Association. Accessed April 23, Parkinson s Disease, Parkinson s Dementia and Lewy Body Dementia Share Same Pathology Different expressions of the same underlying problems with brain processing of the protein alpha-synuclein Parkinson's disease dementia diagnosis when: Person is originally diagnosed with Parkinson's based on movement symptoms, and Dementia symptoms don't appear until a year or more later Alzheimer s Association. Accessed April 23,

3 What is Parkinson's Disease? A progressive disorder that affects several areas of the brain and results in a decrease in dopaminergic neurons, causing clinical features such as slowed movement and tremors. 7 Cardinal Motor Manifestations of PD Mnemonic - PART: Postural imbalance/asymmetric onset Akinesia/ Bradykinesia Rigidity Tremor at rest J Neurol Neurosurg Psychiatry 2008;79: doi: /jnnp Physical Examination Observation Gait disturbances Reduced Arm Swing Postural instability Reduced Strength Rigidity Lack of Manual Dexterity Objective Measures Mild orthostatic hypotension Labs generally not useful CT/MRI normal early on, may show cortical atrophy in later stages 3

4 Clinical Presentation Motor Autonomic/ Sensory Neuropsychiatric Symptoms Sleep Disturbances No lab test currently available to dx PD; Genetic testing not routinely helpful 10 Treatment of PD: Complex Array of Medications 11 Therapeutic Classes of PD Drugs Increase Dopamine (DA) Signaling: Adding DA-levodopa Preventing DA Breakdown-MAO-B Inhibitors Prolonging DA Availability-COMT Inhibitors Activating DA receptors-dopamine Agonists Anticholinergics: not preferred (risk/benefit ratio) Amantadine: NMDA receptor anatagonists Dialogues Clin Neurosci. 2004;6:

5 Sites of Action of PD Drugs: Augment DA system Substantia Nigra amantadine BBB levodopa DA MAO-B inhibitors Selegiline, rasagiline GABA Dopamine agonists: bromocriptine pramipexole ropinirole rotigotine apomorphine ACh DDC COMT dopamine levodopa 3-OMethyl Dopa carbidopa COMT inhibitors entacapone Striatum Anticholinergics trihexiphenidyl benztropine 13 Complications of PD Treatment: A Fine Balance Dopamine excess Dyskinesias Hallucinations Delusions Dopamine deficiency Worsening PD symptoms Dopamine agonists Dopamine antagonists Importance of Non-Motor Symptoms Affect quality of life, hospitalization and nursing home placement, caregiver burden, and relationships Correlate with advanced age, duration and severity of the disease generally Are under-reported!! 5

6 Neuropsychiatric Symptoms of PD Hallucinations/ Delusions Depression Confusion/ Dementia Anxiety Bradyphrenia 16 Sleep Disturbances Excessive Daytime Sleepiness Insomnia Obstructive Sleep Apnea Rapid Eye Movement Sleep Behavior disorder 17 PARKINSON S DISEASE PSYCHOSIS PDP

7 Psychosis is a Non-Motor Symptom of Parkinson s Disease Psychosis A brain disorder characterized by hallucinations and delusions 1 Hallucinations Perceptual experiences in the absence of real external sensory stimuli 1,2 Delusions Fixed false beliefs that run contrary to reality 1-4 Visual Auditory Tactile Olfactory Gustatory Jealousy Persecutory Somatic Reference 1. Ravina B et al. Mov Disord. 2007;22(8): Centers for Medicare & Medicaid Services. Long-Term Care Facility Resident Assessment Instrument 3.0 User s Manual. Version MDS-30-RAI-Manual-V113.pdf. Published October 1, Accessed July 1, Goldman JG et al. Expert Opin Pharmacother. 2011;12(13): Aarsland D et al. Int J Geriatr Psychiatry. 2001;16(5): Visual Hallucinations are the Most Common Symptom of PDP Auditory hallucinations 0% to 22% Hearing voices conversing Hearing music Olfactory hallucinations ~11% Visual hallucinations 16% to 72% Seeing people or animals Illusions Presence hallucinations Delusions 1% to 14% Jealous Persecutory Reference Symptoms of PDP 1-4 Gustatory hallucinations ~3% Tactile hallucinations ~12% Somatic hallucinations ~1% 1. Fénelon G et al. Mov Disord. 2010;25(6): Fénelon G et al. J Neurol Sci. 2010;289(1-2): Goldman JG et al. Expert Opin Pharmacother. 2011;12(13): Voss T et al. Parkinsonism Relat Disord. 2013;19(3):

8 PDP Is Associated With Hospitalizations, Nursing Home Placement, and Caregiver Burden PD patients with hallucinations were 2.5 times more likely to be admitted into a nursing home 2 Hallucinations and delusions in PD are associated with an increased burden on caregivers 3,4 1. Klein C, et al. J Neural Transm. 2009;116: Aarsland D, et al. J Am Geriatr Soc. 2000;48: Martinez-Martin P, et al. Parkinsonism Relat Disord. 2015;21: Aarsland D, et al. Int J Geri Psychiatry. 1999;14: Question 2 Parkinson s disease psychosis is thought to be due to dysfunction is which neurotransmitter system? a. Dopamine b. Serotonin c. Glutamate d. a & b e. All of the above 23 Three Neurotransmitter Pathways Have Been Linked to PDP There are 3 interconnected pathways that are believed to be linked to hallucinations and delusions 1,2 Dopamine theory Hyperactive dopamine in the mesolimbic pathway Serotonin theory 5-HT 2A receptor hyperfunction in the cortex NMDA theory NMDA receptor hypofunction Both the serotonin and NMDA theories can result in hyperactivity of the mesolimbic dopamine pathway 1,2 It is likely that 1 or more of these pathways is involved in patients with psychosis 1,2 1. Stahl SM. 4th ed. New York, NY: Cambridge University Press; Stahl SM. CNS Spectr. 2016;21:

9 Managing Neuropsychiatric Symptoms Reduce/eliminate/modify meds: Anticholinergics CNS meds Amantadine Muscle relaxants Sedatives Bladder medication Reduce dosage of PD meds Initiate antipsychotic therapy?? Worsening of motor symptoms due to blockage of dopamine D2 receptors has to be weighed against potential benefit Expert Rev. Neurother. 12(12), (2012) Question 3 Which medications have demonstrated efficacy in treating PDP? a. Clozapine b. Pimavanserin c. Quetiapine d. a & b e. All of the above 26 Second Generation Antipsychotics Historical Perspective Clozapine Clozaril Sandoz 1990 Risperidone Risperdal Janssen 1994 Olanzapine Zyprexa Lilly 1996 Quetiapine Seroquel AstraZeneca 1997 Ziprasidone Geodon Pfizer 2001 Aripiprazole Abilify BMS

10 Second Generation Antipsychotics Historical Perspective Paliperidone Invega Janssen 2007 Asenapine Saphris Merck 2009 Iloperidone Fanapt Vanda 2009 Lurasidone Latuda Sunovion 2010 Brexpiprazole Rexulti Otsuka/Lundbeck 2015 Cariprazine Vraylar Actavis 2015 Clozapine and Quetiapine Some Caveats Quetiapine and clozapine have the least likelihood of causing extrapyramidal side effects in PD patients and are the most widely used in PD patients Weigh warnings for increased morbidity and mortality although doses used in PD tend to be tenfold lower than those used in other psychiatric disorders. Both quetiapine and clozapine have been compared with placebo and there have also been two head-to-head trials Based on these studies, clozapine is considered efficacious while data for quetiapine is inconsistent From a practical standpoint, quetiapine ( mg daily) is often used first since frequent blood monitoring is required for clozapine ( mg daily) use Expert Rev. Neurother. 12(12), (2012) Antipsychotics and PD: What does the evidence show? Evaluated if there was an increased risk of mortality associated with AP use in PD? Methods: Retrospective matched cohort study using Veterans Affairs Data from JAMA Neurol. Published online March 21, doi: /jamaneurol

11 From: Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease JAMA Neurol. 2016;73(5): doi: /jamaneurol Figure Legend: Mortality Rates in Antipsychotic (AP)-Exposed vs Non AP-Exposed PatientsCovariate-adjusted 180-day survival estimates by baseline AP treatment status (intention-to-treat analysis) are shown. Graph is based on Cox proportional hazards regression modeling without pairing. Copyright 2016 American Medical Association. All rights reserved. Pimavanserin (Nuplazid ) Indications/use Parkinson s disease psychosis (PDP) In phase 2/3 trials for Alzheimer s disease psychosis and schizophrenia Mechanism of action A selective serotonin 5-HT2A inverse agonist No dopaminergic, adrenergic, histaminergic or muscarinic affinity In PD à increase 5-HT2A binding in neocortex àvisual hallucinations Approved: May 1st, 2016 Lancet 2014; 383: Ment Health Clin [Internet]. 2017;7(5): DOI: /mhc Receptor Selectivity of Antipsychotic Drugs Receptor Pimavanserin Clozapine Olanzapine Quetiapine Haloperidol Risperidone 5-HT 2A HT 2B nr nr 12 5-HT 2C nr nr 100 D1 nr nd Ki (nm) D2 nr D3 nr H1 nr nr M1 nr nr nr 1000 M2 nr 400 * 150 nd nr nr > 1000 M3 nr nr nr M4 nr 50 * nr nr Alpha 1A nr nd 40 3 Alpha 2A nr 300 nr nr nd 20 Alpha 2B nr 50 nr nr nd 50 Alpha 2C nr 40 nr nr *partial agonist EC 50 nr=no response; nd=not done Shown are potencies (in nm) at the indicated receptor targets Off-target side effects of other antipsychotic drugs are due to poor selectivity 1. Adapted from Hacksell U, et al. Neurochem Res. 2014, 39(10): and data on file. 11

12 (Pimavanserin) (Pimavanserin) 35 12

13 (Pimavanserin) Pimavanserin Effectively Diminished Symptoms of PD Psychosis and Did Not Show an Effect on Motor Function Change From Baseline Score (LSM±SE) 1,2 Primary endpoint: change in total SAPS-PD score from baseline 1, Week 0 Week 2 Week 4 Week % improvement in psychosis Placebo % improvement NUPLAZID 34 mg in psychosis (P=0.0014) Secondary endpoint: change from baseline to week 6 in UPDRS Parts II+III 1 Change From Baseline in UPDRS Parts II+III Scores (LSM) The mean age was 72.4 years for both NUPLAZID 34 mg (n=95) and placebo (n=90). 1,2 The mean SAPS-PD baseline score for NUPLAZID 34 mg was 15.9 and for placebo was The percent improvement is an exploratory analysis; the primary endpoint was point reduction on the SAPS-PD ( NUPLAZID 34 mg and placebo). 1 The effect of NUPLAZID on SAPS-PD improved through the 6-week trial period. 1 LSM: least-squares mean; SE: standard error NUPLAZID mg mg -1.4 Placebo NUPLAZID Prescribing Information. 2. Cummings J, et al. Lancet. 2014;383: Adverse Reactions for Pimavanserin Reported in At Least 2% and Greater than Placebo Percentage of patients reporting adverse reaction Pimavanserin 34 mg N=202 Placebo N=231 Nausea 7% 4% Peripheral edema 7% 2% Confusional state 6% 3% Hallucination a 5% 3% Constipation 4% 3% Gait disturbance 2% <1% Adverse reactions leading to discontinuation of treatment A total of 8% (16/202) of Pimavanserin 34-mg treated patients and 4% (10/231) of placebotreated patients discontinued because of adverse reactions Hallucination (2% Pimavanserin 34 mg vs <1% placebo) Urinary tract infection (1% Pimavanserin 34 mg vs <1% placebo) Fatigue (1% Pimavanserin 34 mg vs 0% placebo) a Hallucination includes visual, auditory, tactile, and somatic hallucinations. NUPLAZID Prescribing Information. San Diego, CA: ACADIA Pharmaceuticals Inc.;

14 Recent Post-marketing Safety Analysis of Pimavanserin Institute for Safe Medication Practices (ISMP) November 2017 review: Increased signal for hallucinations and confusional state? Pimavanserin being used in combination with quetiapine in some cases! Data being reviewed by FDA (Lancet editorial May 2018) Boxed Warning for Antipsychotics All antipsychotics have a boxed warning regarding increased mortality in elderly patients with dementia-related psychosis All Antipsychotics WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death Pimavanserin Adjusted Statement NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson s disease psychosis Pimavanserin has an adjusted boxed warning, specific to the Parkinson s disease demographic What about? Cognitive Impairment and Dementia Treatment options: - Concomitant Medication Review Evaluate non-pd meds Evaluate PD meds esp. anticholinergics, TCAs, amantadine, seligiline and dopamine agonists If possible- may reduce levodopa/carbidopa Cholinesterase inhibitors (ChEIs) Rivastigmine is the only agent approved by the FDA but all ChEIs have been studied Need to look at risk/benefit with these agents 14

15 Rivastigmine for Dementia Associated with Parkinson's Disease 24-week randomized, multicenter, doubleblind, placebo-controlled clinical trial. Patients were randomly assigned to treatment with 3 to 12 mg of rivastigmine (Exelon, Novartis) per day or placebo in a ratio of 2:1. The 2:1 ratio permitted the collection of more safety data in the rivastigmine group. Treatment started with 1.5 mg of rivastigmine or placebo twice daily. Doses were increased by 3 mg per day at intervals of at least 4 weeks during a 16- week dose-escalation period. The highest well-tolerated dose for each patient was maintained for the rest of the study. Emre M et al. N Engl J Med 2004;351: What about? Depression in PD Occurs in approximately 40-70% of patients Death and Suicidal ideation higher Identification often delayed Antidepressants are first line, although carry several risks (eg.:orthostatsis, sleepiness) Expert Rev. Neurother. 12(12), (2012) Depression Treatment Approaches A systematic review and meta-analysis of randomized controlled studies favored the use of antidepressants Depression in PD may be under-recognized and thus undertreated To date, no single antidepressant is better than another in PD Selective serotonin reuptake inhibitors (SSRIs) considered first line Others: Atypical antidepressants, Tricyclic antidepressants Monoamine oxidase inhibitors should be avoided in PD patients on dopaminergic medications due to potential serious drug interactions (serotonin syndrome risk) Expert Rev. Neurother. 12(12), (2012) 15

16 Antidepressive treatments for Parkinson's disease: A systematic review and meta-analysis Parkinsonism & Related Disorders, Volume 21, Issue 8, 2015, MEDICATION SIDE EFFECTS Consider Deprescribe/Delete/Modify 16

17 REGULATORY CONSIDERATIONS WHEN TREATING PDP IN NHs 49 Requirements for Minimum Data Set Monitoring for Psychosis in Nursing Facilities Minimum Data Set (MDS) 3.0 requires monitoring for psychosis in nursing facility residents, with the rationale that psychosis can affect health-related quality of life 1 Hallucinations and delusions may 1-4 : Be distressing to residents and families Cause functional disability Interfere with delivery of medical, nursing, rehabilitative and personal care Lead to dangerous behavior or possible harm to caregivers or other residents 1. Centers for Medicare & Medicaid Services. Long-Term Care Facility Resident Assessment Instrument 3.0 User s Manual. Version Medicare/Quality-Initiatives-Patient-Assessment-Instruments/NursingHomeQualityInits/Downloads/MDS-30-RAI-Manual-V113.pdf. Published October 1, Accessed July 1, Ravina B et al. Mov Disord. 2007;22(8): Holroyd S et al. J Neurol Neurosurg Psychiatry. 2001;70(6): Aarsland D et al. J Neurol Neurosurg Psychiatry. 2007;78(1): Proactively Discuss PDP with Residents and Caregivers People with PDP may not report their symptoms 1 Who: Talk to residents with PD and their caregivers 2,3 What: Questions about specific PDP symptoms 4 When: HCP visits, MDS reviews, monthly medication regimen reviews, change in behavioral status 5 Why: It is important that residents and caregivers understand that these symptoms are common and will occur in more than half of people with PD over the course of the disease 6 How: Ask residents about PDP symptoms in a simple manner 7 Do you see any persons, animals or objects that are not really there? 4 Do you feel like someone you trust is trying to deceive or harm you? 4 Do you have vivid impressions of a presence, of someone being there, when in fact no one is there? 4 1. Chaudhuri KR et al. Mov Disord. 2010;25(6): Fernandez HH et al. Mov Disord. 2008;23(4): Williams DR et al. J Neurol Neurosurg Psychiatry. 2008;79(6): Fénelon G et al. Mov Disord. 2010;25(6): Centers for Medicare & Medicaid Services. Long-Term Care Facility Resident Assessment Instrument 3.0 User s Manual. Version NursingHomeQualityInits/Downloads/MDS-30-RAI-Manual-V113.pdf. Published October 1, Accessed July 1, Forsaa EB et al. Arch Neurol. 2010;67(8): Carlat JD. Am Fam Physician. 1998;58(7):

18 Effective Team Collaboration can Enhance Care for Residents with PDP CMS STATE OPERATIONS MANUAL RESIDENT ASSESSMENT (INTENT) Activities staff Nursing staff MDS coordinator In addition to direct observation and communication with the resident, the facility should use a variety of other sources, including communication with licensed and non-licensed staff members on all shifts 1 Nursing assistants Physician Behavioral specialists Resident 1,2 Social workers Consultant pharmacist Family members 1. Centers for Medicare & Medicaid Services. State Operations Manual. Appendix PP - Guidance to Surveyors for Long Term Care Facilities. Updated June 10, Accessed July 1, Centers for Medicare & Medicaid Services. Long-Term Care Facility Resident Assessment Instrument 3.0 User s Manual. Version MDS-30-RAI-Manual-V113.pdf. Published October 1, Accessed July 1, CMS Requirements Provide Important Guidance Relevant to Antipsychotic Agents When initiating or continuing an antipsychotic for a resident with PD psychosis, ask yourself: Ø Is this drug clinically indicated for this specific condition? Ø Have the goals of antipsychotic therapy been clearly identified and documented? Ø What adverse effects might this drug cause? F757 and F758 Unnecessary Drugs and Psychotropic Drugs Ø Is this drug the standard of practice for this specific condition? Ø Is this drug the least restrictive alternative to treat the resident s symptoms? Ø Will this drug help the resident to function at his/her highest possible level? F605 Chemical Restraints CMS: Centers for Medicare & Medicaid Services. Centers for Medicare & Medicaid Services. State operations manual: appendix PP - guidance to surveyors for long term care facilities. Guidance/Guidance/Manuals/downloads/som107ap_pp_guidelines_ltcf.pdf. Updated November 28, CMS Requires Gradual Dose Reductions for Psychotropic Medications Gradual dose reductions must be considered and attempted: PDP is a progressive and Twice in the first year enduring condition that may Annually thereafter need treatment indefinitely. Continued use is in accordance with relevant current standards of practice OR The resident s target symptoms returned or worsened after the most recent attempt at tapering the dose within the facility A GDR may be contraindicated if: AND The physician has documented the clinical rationale for why an attempt at a dose reduction would be likely to impair the resident s function or cause psychiatric instability by exacerbating an underlying medical or psychiatric disorder Centers for Medicare & Medicaid Services. State Operations Manual. Appendix PP - Guidance to Surveyors for Long Term Care Facilities. Updated June 10, Accessed July 1,

19 Question 4/Are we Awake? Neuropsychiatric symptoms of PD include all of the following, except: a. Depression b. Orthostatic hypotension c. Insomnia d. Dementia e. Psychosis 19