Parkinson s Disease Psychosis:

Parkinson s Disease Psychosis: What Mental Health Professionals Need to Know Rajeev Kumar, MD Medical Director Rocky Mountain Movement Disorders Center Huntington s Disease Society of America Center of Excellence Colorado Neurological Institute Englewood, Colorado

Disclosure The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). The off-label use of clozapine, quetiapine, and cholinesterase inhibitors for the treatment of Parkinson s disease psychosis will be discussed. Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance.

Parkinson s Disease: A Chronic, Progressive Neurodegenerative Disorder Afflicts ~1.0 to 1.5 million people in North America Usual onset between 40 and 70 years; peak age of onset at 6th decade Affects up to 0.3% of the general population but 1% to 3% of those > 65 years Slight male predominance (3:2) 40,000 to 60,000 new cases/year Prevalence increasing as the population ages Prevalence 160/100,000 Parkinson s Foundation. http://parkinson.org/. Jankovic J. In: Goldman L, et al (Eds). Cecil Textbook of Medicine. 2004:2305-2306. Jankovic J. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376. Bernal-Pacheco O, et al. Neurologist. 2012;18(1):1-16. Jakel RJ, et al. Parkinson s disease psychosis. Journal of Parkinsonism and Restless Legs Syndrome. 2014;4:41-51.

Parkinson s Disease: A Chronic, Progressive Neurodegenerative Disorder (cont d) Causation Genetic 5% to 10% of cases monogenic 90% sporadic likely due to polygenic predisposition with significant environmental influences and there is no cure Underlying dopamine deficit occurs in the basal ganglia region of the brain Non-motor and motor symptoms are progressive and worsen over time Parkinson s Foundation. http://parkinson.org/. Jankovic J. In: Goldman L, et al (Eds). Cecil Textbook of Medicine. 2004:2305-2306. Jankovic J. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376. Bernal-Pacheco O, et al. Neurologist. 2012;18(1):1-16. Jakel RJ, et al. Parkinson s disease psychosis. Journal of Parkinsonism and Restless Legs Syndrome. 2014;4:41-51.

Parkinson s Disease PD is a progressive neurological disorder resulting predominantly from the degeneration of dopamine-producing brain cells (important for control of motor function) Parietal cortex Prefrontal premotoric cortex Striatum: N caudatus Substantia nigra: Reduction in number of dopamine-producing neurons Putamen Thalamus Striatum: Imbalance in activity of dopaminergic and cholinergic neurons PD = Parkinson s disease. Damier P, et al. Brain. 1999;122(Pt 8):1437-1448. Temporal cortex Substantia nigra

Pathology

Courtesy of Kapil D. Sethi, MD. Lewy Body

Braak Staging Hypothesis: Stages 1 and 2 Stage 1: Dorsal motor nucleus of the vagus and olfactory bulb Stage 2: Lower brainstem, including pons (medullary raphe, magnocellular portion of reticular formation, and locus coeruleus) Braak H, et al. J Neurol. 2002;249 Suppl 3:III/1-5.

Braak Staging Hypothesis: Stages 3 and 4 Stage 3: Amygdala, magnocellular nuclei of the basal forebrain, and pars compacta of substantia nigra Stage 4: Olfactory telencephalic cortex, temporal mesocortex Braak H, et al. J Neurol. 2002;249 Suppl 3:III/1-5.

Braak Staging Hypothesis: Stages 5 and 6 Stage 5: Sensory association areas, prefrontal fields of neocortex Stage 6: Primary fields of neocortex Braak H, et al. J Neurol. 2002;249 Suppl 3:III/1-5.

Unified Staging System for Lewy Body Disorders (USSLB) USSLB 4 Stages Stage 1: Olfactory only Stage 2A: Brainstem Stage 2B: Limbic System Stage 3: Brainstem and Limbic System Stage 4: Neocortical Includes Lewy Body and α-synuclein pathology Adler CH, et al. Mov Disord. 2016;31(8):1114-1119.

Parkinson s Disease is a Multisystem Disorder Lang AE, et al. N Engl J Med. 1998;339(15):1044-1053; 1130-1143.

Parkinson s Disease: Both Motor and Non-Motor Motor Symptoms Cardinal Symptoms Resting tremor Rigidity Bradykinesia Postural instability Other Motor Symptoms Festinating gait Micrographia Masked facies Retropulsion Hypophonic speech Non-motor symptoms may have a greater impact on quality of life, but there are very few treatments approved for them. Non-Motor Symptoms Cognitive Impairment Mild cognitive impairment (MCI), Dementia Neuropsychiatric disorders Psychosis Impulse control and related disorders (ICDs) Depression Anxiety Autonomic Complications Orthostatic hypotension Constipation Urinary symptoms Sexual dysfunction Sleep Disorder Restless legs syndrome (RLS) REM behavior disorder (RBD) Excessive daytime sleepiness (EDS) Jakel RJ, et al. Parkinson s disease psychosis. Journal of Parkinsonism and Restless Legs Syndrome. 2014;4:41-51. Bernal-Pacheco O, et al. Neurologist. 2012;18(1):1-16. Martinez-Martin P, et al. Mov Disord. 2011;26(3):399-406.

Clinical Symptoms and Time Course of PD Progression: Pathological Progression from Prodrome to Advanced Disease Kalia LV, et al. Lancet. 2015;386(9996):896-912.

Parkinson s Disease Psychosis Has a Distinct Clinical Profile: NIMH Diagnostic Criteria Primary diagnosis of PD prior to the onset of psychosis A diagnosis of PD psychosis requires the presence of 1 of the following symptoms to be recurrent or continuous for at least 1 month in a person with PD: Hallucinations Delusions Illusions False sense of presence PD psychosis may occur with or without: Insight Dementia PD treatment Other potential medical and psychological causes of psychosis must be excluded Ravina B, et al. Mov Disord. 2007;22(8):1061-1068.

Both Intrinsic and Extrinsic Factors Contribute to Parkinson s Disease Psychosis Intrinsic Factors Comorbid Conditions Presence of comorbid medical or psychiatric conditions Evidence for Disease Progression PD severity PD duration Older age Cognitive impairment or dementia Evidence for Neurobiology Neurotransmitter abnormalities Neural pathways Visual processing deficits Extrinsic Factors Medications Antiparkinson medications (eg, higher levodopa dose, dopamine agonists, amantadine) Other medications (eg, anticholinergics) Environment Dim lighting Time of day Objects in environment Jakel RJ, et al. Parkinson s disease psychosis. Journal of Parkinsonism and Restless Legs Syndrome. 2014;4:41-51. Zahodne LB, et al. Drugs Aging. 2008;25(8):665-682.

PD Psychosis is a Common But Underrecognized Aspect of PD Likely to Become More Prevalent as Cases of PD Increase US prevalence of PD is projected to more than double in the next 2 to 3 decades > 50% of patients with PD will develop PD psychosis during the course of their disease > 2 Patients with PD do not often disclose symptoms of psychosis to their physician US-Based Projection of PD Prevalence 2010 2040 Of the patients that reported each symptom, the percent who did not disclose: Hallucinations: 41.5% Delusions: 65.2% Kowal SL, et al. Mov Disord. 2013;28(3):311-318. Forsaa EB, et al. Arch Neurol. 2010;67(8):996-1001. Chaudhuri KR, et al. Mov Disord. 2010;25(6):704-709.

Visual Hallucinations are the Most Common Element of PD Psychosis, Generally in Combination with Hallucinations and Delusions in Other Modalities Minor Phenomenon Hallucinations Delusions Presence hallucinations: The experience that someone is present when no one actually is Illusions: Misperceptions of real stimuli that are often visual in nature SYMPTOMS OF PD PSYCHOSIS Abnormal perceptions without a physical stimulus that can involve any sensory modality and may be simple or complex in form False, fixed, idiosyncratic beliefs that are maintained despite evidence to the contrary Visual hallucinations are the most common symptom of PD psychosis; other auditory, tactile, and olfactory hallucinations may occur in combination with the visual hallucinations or, more rarely, in isolation Delusions may encompass a variety of themes, including persecutory (someone stealing or harming the patient), jealousy, and reference Ravina B, et al. Mov Disord. 2007;22(8):1061-1068. Graham JM, et al. J Neurol Neurosurg Psychiatry. 1997;63(4):434-440. Llorca PM, et al. Sci Rep. 2016;6:38152. Fénelon G, et al. Mov Disord. 2010;25(6):763-766. Fénelon G, et al. Brain. 2000;123(Pt 4):733-745. Voss T, et al. Parkinsonism Relat Disord. 2013;19(3):295-299.

Benign Hallucinations Do Not Remain Benign A study followed 48 PD patients with benign hallucinations (UPDRS thought disorder score of 2) who were receiving no treatment for hallucinations for at least 3 years or until a thought disorder score of 3 or 4 occurred 81% progressed to thought disorder scores of 3 or 4 78% of patients who retained a thought disorder score of 2 had their PD medications reduced to treat hallucinations Only 4% of patients were stable (ie, stable, untreated benign hallucinations over time) UPDRS = Unified Parkinson s Disease Rating Scale. Goetz CG, et al. Arch Neurol. 2006;63(5):713-716. Kaplan-Meier curve showing the time frame from study enrollment with a UPDRS thought disorder score of 2 and no treatment for hallucinations to a UPDRS thought disorder score of 3 or 4. Median time (vertical bar) for the sample of 48 participants with PD was 16 months.

The Course of Parkinson s Disease Psychosis Hallucinations begin Hallucinations progress Onset of delusions Nursing home placement Insight is retained While insight is retained, patients are often able to cope with symptoms without behavioral disturbances Insight is lost Caregiver burden increases Mortality at 3 years is approximately 40% for PD patients with psychosis Goetz CG, et al. Arch Neurol. 2006;63(5):713-716. Chaudhuri KR, et al. Lancet Neurol. 2006;5(3):235-2345. Schrag A, et al. Parkinsonism Relat Disord. 2006;12(1):35-41. Goetz CG, et al. Neurology. 1993;43(11):2227-2229. Forsaa EB, et al. Neurology. 2010;75(14):1270-1276. Diederich NJ, et al. Mov Disord. 2003;18(7):831-832. Henderson MJ, et al. Int Rev Psychiatry. 2000;12(4):319-334.

The Burden of Parkinson s Disease Psychosis Caregiver burden increases as PD psychosis symptoms progress > 40% report a decline in physical health 66% report that their close relationships suffer Nearly 50% have scores indicating depression Symptoms of psychosis were identified as the reason for 24% of hospital admissions for patients with PD PD patients with hallucinations are 2.5 more likely to be admitted into a nursing home Schrag A, et al. Parkinsonism Relat Disord. 2006;12(1):35-41. Klein C, et al. J Neural Transm. 2009;116(11):1509-1512. Aarsland D, et al. J Am Geriatr Soc. 2000;48(8):938-942.

Pathophysiology of Parkinson s Disease Psychosis

Patients with PD Lose Serotonergic Neurons and Functioning and, as a Result, May Experience Compensatory Upregulation of 5-HT Receptors There is clear evidence of serotonergic dysfunction in PD Loss of 5-HT neurons in multiple brain pathways Reduced SERT binding Lewy body pathology in the raphe nuclei (primarily serotonergic neurons) Lewy body pathology in the cortex in later disease Patients with PD show reduced SERT binding with the greatest reductions in the forebrain in addition to the striatum Loss of raphe nuclei and certain cortical neurons may result in changes in serotonin function to compensate particularly upregulation of 5-HT 2A receptors in several brain regions Dysfunction of the serotonergic system is linked to PD psychosis Top: Normal Control Bottom: Parkinson s Disease SERT = serotonin transporter. Lang AE, et al. Lancet Neurol. 2004;3(5):309-316. Albin RL, et al. J Cereb Blood Flow Metab. 2008;28(3):441-444. Braak H, et al. Neurobiol Aging. 2003;24(2):197-211. Joutsa J, et al. J Nucl Med. 2015;56(7):1036-1041. Ballanger B, et al. Arch Neurol. 2010;67(4):416-421. Huot P, et al. Mov Disord. 2010;25(10):1399-1408.

Patients with Parkinson s Disease and Hallucinations Have Increased 5-HT 2A Receptor Binding Patients with PD and hallucinations have increased 5-HT 2A receptor binding in several regions of the brain, including the ventral visual pathway 5-HT 2A Receptor Binding Potential PD Patients without VH (n=7) PD Patients with VH (n=7) 5-HT 2A Binding Potential* Serotonin 5-HT 2A Binding Potential 0.6 0.5 0.4 0.3 0.2 0.1 0.0 OFC IOG (R) IOG (L) FG (R) ITC DLPFC (R) DLPFC (L) PCC Insula (R) Insula (L) VH = visual hallucination; OFC = orbitofrontal cortex; IOG = inferior occipital gyrus; FG = fusiform gyrus; ITC = inferior temporal cortex; DLPFC = dorsolateral prefrontal cortex; PCC = posterior cingulate cortex; R = right; L = left. Ballanger B, et al. Arch Neurol. 2010;67(4):416-421. *The red highlighted regions indicate areas with increased 5-HT 2A receptor binding compared to patients with PD without hallucinations.

Increased 5-HT 2A Receptor Levels on Autopsy in PD Patients with Visual Hallucinations [ 3 H]-Ketanserin Binding (Mean ± SEM) 70 60 50 40 30 20 10 0 P=.039 P=.0297 Controls All PD PD Without VH PD With VH Orbitofrontal cortex Inferolateral temporal cortex Motor cortex Striatum Substantia nigra 45.6% increase in the levels of [ 3 H]-ketanserin binding in the inferolateral temporal cortex, a critical structure in visual processing, of PD patients with VH compared to PD patients without VH. Huot P, et al. Mov Disord. 2010;25(10):1399-1408.

Reduced Raphe SERT Availability and Parkinson s Disease Symptoms Reduced raphe SERT availability is associated with the severity of resting tremor but not non-motor symptoms (fatigue, depression, and sleep disturbance) in de novo PD Other studies have linked serotoninergic dysfunction, and particularly the 5-HT 1A and 5-HT 1B receptor activity, to L-dopainduced dyskinesias Qamhawi Z, et al. Brain. 2015;138(Pt 10):2964-2973. Miguelez C, et al. Front Neural Circuits. 2014;8:21.

Serotonin Dopamine Balance Dopamine Theory: Hyperactive in mesolimbic pathway Cerebral Cortex 5-HT 2A GABA Glutamate Visual Temporal Motor Prefrontal Striatum Dorsal Ventral Raphe Substantia Nigra Ventral Tegmental Area GABA = gamma-aminobutyric acid. Stahl SM. CNS Spectr. 2018;23(3):187-191. Stahl SM. CNS Spectr. 2016;21(5):355-359. Stahl SM. CNS Spectr. 2016;21(4):271-275.

Parkinson s Disease: Nigrostriatal Dopamine/D 2 Deficiency = Lewy body Cerebral Cortex 5-HT 2A GABA Glutamate Visual Temporal Motor Prefrontal Striatum Dorsal Ventral akinesia rigidity tremor Raphe Substantia Nigra Ventral Tegmental Area Stahl SM. CNS Spectr. 2018;23(3):187-191. Stahl SM. CNS Spectr. 2016;21(5):355-359. Stahl SM. CNS Spectr. 2016;21(4):271-275.

3 Hypotheses of Psychosis Dopamine Theory: Hyperactive in mesolimbic pathway Serotonin Theory: 5-HT 2A receptor hyperfunction in the cortex NMDA Theory: NMDA receptor hypofunction Interconnected Pathways with one or more active in any one psychotic patient NMDA = N-methyl-D-aspartate.

Dopamine Theory: Hyperactive in Mesolimbic Pathway Cocaine and amphetamines stimulate D 2 receptors and cause auditory hallucinations and paranoid delusions with lack of insight Stahl SM. CNS Spectr. 2018;23(3):187-191. Stahl SM. CNS Spectr. 2016;21(5):355-359. Stahl SM. CNS Spectr. 2016;21(4):271-275.

Serotonin Theory: 5-HT 2A Receptor Hyperfunction in the Cortex LSD and psilocybin simulate 5-HT 2A receptors and visual hallucinations, mystical delusions often with preserved insight Haloperidol is unable to block the visual hallucinations, but 5-HT 2A antagonists are effective Stahl SM. CNS Spectr. 2018;23(3):187-191. Stahl SM. CNS Spectr. 2016;21(5):355-359. Stahl SM. CNS Spectr. 2016;21(4):271-275.

NMDA Theory: NMDA Receptor Hypofunction PCP and ketamine are NMDA receptor antagonists (in addition to amantadine) and cause visual hallucinations and paranoid delusions with lack of insight Stahl SM. CNS Spectr. 2018;23(3):187-191. Stahl SM. CNS Spectr. 2016;21(5):355-359. Stahl SM. CNS Spectr. 2016;21(4):271-275.

Parkinson s Disease Psychosis: Cortical Serotonin/5-HT 2A and Mesolimbic Dopamine/D 2 Excess Superimposed Upon Nigrostriatal Dopamine/D 2 Deficiency Cerebral Cortex 5-HT 2A 5-HT 2A 5-HT 2A 5-HT 2A GABA Glutamate Striatum Dorsal Visual Temporal Motor Prefrontal akinesia rigidity tremor visual hallucinations Ventral delusions, auditory hallucinations = Lewy body Raphe Substantia Nigra Ventral Tegmental Area = Alzheimer's amyloid plaques and tangles Stahl SM. CNS Spectr. 2018;23(3):187-191. Stahl SM. CNS Spectr. 2016;21(5):355-359. Stahl SM. CNS Spectr. 2016;21(4):271-275.

L-DOPA Psychosis: Dorsal to Ventral Striatal Shift and Dopamine Overdose = Lewy body Cerebral Cortex 5-HT 2A GABA Glutamate Visual Temporal Motor Prefrontal L-DOPA Raphe Striatum Dorsal Ventral Substantia Nigra akinesia rigidity tremor delusions, auditory hallucinations Ventral Tegmental Area Stahl SM. CNS Spectr. 2018;23(3):187-191. Stahl SM. CNS Spectr. 2016;21(5):355-359. Stahl SM. CNS Spectr. 2016;21(4):271-275.

Treatment of Parkinson s Disease Psychosis

Treating Psychosis in Parkinson s Disease Identify and address systemic illnesses that may trigger psychosis (eg, infection, delirium, toxic etiologies) Consider discontinuing any nonessential non-pd medications that could contribute to psychosis (eg, anticholinergics, tricyclic antidepressants, benzodiazepines, and opioids) Managing psychosis and its behavioral and emotional consequences through nonpharmacologic methods (eg, coping skills, cognitive-behavioral therapy, psychoeducation) should also be discussed with patient and family Goldman JG, et al. Curr Treat Options Neurol. 2014;16(3):281. Zahodne LB, et al. Drugs Aging. 2008;25(8):665-682.

Carefully Consider the Consequences to the Patient s Motor Function if Adjusting Dopaminergic Therapies to Address PD Psychosis Decreasing Dopamine replacement therapy may address psychosis, but generally worsens motor symptoms, presenting a therapeutic bind Motor Symptoms Psychosis Symptoms Reduce/ optimize drugs to reduce psychosis (expert opinion regarding order): Anticholinergics Amantadine Monoamine oxidase B inhibitors (eg, rasagiline and selegiline) Dopamine agonists (eg, pramipexole) Catechol-O-methyltransferase inhibitors (eg, entacapone) Adjust levodopa doses Goldman JG, et al. Curr Treat Options Neurol. 2014;16(3):281. Friedman JH. Expert Opin Pharmacother. 2018;19(5):499-505.

Antipsychotic Receptor Binding and Affinities Types of Antipsychotics Typical antipsychotics (eg, haloperidol) Share the primary pharmacologic property of D 2 receptor antagonism Atypical antipsychotics (eg, clozapine, risperidone, aripiprazole) May act via simultaneous 5-HT 2A and D 2 antagonism, partial agonist actions at 5-HT 1A receptors, partial agonist actions at D 2 receptors, or a combination of these mechanisms It is important to recognize that neither typical or atypical antipsychotics are homogenous groups Receptor Type Selected Potential Effects * Dopamine activity Antipsychotic, anti-manic, EPS, tardive dyskinesia, prolactin elevation Serotonergic activity Anxiolytic, antidepressant, increased appetite, and weight gain (?) Histaminergic activity Muscarinic activity Alpha adrenergic Anxiolytic, sedation, weight gain Cognitive blunting, dry mouth, constipation, urinary retention, blurred vision Orthostatic hypotension, drowsiness, dizziness, syncope, antidepressant * Effects may vary based upon the specific receptor affinities of each antipsychotic and dose of each antipsychotic. EPS = extrapyramidal side effects. Correll CU. Eur Psychiatry. 2010;25 Suppl 2:S12-S21. Stahl SM. Stahl s Essential Psychopharmacology. Fourth Edition. New York, NY: Cambridge University Press; 2013.

Atypical Antipsychotic Groupings by Relative 5-HT 2A and D 2 Receptor Affinities pimavanserin clozapine quetiapine risperidone paliperidone lurasidone aripiprazole brexpiprazole cariprazine Stahl SM. Stahl s Essential Psychopharmacology. Fourth Edition. New York, NY: Cambridge University Press; 2013.

Evidence-Based Treatments for Parkinson s Disease Psychosis Clozapine Efficacy Safety Practice Implications Efficacious Acceptable risk with specialized monitoring Clinically useful Olanzapine Unlikely efficacious Unacceptable risk Not useful Quetiapine Insufficient evidence Acceptable risk Investigational Prior to approval of pimavanserin. Seppi K, et al. Mov Disord. 2011;26 Suppl 3:S42-S80.

Current Prescribing Practices in PD Psychosis and Non-PD Dementia Psychosis Antipsychotic Prescribing With Dementia (n=793) PD Group (N=2597) Without Dementia (n=1804) N % N % Non-PD Dementia Group (N=6907) N % Test of Significance Any AP Use 451 56.9 847 47.0 3350 48.5 χ 2 =23.35, df=2, P<.001 Any Typical AP 35 4.4 69 3.8 500 7.2 χ 2 =33.50, df=2, P<.00 High Potency 32 4.0 56 3.1 456 6.6 χ 2 =37.00, df=2, P<.001 Any Atypical AP 437 55.1 814 45.1 3110 45.0 χ 2 =29.63, df=2, P<.001 Quetiapine 306 38.6 550 30.5 1522 22.0 χ 2 =139.35, df=2, P<.001 Risperidone 81 10.2 143 7.9 1282 18.6 χ 2 =141.88, df=2, P<.001 Aripiprazole 41 5.2 116 6.4 273 4.0 χ 2 =21.16, df=2, P<.001 Olanzapine 56 7.1 93 5.2 458 6.6 χ 2 =5.87, df=2, P=.053 Ziprasidone 18 2.3 31 1.7 100 1.4 χ 2 =3.44, df=2, P=.18 Clozapine 5 0.6 18 1.0 4 0.1 χ 2 =48.27, df=2, P<.001 Antipsychotics were prescribed in 50% of all the patients with PD and comorbid psychosis. AP = antipsychotic. Weintraub D, et al. Arch Neurol. 2011;68(7):899-904.

Pimavanserin is a Selective Serotonin Inverse Agonist Pimavanserin is a serotonin inverse agonist with no appreciable binding affinity to dopamine, histamine, muscarinic, or adrenergic receptors * Pimavanserin binds to 5-HT 2A receptors with a 5-fold higher selectivity over 5-HT 2C receptors 100 Agonists: Stimulate the receptor Response (%) Antagonists: Block agonists but permit basal activity US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. 0 [Drug Concentration] Inverse Agonists: Suppress basal activity

Pimavanserin 34 mg Reduced the Frequency and/or Severity of PD Psychosis, with Continued Improvement Over 6 Weeks* Week 0 Week 2 Week 4 Week 6 Percentage Improvement, SAPS-PD Change from Baseline Score (LSM±SE) -0.5-2 -3.5 Placebo Pimavanserin 34 mg -2.73 mean point change 14% Improvement with placebo 37% Improvement with pimavanserin -5-6.5 Primary endpoint: Change in total SAPS-PD score from baseline -5.79 mean point change (P=.0014) *Mean SAPS-PD baseline score was 15.9 for pimavanserin and 14.7 for placebo. Difference in change at Week 6 between the 2 arms was 3.06 points. SAPS-PD = Scale for the Assessment of Positive Symptoms adapted for Parkinson s disease. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Cummings J, et al. Lancet. 2014;383(9916):533-540.

Approximately 65% of Patients Taking Pimavanserin Experienced a 3-Point Reduction in PD Psychosis Patients (%) 80 70 60 50 40 30 20 10 0 26.3 44.4 Worsened or No Change 73.7 55.6 1-Point Response 65.3 42.2 3-Point Response 53.7 33.3 5-Point Response Change in SAPS-PD 41.1 26.7 7-Point Response Placebo Pimavanserin 34 mg 33.7 16.7 10-Point Response 13.7 1.1 Complete Response Improvements in symptoms of psychosis were seen without worsening of motor function Hallucinations and Delusions improved 14% of patients had complete resolution of psychosis N=185. Complete response = SAPS-PD score reduced to 0 from baseline value. Patients with missing values were counted as non-responders. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Cummings J, et al. Lancet. 2014;383(9916):533-540.

Pimavanserin Safety Profile: Adverse Reactions in Placebo-Controlled Studies of 6-Week Treatment Duration and Reported in 2% and > Placebo Percentage of Patients Reporting Adverse Reaction Pimavanserin 34 mg (N=202) Placebo (N=231) Peripheral edema 7% 2% Nausea 7% 4% Confusional state 6% 3% Hallucination 5% 3% Constipation 4% 3% Gait disturbance 2% < 1% Pimavanserin was not associated with increased sedation or increase in falls. *Based upon placebo-controlled 6-week trials. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/. Adverse Reactions Leading to Discontinuation of Treatment 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)

Pimavanserin Can Interact with Strong CYP3A4 Inhibitors and Inducers or with Drugs That Cause QT Interval Prolongation Strong CYP3A4 Inhibitors Concomitant use of pimavanserin with a strong CYP3A4 inhibitor increases pimavanserin exposure The recommended dose of pimavanserin when coadministered with strong CYP3A4 inhibitors (eg, ketoconazole) is 17 mg, taken orally as 1 tablet once daily Strong CYP3A4 Inducers Concomitant use of a strong CYP3A4 inducer may reduce pimavanserin exposure, resulting in a potential decrease in efficacy Patients should be monitored for reduced efficacy, and an increase in dosage may be needed if pimavanserin is used concomitantly with strong CYP3A4 inducers Concomitant Use with Drugs That Prolong QT Interval* Concomitant use of drugs that prolong the QT interval may add to the QT effects of pimavanserin and increase the risk of cardiac arrhythmias Avoid the use of pimavanserin in combination with other drugs known to prolong the QT interval *In clinical trials, pimavanserin prolonged the QT interval (mean increase ~ 5 8 msec). US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Antipsychotic Risks in Dementia-Related Psychosis Black Box Warning Increased risk of cerebrovascular adverse events and mortality (1.7 ) secondary to cardiovascular events and infections Issued for both typical and atypical antipsychotics Also type 2 diabetes, orthostatic hypotension, sedation, dry mouth, dizziness, constipation

Important Safety Information for Pimavanserin 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] is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson s disease psychosis. US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Media Coverage of Pimavanserin

Mortality in Parkinson s Disease Psychosis Cox regression model adjusted to baseline age of 75 years Mortality for PD patients with (1) hallucinations with retained insight or (2) hallucinations or delusions without insight at baseline 40% at 3 years 80% at 7 years 0 1 No psychotic symptoms 2 Hallucinations with retained insight 3 4 Hallucinations or delusions without insight Forsaa EB, et al. Neurology. 2010;75(14):1270-1276.

Quetiapine Most prescribed antipsychotic for PD psychosis despite the lack of clinical efficacy data supporting its use Most movement disorders specialists and general neurologists find it to be effective in clinical practice Strong 5-HT 2A receptor antagonist and rarely worsens parkinsonism in doses of up to 100 to 200 mg/day. The usual starting dose is 25 mg qhs and this is slowly increased as needed (much lower than doses commonly used in psychiatry) Anti-histaminergic effect likely underlies the sedative effect. Psychosis in PD is commonly worse at night and sleep disruption almost universal in patients with advanced PD Improvement in sleep quality and duration may be important Reduction of caregiver stress when patient is sleeping Risk of daytime sedation and increased falls and worsening of orthostatic hypotension in this vulnerable population Ondo WG, et al. Mov Disord. 2005;20(8):958-963. Rabey JM, et al. Mov Disord. 2007;22(3):313-318. Shotbolt P, et al. Neuropsychiatr Dis Treat. 2009;5:327-332. Kurlan R, et al. Neurology. 2007;68(17):1356-1363.

Clinical Trials of Quetiapine Number of Patients Time Dose Range Average Dose Number of Dropouts Time to Dropout UPDRS BPRS Shotbolt 24 12 wks 25 150 mg 72.7 mg 16 Quetiapine patients dropped out faster than placebo patients No Significant Effect No Significant Effect Rabey 58 12 wks 12.5 mg Starting Flexible Titration 119.2 mg 26 Not Used No Significant Effect No Significant Effect Ondo 26 12 wks 50 200 mg Not Given 5 Not Used No Significant Effect No Significant Effect Kurlan 40 total (9 with PD psychosis) 10 wks 25 150 mg 120 mg 10 Not Used No Significant Effect No Significant Effect BPRS = Brief Psychiatric Rating Scale. Ondo WG, et al. Mov Disord. 2005;20(8):958-963. Rabey JM, et al. Mov Disord. 2007;22(3):313-318. Shotbolt P, et al. Neuropsychiatr Dis Treat. 2009;5:327-332. Kurlan R, et al. Neurology. 2007;68(17):1356-1363.

Clozapine Very low D 2 affinity and high 5-HT 2A affinity which results in no worsening of parkinsonism Most potent atypical antipsychotic and commonly used in high doses in refractory schizophrenia (eg, 400 800 mg/day) No worsening of parkinsonism and actually effective for parkinsonian tremor at 50 mg/day Results in dose-dependent improvement in levodopa-induced dyskinesia Highly effective in PD psychosis and highly underutilized due to need for CBC monitoring and concerns about agranulocytosis Doses in PD psychosis usually < 50 mg/day starting at 6.25 mg qhs and titrating upward Durif F, et al. Neurology. 2004;62(3):381-388. Parkinson Study Group. N Engl J Med. 1999;340(10):757-763. Pollak P, et al. J Neurol Neurosurg Psychiatry. 2004;75(5):689-695.

Clinical Trials of Clozapine # of Patients Time Mean Dose CGI P Value SAPS P Value BPRS P Value UPDRS P Value Positive PANSS P Value PSYCLOPS 60 4 wks 24.7 mg <.001.01.002.36 Not Used French Coop 60 4 wks 35.8 mg.001 Not Used Not Used.81.0001 PSYCLOPS = PSYchosis and CLOzapine in the treatment of Parkinsonism; CGI = Clinical Global Impressions Scale; PANSS = Positive and Negative Syndrome Scale. Parkinson Study Group. N Engl J Med. 1999;340(10):757-763. Pollak P, et al. J Neurol Neurosurg Psychiatry. 2004;75(5):689-695. 54

Rapid Benefit and Dosing Appreciable improvement in a few days Maximum improvement reached at 3 months Mean doses 24 to 35 mg/day Doses were kept under 50 mg/day 12-week open-label extension confirmed durable efficacy in both studies Change in PANSS Score Parkinson Study Group. N Engl J Med. 1999;340(10):757-763. Pollak P, et al. J Neurol Neurosurg Psychiatry. 2004;75(5):689-695. Factor SA, et al. Mov Disord. 2001;16(1):135-139.

Somnolence Postural hypotension Increased salivation Confusion Seizures Rare risk of agranulocytosis Cardiomyopathy Metabolic syndrome Clozapine Adverse Effects US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/.

Can Cholinesterase Inhibitors Improve Parkinson s Disease Psychosis? Rivastigmine is indicated for treatment of PD dementia and reduces psychosis in this population Cholinesterase inhibitors also reduce psychosis in patients with dementia with Lewy bodies The cholinergic deficit in patients with PD or PD dementia is greater than that in Alzheimer s disease It is reasonable to treat patients with PD dementia with cholinesterase inhibitors with or without psychosis. In clinical practice the antipsychotic efficacy of cholinesterase inhibitors in this population is quite mild and often inadequate when psychosis is troublesome and patients lack insight Emre M, et al. N Engl J Med. 2004;351(24):2509-2518. McKeith I, et al. Lancet. 2000;356(9247):2031-2036. Bohnen NI, et al. Arch Neurol. 2003;60(12):1745-1748.

Cholinesterase Inhibitors to Slow Progression of Visual Hallucinations in Parkinson s Disease (CHEVAL) Objectives Delayed progression of minor VH to major VH without insight Motor control, psychotic symptoms, cognitive impairment, mood disorders, daytime sleepiness, adverse events and compliance, disability, caregiver burden, and care use Cost effectiveness Functional brain networks Study Design Randomized double-blind, placebo-controlled, multicenter trial with economic analysis Intervention Rivastigmine 6 mg bid or placebo Primary Endpoint Median time to progression from minor VH to major VH without insight ClinicalTrials.gov Identifier: NCT01856738. 58

Conclusions PD pathology predisposes to a variety of neuropsychiatric disorders including depression, anxiety, and dementia due to the multiple neurotransmitter systems affected PD psychosis is common and is associated with high morbidity and mortality Dopamine and serotonin abnormalities contribute to development of psychosis in PD

Conclusions Judiciously reducing non-pd medication that can interfere with cognition (eg, benzodiazepines) and selected other PD medications (especially anticholinergics and amantadine) may improve psychosis, but over-reduction of medication can worsen parkinsonism Antipsychotic medication targeting 5-HT 2A receptors can improve PD psychosis without compromising motor function