Parkinson, Diagnos$kk og implikasjoner i forhold $l

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Parkinson, Diagnos$kk og implikasjoner i forhold $l
Parkinson, Diagnos-kk og implikasjoner i forhold -l psykiatriske lidelser og deres behandling
Dag Årsland Karolinska Ins0tutet Stavanger Universitetssjukehus Parkinsons sykdom-­‐lynkurs
•  Parkinsonisme -­‐ 2/4 kardinalsymptom: hviletremor, rigiditet, bradykinesia, s0llingsforandringer (posture) •  Patologisk definisjon: nevrontap dopaminerge nevroner I substan0a nigra, og Lewylegemer i gjenværende •  Ca 6000 i Norge, insidens 12/100 000/år, aldersavhengig, gene0sk •  Overlevelse lite påvirket i Norge •  Ikke-­‐motoriske symptomer vanlig og vik0g, inkl psykiatriske •  PD er modell for “Nevropsykiatrisk sykdom” Dopamine functions
Dopaminergic systems
• movement
• memory
• pleasurable reward
• behavior and cognition
• attention
• inhibit prolactin production
• sleep
• mood
• learning
Dopamine transporter SPECT: Imaging the presynap0c dopaminergic nigro-­‐striatal system 13-­‐03-­‐15 Hva er vik-g for psykiatere?
•  Vite at psykiatriske symptomer er hyppige og vik0ge ved PD •  Kunne diagnos0sere og behandle disse •  Kunne diagnos0sere PD og kjenne 0l de vik0gste an0parkinson-­‐
medisinene og deres effekt og bivirkninger Parkinsons sykdom: 3 myter
1.  PD is a nigro-­‐striatal disorder •  Mul0ple systems are involved; neocortex, thalamus, hippocampus, amygdalae, brain stem 2.  PD is a dopaminergic deficit disorder •  Cholinergic, noradrenergic, serotonergic, glutamatergic Psykiatriske deficits are common 3.  PD is a motor disorder Symptomer •  Non-­‐motor symptoms are common, occur early, and have major clinical impact 4.  PD is an a-­‐synucleinopathy •  Amyloid-­‐ and tau-­‐pathology also PD-related brain changes relevant for NPS
Transmi(er changes: Dopamine Serotonin Noradrenaline Acetylcholine Glutamate Braak et al 2006 Høy forekomst av psykiatrisk sykelighet ved PD
16% had 1, 20% had 2, 25% had 3+ NPI items Motor hyper
Irritability
Disinhibition
60
PD
50
NC
40
30
20
Apathy
10
Euphoria
0
Anxiety
Dysphoria
Agitation
Other common NPS: REM-­‐sleep behavioural disorder-­‐ca 30% Impulse control disorders-­‐ ca 15% Hallucination
Delusions
0
5
10
15
20
NPI frequency (% )(n=139) Aarsland et al. J Neurol Neurosurg Psych 1999;67:492-6
25
30
35
40
NMSQuest: Interna0onal study Chaudhuri et al. Mov Disord 2006 Impulskontrollforstyrrelser (ICD) ved PD
•  Gambling •  Seksuell aierd, endring •  Patologisk shopping •  Spiseforstyrrelse •  Hobbyism •  Punding •  Vandring •  Avhengighet av dopaminerge medikament Årsaker -l psykiske symptomer ved Parkinsons sykdom
Komorbiditet
Arv
Generell
psykososial
belastning
Psykiske
symptomer
Tidligere (latent) psykisk
lidelse
Hjerneforandringer
Medikamenter
DBS
Psykologisk reaksjon (på
diagnose, symptomer,
funksjonssvikt)
Consequences of NPS
Reduced quality of life
Caregiver stress
(Herlofson 1998,1999, 2000)
(Aarsland 2001)
Progression of PD
(Starkstein 1992)
Nursing home
placement (Aarsland 2000)
Psychiatric
symptoms
Cognitive
impairment
(Troster 1995)
Mortality
(Marder 1991)
An-parkinson-­‐medisiner og mentale bivirkninger
Preparat Medisin Mental bivirkning Levo-­‐dopa Madopark, Sinemet Stalevo (+COMT-­‐I) Kognisjon, psykose, delirium Dopamin-­‐agonister Apomorfin, pramipexole (Sifrol) ropinirol, ro0go0n pramipexole Kognisjon, psykose, delirium, impuls ICD, søvn-­‐alakker An0depressiv effekt? MAO-­‐ inhibitor Rasagilin, selegilin An0-­‐depressiv effekt? DBS Impulsivitet, depresjon, suicidalitet? Psychiatric assessment in PD
•  Unstructured interview •  Structured diagnos0c interview (SCID-­‐I) •  Ra0ng scales •  Observer-­‐based, carer-­‐based, or self-­‐report •  Spectrum (NPI, NMSS, UPDRS) or symptom-­‐specific •  Aims of scales: • 
• 
• 
• 
Screening Diagnosis Severity Change Management of NPS -­‐ General aspects
•  Diagnosis: •  Severity and profile of neuropsychiatric symptoms •  Exclude other causes (drugs, physical disease, stressors) •  Other brain disease: DLB, AD, schizophrenia •  Management: •  General: •  Remove contribu0ng factors •  Modify an0parkinson treatment •  Informa0on, coping and other psychological strategies •  Symptoma0c drug treatment? Psychotropic drugs in PD: Evidence
•  Demen0a: level 1 •  Depression: level 1 •  Psychosis: level 1 •  Apathy, RBD, ICD: some evidence •  Anxiety: very lille evidence Depresjonsbehandling -­‐ PD
Two key an-depressant studies
Nortriptylin, paroxe0ne, PLA Menza 2009
Venlafaxine, paroxe0ne, PLA Richard 2012
Lancet Neurol 2010
Non-drug alternatives
• 
• 
• 
• 
1. 
2. 
3. 
ECT increases dopaminergic activity and may improve
depression and parkinsonism 1
Supportive psychotherapy/CBT, especially in early
stage2
DBS, rTMS
multidisciplinary rehabilitation (logopedics,
physiotherapy, assessment for social services need,
psychotherapy, relaxation, diet) 3
Kennedy et al. J Neuropsych Clin Neurosci 2003;15:407-­‐21. Dobkin et al. Am J Psychiatry 2011 Trend P et al.: Clin Rehabil 2002; 16(7):717-­‐25 Treatment of Depression in Clinical Prac-ce • Suppor0ve talking, CBT • Adjust an0park-­‐drugs: Pramipexol • If symptoma0c drug treatment indicated: • SSRI, or venlafaxine, or nortriptyline • Severe treatment resistant: consider alterna0ves including ECT, transcranial s0mula0on Antipsychotics in PD: RCT
•  Olanzapine and Risperidon: minor effects, motor
worsening
•  Clozapin: 2 positive studies, well tolerated
•  Quetiapin: Many positive open studies, 4 RCT- 3
negative, 1 positive
•  Possible alternatives:
•  Rivastigmine?
•  Memantine?
•  Pimavanserin?
Quetiapine for PD-psychosis:
time to discontinuation
Shotbolt et al 2009
Pimavanserin for PD-psychosis
RCT, placebo-ctr
PIM (5HT2 inverse agonist)
40 mg/d fixed dose
6w (2w run-in)
N=199, Age:72, MMSE: 26
Primary outcome: SAPS-PD
Well tolerated
Drop-out due to AE:
PIV: 10 (4<10d for psychosis)
PLA: 2
Cummings et al Lancet 2014
SAPS-PD
d=0.5
CGI-severity
CGI-change
Treatment of psychosis in clinical practice
• 
• 
• 
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• 
Consider secondary factors
Consider changing PD-drug treatment
Information, coping strategies
Consider ChEI (if cognitively impaired)
Consider quetiapine or clozapine if needed
(low doses, short duration)
•  Monitor AE, incl cQT, BMI, cholesterol, glucose, BP
Behandling av andre psykiatriske symptomer
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• 
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Demens: kolinesterasehemmer , (memantin) (Level 1)
Impulskontrollforstyrrelse: dose-reduksjon av DA-agonist
REM-søvn atferdsforstyrrelse: melatonin, klonazepam
Angst: små doser BZD, SSRI
Oppsummering: Psykiatriske symptomer
ved Parkinson
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• 
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Hyppig, stor klinisk betydning
Under-diagnostisert og under-behandet
Generelle strategier er viktig
Level-1 evidens finnes for psykose og depresjonsbehandling
Risiko for bivirkninger er stor