2019 Non-motor Aspects of Parkinson's Disease · 2019-06-04 · 6/3/19 1 Non-Motor Aspects of Parkinson’s Disease June 2019 Dana Saffel, PharmD, BCGP, CPh, FASCP President, CEO

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Non-Motor Aspects of Parkinson’s Disease

June 2019

Dana Saffel, PharmD, BCGP, CPh, FASCPPresident, CEO

PharmaCare Strategies, Inc.

Objectives

• Delineate non-motor aspects of Parkinson’s disease (PD)

• 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 psychotropic medications

• Discuss the role of consultant pharmacists and the LTCF care team in managing the neuropsychiatric symptoms of psychosis

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Disclosures

Dana Saffel, PharmD, BCGP, CPh, FASCPPresident, CEOPharmaCare Strategies

• Acadia Pharmaceuticals – Consultant, Speaker• Mylan Pharmaceuticals – Consultant• Sunovion Pharmaceuticals – Consultant, Speaker• Sun Pharmaceutical Industries - Consultant

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Case Study

• JG is a 78 yo male residing in a nursing home with a history of PD, hypertension, diabetes, Afib, and osteoarthritis. His medications include:

– Losartan 50mg po daily– Dulaglutide 0.75mg sq weekly– Metformin 750mg po BID– Levodopa/carbidopa 100mg po QID

– Selegiline 5mg po BID– Pramipexole 1mg po TID

• Nursing staff are reporting that JG is increasingly withdrawn, is unwilling to participate in social activities and has lost 5lbs in the past few weeks.

• The DON asks your opinion in how to best manage JG.

• What non-motor symptoms should JG be assessed for?

• How/what would you suggest to improve JG’s symptoms?

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Parkinson’s Disease (PD) is Commonly Thought of as a Movement Disorder

. . . or by the medicines they take4-9

(eg, carbidopa/levodopa, ropinirole, pramipexole, entacapone, amantadine)

Typical appearance of a person with PD1,3

Tremor

Mask-likeface

Stooped posture

Rigidity

Tremor

Short shuffling steps

Hips and knees slightly

flexed

You may recognize residents with PD by their motor symptoms1-3

Cardinal symptoms

§ Tremor at rest§ Rigidity§ Akinesia /

Bradykinesia§ Postural instability

Other common motor symptoms

§ Mask-like expression§ Soft voice§ Drooling§ Reduced blinking§ Shuffling steps§ Freezing/falling§ Small handwriting

1. Olanow C et al. In: Kasper D et al, eds. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com/content.aspx?bookid=1130&Sectionid=79755616. Accessed July 1, 2016. 2. Srivanitchapoom P et al. Parkinsonism Relat Disord. 2014;20(11):1109-1118. 3. National Institute of Neurological Disorders and Stroke. Parkinson’s disease backgrounder. http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease_backgrounder.htm. Updated October 18, 2014. Accessed February 24, 2016. 4. Zarowitz BJ et al. Pharmacist. 2013;28(9):556-568. 5. SINEMET Prescribing Information. Morgantown, WV: Merck &Co.; 2014. 6. REQUIP XL Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2014. 7. MIRAPEX Prescribing Information. Ridgefield, CT: Boehringer Ingelheim; 2016. 8. COMTAN® Prescribing Information. East Hanover, NJ: Novartis; 2016. 9. Amantadine Hydrochloride Prescribing Information. Princeton, NJ: Sandoz Inc.; 2015.

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Parkinson’s Disease (PD) is More Than Motor Symptoms

Motor Symptoms1 Common Nonmotor Symptoms2

• 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/hallucinations• 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. 19th ed. New York, MY: McGraw-Hill, 2015. http://accemedicine-mhmedical.com. Accessed March 2, 2017.

2. Chaudheri KR, et al. Mov Disord. 2007.22(13):1901-1911.

“Parkinson’s disease is a very complex, neuropsychiatric, neurodegenerative disease that involves far more than just the motor symptoms … that may even emerge before a patient develops motor symptoms.” Dan Kremons, MD - Neurologist

http://accemedicine-mhmedical.com

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Clinical Symptoms and Time Course of Parkinson’s Disease

Degr

ee o

f Dis

abili

ty

Pre-motor/prodromal period Parkinson’s disease diagnosis

-20 -10 0 10 20Time (years)

Constipation RBD

EDSHyposmiaDepression

PainFatigue

MCI

BradykinesiaRigidityTremor

Urinary symptomsOrthostatic hypotension

Dementia

DysphagiaPostural instabilityFreezing of gait

Falls

FluctuationsDyskinesia

Psychosis

Early Advanced/late

Non-motor

Motor

Complications

1. Image adapted from Kalia LV, Lang AE. Lancet. 2015;386:896-812. 7

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 control

Parkinson’s disease

Reduction of pigment

in substantianigra in PD

Reduced number of

cells in substantia

nigra in PD

Lewy bodies within melanized dopamine

neurons 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; 2015. http://accessmedicine.mhmedical.com/content.aspx?bookid=1130&Sectionid=79755616. Accessed March 2, 2017.

All images are artistic representations.

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Serotonin Theory of Dementia, Depression & Psychosis

GABA

Glutamate

VisualTemporalMotorPrefrontal

Ventral

Cerebral Cortex

Striatum

Ventral TegmentalArea

Substantia NigraRaphe

Dorsal

= Lewy body

akinesiarigiditytremor

5HT2A5HT2A 5HT2A

delusions,auditory hallucinations

visual hallucinations

• Lewy body deposition in cerebral cortex contributes to:– Cognitive impairment– Depression– Visual Hallucinations– Downstream effects that

increase dopamine release in mesolimbic system - Delusions

Stahl SM. 4th ed. New York, NY: Cambridge University Press; 2013.

Cerebral CortexCognitionDepression

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Serotonin Dysfunction is Linked to Motor and Nonmotor Symptoms

1 . D oder M , e t a l. N euro logy. 2003 ;60 (4 ):601 -605 .2 . Iravan i M M , e t a l. J P harm aco logy and E xperim en ta l The rapeu tics . 2006 ;319 (3 ):1225 -

1234 .3 . Tong Q , e t a l. P ark R e la t D iso rd . 2015 ;21 :882 -887 .4 . Jo ling M , e t a l. J N euro l N eurosu rg P sych ia try . 2018 ;89 :89 -94 .5 . P au lus W , e t a l. J N europa th E xper N euro logy. 1991 ;50 (6 ):743 -755 .

1 . M ayeux R , e t a l. A m J P sych ia try . 1986 ;143 :756 -759 .2 . S tah l S M . 4 th ed . N ew Y ork, N Y : C am bridge U n ive rs ity P ress; 2013 .3 . M a tsuyam a S , e t a l. J P harm aco logy E xp Ther. 1996 ;276 (3 ): 989 -995 .4 . Tan iyam a K , e t a l. J P harm aco logy E xp Ther. 1991 ;258 (3 ):1098 -1104 .5 . L iu Z , e t a l. M ov D iso rd . 2005 ;20 (6 ):680 -686 .

Levodopa-induced

dyskinesia2

Tremor1

Constipation8-10

Depression3,5,6

Anxiety4

Psychosis7

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Question 1

• The pathogenesis of Parkinson’s disease includes imbalance of which of the following neurotransmitters?a) Dopamineb) Serotoninc) Glutamated) a & be) All of the above

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Question 1

• The pathogenesis of Parkinson’s disease includes imbalance of which of the following neurotransmitters?a) Dopamineb) Serotoninc) Glutamated) a & be) All of the above

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RECOGNITION AND TREATMENT OF

NON-MOTOR SYMPTOMS OF PD

Non-Motor Symptoms of Parkinson’s Disease

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Neuropsychiatric Symptoms• Depression and depressive symptoms• Anxiety and anxiety symptoms• Apathy• Psychosis• Impulse control and related disorders • Dementia• Cognitive impairment (other than dementia;

mainly mild cognitive impairment)

Other• Pain • Fatigue • Olfactory dysfunction • Ophthalmologic dysfunction

Autonomic Dysfunction• Drooling • Orthostatic hypotension • Urinary dysfunction • Erectile dysfunction • Gastrointestinal dysfunction • Excessive sweating • Disorders of sleep and wakefulness • Sleep fragmentation and insomnia • Rapid eye movement sleep

behavior disorder • Excessive daytime sleepiness


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Question 2

• Non-motor symptoms of Parkinson’s disease can cause the patient more distress than the typical motor symptoms? True or False

True

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Movement Disorder Specialist Guidelines

Seppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine Review. Movement Disorders, 2019.

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Depression

• Between 20% and 50% of PD patients experience major depression during the course of the disease.– Depression precedes motor symptoms in approximately 30% of cases

• PD depression typically differs from depression in the general population:– Less expressed feelings of sadness– Little tearfulness or guilt– Low suicide rate– Prominent anxiety, anhedonia, and apathy.

• Cause: complex dysfunction of numerous structures including noradrenergic, serotoninergic, and dopaminergic regions of the brainstem. – Mood swings and depression can occur with wearing off or during off

periods.

191. Parkinson’s Clinical Guidelines. http://parkinsonclinicalguidelines.ca/sites/default/files/PhysicianGuide_Non-motor_EN.pdf. Accessed April 24, 2019.2. Parkinson’s Community. Non-motor Symptoms of Parkinson’s Disease. https://parkinsons.community/non-motor-symptoms-of-parkinsons-disease.

Accessed April 15, 2019.

Depression TreatmentsDrug Class / Intervention Drug / Intervention Efficacy Safety Practice

Implications

Dopamine AgentsPramipexole Efficacious Acceptable risk Clinically usefulPergolide Insufficient Evidence Acceptable risk Not usefulRotigotine Unlikely efficacious Acceptable risk Investigational

MAO-B InhibitorsRasagiline Insufficient Evidence Acceptable risk InvestigationalSelegeline Insufficient Evidence Acceptable risk InvestigationalMoclobemide Insufficient Evidence Acceptable risk Investigational

Tricyclic AntidepressantsNortriptyline Likely Efficacious Acceptable risk Possibly usefulDesipramine Likely Efficacious Acceptable risk Possibly usefulAmitriptyline Insufficient Evidence Acceptable risk Possibly useful

SSRI / SNRI

Citalopram Insufficient Evidence Acceptable risk Possibly usefulSertraline Insufficient Evidence Acceptable risk Possibly usefulParoxetine Insufficient Evidence Acceptable risk Possibly usefulFluoxetine Insufficient Evidence Acceptable risk Possibly usefulVenlafaxine Efficacious Acceptable risk Clinically useful

Other antidepressantsAtomoxetine Insufficient Evidence Acceptable risk InvestigationalNefazodone Insufficient Evidence Unacceptable risk Not useful

Alternative Therapies Omega-3 fatty acid Insufficient Evidence Acceptable risk Investigational

Alternative TherapiesrTMS Insufficient Evidence Acceptable risk Possibly usefulCBT Likely Efficacious Insufficient evidence Possibly useful

Seppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine Review. Movement D iso rde rs, 2019

Anxiety

• Between 30 and 40% of PD patients experience a significant anxiety disorder during the course of the illness. – These anxiety disorders can be expressed as panic,

phobic (particular situations trigger the anxiety), or generalized anxiety.

– Frequently occur with depression• Anxiety can be present with or without depression and is often worse

when the motor symptoms of PD are worse.

There are no RCTs that met inclusion criteria for the treatment of anxiety disorders and therefore no recommended treatment guidelines in PD. Seppi K, et al.

Anxiolytic agents may be contraindicated in PD and may worsen symptoms of the illness. Benzodiazepines are associated with falls, ataxia, and cognitive dysfunction

1. Parkinson’s Community. Non-motor Symptoms of Parkinson’s Disease. https://parkinsons.community/non-motor-symptoms-of-parkinsons-disease. Accessed April 15, 2019.

2. Seppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine Review. Movement Disorders, 2019.

http://parkinsonclinicalguidelines.ca/sites/default/files/PhysicianGuide_Non-motor_EN.pdf

https://parkinsons.community/non-motor-symptoms-of-parkinsons-disease


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Apathy

• Reported in 12% to 16% of PD patients.• Apathy is a reduced emotion, interest in activity or motivation. • It is important to distinguish if the apathy is a symptom of depression or an

independent symptom. • Apathy is most noticeable when PD patients quit participating in activities they

normally enjoyed such as– Exercising– Cooking– Watching TV– Hobbies

• Cause: Degeneration of ‘goal-directed’ areas (frontal subcortical areas) or reward centers (dopamine projections between the ventral tegmental area and nucleus accumbens) may cause apathy.

Drug Class / Intervention Drug / Intervention Efficacy Safety Practice

Implications

Dopamine AgentsPiribedil Likely Efficacious Acceptable risk Possibly usefulRotigotine Unlikely Efficacious Acceptable risk Investigational

Acetylcholinesterase Inhibitors Rivastigmine Efficacious Acceptable risk Possibly useful

1. Parkinson’s Community. Non-motor Symptoms of Parkinson’s Disease. https://parkinsons.community/non-motor-symptoms-of-parkinsons-disease. Accessed April 15, 2019. 2. Seppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine Review. Movement D iso rde rs, 2019.

Impulse Control and Related Disorders

• Impulse Control Disorder (ICD) is characterized by an excessive drive or interest in certain activities. – Examples of these activities include:

• Compulsive shopping• Hypersexuality

• Pathologic gambling• Binge eating• Compulsive cleaning

• Between 10% and 15% of PD patient experience ICD• ICD arises as a side effect from some PD medications, specifically dopamine

agonists.– Reducing or discontinuing dopamine agonists may improve ICD

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Implications

NMDA Antagonists Amantadine Insufficient Evidence Acceptable InvestigationalAnti-opioids Naltrexone Insufficient Evidence Insufficient evidence InvestigationalNonpharmacological Interventions CBT Likely Efficacious Insufficient evidence Possibly useful

1. Parkinson’s Community. Non-motor Symptoms of Parkinson’s Disease. https://parkinsons.community/non-motor-symptoms-of-parkinsons-disease. Accessed April 15, 2019.2. Seppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine Review. Movement D iso rde rs, 2019.

Cognitive Impairment (Parkinson’s Disease Dementia – PDD)

• Up to 70 % of patients with PD will eventually develop cognitive impairment (mild cognitive impairment or dementia)

• Major cause: Lewy Body degeneration of cortical structures• Secondary changes: Alzheimer-like changes and vascular lesions.• Probable risk factors for PDD include:

– Age (>65)– Hallucinations and delusions– Family history of dementia– Depression, advanced disease– REM sleep behavior disorder.

• If the dementia occurs at the same time or within a year of motor symptoms, the diagnosis is formally defined as Dementia with Lewy Bodies,

241. Parkinson Clinical Guideliens. http://parkinsonclinicalguidelines.ca/sites/default/files/PhysicianGuide_Non-motor_EN.pdf. Accessed April 24, 2019.2. Seppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine Review. Movement D iso rde rs, 2019




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Cognitive Impairment & Dementia

• Acetylcholinesterase Inhibitors are useful in treating dementia.– Rivastigmine has been proven efficacious and is considered clinically useful for PD

dementia.• There were no clinically useful interventions identified to treat non-dementia-

level cognitive impairment.

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ImplicationsDEMENTIA

Acetylcholinesterase Inhibitors

Donepezil Insufficient Evidence Acceptable risk Possibly usefulRivastigmine Efficacious Acceptable risk Clinically usefulGalantamine Insufficient Evidence Acceptable risk Possibly useful

NMDA Antagonists Memantine Insufficient Evidence Acceptable risk InvestigativeNONDEMENTIA COGNITIVE IMPAIRMENTAcetylcholinesterase Inhibitors Rivastigmine Insufficient Evidence Acceptable risk Investigational

MAO-B Inhibitors Rasagiline Insufficient Evidence Acceptable risk Investigational

Nonpharmacological Interventions

Transcranial direct-current stimulation (T-DCS)

Insufficient Evidence Insufficient Evidence Investigational

Cognitive rehabilitation Insufficient Evidence Insufficient Evidence InvestigationalSeppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine Review. Movement Disorders, 2019.

Sleep and Insomnia

• Up to 90% of PD patients experience sleep problems at some point in their illness.

• 40 - 90% of PD patients experience sleep maintenance insomnia or difficulty falling and staying sleep. – Most of these individuals do not feel refreshed after awakening from sleep.

• Insomnia in PD is related to:– Immobility – Muscle cramps– Side effects of medication– Frequent need to get up and urinate– Anxiety


Excessive Daytime Sleepiness & Sleep Apnea

• Excessive Daytime Sleepiness– Up to 50% of PD patients experience intense daytime fatigue and sleepiness.– Excessive daytime sleepiness in PD may be due to a variety of factors including:

• Insomnia• Sleep apnea • Depression• Medication

– Dopamine agonists– Cause: Degeneration of regulators of the sleep-wake cycle, particularly the reticular

activating system and circadian rhythm generators.

• Sleep Apnea– As many as 20% of PD patients may have sleep apnea.– Sleep apnea is a major cause of both nighttime insomnia and daytime

sleepiness in PD– Sleep apnea contributes to insomnia and daytime sleepiness by:

• oxygen flow to the brain impaired daytime concentration and thinking



https://www.verywellhealth.com/stroke-risk-factors-4014093


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Treatment for Disorders of Sleep and Wakefulness



ImplicationsINSOMNIA

LevodopaContinuous release formulation of levodopa/carbidopa

Insufficient Evidence Acceptable risk Investigational

Dopamine AgonistsPergolide Insufficient Evidence Acceptable risk Not usefulPerebidil Insufficient Evidence Acceptable risk InvestigationalRotigotine Likely Efficacious Acceptable risk Possibly useful

Hypnotics Eszopiclone Insufficient Evidence Acceptable risk Possibly useful

Melatonin3mg – 5mg Insufficient Evidence Acceptable risk Possibly useful50mg Insufficient Evidence Insufficient Evidence Investigational

Nonpharmacological Interventions CPAP Likely Efficacious Acceptable risk Possibly useful

EXCESSIVE DAYTIME SOMNOLENCE AND SUDDEN ONSET OF SLEEP

Psychoactive DrugsModafinil Insufficient Evidence Insufficient Evidence Possibly usefulCaffeine Insufficient Evidence Acceptable risk Investigational

Nonpharmacological Interventions CPAP Likely Efficacious Acceptable risk Possibly useful

REM Behavioral Disorder

• RBD is predictive of developing PD– Up to 70% of patients with REM Behavior Disorder (RBD) will develop PD within 10

years.• Between 15 and 48% of PD patients also have RBD.• REM sleep, or Rapid Eye Movement sleep, is a form of deep sleep in which

dreams occur. – Physical movement is temporarily paralyzed during REM sleep due to muscle

suppression that occurs to prevent acting out the dream.• Cause: Degeneration of lower brainstem nuclei - particularly in the perilocus

ceruleus area. • Patients with RBD often act out violent or frightening dreams and may:

– Kick– Punch– Talk or Scream

291. https://www.verywellhealth.com/non-motor-symptoms-of-parkinsons-disease-2612179. Accessed April 15, 2019.2. Seppi K, et al. Update on Treatments for Nonmotor Symptoms of Parkinson’s Disease—An Evidence-Based Medicine

Review. Movement Disorders, 2019

There are no RCTs that met inclusion criteria for the treatment of anxiety disorders and therefore no recommended treatment guideline. – Seppi K, et al.

Psychosis

• >50% of patients with Parkinson’s disease will develop PD psychosis during the course of their disease1

• 81% of patients with hallucinations with insight progressed to hallucinations without insight or delusions within 3 years.2

301. Forsaa EB, et al. Arch Neurol. 2010;67:996-1001.2. Goetz CG, et al. Arch Neurol. 2006;63(5):713-716.

19%81%

39 PD Patients Progressed to

Hallucinations Without Insight or Delusions

9 PD Patients Maintained

Hallucinations With Insight

https://www.verywellhealth.com/non-motor-symptoms-of-parkinsons-disease-2612179

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Psychosis is a Non-Motor Symptom of Parkinson’s Disease

HallucinationsPerceptual experiences in

the absence of real external

sensory stimuli1,2

Visual

Auditory

Tactile

Olfactory

Gustatory

DelusionsFixed false beliefs that run

contrary to reality1-4

Jealousy

Persecutory

Somatic

Reference

PsychosisBrain disorder characterized by hallucinations and delusions1

1. Ravina B et al. Mov Disord. 2007;22(8):1061-1068. 2. Centers for Medicare & Medicaid Services. Long-Term Care Facility Resident Assessment Instrument3.0 User’s Manual. Version 1.13. https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/NursingHomeQualityInits/Downloads/MDS-30-RAI-Manual-V113.pdf. Published October 1, 2015. Accessed July 1, 2016. 3. Goldman JG et al. Expert Opin Pharmacother. 2011;12(13):2009-2024. 4. Aarsland D et al. Int J Geriatr Psychiatry. 2001;16(5):528-536.

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Visual Hallucinations are the Most Common Symptom of PDP

Symptomsof PDP1-4

Visual hallucinations16% to 72%

§ Seeing people or animals§ Illusions§ Presence hallucinations Delusions

1% to 14%§ Jealous§ Persecutory§ Reference

Auditory hallucinations

0% to 22%§ Hearing voices

conversing§ Hearing music

Tactile hallucinations

~12%

Somatic hallucinations

~1%

Olfactory hallucinations

~11%

Gustatory hallucinations

~3%

1. Fénelon G et al. Mov Disord. 2010;25(6):763-766. 2. Fénelon G et al. J Neurol Sci. 2010;289(1-2):12-17. 3. Goldman JG et al. Expert Opin Pharmacother. 2011;12(13):2009-2024. 4. Voss T et al. Parkinsonism Relat Disord. 2013;19(3):295-299.

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D2

Muscarinic Acetylcholine Receptors:M1 M2 M3 M4

H1Histamine Receptors:

Adrenergic Alpha Receptors:a1 a 2A a 2B a 2C

TransportersSERT NET

Dopamine Receptors:D1 D2 D3 D4

5HT1A

Serotonin Receptors:

2A 1B 1D 2B 2C 1E 3 5 6 7

Antipsychotic Receptor Binding Properties

1. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. 2013.

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D2

Muscarinic Acetylcholine Receptors:M1 M2 M3 M4

H1Histamine Receptors:

Adrenergic Alpha Receptors:a1 a 2A a 2B a 2C

Dopamine Receptors:D1 D2 D3 D45HT1A

Serotonin Receptors:

2A 1B 1D 2B 2C 1E 3 5 6 7

Common Effects of Antipsychotic Receptor Blockade

Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. Cambridge, UK; 2013.

• Cognitive impairment

• Disinhibition• Mania• Antisocial• Euphoria• Tachycardia• Constipation

• Sedation

• Orthostatic hypotension (falls)

• Depression• Low energy

• Movement disorders (falls)

• Parkinson’s Ds• Endocrine

changes• Antipsychotic

• Anxiolytic

• Antipsychotic

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Receptor Selectivity of Antipsychotic Drugs

• Shown are potencies (in nM) at the indicated receptor targets• Off-target side effects of other antipsychotic drugs are due to

poor selectivity1. Adapted from Hacksell U, et al. Neurochem Res. 2014, 39(10):2008-2017 and data on file.

Receptor Pimavanserin Clozapine Olanzapine Quetiapine Haloperidol Risperidone5-HT2A 0.4 7 2.5 250 50 0.25-HT2B nr 40 80 1100 nr 125-HT2C 16 40 80 nr nr 100

D1 nr 250 100 nd 100 60 Ki (nM)D2 nr 50 4 30 0.1 0.5 ≤ 1D3 nr 200 25 9 0.2 13 ≤ 10H1 nr 0.5 4 5 nr 60 ≤ 100M1 nr 16 60 250 nr nr ≤ 1000M2 nr 400* 150 nd nr nr > 1000M3 nr 6 250 200 nr nrM4 nr 50* 40 150 nr nr

Alpha 1A nr 8 100 nd 40 3Alpha 2A nr 300 nr nr nd 20Alpha 2B nr 50 nr nr nd 50Alpha 2C nr 40 nr nr 50 13

*partial agonist EC50 nr=no response; nd=not done

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Binding Profile of Quetiapine at Different Doses

800 mg 300 mg 50 mg

Papa Bear

Mama Bear

Baby Bear

antipsychotic antidepressant hypnotic

Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. Cambridge, UK; 2013.

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Psychosis Treatment

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• Clozapine and Pimavanserin are both efficacious and considered clinically useful

• Quetiapine was equal to placebo in 5 trials and equal to clozapine in 2 trials (w/o placebo arm) earning it a possibly useful designation

• All antipsychotics have a boxed warning warning of an increased mortality risk in elderly dementia patients and may be associated with QT interval prolongation


Implications

Antipsychotic Clozapine Efficacious Acceptable risk with specialized monitoring Clinically useful

Antipsychotic Olanzapine Not Efficacious Unacceptable risk Not usefulAntipsychotic Quetiapine Insufficient Evidence Acceptable risk Possibly usefulAntipsychotic Pimavanserin Efficacious Acceptable risk Clinically useful

Question 3

Which medications have demonstrated efficacy in treating Parkinson’s Disease psychosis?a) Clozapineb) Pimavanserinc) Quetiapined) a & be) All of the above

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Question 3

Which medications have demonstrated efficacy in treating Parkinson’s Disease psychosis?

a) Clozapineb) Pimavanserinc) Quetiapined) a & be) All of the above

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Autonomic Dysfunction

• Up to 60% of PD patients experience autonomic dysfunction• Downstream neurotransmitter deficits in PD affecting dopamine,

serotonin, acetylcholine, and norepinephrine contribute to:– Orthostatic Hypotension (drop in systolic blood pressure by > 20 mmhg or

diastolic pressure >10 mmhg from supine to standing.)– Sexual Dysfunction– Constipation– Anorexia, Nausea, Vomiting associated with Levodopa or Dopamine

Agonist– Drooling– Urinary Frequency, Urgency, and/or Urge Incontinence


Autonomic Dysfunction Treatments


Symptom Drug / Intervention Efficacy Safety Practice Implications

Orthostatic Hypotension

Fludrocortisone Insufficient Evidence Insufficient evidence Possibly usefulMidodrine Insufficient Evidence Insufficient evidence Possibly useful

Domperiodone Insufficient Evidence Acceptable risk with specialized monitoring Investigational

Yohimbine Non Efficacious Insufficient evidence InvestigationalDroxidopa Efficacious (short term) Acceptable risk Possibly useful

Sexual Dysfunction Sildenafil Efficacious Acceptable risk Clinically useful

Constipation

Macrogol Likely efficacious Acceptable risk Possibly usefulLubiprostone Likely efficacious Acceptable risk Possibly usefulProbiotics & prebiotic fiber Efficacious Acceptable risk Clinically useful

Abdominal massage Insufficient Evidence Insufficient Evidence InvestigationalAnorexia, Nausea, Vomiting associated with Levodopa or Dopamine Agonist

Domperiodone Likely efficacious Acceptable risk with specialized monitoring Possibly useful

Drooling

Ipratropium Spray Insufficient Evidence Insufficient evidence InvestigationalGlycopyrrolate Efficacious Insufficient evidence Clinically usefulBotulinum Toxin A or B Efficacious Acceptable risk with

specialized monitoring Clinically useful

Urinary Frequency, Urgency, and/or Urge Incontinence

Solifenacin Insufficient Evidence Acceptable risk Possibly useful

Fatigue

• Up to 33% of PD patients report fatigue– Often considered fatigue the single most

bothersome symptom• May occur alone or in combination with

depression, apathy or sleep disorders

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ImplicationsMOA-B Inhibitors Rasagiline Efficacious Acceptable risk Possibly useful

Psychoactive DrugsMethylphenidate Insufficient Evidence Insufficient evidence Investigational

Modafinil Insufficient Evidence Insufficient evidence InvestigationalNonpharmacological Interventions Acupuncture Insufficient Evidence Acceptable risk Investigational


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Pain


• Between 33% - 66% of PD patients experience pain directly related to PD– Presents as stiffness, spasms or muscle pain in calves, neck or back

• Decreased pain thresholds in PD can be due to:– Degeneration of dopamine-dependent centers that regulate pain inhibition. – Norepinephrine degeneration in the locus coeruleus

• Adjust PD medication: Increasing dopaminergic therapy may help both primary and secondary pain in PD.

• If the pain is occurring during off periods, reducing fluctuations may be helpful.


ImplicationsDopamine Agonist Rotigotine Insufficient Evidence Acceptable risk Investigational

Opioid Oxycodone-naloxone prolonged release Insufficient Evidence Acceptable risk Possibly useful

Pain may be a signal that dopaminergic medications should be adjusted.

Case Study

• JG is a 78 yo male residing in a nursing home with a history of PD, hypertension, diabetes, Afib, and osteoarthritis. His medications include:

– Losartan 50mg po daily– Dulaglutide .75mg sq weekly– Metformin 750mg po BID– Levodopa/carbidopa 100mg po QID

– Selegiline 5mg po BID– Pramipexole 1mg po TID

• Nursing staff are reporting that JG is increasingly withdrawn, is unwilling to participate in social activities and has lost 5lbs in the past few weeks.

• The DON asks your opinion in how to best manage JG.

• What non-motor symptoms should JG be assessed for?

• How/what would you suggest to improve JG’s symptoms?

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Effective Team Collaboration can Enhance Care for Patients with PD

CMS STATE OPERATIONS MANUAL

483.20 RESIDENT ASSESSMENT (INTENT)

“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

Patient1,2

Nursing staff

Family membersPhysician

Consultant pharmacist

Nursing assistants

MDS coordinator

Activities staff

Behavioral specialists

Social workers

1. Centers for Medicare & Medicaid Services. State Operations Manual. Appendix PP - Guidance to Surveyors for Long Term Care Facilities. https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_pp_guidelines_ltcf.pdf. Updated June 10, 2016. Accessed July 1, 2016. 2. Centers for Medicare & Medicaid Services. Long-Term Care Facility Resident Assessment Instrument 3.0 User’s Manual.Version 1.13. https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/NursingHomeQualityInits/Downloads/MDS-30-RAI-Manual-V113.pdf. Published October 1, 2015. Accessed July 1, 2016.


6/3/19

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QUESTIONS?

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Documents

2019 Non-motor Aspects of Parkinson's Disease · 2019-06-04 · 6/3/19 1 Non-Motor Aspects of Parkinson’s Disease June 2019 Dana Saffel, PharmD, BCGP, CPh, FASCP President, CEO