6/19/18. Objectives. Disclosures. Parkinson s Disease Psychosis Treatment in Long-Term Care: Clinical and Operational Considerations

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1 Parkinson s Disease Psychosis Treatment in Long-Term Care: Clinical and Operational Considerations Dana Saffel, PharmD, BCGP, CPh, FASCP President, CEO PharmaCare Strategies, Inc. June 24, 2018 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 Disclosures Dana Saffel, PharmD, BCGP, CPh, FASCP President, CEO PharmaCare Strategies Acadia Pharmaceuticals Consultant, speaker Astellas Pharmaceuticals Consultant Axovant Pharmaceuticals Consultant Mylan Pharmaceuticals Consultant Sunovion Pharmaceuticals Consultant, speaker 3 1

2 6/19/18 Types of Dementias 1 Alzheimer s 2 Vascular 3 Lewy Body 4 Differentiating Top Three Dementias Dementia Alzheimer s dementia Vascular dementia Lewy body dementia Clinical Features Pathology Insidious onset Apathy & depression common Memory deficit Aphasia Apraxia Agnosia Beta-amyloid plaques Tau Tangles Sudden onset Memory deficit Memory deficit Fluctuating impairment Psycosis () Extrapyramidal symptoms Neurological Image Vacuoles Alpha-synuclein (Lewy) bodies 5 Alzheimer s Association. Accessed April 23, 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 6 2

3 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 Recommend diagnosing dementia with Lewy bodies and Parkinson's dementia as separate disorders The diagnosis is Parkinson's disease dementia when: Person is originally diagnosed with Parkinson's based on movement symptoms, and Dementia symptoms don't appear until a year or more later The diagnosis is dementia with Lewy bodies when: Dementia symptoms appear within one year after movement symptoms, or Both dementia symptoms and movement symptoms are present at the time of diagnosis, or Movement symptoms develop within a year of a dementia with Lewy bodies diagnosis 7 Alzheimer s Association. Accessed April 23, Clinical Symptoms and Time Course of Parkinson s Disease Pre-motor/prodromal period Parkinson s disease diagnosis Degree of Disability Early Bradykinesia Rigidity Tremor Fluctuations Dyskinesia Advanced/ late Psychosis Dysphagia Postural instability Freezing of gait Falls Complications Motor Constipation RBD EDS Hyposmia Depression Pain Fatigue MCI Urinary symptoms Orthostatic hypotension Dementia Nonmotor Time (years) 1. Image adapted from Kalia LV, Lang AE. Lancet. 2015;386: PD is Commonly Thought of as a Movement Disorder Cardinal symptoms Resting tremor Rigidity Slowness of movement Gait disturbances/ postural instability You may recognize residents with PD by their motor symptoms 1-3 Other common motor symptoms Mask-like expression Soft voice Drooling Reduced blinking Shuffling steps Freezing/falling Small handwriting... or by the medicines they take 4-9 (eg, carbidopa/levodopa, ropinirole, pramipexole, entacapone, amantadine) Typical appearance of a person with PD 1,3 Tremor Mask-like face Tremor Stooped posture Rigidity Hips and knees slightly flexed Short shuffling steps 1. Olanow C et al. In: Kasper D et al, eds. Harrison s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; mhmedical.com/content.aspx?bookid=1130&sectionid= Accessed July 1, Srivanitchapoom P et al. Parkinsonism Relat Disord. 2014;20(11): National Institute of Neurological Disorders and Stroke. Parkinson s disease backgrounder. parkinsons_disease/parkinsons_disease_backgrounder.htm. Updated October 18, Accessed February 24, Zarowitz BJ et al. Pharmacist. 2013;28(9): SINEMET Prescribing Information. Morgantown, WV: Merck &Co.; REQUIP XL Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; MIRAPEX Prescribing Information. Ridgefield, CT: Boehringer Ingelheim; COMTAN Prescribing Information. East Hanover, NJ: Novartis; Amantadine Hydrochloride Prescribing Information. Princeton, NJ: Sandoz Inc.;

4 Parkinson s Disease (PD) is More Than Motor Symptoms Motor Symptoms 1 Nonmotor Symptoms 2 Bradykinesia Resting tremor Rigidity Gait disturbance/postural instability Small writing (micrographia) Masked facies (hypomimia) Reduced eye blink Soft voice (hypophonia) Dysphagia Dyskinesia Freezing Cardiovascular (including falls) Sleep/fatigue Mood/cognition Perceptual problems/ Attention/memory Gastrointestinal tract Urinary Sexual dysfunction Miscellaneous (i.e., pain, changes to taste/smell) 1. Olanow CW, et al. Parkinson s disease and other movement disorders. In: Kasper DL, Fauci AS, Hauser SI, Longo DI, Jameson EL. Localzo J. eds. Harrison s Principles of Internal Medicine. 19 th ed. New York, MY: McGraw-Hill, Accessed March 2, Chaudheri KR, et al. Mov Disord (13): Hallmark Neuropathology of Parkinson s Disease (PD) PD is characterized by a loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies Normal Parkinson s control disease Reduction of pigment in substantia nigra in PD Lewy bodies within melanized dopamine neurons in PD Reduced number of cells in substantia nigra in PD 1. Olanow CW, et al. In: Kasper DL, et al, eds. Harrison s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; Accessed March 2, All images are artistic representations. 11 Lewy Bodies Are Not Limited to the Substantia Nigra Lewy bodies are also found outside of the substantia nigra in many cortical regions in later stages of the disease 1 Lewy body pathology in stage 2 affects the raphe nuclei 1 Serotonergic neurons are the major constituents of the raphe nuclei and project from this region throughout the brain 2 1. Braak H, et al. Neurobiol Aging. 2003;24(2): Stahl SM. 4th ed. New York, NY: Cambridge University Press; Braak Stages in the Evolution of PD-related Pathology 1 Lesions in the dorsal IX/X motor nucleus and/or intermediate reticular zone 1 + Lesions in the caudal raphe nuclei, gigantocellular reticular nucleus, and coeruleussubcoeruleus complex 2 + Midbrain lesions, in particular in the pars compacta of the substantia nigra 3 + Prosencephalic lesions, cortical involvement confined to the temporal mesocortex and allocortex 4 + Lesions in high order sensory association areas of the neocortex and prefrontal neocortex 5 + Lesions in first-order sensory association areas of the neocortex and premotor areas, occasionally mild changes in primary sensory areas and the primary motor field 12 4

5 PD Is More Than the Loss of Dopaminergic Neurons in the Substantia Nigra In many brain regions, only 50% to 75% of the serotonergic neurons in healthy controls are present in patients with PD Upregulation of 5-HT 2A receptors in several brain regions may be an additional compensatory mechanism Loss of Neurons Compared to Controls Loss of Both Dopaminergic and Serotonergic Neurons Compared to Healthy Controls P: putamen; C: caudate; SN: substantia nigra; Pa: pallidum; PG: parolfactory gyrus; VTA: ventral tegmental area; NA: nucleus accumbens; Hip: hippocampus; Hyp: hypothalamus; A: amygdala; FC: frontal cortex; CC: cingular cortex; EC: entorhinal cortex; LC: locus coeruleus; AP: area postrema; SC: spinal cord; RN: raphe nuclei 1. Lang AE, et al. Lancet Neurol. 2004;3: Serotonin Dysfunction Includes Reduced Serotonin Transporter Binding in PD Serotonin transporter (SERT) binding was reduced in PD with the greatest reductions in the forebrain compared to control 1 Percent of Control 40%-50% 30%-35% ~20% Cingulate cortices, insula Amygdala, hippocamp us, basal ganglia, thalami, rostral brainstem nuclei Caudal brainstem structures Normal Control Parkinson s Disease PD patients show reduced serotonin transporter (SERT) binding with the greatest reductions in the forebrain 1 * Normal Control A reduced density of SERT in PD in the caudate and putamen have also been correlated with disease stage 2 Parkinson s Disease 1. Albin RL, et al. J Cereb Blood Flow Metab. 2008;28: Kerenyi L, et al. Arch Neurol. 2003;60(9): *Albin RL, Koeppe RA, Bohnen NI, Wernette K, Kilbourn MA, Frey KA, Journal of Cerebral Blood Flow & Metabolism (28) pp , Copyright 2008 by (ISCBFM). Reprinted by Permission of SAGE Publications, Ltd. 14 Serotonin Dysfunction is Linked to Motor and Nonmotor Symptoms 1. Doder M, et al. Neurology. 2003;60(4): Iravani MM, et al. J Pharmacology and Experimental Therapeutics. 2006;319(3): Tong Q, et al. Park Relat Disord. 2015;21: Joling M, et al. J Neurol Neurosurg Psychiatry. 2018;89: Paulus W, et al. J Neuropath Exper Neurology. 1991;50(6): Levodopainduced dyskinesia 2 Tremor 1 Psychosis 7 Constipation 8-10 Depression 3,5,6 Anxiety 4 1. Mayeux R, et al. Am J Psychiatry. 1986;143: Stahl SM. 4th ed. New York, NY: Cambridge University Press; Matsuyama S, et al. J Pharmacology Exp Ther. 1996;276(3): Taniyama K, et al. J Pharmacology Exp Ther. 1991;258(3): Liu Z, et al. Mov Disord. 2005;20(6):

6 PARKINSON S DISEASE PSYCHOSIS 16 Three Neurotransmitter Pathways Have Been Linked to Psychosis There are 3 interconnected pathways that are believed to be linked to 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: 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 18 6

7 Pharmacological Models Link To Psychosis Pharmacological models link dopamine (D2), serotonin (5-HT 2A) receptor agonists and NMDA receptor antagonists to psychosis symptoms Psychostimulants 1,2 (cocaine, amphetamine) Dissociative Anesthetics 1,3 (PCP, ketamine) Psychedelics 1,4,5 (LSD, psilocybin) Proposed mechanism D2 agonist NMDA antagonist 5-HT 2A agonist (and to a lesser extent 5- Main type of Most frequently associated delusions HT 2C) Auditory Visual Visual Paranoid Paranoid Mystical Insightfulness No No Yes PDP is associated with mainly visual, and persecutory or jealousy delusions; often insight is retained early but lost later in the course of the disease Rolland B, et al. BioMed Res Int Article ID Mahoney JJ 3rd, et al. Am J Addict. 2008;17(2): Powers AR, et al. Psychopathology. 2015;48(6): Carhart-Harris RL, et al. Proc Natl Acad Sci U S A. 2016;113(17): Griffiths RR, et al. J Psychopharmacol. 2008;22(6): Ravina B, et al. Mov Disord. 2007;22: Goetz CG, et al. Arch Neurol. 2006;63: Fénelon G, et al. Mov Disord. 2010;25(6): Voss T, et al. Parkinsonism Relat Disord. 2013;19: Visual Hallucinations With Psychedelics Are Blocked With 5-HT 2 But Not D2 Receptor Antagonists Psychedelics are thought to function primarily as 5-HT 2 * agonists 1,2 Like PDP, psychedelics result in predominantly visual 3,4 Interestingly, the firstgeneration antipsychotic haloperidol is unable to block the effects of the psychedelic psilocybin but a 5-HT 2 * antagonist was, in particular with regard to visual 5 1. Egan CT, et al. Psychopharmacology. 1998;136: Arvanov VL, et al. Eur J Neurosci. 1999;11: Carhart-Harris RL, et al. Proc Natl Acad Sci U S A. 2016;113(17): Ravina B, et al. Mov Disord. 2007;22: Vollenweider FX, et al. Neuroreport. 1998;9(17): Presynaptic serotonergic neuron 5-HT 2A receptors Postsynaptic neuron 5-HT = 5-HT 2* agonist *5-HT 2A and to a lesser extent 5-HT 2C 20 Dopamine Theory of Psychosis: Lewy bodies are found in the substantia nigra, resulting in dopamine hypofunction in the dorsal striatum This hypofunction leads to motor symptoms such as akinesia, rigidity, and tremor When L-dopa is given, it increases dopamine in the striatum The dorsal striatum dopamine deficiency is restored However, too much dopamine in the ventral striatum could result in symptoms of psychosis L-DOPA Raphe Cerebral Cortex GAB A Glutamate Striatum Dorsal Ventral Substantia Nigra Visual Temporal Motor Prefrontal akinesia rigidity tremor delusions, auditory Ventral Tegmental Area = Lewy body 21 7

8 Serotonin Theory of Psychosis = Alzheimer's amyloid plaques and tangles Up-regulated 5-HT 2A receptors on glutamate neurons are presumed to increase signaling to the VTA Increased signaling to the VTA results in excess dopamine release in the ventral striatum Delusions and auditory are associated with hyperactivity of the ventral striatum Raphe Cerebral Cortex Visual 5HT2A 5HT2A 5HT2A Temporal Motor GAB Prefrontal A Glutamate Striatum Dorsal Ventral Substantia Nigra akinesia rigidity tremor delusions, auditory Ventral Tegmental Area = Lewy body visual 22 Psychosis Ameliorated with 5-HT 2A Antagonist Cerebral Cortex = Lewy body = Alzheimer's amyloid plaques and tangles = 5-HT2A antagonist Raphe 5HT 2A 5HT 5HT 2A 2A GAB A Glutamate Striatum Dorsal Ventral Substantia Nigra Visual Temporal Motor Prefrontal akinesia rigidity tremor delusions, auditory visual Ventral Tegmental Area 23 The NMDA Theory of Psychosis Excess glutamate signaling in the cerebral cortex, particularly the visual cortex, is thought to be associated with visual Glutamate GABA Glutamate Cerebral Cortex Visual Temporal Motor Prefrontal Striatum - Ventral Hallucinations Delusions Mesolimbic mesolimbic Ventral Tegmental Area 1. Stahl SM. 4th ed. New York, NY: Cambridge University Press;

9 PDP Proposed Mechanism of Disease Loss of serotonin neurons projecting from the raphe is thought to result in reduced serotonin activity in the cortex which in turn may lead to compensatory upregulation of 5-HT 2A receptors 1-4 Glutamate hyperactivity Upregulation of the mesolimbic dopamine pathway The proposed mechanism of disease for PDP suggests that symptoms of psychosis may be the result of an interaction between all 3 theories of psychosis 2 Glutamate 5-HT 2a GABA Glutamate Striatum - Ventral Cerebral Cortex Visual Temporal Motor Prefrontal Hallucinations Delusions Mesolimbic mesolimbic Ventral Tegmental Area 1. Stahl SM. 4th ed. New York, NY: Cambridge University Press; Summary Several classes of atypical antipsychotics (Pines and Dones) have a higher affinity for the 5-HT 2A receptor as compared to the D 2 receptor The interplay between glutamate, dopamine and serotonin mediates the symptoms of psychosis Serotonin plays a key role in the pathophysiology of PDP Antagonizing the 5-HT 2A receptor reduces psychosis by normalizing glutamatergic and dopaminergic activity 26 Psychosis is a Non-Motor Symptom of Parkinson s Disease Psychosis A brain disorder characterized by 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):

10 Visual Hallucinations are the Most Common Symptom of PDP Auditory 0% to 22% Hearing voices conversing Hearing music Olfactory ~11% Visual 16% to 72% Seeing people or animals Illusions Presence Delusions 1% to 14% Jealous Persecutory Reference Symptoms of PDP 1-4 Gustatory ~3% Tactile ~12% Somatic ~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): PDP Is Distinct From Other Psychotic Conditions More than 50% of people with PD will develop PDP during the course of their disease provisional NINDS-NIMH diagnostic criteria for PDP 2 Symptoms Other causes excluded Associated features Requires the presence of at least 1 of the following symptoms: Hallucinations Delusions Illusions False sense of presence Must occur in people with previously diagnosed PD Must be recurrent or continuous for at least 1 month Exclusions Delirium Schizophrenia Alzheimer s disease psychosis Major depression with psychosis Other psychiatric disorders May occur with or without: Insight Dementia PD treatment NINDS-NIMH, National Institute of Neurological Disorders and Stroke National Institute of Mental Health. 1. Forsaa EB et al. Arch Neurol. 2010;67(8): Ravina B et al. Mov Disord. 2007;22(8): PDP Is Associated With Hospitalizations, Nursing Home Placement, and Caregiver Burden PD patients with 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:

11 SELECTING APPROPRIATE ANTIPSYCHOTIC TREATMENT FOR PDP 31 Question 3 What makes an antipsychotic atypical? a. Discovered after 1995 b. Serotonin 2a receptor affinity is more potent than dopamine receptors c. Dopamine receptors affinity is more potent than serotonin receptors d. Indication as adjunctive treatment for resistant depression. 32 Antipsychotic Receptor Binding Properties Muscarinic Acetylcholine Receptors: M1 M2 M3 M4 Histamine Receptors: H1 Adrenergic Alpha Receptors: a1 a 2A a 2B a 2C Transporters D2 SERT NET Serotonin Receptors: 5HT1A 2A 1B 1D 2B 2C 1E Dopamine Receptors: D1 D2 D3 D4 1. Stahl SM. Stahl s Essential Psychopharmacology. 4th ed

12 5-HT 2A Binding by Pines D2 clozapine olanzapine quetiapine asenapine 1. Stahl SM. Stahl s Essential Psychopharmacology. 4th ed HT 2A Binding by Pines clozapine 5HT2A D2 olanzapine 5HT2A quetiapine asenapine 5HT2A 5HT2A More Potent than D 2 Less Potent than D 2 1. Stahl SM. Stahl s Essential Psychopharmacology. 4th ed HT 2A Inverse Agonist/Antagonist Activity Predicts Atypical Antipsychotics Preference for 5-HT 2A over D 2 5-HT 2A EC 50 D 2 K i Adapted from Weiner DM, et al. J Pharmacol Exp Ther. 2001;299(1):

13 Hypothetical Thresholds For Atypical Antipsychotic Drug Effects Striatal D 2 receptor blockade (%) Stahl SM. Stahl s Essential Psychopharmacology. 4th ed standar d dose dose for pharmacokinetic failure Dose; plasma concentration pharmacokinetic failure: below usual threshold at standard doses usual EPS and hyperprolactinemia threshold usual antipsychotic effect threshold 37 Question 4: Which Medications Have Demonstrated Efficacy in Treating PDP? a. Clozapine b. Pimavanserin c. Quetiapine d. a & b e. All of the above 38 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

14 Binding Profile of Quetiapine at Different Doses Papa Bear Mama Bear Baby Bear 800 mg 300 mg 50 mg antipsychotic antidepressant hypnotic 1. Stahl SM. Stahl s Essential Psychopharmacology. 4th ed Pimavanserin Is Selective for Serotonin (5-HT 2A ) Receptors 5-HT 5-HT 2A 1. NUPLAZID Prescribing Information 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 Placebo % improvement NUPLAZID 34 mg in psychosis (P=0.0014) 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 1. NUPLAZID Prescribing Information. 2. Cummings J, et al. Lancet. 2014;383: % improvement in psychosis Secondary endpoint: change from baseline to week 6 in UPDRS Parts II+III 1 Change From Baseline in UPDRS Parts II+III Scores (LSM) NUPLAZID mg mg -1.4 Placebo

15 Pimavanserin Is Effective in Treating PDP Pimavanserin 34mg effectively alleviated symptoms of psychosis with a point change from baseline vs with placebo 1,2 SAPS-PD change from baseline score (LSM+SE) Placebo n=90 NUPLAZID 34 mg n=95 Baseline Week 2 Week Week 6 Results from a phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel-group study of patients with PDP (N=199). Primary endpoint was change in baseline in the 9-item SAPS-PD. Baseline mean values were 15.9 for NUPLAZID and 14.7 for placebo. Doses of PD medications taken prior to baseline were required to be stable 30 days prior to study start and throughout the study period. Although the primary endpoint was designed to measure change from baseline to Week 6, a statistically significant difference between NUPLAZID and placebo was observed at Week 4 (P=0.0369). 2 LSM, least-squares mean; SE, standard error. 1. NUPLAZID Prescribing Information. San Diego, CA: ACADIA Pharmaceuticals Inc.; Cummings J et al. Lancet. 2014;383(9916): IMPROVEMENT 14% Placebo 37% NUPLAZID 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 placebo-treated 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. NUPLAZID Prescribing Information. San Diego, CA: ACADIA Pharmaceuticals Inc.; 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 and delusions associated with Parkinson s disease psychosis Pimavanserin has an adjusted boxed warning, specific to the Parkinson s disease demographic

16 Treatment Summary The 5-HT 2A receptor has been shown to play a significant role in mediating psychosis By acting via 5-HT 2A receptors, atypical antipsychotics like pimavanserin help to normalize glutamatergic and dopaminergic transmission in the cortex and striatum, respectively Pimavanserin is selective for serotonin receptors, thus minimizing offtarget effects Pimavanserin shows significant improvement in SAPS-PD Over a 6 week period, PD patients taking NUPLAZID showed significant improvement from baseline This indicates that 5-HT 2A may serve as an efficacious therapeutic option for psychosis in PD 46 OTHER CONSIDERATIONS WHEN TREATING PDP 47 Managing Hallucinations and Delusions in Residents with PDP Hallucinations or delusions in a resident with PD 1 Full medical evaluation If no underlying cause identified Minimize non-pd medications that could cause psychosis If no improvement of symptoms Treat any underlying medical causes of psychosis Adjustment of PD medications If no improvement of symptoms or worsening of motor symptoms Pimavanserin is the first and only FDA-approved treatment for and delusions associated with PDP 2 Initiation of antipsychotic medications FDA, US Food and Drug Administration. 1. Goldman JG et al. Expert Opin Pharmacother. 2011;12(13): NUPLAZID Prescribing Information. San Diego, CA: ACADIA Pharmaceuticals Inc.;

17 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): Monitoring for PDP in Nursing Facilities REVIEW the medical record 7-day look-back period INTERVIEW caregivers Staff members and others who have observed the resident in a variety of situations OBSERVE the resident During conversations and structured interviews in other assessments Listen for statements indicating an experience of or the expression of false beliefs CLARIFY potential false beliefs CMS outlines steps for assessing psychosis in nursing facility residents Verify facts Determine if false beliefs can be readily corrected Observe the resident s responses to potential alternative explanations CMS, Centers for Medicare & Medicaid Services. 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, 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 Assessment-Instruments/ 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: Twice in the first year Annually thereafter 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 PDP is a progressive and enduring condition that may need treatment indefinitely. 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,

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