#CHAIR2016. September 15 17, 2016 The Biltmore Hotel Miami, FL. Sponsored by

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1 #CHAIR2016 September 15 17, 2016 The Biltmore Hotel Miami, FL Sponsored by

2 #CHAIR2016 Parkinson s Disease Psychosis: The Latest Evidence for Screening and Treatment Stuart Isaacson, MD FIU Herbert Wertheim College of Medicine Boca Raton, FL

3 Stuart Isaacson, MD Disclosures Research/Grants: ACADIA Pharmaceuticals Inc. Consultant: ACADIA Pharmaceuticals Inc. Speakers Bureau: ACADIA Pharmaceuticals Inc.

4 #CHAIR2016 Learning Objective 1 Screen all Parkinson s disease (PD) patients for neuropsychiatric symptoms, such as psychosis, at regular intervals.

5 #CHAIR2016 Learning Objective 2 Engage patients and caregivers to develop strategies to help manage the impact of PD psychosis on daily functioning.

6 #CHAIR2016 Learning Objective 3 Describe the current best practice and emerging treatment approaches for the clinical management of PD psychosis.

7 Parkinson s Disease: Introduction Parkinson s disease (PD) is the second most common neurodegenerative disorder and affects about 1 million persons in the US While PD is known for its motor symptoms, many nonmotor neuropsychiatric symptoms occur such as sleep, cognitive, and autonomic dysfunction Non-motor symptoms have a significant impact on quality of life Jankovic J. J Neurol Neurosurg Psychiatry. 2008;79(4): Bernal-Pacheco. O, et al. Neurologist. 2012;18(1):1-16.

8 Overview A single cause for PD has not been found Involves selective degeneration of the nigrostriatal pathway with reduction in the striatal concentration of dopamine Many non-motor features of PD relate to degeneration of non-dopaminergic transmitter systems, including norepinephrine and serotonin Obeso JA, et al. Nat Med. 2010;16(6): Lang AE, et al. Lancet Neurol. 2004;3(5):

9 Decline of Striatal Dopamine Innervation Striatal dopamine innervation assessed by 18 F-dopa PET Controls (n = 8) Patient with PD Obeso JA, et. al. Nat Med. 2010;16(6):

10 Parkinson s Disease Therapies The range of pharmacologic therapies for PD is wider than other neurodegenerative diseases Levodopa Dopamine agonists Monoamine oxidase (MAO) B inhibitors Catechol-O-methyl transferase (COMT) inhibitors Anticholinergic agents Amantadine Connolly BS,. Lang AE. JAMA. 2014;311(16):

11 Motor and Non-Motor PD Symptoms Motor Symptoms Resting tremor Rigidity Bradykinesia Postural instability Festinating gait Micrographia Masked facies Retropulsion Hypophonic speech Non-motor Symptoms Constipation Autonomic dysfunction Impaired olfaction Dementia Depression Sleep disorders Impulse control disorders Psychosis Jakel RJ, Stacy. M. Journal of Parkinsonism and Restless Legs Syndrome. 2014;4:41-51.

12 Parkinson s Disease: Neuropsychiatric Disorder? Anxiety Depression Executive function, cognitive impairment, dementia Apathy Compulsive disorders PD psychosis ***Affects QOL and associated with significant burden on patients, families, and caregivers Forsaa EB, et al. Arch Neurol. 2010;67(8): Schrag A, et al. Parkinsonism Relat Disord. 2006;12(1):35-41.

13 PD Psychosis is Underreported Only 10% to 20% of patients spontaneously report symptoms to the physicians Patients may be reluctant to disclose their psychosis symptoms due to stigma and fear of hospitalization Patients may not be aware that psychosis symptoms are due to their Parkinson s disease Caregivers may be unaware of symptoms until they become distressful Chaudhuri KR, et al. Mov Disord. 2010;25(6): Fénelon G, et. al. J Neurol Sci. 2010;289(1-2):12-17.

14 Incidence of PD Psychosis Population-based prevalence cohort study (n = 230) PD patients followed prospectively for 12 years Point prevalence was 17.8% at baseline and increased to 48% at 12 years 60% of patients developed PD psychosis over the course of their disease Incidence of PD psychosis was 79.7 per 1,000 personyears Forsaa EB, et. al. Arch Neurol. 2010;67(6):

15 Prevalence of Hallucinations in PD Reference n Total Prevalence (%) Williams et al, Pacchetti et al, Paleacu et al, Bailbé et al, Schrag et al, Fénelon et al, Aarsland et al, Inzelberg et al, Graham et al, Sanchez-Ramos et al, Fénelon G. CNS. Spectr. 2008;13(3 suppl 4):18-25.

16 Risk Factors for PD Psychosis Risk Factor Advancing age Cognitive decline Duration and severity of illness Severity of illness Treatment with dopaminergic agonists Presence of sleep disorders Presence of other psychiatric conditions (apathy, depression) Jakel RJ, Stacy M. Journal of Parkinsonism and Restless Legs Syndrome. 2014;4:41-51.

17 Pathophysiology of PD Psychosis Multiple neurochemical and neuropsychological abnormalities; no single brain structure involved Sleep dysregulation, sleep fragmentation, and altered dream phenomena Abnormalities of visual processing may contribute to hallucinations Latoo J, et al. Prog Neurol Psychiatry. 2012;16(5):4-35. Arnuf I, et al.. Neurol. 2000;55(2): Wint DP, et al. J Geriatr Psychiatry Neurol. 2004;17(3):

18 Intrinsic and Extrinsic Dimensions of PD Psychosis INTRINSIC EXTRINSIC Visual dysfunction Environment Neurochemical abnormalities Brainstem/ sleep dysfunction Cortical pathology PD Psychosis PD medications Other psychiatric conditions Hindle JV. J Neural Transm. 2013;120(4):

19 Pathophysiology of PD Psychosis: Neurotransmitters Excessive dopaminergic activity, particularly in the mesocortical and mesolimbic systems contributes to hallucinations Dopamine is not the only factor (drug-naive patients with PD report hallucinations) Serotonin is disrupted in PD, with extensive loss of serotonergic raphe neurons The role of acetylcholine is under investigation; marked degeneration of cholinergic neurons is evident in brains of patients with PD Wint DP, et al.. J Geriatr Psychiatry Neurol. 2004;17(3):

20 Serotonin is Disrupted in PD The serotonergic system is disrupted in PD Patients with PD have reduced serotonin transporter binding PD = Parkinsons disease NC = Normal control Albin RL, et al.. J Cerebral Blood Flow Metab. 2008;28:

21 Mechanisms Of Visual Hallucinations in Parkinson s Disease Complex visual hallucinations are probably related to abnormal activity in the ventral extrastriate visual cortex May result from various and concomitant mechanisms including Dopaminergic overactivity Overactivity and/or imbalance in monaminergic and cholinergic neurotransmission Alteration of brain stem wake and dream regulation Dysfunction of visual pathways Nonspecific coincidental ocular disease such as Parkinson s diseaseassociated retinal dysfunction and functional alterations in the ventral stream of visual cortical pathways Fénelon G. CNS. Spectr. 2008;13(3 suppl 4):18-25.

22 Prevalence of Psychosis Symptoms Symptom Fénelon G, et al. Mov Disord. 2010;25(6): Fénelon G, et al. J Neurol Sci. 2010;289(1-2): Prevalence Visual hallucinations 16% to 38% Illusions, passage, presence 17% to 72% Auditory hallucinations 0% to 22% Delusions (reference, persecutory, jealousy) 1% to 14% Tactile hallucinations 12% Olfactory hallucinations 11% Gustatory hallucinations 3% Somatic hallucinations 1%

23 The Concept of Benign Hallucinations is Misleading Study of 48 patients with benign hallucinations and Unified Parkinson s Disease Rating Scale (UPDRS) scores during 3 yr follow-up Goetz CG, et al. Arch Neurol. 2006;63(5): % of patients progressed to UPDRS scores of 3 or 4 Progression of PD from a baseline UPDRS score of 2 (benign hallucinations, insight retained) to a UPDRS score of 3 or 4 (loss of insight, delusions)

24 The Course of PD Psychosis Hallucinations begin Insight is retained Hallucinations progress Insight is lost Onset of delusions. Nursing home placement Aarsland D, et al. J Am Geriatr Soc. 2000;48(8): ; Chaudhuri KR, et al. Lancet Neurol. 2006;5(3): ;Goetz CG, et al. Arch Neurol. 2006;63(5): ; Jakel RJ, Stacy M. Journal of Parkinsonism and Restless Legs Syndrome 2014;4:41-51.

25 Phenomenology: Visual Hallucinations Usually persons (living or deceased) May be animals or objects Superimposed on real background Moving or blurred Appear suddenly Usually vanish rapidly Patient usually observer rather than actor Fénelon G. CNS Spectr. 2008;13(3 suppl 4):18-25.

26 Phenomenology: Auditory Hallucinations Elementary (ringing, knocks, etc) or complex Verbal, usually neutral or incomprehensible Conversations of unreal persons Differ from those of schizophrenia not pejorative or threatening Fénelon G. CNS Spectr. 2008;13(3 suppl 4):18-25.

27 Phenomenology: Other Hallucinations Tactile Contact with small animals Being touched by someone Often combined with other types of hallucinations Olfactory and gustatory Illusions (mistaken identification of actual stimuli) Presence or passage (perception of object or person in visual periphery) Fénelon G. CNS Spectr. 2008;13(3 suppl 4):18-25

28 Differential Diagnosis of PD Psychosis Medical conditions Delirium Infection Drug toxicity Dehydration Nutritional deficiencies Thyroid dysfunction Psychiatric conditions Schizophrenia Major depression with psychosis Bipolar disorder with psychosis Neurodegenerative conditions Lewy body dementia Alzheimer s disease psychosis Ravina B, et. al. Mov Disord. 2007;22(8):

29 NINDS-NIMH Diagnostic Criteria Characteristic symptoms of psychosis (at least 1) Illusions False sense of presence Hallucinations Delusions Characteristic symptoms of PD Chronology: Symptoms of psychosis must occur after diagnosis of PD Duration: Symptoms of psychosis must be recurrent or continuous for 1 mo. Other potential causes must be eliminated Associated features Insight Dementia Anti-parkinson medications Ravina B, et al. Mov Disord. 2007;22(8):

30 Managing PD Psychosis Medication review and evaluate systemic triggers Urinary and other infections, dehydration, sleep change Adjust parkinsonian medications Suggested sequence: anticholinergics, amantadine, selegiline, dopamine agonists Important consequence of PDP is suboptimal motor treatment! Antipsychotics may be helpful but may be associated with worsening of motor function Pimavanserin is the only medication approved by the FDA for Parkinson s psychosis Jakel RJ, Stacy M. Journal of Parkinsonism and Restless Legs Syndrome 2014;4:41-51.

31 Antipsychotic Adverse Effects Atypical antipsychotics have black box class warning for increased mortality in elderly with dementia Efficacy unclear for PDP, except for clozapine and pimavanserin Antipsychotics can cause postural hypotension and sedation All current antipsychotics (except pimavanserin) block post synaptic D2 receptors and can worsen motor Parkinsonism Friedman PD, et al. N Engl J Med. 1999;340(10): Jakel RJ, Stacy M. Journal of Parkinsonism and Restless Legs Syndrome 2014;4:41-51

32 Richard IH, Nutt J. Neurology. 2000;55(6):

33 Movement Disorder Society EBM Recommendations Agent Clozapine Quetiapine Olanzapine Recommendation Efficacious, acceptable risk with specialized monitoring (risk of agranulocytosis) Insufficient evidence for efficacy, acceptable risk without specialized monitoring Unlikely to be efficacious with unacceptable risk (worsening movement symptoms) Seppi K, et al.. Mov Disord. 2011;26(Suppl 3):S42-S80

34 Clozapine* Efficacy Experimental Study or Subgroup Mean s.d. Total Control Mean s.d. Total Weight (%) Mean Difference IV, Random, 95% Cl Mean Difference IV, Random, 95% Cl Parkinson Study Group [-1.24, -0.96] Pollack [-1.76, -0.24] Total (95% Cl) [-1.23, -0.96] Heterogeneity: Tau 2 = 0.00; χ 2 = 0.06, df = 1 (P = 0.80); I 2 = 0% Test for overall effect: Z = (p <.00001) Favours [experimental] Favours [control] Clozapine associated with agranulocytosis in ~1% of patients; requires regular blood monitoring *Not FDA approved for the treatment of PDP. Friedman PD, et al. N Engl J Med. 1999;340(10): Pollak P, et al. J Neurol Neurosurg Psychiatry. 2004;75(5):

35 Quetiapine* Efficacy Study N Outcomes Morgante et al, Significant improvement in BPRS and CGI-S (P<0.001 for each); no significant improvement in UPDRS Ondo et al, No significant improvement in BPRS or BPDHQ Merims et al, Significant improvement CGIC (P<0.05) Rabey et al, No significant improvement in BPRS or CGI-S Kurlan et al, No significant improvement in BPRS Fernandez et al, Significant improvement in CGI-S or BPRS (P<0.05) Shobolt P et al, No significant improvement in BPRS or BPDHQ BPRS = Brief Psychiatry Rating Scale; CGI-S = Clinical Global Impression Scale-Severity Subscale; BPPHQ = Baylor Parkinson s Disease Hallucination Scale; CGIC = Clinical Global Impression of Change *Not FDA approved for the treatment of PDP Desmarais P, et al. J Geriatr Psychiatry Neurol. 2016;29(4):

36 Pimavanserin Clinical Study Pimavanserin is a selective serotonin inverse agonist High affinity for 5-HT2A; no appreciable affinity for dopaminergic, muscarinic, histaminergic, or adrenergic receptors Placebo controlled, randomized, parallel group of 199 patients with PD psychosis that evaluated pimavanserin 40 mg or placebo Symptoms of 1 mo. duration, at least weekly Primary endpoint change from baseline in Scale for Assessment of Positive Symptoms-PD (SAPS-PD) Only FDA-approved treatment for PD psychosis Cummings J et, al. Lancet. 2014;383(9937):

37 Inverse Agonists Have Negative Intrinsic Activity Hanania NA. Curr Opin Pulm Med. 2010;16:1-5.

38 SAPS-PD The Scale for Assessment of Positive Symptoms (SAPS) is reliable in PD populations and is recommended for use in PD psychosis SAPS is a structured clinical interview and covers 35 items; originally developed for schizophrenia A shortened, 9-item PD-specific version of SAPS is appropriate for assessing PD psychosis (SAPS-PD) Voss T, et al. Parkinsonism Relat Disord. 2013;19(3):

39 Pimavanserin: SAPS-PD Change from Baseline Pimavanserin resulted in a significant 37% improvement in SAPS-PD vs 14% for placebo (p = 0.006) No change in motoric function by UPDRS (parts 2 + 3) UPDRS = Unified Parkinson s Disease Rating Scale Cummings J, et al. Lancet. 2014;383:

40 Primavanserin: CGI Change From Baseline Significant improvements were observed in CGI-S and CGI-I scores CGI-S Cummings J, et al. Lancet. 2014;383: CGI-I 41

41 Primavanserin vs Placebo AE s Occurring in 5% in Either Group Adverse Event (AE) Placebo (n = 94) Pimavanserin (n = 104) Nausea 6% 6% Peripheral edema 3% 7% Urinary tract infection 12% 13% Fall 9% 11% Confusional state 3% 6% Headache 5% 1% Hallucination 4% 7% Cummings J, et al. Lancet. 2014;383:

42 Patient and Caregiver Disclosure Patients and caregivers may be hesitant to disclose symptoms of psychosis Important to ask about symptoms at each visit and early in the disease process Patients need education about PD psychosis symptoms and their relationship to PD Asking appropriate questions, probing in nonthreatening manner All sensory modalities Evaluate hallucinations, delusions, and other psychiatric conditions (passage or presence) Chaudhuri KR, et al. Mov Disord. 2010;25(6): ; Goetz CG, et al. Arch Neurol. 2006;63(5): ; Mack J, et al. Am J Geriatr Psychiatry. 2012;20(2):

43 Clinical Connections Psychosis is a common feature of the PD disease course Healthcare providers should be proactive and ask patients with PD about psychosis symptoms There are no benign hallucinations as PD psychosis is a progressive disorder Because it is progressive, diminishes QOL, and increases caregiver burden, treatment of Parkinson s Disease psychosis should not be delayed

44 #CHAIR2016 Questions Answers &