Presentation is loading. Please wait.

Presentation is loading. Please wait.

1 Current Concepts and Perspectives in Parkinson’s Disease Anthony H.V. Schapira, DSc, MD, FRCP, FMedSci Professor of Neurology University Department of.

Similar presentations


Presentation on theme: "1 Current Concepts and Perspectives in Parkinson’s Disease Anthony H.V. Schapira, DSc, MD, FRCP, FMedSci Professor of Neurology University Department of."— Presentation transcript:

1 1 Current Concepts and Perspectives in Parkinson’s Disease Anthony H.V. Schapira, DSc, MD, FRCP, FMedSci Professor of Neurology University Department of Clinical Neurosciences Royal Free and University College Medical School, and Institute of Neurology University College London London, UK Matthias R. Lemke, MD Professor of Psychiatry Centre of Psychiatry and Neurology Rhine Clinic Bonn Bonn, Germany

2 2 Contents Section I – Epidemiology, Pathophysiology and Diagnosis of Parkinson’s Disease –Introduction and Historical PerspectivesIntroduction and Historical Perspectives –DefinitionDefinition –EpidemiologyEpidemiology –Pathophysiology and GeneticsPathophysiology and Genetics –Diagnosis and SymptomsDiagnosis and Symptoms –Differential DiagnosisDifferential Diagnosis –Clinical Evaluation – Scales and ScoresClinical Evaluation – Scales and Scores –Disease BurdenDisease Burden Section II – Treatment of Parkinson’s Disease –General PrinciplesGeneral Principles –Drug Therapy in Parkinson’s DiseaseDrug Therapy in Parkinson’s Disease –SurgerySurgery –Management of Non-Motor SymptomsManagement of Non-Motor Symptoms –Disease Modification (Neuroprotection)Disease Modification (Neuroprotection) –Physical TherapyPhysical Therapy –Future TreatmentsFuture Treatments Section III – Depression in Parkinson’s Disease –OverviewOverview –Epidemiology and PathophysiologyEpidemiology and Pathophysiology –BurdenBurden –Diagnosis and EvaluationDiagnosis and Evaluation –TreatmentTreatment

3 3 Section I Epidemiology, Pathophysiology and Diagnosis of Parkinson’s Disease

4 4 Section I – Summary Introduction and Historical Perspectives Definition Epidemiology Pathophysiology and Genetics Diagnosis and Symptoms Differential Diagnosis Clinical Evaluation – Scales and Scores Disease Burden

5 5 Introduction and Historical Perspectives

6 6 Parkinson’s Disease – Introduction Parkinson’s disease: a progressive neurodegenerative disease –Early clinical features: Typical motor symptoms result from the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain Other dopaminergic structures (e.g. the limbic system) may be affected, resulting in early symptoms such as depression –As the disease progresses, additional brain areas degenerate, resulting in non-dopaminergic, non-motor features Introduction of levodopa treatment has resulted in significant improvements in both quality of life (QoL) and life expectancy Current challenges: –Prevention of motor complications –Treatment of non-motor features –Slowing of disease progression Schapira AHV, Olanow WC. In: Principles of Treatment in Parkinson’s Disease; 2005.

7 7 1500s: Leonardo da Vinci identifies a “paralytic” condition involving trembling limbs. 1700s: John Hunter, a British surgeon, describes patients with ‘severe tremor on awakening who do not complain from tiredness in the muscles.’ 1817: James Parkinson publishes the Essay on the Shaking Palsy, the first and definitive clinical description of paralysis agitans, the condition that subsequently comes to bear his name. First Description of the “Shaking Palsy” as a Clinical Syndrome by James Parkinson in 1817 Parkinson J. An Essay on the Shaking Palsy; 1817.

8 8 Parkinson’s Disease – Historical Perspective James Parkinson, 1817 –Shaking Palsy Detailed analyses of the clinical effects Jean-Martin Charcot, 1867 –Clinical classification and differential diagnosis –Proposes the eponymous label “Parkinson’s disease” –First effective treatment: belladonna alkaloids Friedrich Heinrich Lewy, 1912 –Intracytoplasmic inclusions: the hallmark of Parkinson's disease Constantin Trétiakoff, 1919 –Cell degeneration in the substantia nigra Herbert Ehringer and Oleh Hornykiewicz, 1960 –Dopamine deficiency in the striatum Parkinson J. An Essay on the Shaking Palsy; Lewy FH. In: Handbuch der Neurologie; 1912: Trétiakoff C. PhD Thesis, University of Paris; Ehringer H, Hornykiewicz O. Klin Wochenschr 1960;38:

9 9 Definition

10 10 Parkinson’s Disease – Definition Parkinson’s disease: –A clinical and neuropathological entity characterised by: Bradykinesia Rigidity Tremor –Onset usually asymmetric and responsive to dopaminergic treatment –No historical or examination clues to indicate secondary parkinsonism (e.g. Wilson’s disease, multiple system atrophy) –The brunt of the early pathology falls on the dopaminergic nigrostriatal pathway Parkinsonism: –Any bradykinetic-rigid syndrome that is not Parkinson’s disease Samii A, et al. Lancet 2004;363: Nutt JG, Wooten GF. N Engl J Med 2005;353:

11 11 Epidemiology

12 12 de Lau LM, Breteler MM. Lancet Neurol 2006;5: © 2006, with permission from Elsevier. Epidemiology of Parkinson’s Disease – Prevalence Population-based prevalence studies of Parkinson’s disease Idiopathic Parkinson’s disease is a common age- related condition Rotterdam, the Netherlands Central Spain Copiah County, USA France Sicily Aragon, Spain Europe China Taiwan, China Prevalence (%) Age (years)

13 13 Epidemiology of Parkinson’s Disease – Incidence Idiopathic Parkinson’s disease is uncommon before the age of 50 There is a sharp increase in incidence after the age of Spain Rotterdam, the Netherlands Hawaii, USA Manhattan, USA Taiwan, China London, UK Rochester, USA Italy China Incidence Rate (cases per 100,000 person-years) Prospective population-based incidence studies of Parkinson’s disease Age (years) de Lau LM, Breteler MM. Lancet Neurol 2006;5: © 2006, with permission from Elsevier.

14 14 Mortality in Parkinson’s Disease Studies of mortality hazard ratios in patients with Parkinson’s disease Morens (1996)Honolulu (USA)Cohort studyPopulation92Incident * Louis (1997)New York (USA)Case-controlHospital180Prevalent ( ) Hely (1999)Sydney (Australia)Case seriesHospital130Prevalent ( )** Berger (2000)Europe (5 countries)5 cohort studiesPopulation252PrevalentVariable2.30 ( ) Morgante (2000)Sicily (Italy)Case-controlPopulation59Prevalent ( ) Guttman (2001)Ontario (Canada)Case-controlRegister15,304Prevalent ( ) Elbaz (2003)Olmsted (USA)Case-controlRegister196Incident ( ) Fall (2003)Ostergotland (Sweden)Case-controlPopulation170Prevalent ( ) Herlofson (2004)Rogaland (Norway)Case seriesPopulation245Prevalent ( )* Hughes (2004)Leeds (UK)Case-controlHospital90Prevalent ( ) de Lau (2005)Rotterdam (Netherlands)Cohort studyPopulation166Both ( ) Location (country)Type of studySource of studyCasesType of casesFollow-up (years)HR (95% CI) * In people aged years (95% CI not provided); ** standardised mortality ratio; HR, mortality hazard ratio. de Lau LM, Breteler MM. Lancet Neurol 2006;5:

15 15 Pathophysiology and Genetics

16 16 Pathology of Parkinson’s Disease – Macroscopy A: Rostral (R), intermediate (I) and caudal (C) transverse planes of the mesencephalon on a sagittal MRI of the brainstem. B: MRI of the intermediate transverse plane. Arrows show the emergence of the third cranial nerve fibres. NormalParkinson’s disease Normal substantia nigraDepigmentation of substantia nigra Damier P, Brain 1999;122: Images courtesy of JJ Hauw, Department of Neuropathology, Hôpital de la Pitié-Salpêtrière, Paris, France.

17 17 Loss of pigmented dopaminergic neurons Normal substantia nigra Normal Degeneration of nigral cells Parkinson’s disease Pathology of Parkinson’s Disease – Microscopy Histopathological hallmark: Lewy bodies Gibb WR, Lees AJ. Neuropathol Appl Neurobiol 1989;15: Images courtesy of JJ Hauw, Department of Neuropathology Hôpital de la Pitié-Salpêtrière, Paris, France. Images courtesy of É tienne Hirsch, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France.

18 18 Control Parkinson’s disease SNpc SNpl rn A8 cp PGSCGS Abbreviations: SNpc, substantia nigra pars compacta; SNpl, substantia nigra pars lateralis; A8, dopamingergic group A8; rn, red nucleus; PGS, periaqueductal gray substance; cp, cerebellus peduncule; CGS, central gray substance Staining for tyrosine hydroxylase on a section of human post-mortem mesencephalon Neuronal Cell Death and Motor Symptoms Hirsch E, et al. Nature 1988;334:345-8.

19 19 Multicentric Neurodegeneration Lang AE, Obeso JA. Lancet Neurol 2004;3: © 2004, with permission from Elsevier. STN subthalamic nucleus GPi globus pallidus interna Gpeglobus pallidus externa SNpcsubstantia nigra pars compacta VTAventral tegmental area Dopamine Parkinson’s disease brain Serotonin Noradrenaline GPi GPe Putamen STN Amygdala Thalamus Substantia innominata Caudate SNpc VTA Locus coeruleus Raphe nuclei Pedunculopontine nucleus

20 20 Basal Ganglia Circuit Cortex GPe STN GPi SNpr PPN VL Putamen SNpc Cortex GPe STN GPi SNpr PPN VL Putamen SNpc Cortex GPe STN GPi SNpr PPN VL Putamen SNpc (a)(b)(c) NormalParkinsonismLevodopa dyskinesia DA Excitatory Neuronal FiringInhibitory Neuronal Firing Olanow CW. Annu Rev Med 2004;55: Copyright © 2004 by Annual Reviews. All rights reserved

21 21 Cell Death in Parkinson’s Disease Apoptotic DA neuron Healthy DA neuron Cell death program Free radicals Iron Nitric oxide Excitotoxicity Complex I deficiency Proteasomal inhibition Glial factors Inflammation Activation signal Genetics  Environment ? Damaged DA neuron Abbreviation: DA, dopamine Courtesy of Andreas Hartmann, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France

22 22 Potential Neuroprotective Approaches Abbreviations: AMPA,  -amino-3-hydroxy-5- methyl-4-isoxazolepropionate; DAT, dopamine transporter; GAPDH, glyceraldehyde-3- phosphate dehydrogenase; iNOS, inducible nitric oxide synthase; MAO-B, monoamine oxidase B; MLK, mixed lineage kinase; MPTP, 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; PARP, poly (ADP-ribose) polymerase; ROS, reactive oxygen species; PPAR , peroxisome proliferator- activated receptors-gamma Reprinted by permission from Macmillan Publishers Ltd: Dawson TM, Dawson VL. Nat Neurosci 2002;(5 Suppl): , © Pathways involved in MPTP toxicity and potential neuroprotective drugs or strategies NMDA receptor Ca 2+ Na + /Ca 2+ NMDA antagonistsAMPA AMPA receptor MAO-B inhibitors DAT inhibitors MPTP MPP+ DA transporter MAO-B H Complex I ROS, ONOO- ROS scavengers Energy mimetics Coenzyme Q 10 Metal chelators nNOS inhibitors PARP inhibitors Iron Heavy metals? Necrotic Death Pathways nNOS activation DNA damage PARP activation Apoptotic Death Pathways Generation of the apoptosome Caspase activation p53 activation ER stress Cell death Inhibitors of  -syn toxicity Caspase inhibitors Inhibitors of ER stress response p53 inhibitors MLK inhibitors GAPDH translocation inhibitors Minocycline iNOS inhibitors PPAR  inhibitors Microglial activation ROS  –syn Altered  -syn Conformation oligomer/fibrils Cell death

23 23 Genetic Factors in Parkinson’s Disease Gene Locus (Chromosomal position) Age of onset InheritanceClinical phenotype  -synuclein PARK1 (4q21-q23)YoungADSimilar to IPD, rapid progression ParkinPARK2 (6q25.2-q27)YoungAR Symptomatic improvement following sleep, mild dystonia, good response to levodopa, slow progression UCHL1PARK5 (4p14) Similar to IPD ADSimilar to IPD PINK1PARK6 (1p35-p36)YoungARBenign course, levodopa-responsive DJ1PARK7 (1p36)YoungARLevodopa-responsive LRRK2PARK8 (12q12) Similar to IPD AD Similar to IPD (LRRK2 mutations are the commonest cause of either familial or ‘sporadic’ PD) PARK9, 10, and 11 (1p36, 1p32, and 2q36-q37, respectively ) AR (PARK9) PARK9: spasticity, dementia and supranuclear palsy PARK10: similar to IPD Abbreviations: AD, autosomal dominant; AR, autosomal recessive; IPD, idiopathic Parkinson’s disease; LRRK2, leucine-rich repeat kinase 2; PARK2, parkin-encoding gene; PINK1, PTEN induced putative kinase 1; UCHL1, ubiquitin carboxyl-terminal esterase L1; UPS, ubiquitin-proteasome system. Farrer MJ. Nat Rev Genet 2006;7: de Lau LM, Breteler MM. Lancet Neurol 2006;5:

24 24 Diagnosis and Symptoms

25 25 Diagnostic Criteria Clinical diagnostic criteria for idiopathic Parkinson’s disease Clinically possible One of: Asymmetric resting tremor Asymmetric rigidity Asymmetric bradykinesia Clinically probable Any two of: Asymmetric resting tremor Asymmetric rigidity Asymmetric bradykinesia Clinically definite Criteria for clinically probable, plus Definitive response to antiparkinson drugs Exclusion criteria Exposure to drugs that can cause parkinsonism, such as neuroleptics, some anti-emetic drugs, tetrabenazine, reserpine, flunarizine and cinnarizine Cerebellar signs Corticospinal tract signs Eye-movement abnormalities other than slight limitation of upward gaze Severe dysautonomia Early moderate to severe gait disturbance or dementia History of encephalitis, recurrent head injury (such as seen in boxers) Evidence of severe subcortical white-matter disease, hydrocephalus or other structural lesions on MRI that may account for parkinsonism Samii A, et al. Lancet 2004;363: Calne DB, et al. Ann Neurol 1992;32(Suppl):S Ward CD, Gibb WR. Adv Neurol 1990;53:245-9.

26 26 Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5: Non-Motor Symptoms of Parkinson’s Disease (1) Neuropsychiatric symptoms Depression, apathy, anxiety Anhedonia Attention deficit Hallucinations, illusions, delusions Dementia Obsessional behaviour (can be drug-induced) and repetitive behaviour Confusion Delirium (could be drug-induced) Panic attacks Sleep disorders Restless legs and periodic limb movements Rapid eye movement (REM) sleep behaviour disorder and REM loss of atonia Non-REM sleep-related movement disorders Excessive daytime somnolence Vivid dreaming Insomnia Sleep-disordered breathing Autonomic symptoms Bladder disturbances Urgency Nocturia Frequency Sweating Orthostatic hypotension Falls related to orthostatic hypotension Coat-hanger pain Sexual dysfunction Hypersexuality (likely to be drug-induced) Erectile impotence Dry eyes

27 27 Non-Motor Symptoms of Parkinson’s Disease (2) Gastrointestinal symptoms (overlap with autonomic symptoms) Drooling Ageusia Dysphagia and choking Reflux, vomiting Nausea Constipation Unsatisfactory voiding of bowel Faecal incontinence Sensory Symptoms Pain Paraesthesia Olfactory disturbance Other symptoms Fatigue Diplopia Blurred vision Seborrhoea Weight loss Weight gain (possibly drug-induced) Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5:

28 28 Neuroimaging in Parkinson’s Disease Diagnosis of Parkinson’s disease (PD) is mainly clinical MRI can be helpful in detecting other causes of parkinsonism such as vascular parkinsonism Neuroimaging of the nigrostriatal dopaminergic pathway: Single photon emission computed tomography (SPECT) with [ 123 I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) and positron emission tomography (PET) with 6-[ 18 F]fluoro-L-dopa (F-DOPA) Mostly used in therapeutic trials measuring disease progression SPECT may be helpful to distinguish PD from essential tremor (ET) Tolosa E, et al. Lancet Neurol 2006;5: Samii A, et al. Lancet 2004;363:

29 29 Differential Diagnosis

30 30 Classification – Differential Diagnosis of Parkinsonism Idiopathic –Parkinson’s disease: approximately 75% of cases Symptomatic –Drug-induced: up to 20% of cases Dopamine blockers: major neuroleptics, metoclopramide –Hydrocephalus –Metabolic (hepatocerebral) degeneration, parathyroid disorders –Structural lesions of the brain: tumour, infarct or haemorrhage –Toxins (carbon monoxide, MPTP) –Infections Hereditary disorders –Frontotemporal dementias –Dystonias –Huntington’s disease –Wilson’s disease –Inherited ataxias Parkinson-plus syndromes –Dementia with Lewy bodies –Multiple system atrophy (olivopontocerebellar atrophy, Shy- Drager syndrome, striatonigral degeneration) –Progressive supranuclear palsy –Corticobasal degeneration Colcher A, Simuni T. Med Clin North Am 1999;83: Hughes AJ, et al. J Neurol Neurosurg Psychiatry 1992;55: Hughes AJ, et al. Brain 2002;125: Bower JH, et al. Neurology 1999;52:

31 31 Parkinson’s Disease and Essential Tremor Differential criteria –Essential tremor (ET): Tremor with no other sign of parkinsonism Presence of a head or voice tremor Strong and usually autosomal dominant family history Improvement with alcohol –Parkinson’s disease (PD): Resting tremor Clear asymmetry Presence of bradykinesia or rigidity Leg tremor Improvement with dopaminergic treatment Both PD and ET have a kinetic and rest component Kinetic tremor can interfere with rapid alternating movements Cogwheel rigidity is rare in ET Deuschl G, et al. Mov Disord 1998;13(Suppl 3):2-23. Chaudhuri KR, et al. J Neurol Neurosurg Psychiatry 2005;76:115-7.

32 32 Clinical Evaluation – Scales and Scores

33 33 Parkinson’s Disease Scales and Scores – Hoehn and Yahr Staging of Parkinson’s Disease Stage One 1. Signs and symptoms on one side only 2. Symptoms mild 3. Symptoms inconvenient but not disabling 4. Usually presents with tremor of one limb 5. Friends have noticed changes in posture, locomotion and facial expression Stage Two 1. Symptoms are bilateral 2. Minimal disability 3. Posture and gait affected Stage Three 1. Significant slowing of body movements 2. Early impairment of equilibrium on walking or standing 3. Generalised dysfunction that is moderately severe Stage Four 1. Severe symptoms 2. Can still walk to a limited extent 3. Rigidity and bradykinesia 4. No longer able to live alone 5. Tremor may be less than earlier stages Stage Five 1. Cachectic stage 2. Invalidism complete 3. Cannot stand or walk 4. Requires constant nursing care Hoehn MM, Yahr MD. Neurology 1967;17:

34 34 100% – Completely independent. Able to do all chores without slowness, difficulty or impairment. 90% – Completely independent. Able to do all chores with some slowness, difficulty or impairment. May take twice as long. 80% – Independent in most chores. Takes twice as long. Conscious of difficulty and slowing. 70% – Not completely independent. More difficulty with chores. Three to four times as long on chores for some. May take large part of day for chores. 60% – Some dependency. Can do most chores, but very slowly and with much effort. Errors. Some chores impossible. 50% – More dependent. Help with 1/2 of chores. Difficulty with everything. 40% – Very dependent. Can assist with all chores, but do few alone. 30% – With effort, now and then does a few chores alone or begins alone. Much help needed. 20% – Nothing alone. Can do some slight chores with some help. Severe invalidity. 10% – Totally dependent, helpless. 0% – Vegetative functions such as swallowing, bladder and bowel function are not functioning. Bedridden. Gillingham FJ, Donaldson MC, eds. Third Symposium of Parkinson’s Disease. Edinburgh, Scotland: E&S Livingstone; 1969: Parkinson’s Disease Scales and Scores – Schwab and England Activities of Daily Living

35 35 I.Mentation, Behaviour, Mood Non-motor symptoms with one question on intellect, one on thought disorders, one on depression, and one on motivation II.Activities of Daily Living (ADL) 13 questions, almost all about motor symptoms Two questions on salivation (autonomic function) and sensory complaints III.Motor Examination Motor symptoms IV.Treatment Complications Yes/no questions on anorexia, nausea, vomiting and sleep A total of 199 points are possible, with 199 representing total disability and 0 meaning no disability Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. Mov Disord 2003;18: Parkinson’s Disease Scales and Scores – Unified Parkinson’s Disease Rating Scale (UPDRS)

36 36 Disease Burden

37 37 Burden of Parkinson’s Disease Reduced quality of life 1 Higher susceptibility to depression and cognitive impairment 2 Increased risk for comorbidities such as pneumonia 2 Increased medical expenses (physician visits and emergency care) 2 Caregiver burden and risk of early nursing home placement 2,3 1. Dodel RC, et al. Pharmacoeconomics 2001;19: Parashos SA, et al. Mayo Clin Proc 2002;77: Carter JH, et al. Mov Disord 1998;13:20-8.

38 38 Section I – Conclusion Parkinson’s disease affects about 1% of adults over the age of 60. Clinical features: –Motor symptoms define the disorder: bradykinesia, rigidity and rest tremor. –Non-motor symptoms: autonomic dysfunction, cognitive and other psychiatric changes, sensory symptoms and sleep disturbances. Therapeutic challenge The diagnosis of Parkinson’s disease is clinical but can be supported in certain circumstances with SPECT imaging. Parkinson’s disease is a complex, multifactorial disease. –Several genetic causes have been characterised and appear to result in downstream effects that include abnormal free radical metabolism, defective mitochondrial function, and dysfunction of the ubiquitin proteasomal system. –The determination of mechanisms of dopamine neurons has major consequences on the development of drugs slowing cell degeneration and improving symptomatology.

39 39 Section II Treatment of Parkinson’s Disease

40 40 Section II – Summary General Principles Drug Therapy in Parkinson’s Disease Surgery Management of Non-Motor Symptoms Disease Modification (Neuroprotection) Physical Therapy Future Treatments

41 41 General Principles

42 42 Accurate and early diagnosis: an opportunity for coherent long- term treatment strategy –Diagnostic accuracy as high as 98.5% based on clinical criteria alone –Single photon emission computed tomography (SPECT) useful to differentiate PD from essential tremor Purpose of treatment: –Symptomatic treatment of motor features –Prevention of motor complications –Symptomatic control of motor complications –Symptomatic treatment of non-motor features –Prevention of disease progression: disease modification (neuroprotection) General Principles for the Treatment of Parkinson’s Disease Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; Hughes AJ, et al. Brain 2002;125:

43 Evidence on Efficacy of Treatment Interventions Category evaluatedLevodopa COMT inhibitors MAO-B inhibitors Anticholinergics & amantadine Dopamine agonists (details on slide 70)slide 70 Monotherapy in early PD √NA√± √ (pramipexole, ropinirole, pergolide) Combination with levodopa in advanced PD NA√(MF)?± √ (pramipexole, bromocriptine, cabergoline, pergolide) Treatment of motor complications -√(MF)? √ (D; amantadine) - (MF) √ (pramipexole, ropinirole, pergolide) Prevention of motor complications -? - (D) ? (MF) ? √ (pramipexole, ropinirole, cabergoline) Imaging indicates slowed loss of dopamine neurons -(?)??? √ (pramipexole, ropinirole) √ efficacious (maximum strength of evidence) ±probably efficacious - not efficacious ?insufficient data 0no studies Ddsykinesias MFmotor fluctuations COMTcatechol-O-methyltransferase MAO-Bmonoamine oxidase B DAsdopamine agonists Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;20: Fahn S, et al. N Engl J Med 2004;351: Horstink M, et al. Eur J Neurol 2006;13: Horstink M, et al. Eur J Neurol 2006;13:

44 44 Drug Therapy in Parkinson’s Disease

45 45 Drug Therapy in Parkinson’s Disease – Summary Therapeutic Approaches and Strategies Levodopa –Efficacy –Management of motor complications Dopamine Agonists –Clinical pharmacology –Efficacy –Tolerability Other Drug Therapies for Parkinson’s Disease –MAO-B* inhibitors –Anticholinergics –Amantadine * Monoamine oxidase B

46 46 Drug Therapy in Parkinson’s Disease Therapeutic Approaches and Strategies

47 47 Drug Therapy in Parkinson’s Disease – Initiation Traditionally –When symptoms interfere with social, domestic or professional life Patient judgment Physician advice to prevent: –Unnecessary prolongation of disability –Impaired quality of life Alternative approach –Consider advantages of early treatment Symptomatic relief of motor symptoms Improvement of quality of life Avoidance of irreversible motor programme loss Potential disease modification (neuroprotection) with some agents –Delay levodopa therapy and use alternatives to avoid or delay motor complications Nutt JG, Wooten GF. N Engl J Med 2005;353: Schapira AH, Obeso J. Ann Neurol 2006;59:

48 48 Drug Therapy – Symptomatic Treatment of Motor Symptoms Dopaminergic agents –Levodopa Levodopa + carbidopa Levodopa + benserazide COMT inhibitors* (entacapone, tolcapone) –Dopamine agonists Non-ergot † –Pramipexole –Ropinirole –Rotigotine –Piribedil Ergot –Bromocriptine –Pergolide –Cabergoline –Dihydroergocryptine –Lisuride –Selective MAO-B ‡ inhibitors Selegiline Rasagiline Non-dopaminergic agents –Anticholinergic agents: Trihexyphenidyl Benztropine –NMDA § antagonists Amantadine * catechol-O-methyltransferase inhibitors; always used in conjunction with levodopa † apomorphine is available for subcutaneous injections and may be useful in patients with levodopa-related motor fluctuations ‡ monoamine oxidase type-B § N-methyl-D-aspartate Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.

49 49 Algorithm for the Management of Early Parkinson’s Disease 1.Dopamine agonists are not recommended in patients with cognitive disturbance. 2.Gradual dose escalation is important for patient compliance and maintaining motor control. 3.Dopamine agonist dosage should be gradually increased over time in order to maintain motor control. 4.Levodopa introduction is necessary in the majority of patients to maintain and optimise motor control. Adapted from Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005:127. © 2005, with permission from Elsevier. Diagnosis Decision to treat YES Evaluate degree of disability Moderate motor disability No cognitive disability Begin dopamine agonist Treat to maximum response or tolerance of dopamine agonist Consider MAO-B inhibitor Disability requiring additional therapy NO Review Mild motor disability Begin dopamine agonist or MAO-B inhibitor * Additional symptomatic benefit required Begin dopamine agonist if not already started Titrate to maximum response or tolerance of dopamine agonist Disability requiring additional therapy Begin levodopa 1, * Monoamine oxidase B

50 50 Adapted by permission from Macmillan Publishers Ltd: Youdim MB, et al. Nat Rev Neurosci 2006;7: © The Basis for Symptomatic Drug Therapy of Motor Symptoms in Parkinson’s Disease Abbreviations: DDC, dopa decarboxylase; TH, tyrosine hydroxylase; L-DOPA, levodopa; MAO-A, monoamine oxidase A; MAO-B, monoamine oxidase B; COMT, catechol-O- methyltransferase; D, dopamine receptors; 3-OMD, 3-O-methyldopa Dopamine transporter Postsynaptic terminal in the striatum Synaptic vesicle DopamineL-DOPA Tyrosine MAO-A TH DDC Presynaptic terminal from the substantia nigra D D D D D Blood-brain barrier L-DOPATyrosine 3-OMD Dopamine Entacapone Benzerazide Carbidopa DDC COMT Moclobemide Selegiline Rasagiline Lazabemide Safinamide MAO-A MAO-B MAO-A MAO-B COMT Glial cell Astrocyte

51 51 Main Mechanisms of Action of Therapeutic Interventions in Parkinson’s Disease Action Drugs Promote dopamine synthesis Activate specific receptors Prolong dopamine availability Prolong levodopa bioavailability DopaminergicLevodopaDAsMAO-B inhibitorsCOMT inhibitors AntiglutamatergicAmantadine* Anticholinergic † Trihexyphenidyl Benztropine Surgery Lesion Thalamotomy Pallidotomy Subthalamic nucleotomy DBS Thalamus Pallidum Subthalamic nucleus Transplantation ‡ Foetal mesencephalic cells Rehabilitation procedures Physical therapy Occupational therapy Speech therapy Abbreviations: DAs, dopamine agonists; MAO-B, monoamine oxidase B; COMT, catechol-O-methyltransferase; DBS, deep brain stimulation * mechanism of action not fully known, the antiglutamatergic action being only part of the drug's effect † only drugs commonly used are listed ‡ experimental Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;20:

52 52 Drug Therapy in Parkinson’s Disease Levodopa

53 53 Levodopa in the Management of Parkinson’s Disease (1) First of the dopaminergic drugs –Used since late 1960s 1 Highly effective drug –Relatively rapid relief 2 of bradykinesia, rigidity and associated pain –Reduces tremor in many patients Levodopa improves quality of life 3 and life expectancy 4 in patients with PD 1. Tolosa E, et al. Neurology 1998;50(Suppl 6):S Stacy M. Pharmacotherapy 2000;20(Suppl):8S-16S. 3. Rajput AH. Parkinsonism Relat Disord 2001;8: Karlsen KH, et al. J Neurol Neurosurg Psychiatry 2000;69:584-9.

54 54 Levodopa in the Management of Parkinson’s Disease (2) 1. Jankovic J. Neurology 2002;58(Suppl 1):S Deleu D. Clin Pharmacokinet 2002;41: Olanow CW, Stocchi F. Eur J Neurol 2000;7(Suppl 1):3-8. Must be metabolised to dopamine to be effective 1 Addition of dopa decarboxylase inhibitors (DDIs) (benserazide, carbidopa) is required to limit additional peripheral side effects 1 Absorption delayed or diminished by large neutral amino acids or agents that slow transit time, antacids and anticholinergics 1,2 Short half-life causes pulsatile stimulation of dopamine receptors 3

55 55 1. Olanow CW, Stocchi F. Eur J Neurol 2000;7(Suppl 1): Fahn S. Adv Neurol 1996;69: Poewe WH, Wenning GK. Neurology 1996;47(Suppl 3):S Parkinson Study Group. Ann Neurol 1996;39: Kostic V, et al. Neurology 1991;41: Levodopa in the Management of Parkinson’s Disease (3) Levodopa induces motor complications –Up to 80% of PD patients suffer from motor fluctuations and dyskinesias after approximately 5 to 10 years of treatment with levodopa 1 –50 to 75% of patients develop motor fluctuations 3 to 6 years after initiating therapy 2-4 –70% of young-onset PD patients develop motor complications after 3 years 5

56 56 Causes of Treatment-Related Motor Complications in Parkinson’s Disease Pulsatile stimulation of dopamine receptors with short half-life drugs Progressive dopaminergic neuronal degeneration Obeso JA, et al. Neurology 2000;55(Suppl 4):S13-20.

57 57 Dyskinesia Threshold Response Threshold Shorter duration motor response Increased incidence of dyskinesias Short duration motor response “On” time consistently associated with dyskinesias Long duration motor response Low incidence of dyskinesias Advanced PD Time (h) Clinical Effect Levodopa 246 Response to Levodopa and Progression of Parkinson’s Disease Obeso JA, et al. Trends Neurosci 2000;23(Suppl):S2-7. Response Threshold Dyskinesia Threshold Time (h) Early PD Levodopa Clinical Effect 246 Response Threshold Time (h) 4 Dyskinesia Threshold 2 Moderate PD Clinical Effect Levodopa6

58 58 Management of Motor Fluctuations Increase the frequency of dose administration (e.g. change from t.i.d. levodopa to q.i.d. levodopa, with the last dose during the day rather than at bedtime) –Useful in short but not long term Maintain levodopa and –Add a dopamine agonist –Add a COMT inhibitor –Add a MAO-B inhibitor Levodopa dose may need modification depending on patient response Surgery Continuous infusion of carbidopa-levodopa for rescue therapy Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase B; t.i.d., ter in die; q.i.d., quater in die Treatment options Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;20:

59 59 Management of Dyskinesias Treatment options for the management of peak-dose dyskinesias Administer fractionated levodopa doses (with or without increased total daily doses) in order to avoid peak plasma levodopa concentrations –Useful in short but not long term Or, reduce levodopa dose and Increase dopamine agonist dose Add a dopamine agonist if not already used Surgery Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.

60 60 Drug Therapy in Parkinson’s Disease Dopamine Agonists

61 61 Dopamine Agonists in the Treatment of Parkinson’s Disease First-line therapy in early PD in younger patients –Rare motor complications Delay the use of levodopa and related motor complications –Good side-effect tolerance Avoid ergot dopamine agonists: rare but serious fibrotic reactions 1,2 Agonist monotherapy can provide control of motor symptoms for several years in some patients 2 Adjunctive treatment in more advanced PD 4 Putative neuroprotection with some agents, particularly pramipexole 3 and ropinirole 4 1. Pritchett AM, et al. Mayo Clin Proc 2002;77: Horstink M, et al. Eur J Neurol 2006;13: Parkinson Study Group. JAMA 2002;287: Whone AL, et al. Ann Neurol 2003;54:

62 62 Chemical Structures of Dopamine Agonists

63 63 Dopamine Receptor Nomenclature D1 family receptor subtypes D 1 D 5 D2 family receptor subtypes D 2 D 3 D 4 Localisation D 1, D 2 striatum and substantial nigra D 3, D 4 limbic brain areas D 5 hippocampus, hypothalamus, parafascicular nucleus of the thalamus Missale C, et al. Physiol Rev 1998;78: Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.

64 64 Dopaminergic Pathways Putamen Substantia nigra Ventral tegmental area Amygdala Nucleus accumbens Caudate nucleus mesolimbic pathway nigrostriatal pathway D 3 receptor D 2 receptor Missale C, et al. Physiol Rev 1998;78: Shafer RA, et al. Psychopharmacology (Berl) 1998;135:1-16.

65 65 Dopamine Agonists – Pharmacological Advantages Direct dopamine-receptor stimulation No need for conversion to dopamine No interference with food for absorption Longer half-life compared with levodopa (pramipexole, ropinirole, rotigotine, pergolide, cabergoline) Putative neuroprotective action (pramipexole, ropinirole) Poewe W. In: Principles of Treatment in Parkinson’s Disease; Pharmacological profile of dopamine agonists Advantages over levodopa

66 66 Clinical Pharmacology of Dopamine Agonists Drug Dopamine receptor interaction Interaction with other receptors Half-life (h) NA5-HTP Non-ergot PramipexoleD2±-10 RopiniroleD2--6 RotigotineD2 > D (td) ApomorphineD2/D (sc) Ergot BromocriptineD PergolideD2 > D1++15 CabergolineD2++65 All mentioned D2-family agonists have D 3 /D 2 subtype affinity ratio > 1 except for bromocriptine. Abbreviations: NA, noradrenaline; 5-HT, 5-hydroxytryptophan; td, transdermal; sc, subcutaneous Poewe W. In: Principles of Treatment in Parkinson’s Disease; Kyniyoshi S and Jankovic J. In: Parkinson’s Disease; Jenner P. Neurology 2005;65(2 Suppl 1):S3-5.

67 67 Dopamine Agonists in the Treatment of Parkinson’s Disease – Mean Daily Dosage Drug Monotherapy (mg) Adjunct to levodopa (mg) Non-ergot Pramipexole Ropinirole Rotigotine4-8- Apomorphine (sc* bolus) Ergot Bromocriptine Pergolide Cabergoline * subcutaneous Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.

68 68 Clinical Importance of D2 Selectivity All dopamine agonists stimulate D2 receptors –stimulation of D2 receptors is thought to mediate improvement of cardinal motor symptoms 1 Stimulation of D1 receptors results in dyskinesias in experimental animal models 2 1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7: Fici GJ, et al. Life Sci 1997; 60:

69 69 Clinical Implications of D 3 Preference D 3 receptors in the mesolimbic dopamine system may be involved in cognition, mood and behaviour 1,2 Preferential stimulation of D 3 receptors (D 3 preference) may explain the antidepressive and anti-anhedonic properties of dopamine agonists such as pramipexole 3,4 1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7: Missale C, et al. Physiol Rev 1998;78: Piercey FM. Clin Neuropharmacol 1998;21: Willner P. Int Clin Psychopharm 1997;12(Suppl 3):S7-14.

70 70 Evidence on Efficacy of Dopamine Agonists in Patients With Parkinson’s Disease Evaluation of published studies according to evidence-based medicine criteria √ efficacious (maximum strength of evidence) ±probably efficacious ?insufficient data 0no studies Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;2: Horstink M, et al. Eur J Neurol 2006;13: Horstink M, et al. Eur J Neurol 2006;13: Category evaluated BromocriptineCabergolineLisuridePergolidePramipexoleRopinirole Monotherapy in early PD ±?±√√√ Combination with L-Dopa in advanced PD √√±√√? Treatment of motor fluctuations ±±?√√√ Prevention of motor complications and dyskinesias ±√??√√ Imaging indicates slowed loss of dopamine neurons 0000√√

71 71 Adverse events (%) NauseaSomnolenceHallucinations CALM-PD 1 Pramipexole Levodopa RQP Ropinirole Levodopa CBS 09 3 Cabergoline *4.3 Levodopa *4.8 * includes sleep problems and insomnia 1. Parkinson Study Group. JAMA 2000;284: Rascol O, et al. N Engl J Med 2000;342: Rinne UK, et al. Drugs 1998;55 (Suppl 1): Tolerability of Dopamine Agonists in Early Parkinson’s Disease – Main Adverse Events There are no head-to-head studies comparing the various agents: these data do not allow for direct comparisons of dopamine agonists.

72 Valvular Regurgitation (%) 31* 43* Pergolide Cabergoline Pramipexole Ropinirole Controls Peralta et al. 1 * P < 0.05 vs. controls Yamamoto et al. 2 ** P < vs. controls 29 69** Peralta C, et al. Mov Disord 2006;21: Yamamoto M, et al. Neurology 2006;67: Drug-Induced Valvular Heart Disease – Ergot versus Non-Ergot Dopamine Agonists

73 73 Drug Therapy in Parkinson’s Disease Other Drug Therapies for Parkinson’s Disease

74 74 Other Drug Therapies for Parkinson’s Disease Other dopaminergic agents –MAO-B* inhibitors Compounds interacting with receptors other than dopaminergic receptors may be useful in some patients –Anticholinergics –Amantadine * monoamine oxidase B Cersosimo MG, Koller WC. In: Principles of Treatment in Parkinson’s Disease; 2005.

75 75 Other Dopaminergic Agents – MAO-B* Inhibitors (1) Selegiline and rasagiline –Selective MAO-B inhibitors; however, selectivity is lost at high doses Risk of tyramine-induced hypertension (the “cheese effect”) at high doses –Symptomatic effect in Parkinson’s disease –Neuroprotective effect in the laboratory Mechanisms of action –Irreversible inhibition of MAO-B, which catalyses the oxidative deamination of neuroactive amines Prolongation of dopamine availability –Possible enhancement of catecholaminergic neurons by other mechanisms –Effect on mitochondrial membrane, anti-apoptotic effect and reduction of oxidative stress with potential neuroprotective properties * monoamine oxidase B Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; Horstink M, et al. Eur J Neurol 2006;13:

76 76 Selegiline –Mild antiparkinsonian effect in de novo Parkinson’s disease –No evidence that MAO-B inhibition delays the development of motor fluctuations other than through the delay in introducing levodopa and an ability to use a lower dose Rasagiline –10–15 times more potent than selegiline Antiparkinsonian effect comparable to selegiline: not as great as the dopamine agonists –Less effective than dopamine agonists in reducing off- periods in patients optimised on levodopa Other Dopaminergic Agents – MAO-B* Inhibitors (2) * monoamine oxidase B Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; Parkinson Study Group. Arch Neurol 2004;61:561-6.

77 77 Conclusion –Mild to moderate symptomatic motor control in early Parkinson’s disease (PD) –Not particularly effective for treating motor fluctuations –Relatively safe drugs Other Dopaminergic Agents – MAO-B* Inhibitors (3) * monoamine oxidase B Horstink M, et al. Eur J Neurol 2006;13: Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; Arch Neurol 2004;61:561-6.

78 78 Non-Dopaminergic Antiparkinsonian Drugs – Anticholinergics Mechanism of action: –State of relative cholinergic sensitivity due to dopamine depletion Cholinergic drugs exacerbate and anticholinergic agents (e.g. trihexyphenidyl, benztropine) improve parkinsonian symptoms Typically used in younger patients with Parkinson’s disease in whom tremor is the major symptom However: –Little data on potency and tolerance –Common side effects that limit their usefulness Cognitive side effects: memory impairment, acute confusion, hallucinations, sedation, dysphoria Dyskinesias Peripheral antimuscarinic side effects: dry mouth, constipation, accommodation impairment, nausea, urinary retention, impaired sweating, tachycardia Contraindicated in patients with prostate hypertrophy, closed-angle glaucoma, tachycardia, gastrointestinal obstruction, megacolon Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; Samii A, et al. Lancet 2004;363: Horstink M, et al. Eur J Neurol 2006;13:

79 79 Mechanism of action –Although the exact mechanism of action is not established, amantadine seems to have dopaminergic, anticholinergic and antiglutamatergic activities Mild and transitory improvement of parkinsonian symptoms –More effective in the control of bradykinesia and rigidity than tremor –Generally considered unsuitable for monotherapy in Parkinson's disease –Mostly used as an adjunct Potential cognitive side effects also limit its use Non-Dopaminergic Antiparkinsonian Drugs – Amantadine Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; Samii A, et al. Lancet 2004;363: Horstink M, et al. Eur J Neurol 2006;13:

80 80 Surgery

81 81 Surgical Treatment for Parkinson’s Disease Early 20 th century –First interventions directed at motor cortex and corticospinal tract Some success, particularly with regard to tremor Success complicated by motor paresis –Ventrointermediate thalamotomy in the 1950s and 1960s Antitremor effects Currently –Levodopa-induced motor complications –Severe tremor –Procedure-dependent results Goetz CG, et al. Mov Disord 2005;20:

82 82 Surgical Procedures for Parkinson’s Disease Ablative procedureDeep brain stimulationRestorative procedure Thalamotomy Unilateral pallidotomy Subthalamotomy VIM nucleus of thalamus GPi STN Cell-based therapies Human foetal nigral cells Porcine foetal nigral cells Retinal pigmented epithelial cells Stem cells Trophic factors Gene therapies Abbreviations: VIM, ventrointermediate; GPi, globus pallidus pars interna; STN, subthalamic nucleus In practice: Potential benefit for advanced disease not controlled with medical therapy Ablative procedures have been largely abandoned Effects not superior to optimised medical therapy Non-dopaminergic features not affected Goetz CG, et al. Mov Disord 2005;20: Pahwa R, et al. Neurology 2006;66:

83 83 Management of Non-Motor Symptoms

84 84 Non-Motor Features of Parkinson’s Disease Cognitive and other psychiatric symptoms Sleep disorders Autonomic dysfunctions (including gastrointestinal symptoms) Depression Cognitive decline Delirium, hallucinations, psychosis* Dementia Obsessional behaviour* Confusion Panic attacks Insomnia Daytime sleepiness and excessive daytime sleepiness Parasomnias Abnormal simple and complex nocturnal movements RLS and PLMS RBD and REM loss atonia Non-REM sleep-related movement disorders Vivid dreaming Sleep-disordered breathing Bladder dysfunction Urgency Nocturia Frequency Sweating Orthostatic hypotension Sexual dysfunction Hypersexuality* Erectile impotence Constipation Sialorrhoea Weight loss Weight gain* Dry eyes Other symptoms Pain, paresthesia, diplopia, olfactory disturbances and fatigue Abbreviations: REM, rapid eye movement; RBD, REM sleep behaviour disorder; RLS, restless legs syndrome; PLMS, periodic leg movements of sleep * possibly drug-induced Chaudhuri KR, et al. Lancet Neurol 2006;5: Tetrud JW. In: Parkinson’s Disease; 2005.

85 85 Management of Non-Motor Symptoms in Parkinson’s Disease – Diagnosis and Evaluation Non-motor symptoms are frequently overlooked –Depression, anxiety, fatigue and sleep not discussed with more than 50% of patients 1 Despite a probable frequency of depression of 40–50% in PD patients 2 –Difficult diagnosis in some cases Role of neurologists in identifying and differentiating symptoms Non-motor scales –Improve the identification of non-motor symptoms –Evaluate therapeutic interventions 1. Shulman LM, et al. Parkinsonism Relat Disord 2002;8: Cummings JL. Am J Psychiatry 1992;149:

86 86 Non-Motor Symptoms in Parkinson’s Disease – Assessment Tools Non-motor feature Scale Neuropsychiatric symptoms Mini Mental Test; Hospital Anxiety and Depression Scale Hamilton Depression Rating Scale; Beck Depression Inventory Autonomic symptomsSCOPA-Aut Sleep Parkinson's Disease Sleep Scale; SCOPA-Sleep; Epworth Sleepiness Scale FatigueFatigue Severity Scale; PF-16 Health-related quality of life PDQ 39; PDQ 8; PDQUALIF; PD Quality of Life Questionnaire; SCOPA-PS (psychological aspect); EQ-5D Comprehensive assessment The Parkinson's disease NMS scale (in development); the Parkinson's disease NMS questionnaire (NMSQuest); Revised UPDRS (not validated); wearing-off patient questionnaire Abbreviations: NMSQuest, non-motor symptom questionnaire for Parkinson's disease; UPDRS, unified Parkinson's disease rating scale; SCOPA, scales for outcomes in Parkinson's disease; PDQUALIF, Parkinson's disease quality of life scale; PDQ, Parkinson's disease questionnaire Chaudhuri KR, et al. Lancet Neurol 2006;5:

87 87 Treatment of Non-Motor Symptoms in Parkinson’s Disease – Neuropsychiatric Disorders Treatment approach Anxiety, panic attacks Treat wearing-off SSRIs Benzodiazepines Depression Tricyclic antidepressants SSRIs Pramipexole Hallucinations and psychosis Discontinue: sedatives, hypnotics, narcotic analgesics, anticholinergics, amantadine, MAO-B inhibitors Taper or discontinue dopamine agonists if possible Clozapine or quetiapine if needed Abbreviations: SSRI, selective serotonin reuptake inhibitors; MAO-B, monamine oxidase B Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Sawabini KA, et al. In: Principles of Treatment in Parkinson's Disease; Lieberman A. Acta Neurol Scand 2006;113:1-8. Miyasaki JM, et al. Neurology 2006;66:

88 88 Treatment of Non-Motor Symptoms in Parkinson’s Disease – Autonomic Dysfunction Treatment option Bladder urgency Oxybutinin Tolterodine Amitriptyline (if concomitant depression) Erectile dysfunction Sildenafil Apomorphine Sialorrhoea Simple measures: chewing gum, sucking sweets Anticholinergic drugs (glycopyrrolate) Botulinum toxin for refractory cases Constipation Consider dopamine agonists Adequate fluid intake, exercise Aperients: psyllium fibre, lactulose, polyethylene glycol Orthostatic hypotension Adjust dopamine agonist dose if needed Fludrocortisone Midodrine Stocchi F. In: Principles of Treatment in Parkinson’s Disease; Raffaele R, et al. Eur Urol 2002;41: O'Sullivan JD. J Neurol Neurosurg Psychiatry 2002;72:681. Tetrud JW. In: Parkinson’s Disease; Goldstein DS. Lancet Neurol 2003;2:

89 89 Treatment of Non-Motor Symptoms in Parkinson’s Disease – Sleep Disturbances Treatment option Insomnia Non-pharmacological: sleep hygiene Pharmacological: benzodiazepines, zopiclone, zolpidem RBD Benzodiazepine (clonazepam) RLS Dopamine agonists Levodopa Opiates EDS Caffeine Modafinil Reduce dopaminergic drug dose Switch from one dopamine agonist to another Abbreviations: RBD, rapid eye movement (REM) sleep behaviour disorder; RLS, restless legs syndrome; EDS, excessive daytime sleepiness Adler CH, Thorpy MJ. Neurology 2005;64(12 Suppl 3):S Stocchi F. In: Principles of Treatment in Parkinson’s Disease; Barone P, et al. Neurology 2004;63(8 Suppl 3):S35-8. Phillips B. Neurology 2004;62(5 Suppl 2):S9-16.

90 90 Disease Modification (Neuroprotection)

91 91 Disease Modification in Parkinson’s Disease – Summary Rationale for Neuroprotection Evaluating Neuroprotection Approaches in Neuroprotection Clinical trials –Antioxidants and monoamine oxidase type-B inhibitors –Anti-excitotoxic agents –Bioenergetic agents –Coenzyme Q 10 Dopamine Agonists –Rationale for the use of dopamine agonists as potential neuroprotective agents –Possible mechanisms for neuroprotection –Experimental basis –Neuroimaging –Clinical trials Perspectives in Neuroprotection

92 92 Disease Modification (Neuroprotection) Rationale

93 93 Limit Neuropsychiatric and Non-Dopaminergic Symptoms Slow Disease Progression Restorative Therapies Cells, genes, trophic factors Reduce Motor Complications Early dopamine agonist therapy Continuous dopamine stimulation Deep brain stimulation Antidyskinesia drugs, amantadine, dopamine transport inhibitors, glutamatergic drugs, and GABA* Dementia Depression Postural instability Freezing Autonomic failure Block Neurodegenerative Process Improved mitochondrial function Oxidative stress Protein aggregation Apoptosis, necrosis Reduce Motor Symptoms (see algorithm on slide 49)slide 49 Treatment of Parkinson’s Disease Schapira AH, Olanow CW. JAMA 2004;291: Olanow CW, Jankovic J. Mov Disord 2005;20(S11):S3-10. * Gamma-aminobutyric acid

94 94 Neuroprotection – Definitions Neuroprotection (disease modification) –Prevent further neuronal cell death in order to slow or halt disease progression –Does not necessarily affect the underlying pathophysiological biochemical mechanisms Neurorescue –Salvage of dying neurons by reversal of established metabolic abnormalities Neurorestoration (is not neuroprotection) –Increasing the number of dopaminergic neurons Cell implantation Nerve growth factors Schapira AH. BMJ 1999;318:311-4.

95 95 Disease Modification (Neuroprotection) Evaluation

96 96 Neuroprotection – Evaluation Decreased loss of neurons in the dopaminergic and other neurotransmitter systems –Impossible to assess directly in life Surrogate markers: –Clinical rating scales (e.g. UPDRS*) –Time to clinical endpoints (e.g. time to levodopa therapy requirement) –Neuroimaging (  -CIT SPECT, † fluorodopa PET ‡ ) * Unified Parkinson's Disease Rating Scale † single photon emission computed tomography ‡ positron emission tomography Clarke CE. Lancet Neurol 2004;3:

97 97 Issues in the Evaluation of Neuroprotective Effects of Drugs in Parkinson’s Disease Outcome measureIssueSuggested solution Clinical measure* Differentiation of symptomatic from neuroprotective effects Prolonged washout of drug Delayed-start studies Neuroimaging † SWEDD ‡ Discrimination with progressive supranuclear palsy or multiple system atrophy Appropriate sample size calculations taking into account misdiagnosis Lack of correlation between clinical outcomes and neuroprotection Larger or longer studies Modification of radionuclide tracer pharmacokinetics by the putative neuroprotective agent Repeat imaging to assess any differential effect of the drug All Small magnitude of neuroprotective effect Appropriate sample size All Lack of meaning to patientsInclusion of quality-of-life parameters and mortality evaluation * clinical rating scales, time to endpoint, mortality; † β-CIT single photon emission computed tomography (SPECT) or fluorodopa positron emission tomography (PET); ‡ scans without evidence of dopaminergic deficit Clarke CE. Mov Disord 2004;19: Clarke CE. Lancet Neurol 2004;3:

98 98 Disease Modification (Neuroprotection) Approaches

99 99 Neurorescue and Neuroprotection in Parkinson’s Disease Neurorescue (yellow line) Restore damaged neurons that are at risk of death (area between curves) to normal function Age-related loss will probably be attenuated with ongoing treatment Neuroprotection (green line) Prevents further neuronal loss other than by attenuated age- related loss Putative time course for loss of dopamine neurons from substantia nigra and clinical expression Threshold for clinical symptoms 0% 100% Percentage of Substantia Nigra Neurons Remaining 4080 Years Diagnosis Schapira AH. BMJ 1999;318: © 1999 BMJ Publishing Group Ltd.

100 100 Neuroprotection in Parkinson’s Disease – Clues and Targets Aetiological and pathogenetic factors in Parkinson’s disease and possible neuroprotective approaches Abbreviations: COX-2, cyclo-oxygenase-2; GDNF, glial-derived neurotrophic factor Genetic factors Environmental factors Gene-environment interaction Oxidative stress Mitochondrial dysfunction Excitotoxicity Inflammation Protein handling dysfunction with Levy body formation Neuronal dysfunction Apoptosis AETIOLOGY PATHOGENESIS Antioxidants (e.g. vitamin E, vitamin C, iron chelators) Monoamine oxidase B inhibitors (e.g. selegiline, rasagiline) Bioenergetic agents (e.g. coenzyme Q 10 ) Antiglutamatergic agents (e.g. N-methyl-D-aspartate [NMDA] receptor antagonists) Calcium channel blockers Anti-inflammatory agents (e.g. COX-2 inhibitors) Proteosomal enhancers Heat shock proteins Trophic factors (e.g. GDNF, nurturin) Anti-apoptotic agents (e.g. dopamine agonists, caspase inhibitors, propargylamines) Schapira AH, Olanow CW. JAMA 2004;291: © 2004 American Medical Association. All rights reserved.

101 101 Disease Modification (Neuroprotection) Clinical Trials

102 102 Neuroprotection Trials – Antioxidants and Monoamine Oxidase Type-B Inhibitors (1) Rationale 1 –Role of oxidative stress in the pathogenesis of neuronal cell death –Increased levels of iron (promote oxidative stress) in SN* –Decreased levels of glutathione (the major brain antioxidant) –Evidence of oxidative damage to carbohydrates, lipids, proteins and DNA in SNpc † –Oxidative metabolism of levodopa and/or dopamine Candidate drugs 1,2 –  -tocopherol (vitamin E) The most potent lipid-soluble antioxidant in plasma –Selegiline Inhibits the MAO-B ‡ oxidation of MPTP § (responsible for MPTP toxicity) Possibly inhibits the oxidation of other toxins that contribute to neuronal degeneration Might block the MAO-B-dependent oxidative metabolism of levodopa/dopamine –Rasagline Another potent MAO-B inhibitor Has also shown protective effects in laboratory models 2 * substantia nigra; † substantia nigra pars compacta; ‡ monoamine oxidase type-B; § 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1. Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S Olanow CW. Neurology 2006;66(10 Suppl 4):S69-79.

103 103 Neuroprotection Trials – Antioxidants and Monoamine Oxidase Type-B Inhibitors (2) DATATOP* study –  -tocopherol: no effect on the time-to-levodopa requirement –Selegiline: delayed need for levodopa SELEDO † study –Selegiline: less requirement for increased levodopa doses SINDEPAR ‡ –Selegiline: less deterioration in UPDRS § score TEMPO** –Rasagiline: more deterioration in UPDRS score if delayed start Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S Parkinson Study Group. Arch Neurol 2004; 61: Limitations –Selegiline has symptomatic effects in Parkinson’s disease Prevents any conclusion as to neuroprotective effect –Same limitation is valid for other MAO-B inhibitors (lazabemide, rasagiline) * Deprenyl and Tocopherol Antioxidant Therapy of PD; † Selegiline-L-dopa; ‡ Sinemet-Deprenyl-Parlodel; § Unified Parkinson's Disease Rating Scale; ** rasagiline mesylate (TVP-1012) in Early Monotherapy for Parkinson's disease Outpatients

104 104 Neuroprotection Trials – Anti-excitotoxic Agents (1) Rationale –Neuronal activity in the STN* is increased in PD –STN uses the excitatory neurotransmitter glutamate and projects to the GPi †, pedunculopontine nucleus and SNpc ‡ Potential excitotoxic damage of these targets –NMDA § receptor antagonists may protect dopamine neurons from glutamate-mediated toxicity –A retrospective study suggests decreased rate of PD progression after administration of amantadine (an NMDA receptor antagonist) * subthalamic nucleus; † globus pallidus interna; ‡ substantia nigra pars compacta § N-methyl-D-aspartate Rodriguez MC, et al. Ann Neurol 1998;44(3 Suppl 1):S Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97.

105 105 Neuroprotection Trials – Anti-excitotoxic Agents (2) Remacemide hydrochloride (low-affinity NMDA channel blocker) –No symptomatic effect in Parkinson’s disease –No neuroprotective benefit in Huntington’s disease –No formal study of neuroprotection in Parkinson’s disease Riluzole (sodium channel blocker) –No neuroprotective effect confirmed in Parkinson’s disease patients Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S Suchowersky O, et al. Neurology 2006;66:

106 106 Neuroprotection Trials – Bioenergetic Agents Rationale –Reduction in the activity of mitochondrial respiratory complex I in the SNpc* in Parkinson’s disease –Selective complex I inhibitors such as MPTP † and rotenone induce parkinsonism –Inhibition of complex I results in increased free radical generation –Free radicals, in turn, can damage the respiratory chain, reducing complex I and IV activities in particular –Creatine and coenzyme Q 10 protect dopamine neurons in MPTP-treated rodents Candidate drugs: bioenergetic agents –Mitochondrial enhancers –Counteract oxidative stress * substantia nigra pars compacta; † 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S Schapira AH. Mitochondrial disease. Lancet 2006;368:70-82.

107 107 Neuroprotective Trials – Coenzyme Q 10 Coenzyme Q 10 both enhances respiratory chain function and scavenges free radicals Pilot phase II study in early patients with de novo Parkinson’s disease –1200 mg/day, but not lower doses, produce significant improvement in UPDRS* scores compared with placebo at 16 months –Limitations Short-term improvement in ADL † scores consistent with a symptomatic effect Therefore, neuroprotective beneficial effect of coenzyme Q 10 needs confirmation Shults CW, et al. Arch Neurol 2002;59: * Unified Parkinson's Disease Rating Scale; † activities of daily living (part II of UPDRS)

108 108 Disease Modification (Neuroprotection) Dopamine Agonists

109 109 Rationale for Use of Dopamine Agonists as Neuroprotective Agents in Parkinson’s Disease Already in use for symptomatic relief –Appropriate initial symptomatic treatment in most PD patients Limitations of levodopa therapy in Parkinson’s disease –Possible contribution to cell damage The ELLDOPA study does not resolve the issue of whether or not levodopa is toxic in Parkinson’s disease –Long-term use associated with motor complications Laboratory evidence suggests neuroprotective benefits Neuroimaging studies support putative neuroprotection with pramipexole and ropinirole Olanow CW, et al. Mov Disord 2005;20(Suppl 11):S3-10. Schapira AHV, et al. Ann Neurol 2003;53(Suppl 3):S

110 110 Levodopa and Neurodegeneration Powerful symptomatic effect Concerns that levodopa may hasten neurodegeneration –Oxidative metabolism Potential to generate cytotoxic free radicals –Evidence of levodopa toxicity to cultured dopamine neurons –No convincing evidence that levodopa is toxic in in vivo models or in patients with Parkinson’s disease Agid Y. Lancet 2002;360:575.

111 111 Early Parkinson’s disease Randomised, double blind, placebo-controlled N = 361 Carbidopa/levodopa: 37.5/150 mg, 75/300 mg, 150/600 mg 40 weeks followed by a 2-week withdrawal Primary outcome: UPDRS* between baseline and 42 weeks Neuroimaging study in 142 patients –Baseline and week 40 –Striatal DAT † density assessed by 123 I-  -CIT ‡ SPECT § Levodopa and Neurodegeneration – The ELLDOPA Study (1) * Unified Parkinson's Disease Rating Scale; † dopamine transporter; ‡ 2β-carbomethoxy-3β-(4-iodophenyl)tropane; § single photon emission computed tomography Fahn S, et al. N Engl J Med 2004;351:

112 112 Levodopa and Neurodegeneration – The ELLDOPA Study (2) Fahn S, et al. N Engl J Med 2004;351: Parkinson Study Group. JAMA 2002;287: * Unified Parkinson’s Disease Rating Scale † 2β-carbomethoxy-3β-(4-iodophenyl)tropane Copyright © 2004 Massachusetts Medical Society.

113 113 Patients on levodopa had significantly better UPDRS* scores compared with those who received placebo –Less deterioration in patients on levodopa even after the two-week washout period Possible persistent benefit of levodopa, suggesting that levodopa is protective; or Insufficient washout period to exclude persistent symptomatic effect Significantly greater rate of decline in the imaging biomarker uptake in patients on levodopa –Consistent with a possible levodopa toxic effect Conclusion –Conflicting results: do not permit a clear determination of whether or not levodopa is toxic Levodopa and Neurodegeneration – The ELLDOPA Study (3) * Unified Parkinson's Disease Rating Scale Fahn S, et al. N Engl J Med 2004;351:

114 114 Dopamine Agonists – Possible Mechanisms for Neuroprotection in Parkinson’s Disease (1) Levodopa-sparing –Delay in levodopa use –Reduced levodopa dose requirement  Potential reduction of oxidative radicals derived from levodopa metabolism Antioxidant effects –Direct free radical scavenging effect at higher concentrations than those achieved in routine treatment Autoreceptor effect –Antioxidant effect through activation of presynaptic receptors Schapira AH, Olanow CW. Ann Neurol 2003;53(Suppl 3):S

115 115 Amelioration of subthalamic nucleus-mediated excitotoxicity Anti-apoptotic effects –Possible direct or receptor-mediated effect on mitochondrially based pro-apoptotic intracellular signals –Pramipexole Decreases apoptotic cell death in SHSY-5Y neuronal-derived dopaminergic cells exposed to toxins Induces increased expression of anti-apoptotic proteins BcL-xL and BcL-2 Induces up-regulation of several genes associated with neuroprotective effects Dopamine Agonists – Possible Mechanisms for Neuroprotection in Parkinson’s Disease (2) Schapira AH, Olanow CW. Ann Neurol 2003;53(Suppl 3):S

116 116 Blum D, et al. Prog Neurobiol 2001;65: Tatton WG, et al. Ann Neurol 2003;53(Suppl 3):S Abbreviations: BDNF, brain-derived neurotrophic factor; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; MPP+, 1-methyl-4- phenylpyridinium; TNF- , tumour necrosis factor-  ; NMDA, N-methyl-D-aspartate. Cellular Dysfunctions in Parkinson’s Disease and Targets for Dopamine Agonists in Neuroprotection Caspase activation Apoptosis (nuclear changes & cell death) Free radicals Cytochrome c Mitochondrial damage MPTP/MPP + TNF-  receptor Excitotoxicity Glutamate receptor (NMDA)  Ca 2+ BcL-2, BcL-xL inhibit release of cytochrome c Trophic factors (e.g. BDNF) inhibit apoptosis Protein aggregation

117 117 Dopamine Agonists – Inhibition of Multiple Pathways of Cellular Dysfunction Caspase activation Apoptosis (nuclear changes & cell death) Free radicals Cytochrome c Mitochondrial damage MPTP/MPP + TNF-  receptor Excitotoxicity Glutamate receptor (NMDA)  Ca 2+ Pramipexole increases Bcl-2, Bcl-xl Pramipexole may induce up-regulation of a trophic factor Protein aggregation = Inhibition Gu M, et al. J Neurochem 2004;91: Blum D, et al. Prog Neurobiol 2001;65: Tatton WG, et al. Ann Neurol 2003; 53(Suppl 3):S Abbreviations: NMDA, N-methyl-D-aspartate; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenylpyridinium; TNF- , tumour necrosis factor- 

118 118 Mitochondrial-Mediated Apoptotic Cell Death in SHSY-5Y Cells MPP+ Rotenone Free radicals Cytochrome c release* Caspase activation* Apoptotic cell death* Pore opening*  ATP production * blocked by pramipexole Gu M, et al. J Neurochem 2004;91: Copyright © 2004, Blackwell Publishing Ltd.

119 119 Pramipexole Protects Against MPTP Toxicity in Primates Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; TH-ir, tyrosine hydroxylase-immunoreactive TH-ir cell counts at the level of the 3 rd cranial nerve Group A, animal controls Group B, MPTP only Group C, pramipexole prior to MPTP Group D, pramipexole coincident with MPTP Group E, pramipexole after MPTP * P < 0.05; NS, non significant TH-ir neuronal counts in the rostrocaudal plane Group AGroup BGroup CGroup DGroup E Treatment Group NS * Mean TH+ve Cell Counts at 3 rd Nerve Mean Counts of TH+ve Neurons Rostrocaudal Distance (  m) Iravani MM, et al. J Neurochem 2006;96: Copyright © 2006, Blackwell Publishing Ltd.

120 120 Neuroprotection Trials – Evaluation of Dopamine Agonist Efficacy Limitations of clinical measures –Confounded by symptomatic benefits Biological markers –Accurate assessment of dopaminergic nigrostriatal system –Possible confound of drug effects on imaging Suchowersky O, et al. Neurology 2006;66: Ahlskog JE. Neurology 2003;60:381-9.

121 121 Dopamine Nuclear Imaging Radioligands that label nigrostriatal neurons – 123 I-  -CIT* Labels the dopamine transporter (DAT) protein, selectively expressed on dopaminergic neurons Uses SPECT † technology – 18 F-dopa ‡ Is transported into dopaminergic neurons and concentrated within synaptic vesicles as 18 F-dopamine Uses PET § technology Objective estimation of the extent of neuronal loss in patients with Parkinson’s disease * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography ‡ 18 F-6-fluorodopa § positron emission technology Lee CS, et al. Ann Neurol 2000;47: Ahlskog JE. Neurology 2003;60:381-9.

122 122 Dopamine Nuclear Imaging: Where Do Ligands Bind? Marek K, et al. Science ;289: * 123 I-iodobenzamide PostsynapticPresynaptic D2 receptors (IBZM*, raclopride) DOPADopamine Dopamine receptors Dopamine transporters (β-CIT, others) Neuronal dopamine metabolism (F-dopa) © 2000 American Association for the Advancement of Science.

123 123 * positron emission tomography † 2β-carbomethoxy-3β-(4-iodophenyl)tropane ‡ single photon emission computed tomography Neuroimaging in Parkinson’s Disease Schapira AH, Olanow CW. JAMA 2004;291: Early-Stage PD Control Late-Stage PD Fluorodopa PET* Control Late-Stage PD Early-Stage PD Mid-Stage PD 123 I-  -CIT † SPECT ‡ Early-Stage PDLate-Stage PD Early-Stage PD Mid-Stage PD © 2004 American Medical Association. All rights reserved.

124 124 Neuroprotection Trials with Dopamine Agonists – CALM-PD and REAL-PET Studies Patients with early Parkinson’s disease CALM-PD –Pramipexole versus levodopa – 123 I-  -CIT* SPECT † to follow the rate of loss of dopaminergic nigrostriatal cell density REAL-PET –Ropinirole versus levodopa – 18 F-dopa ‡ PET § to follow the rate of loss of dopaminergic nigrostriatal cell density * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography ‡ 18 F-6-fluorodopa § positron emission tomography Parkinson Study Group. JAMA 2002;287: Whone AL, et al. Ann Neurol 2003;54:

125 125 Neuroprotection Trials with Dopamine Agonists – CALM-PD Study Early, symptomatic patients with Parkinson’s disease Multicentre, double-blind, randomised –Initial treatment with pramipexole (n = 42) or carbidopa/levodopa (n = 40) Four-year follow-up In vivo imaging of the dopamine transporter with 123 I-  -CIT* SPECT † –Progression of dopaminergic degeneration * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography Parkinson Study Group. JAMA 2002;287:

126 126 CALM-PD – Striatal 123 I-  -CIT* Uptake (SPECT † ) * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography Parkinson Study Group. JAMA 2002;287: (%) Mean Change from Baseline Scan Interval (months) pramipexole levodopa (39) (36) (35) (33) (39) (n=82) (32) © 2002 American Medical Association. All rights reserved.

127 127 Neuroprotection Trials with Dopamine Agonists – REAL-PET Study Early, symptomatic patients with Parkinson’s disease Multicentre, double-blind, randomised –Initial treatment with ropinirole (n = 68) or carbidopa/levodopa (n = 59) Two-year follow-up In vivo imaging of dopamine terminals with 18 F-dopa* PET † –Progression of dopaminergic degeneration * 18 F-6-fluorodopa † positron emission tomography Whone AL, et al. Ann Neurol 2003;54:

128 128 * * P < Whone AL, et al. Ann Neurol 2003;54: REAL-PET – Putamen 18 F-dopa ‡ Uptake (PET † ) % change in putamen F-dopa Ki (n) % Change from Baseline in 18 F-dopa Uptake Ropinirole (63)L-dopa (58) Copyright © 2003 American Neurological Association. ‡ 18 F-6-fluorodopa † positron emission tomography

129 129 Percentage Change in Putamen 123 I-  -CIT* and 18 F-dopa † Uptake by Treatment * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † 18 F-6-fluorodopa Parkinson Study Group. JAMA 2002;287: Whone AL, et al. Ann Neurol 2003;54: % Change from Baseline Scan Interval (months) Pramipexole CALM-PD CIT Levodopa Ropinirole REAL-PET Levodopa

130 130 Early Parkinson’s disease –Initial treatment with pramipexole or ropinirole Significant delay in the rate of decline of a surrogate marker of nigrostriatal function Possible interpretations –Real reduction in the rate of cell loss in the substantia nigra Consistent with laboratory findings No corresponding clinical benefits over levodopa with either drug –Longer follow-up is needed –Levodopa toxicity Controversial –Pharmacological difference in the ability of dopamine agonists or levodopa to regulate the dopamine transporter or fluorodopa metabolism Insufficient information to confirm Neuroprotection Trials with Dopamine Agonists – Conclusions from Neuroimaging Studies Olanow CW. Trends Neurosci 1993;16: Agid Y, et al. Lancet 2002;360:575. Schapira AH, Olanow CW. JAMA 2004;291:

131 131 Combination of in vitro, in vivo and clinical trials: –Supports but does not prove disease-modifying effect of pramipexole and ropinirole in Parkinson’s disease –Compelling evidence to stimulate further research In practice: –The decision to introduce putative neuroprotective therapy for Parkinson’s disease: A matter of judgment and personal approach on the part of the patient and the physician –The challenge of defining reliable methods for detecting disease progression Neuroprotection Trials with Dopamine Agonists – Conclusions Schapira AH, Olanow CW. JAMA 2004;291:

132 132 Disease Modification (Neuroprotection) Perspectives

133 133 Perspectives in Neuroprotection Presymptomatic detection of Parkinson’s disease –Value of Parkinson’s disease biomarkers Prove neuroprotective benefits of current and future agents –Appropriate trial designs Initiate treatment before clinical symptoms occur Identify and remove/modify possible environmental contribution to Parkinson’s disease aetiology Schapira AH. BMJ 1999;318: Clarke CE. Mov Disord 2004;19: Kieburtz K. Ann Neurol 2003;53(Suppl 3):S100-7.

134 134 Clinical –Olfaction (UPSIT*) –Sleep - RBD † –Gut –Cardiac –Skin –Motor analysis –Speech –Cognition –Depression –Personality changes Imaging – Phenotomics –SPECT ‡ /PET § -DAT** –PET F-Dopa –MRI-spectroscopy –Functional MRI –Nigral transcranial ultrasound Genetics –Synuclein, LRRK2 –Parkin DJ1, PINK1 Laboratory –Proteomics –Transcriptomics –Metabolomics Perspectives in Neuroprotection – Parkinson’s Disease Biomarkers * University of Pennsylvania Smell Identification Test; † rapid eye movement (REM) sleep behaviour disorder; ‡ single photon emission computed tomography; § positron emission tomography; ** dopamine transporter Michell AW, et al. Brain 2004;127: Ponsen MM, et al. Ann Neurol 2004;56: Stiasny-Kolster K, et al. Brain 2005;128: Sommer U, et al. Mov Disord 2004;19:

135 135 Physical Therapy

136 136 Role of Physical Therapy in Parkinson’s Disease Hypometria, bradykinesia, rigidity and disturbed postural control compromise patient mobility and quality of life 1 –Bedtime mobility –Transfers –Gait –Balance loss, falling Need for an individualised programme –Exercise –Posture awareness –Pain control –Patient/family education for safety, stress reduction, movement enhancement and comprehension strategies Only 3–29% of patients regularly consult a paramedical therapist (physical, occupational, speech) 2 1. De Goede CJ, et al. Arch Phys Med Rehabil 2001;82: Deane KH, et al. Mov Disord 2002;17:

137 137 Physical Therapy in Early Parkinson’s Disease Enhances patient mobility by encouraging an active lifestyle Provides information on treatment options beyond medication Exercise may enhance dopaminergic pathways in PD TechniqueGoal Multidimensional exercise routine Address deficit in balance, mobility and risk of falls Promote spinal flexibility to delay and reduce significant limitations Strengthen core muscles of stability Fitness Maintain activity tolerance and cardiovascular fitness Caution: some fitness equipment may be inappropriate, e.g. treadmill Posture trainingImprove posture control and prevent falls Worksite evaluation* Identify areas of difficulty Optimise work conditions, task performance and safety Relaxation techniques Reduce stress and exacerbation of PD-related symptoms * Approximately 30% of patients with PD remain professionally active. Wichmann R. In: Parkinson’s Disease; Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.

138 138 Physical Therapy in Moderate Parkinson’s Disease Progression of the disease Decreased mobility skills Increased gait disturbances; possible festination and/or freezing Significant balance problems in many patients and episodes of falling Possible motor fluctuations TechniqueGoal Compensatory mobility strategiesMaximise functional independence Attention strategies and sensory cueing Improve magnitude in motor tasks by substitution of deficient motor cues provided by basal ganglia with external cues Gait trainingOvercome motor fluctuations and freezing Gait-assistive devicesMaximise safety when ambulating Early physical therapy in the event of fracture or other illness Initiate timely mobilisation to reduce the risk of complications Adjustment of daily exercisePerform adapted and safe routine exercises Wichmann R. In: Parkinson’s Disease; Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.

139 139 Physical Therapy in Advanced Parkinson’s Disease Optimise functional independence by compensation strategies for worsening motor impairment Emphasis on discipline in order to avoid risky activities such as walking and swallowing Detect depression TechniqueGoal Continued instruction Teach the fundamental difference between automatic and consciously controlled movements Emphasise the need to switch to conscious movements for almost all daily motor activities Behavioural strategies Substitute deficient motor cues provided by basal ganglia with external cues Wheelchair and body mechanicsEngage in safe ambulation and transfers Instruction in proper positioning Prevent risk of aspiration while eating Avoid habits that worsen flexed posture (excessive pillows) Appropriate daily exercise programmeMaximise flexibility and improve patient comfort Pain control (heat, cold, massage, etc.)Control excessive rigidity and agitation Wichmann R. In: Parkinson’s Disease; Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.

140 140 Future Treatments

141 141 Rationale for New Therapeutic Approaches Success of dopaminergic treatment in controlling motor symptoms –Research focus on dopamine systems Limitation –Pathophysiology Involvement of non-dopaminergic systems –Clinical Loss of drug efficacy with disease progression Lack of control over most non-motor symptoms Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; Jenner P. In: Principles of Treatment in Parkinson’s Disease; 2005.

142 142 Novel Therapeutic Approaches for Parkinson’s Disease Target/ApproachGoal Dopaminergic system Dopamine agonistsRefined interaction with dopamine agonist receptors Dopamine reuptake blockers Highly potent specific blockers with antiparkinsonian effect and reduced induction of involuntary movements Continuous dopaminergic stimulationLong-acting agonists for a more physiological replacement therapy Non-dopaminergic systems Other monoamine transmitters Interaction with noradrenergic and serotoninergic receptors for the control of motor symptoms and reduced motor complications Cholinergic and GABAergic systems Avoidance of dyskinesias Potential for the control of cognitive deficits Glutamatergic systems Selective agonists to suppress dyskinesia and improve the response to dopaminergic treatment Opioid receptorsControl of levodopa-induced dyskinesias Cannabinoid receptorsControl of motor symptoms Adenosine receptorsAntagonists for symptomatic antiparkinsonian effect Schapira, et al. Nature Rev Drug Discov 2006;5:

143 143 Section III – Depression in Parkinson’s Disease

144 144 Overview Epidemiology and Pathophysiology Burden Diagnosis and Evaluation Treatment Depression in Parkinson’s Disease – Summary

145 145 Overview

146 146 Neuropsychiatric Non-Motor Symptoms of Parkinson’s Disease Anxiety Anhedonia Apathy Depression –The strongest predictor of quality of life in Parkinson’s disease Dementia Global Parkinson’s Disease Survey Steering Committee. Mov Disord 2002;17:60-7. Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:

147 147 Patterns of Depression in Parkinson’s Disease Off-period related –Typically associated with motor symptoms (akinesia, rigidity, dystonia) –Often associated with other non-motor symptoms, e.g. pain, anxiety, panic (delusions, hallucinations) –Related to medication timing –Treatment: Adjustment of antiparkinsonian medication Additional treatment interventions when needed Not off-period related –In the majority of patients with depression and Parkinson’s disease –No clear relationship with motor symptoms or medication timing –May precede motor symptoms –No clear relationship with PD severity and stage –Need for treatment approaches specific to the depressive symptoms Sawabini KA, et al. In: Principles of Treatment in Parkinson’s Disease; Lieberman A. Acta Neurol Scand 2006;113:1-8.

148 148 Epidemiology and Pathophysiology

149 149 Depression in Parkinson’s Disease – Epidemiology Frequency of depression in Parkinson’s disease: probably 40–50% –Compared to a 16% prevalence of depression in the general population (USA) –Depression is the most common psychiatric complication in PD patients –Exact epidemiological data are lacking –Frequency varies between 4 and 70% depending on: Criteria used Population studied –Frequency higher in studies from research centres than from community-based studies –Severity of depression in PD patients 50% moderate to severe 50% mild –Bimodal distribution: increased rates at the onset and a later peak in advanced disease Severity of depression correlates with reduced quality of life Cummings JL. Am J Psychiatry 1992;149: Lieberman A. Acta Neurol Scand 2006;113:1-8. Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:

150 150 Depression in Parkinson’s Disease Is Under- Recognised Association between Parkinson’s disease and depression is well known 1,2 –Depression in PD is insufficiently treated –Pathophysiology not well understood Prospective study on PD patients (n = 101) 3 –Standardised testing: depression in 44% of patients –Treating neurologist Depression identified in 21% of patients Diagnostic accuracy of 35% –During routine office visits, neurologists fail to identify depression more than half of the time –Need for improving diagnostic accuracy and timely therapeutic interventions 1. Livingston G, et al. J Affect Disord 1997;46: Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69: Shulman LM, et al. Parkinsonism Relat Disord 2002;8:193-7.

151 151 Causes of Depression in Parkinson’s Disease Reactive (chronic disease) Coincidental (high prevalence in age group) Parkinson’s disease-related causes –Disturbance of monoaminergic pathways –Dopaminergic, serotonergic and noradrenergic systems Lieberman A. Acta Neurol Scand 2006;113:1-8.

152 152 Depression in Parkinson’s Disease – Dopaminergic Neurotransmitter Systems Dopaminergic mesolimbic and mesocortical pathways –Project from ventral mesencephalon to limbic and cortical structures that regulate cognition, emotions and reward- seeking behaviour Implicated in apathy, anhedonia and depression in Parkinson’s disease D 3 dopamine receptors are preferentially localised in the limbic system Lieberman A. Acta Neurol Scand 2006;113:1-8.

153 153 Depression in Parkinson’s Disease – Neurotransmitters Other Than Dopamine Extensive cell loss in the nucleus coeruleus, the major source of brain noradrenaline 1 Alterations of the raphe nucleus, the major source of brain serotonin 2 –Other studies do not support the role of the serotonergic system in depressed patients with Parkinson’s disease 3 –Serotonergic hypothesis for depression in PD remains controversial 1. Taylor AE, Saint-Cyr JA, J Neuropsychiatry Clin Neurosci 1990;2: Yamamoto M. J Neurol 2001;248(S3):III Leentjens AF, et al. Neuropsychopharmacology 2006;31:

154 154 Depression in Parkinson’s Disease – Amygdala Dopaminergic System Absence of robust amygdala response to emotions in patient with Parkinson’s disease Dopamine repletion partially restores this response Difference in BOLD* fMRI † response of the amygdala in normal subjects and PD patients in drug-off (  12h after the last dose of dopaminergic treatment) and in drug-on (1–2h after the first daily dose) states; z = Talairach coordinate * blood oxygen-level dependent; † functional magnetic resonance imaging Normal controlsPD Drug-offPD Drug-on z = -14z = -12 T value Tessitore A, et al. J Neurosci 2002;22: Copyright © 2002 Society for Neuroscience.

155 155 Depression in Parkinson’s Disease – Loss of Dopamine and Noradrenaline Innervation in the Limbic System Depressed Parkinson’s disease patients had lower [ 11 C]RTI-32* binding than non-depressed Parkinson’s disease cases in: –Locus coeruleus –Several regions of the limbic system, including: Anterior cingulate cortex Thalamus Amygdala Ventral striatum. * 11 C-methyl (1R-2-exo-3-exo)-8- methyl-3-(4-methylphenyl)-8- azabicyclo[3.2.1]octane-2- carboxylate (RTI-32) Remy P, et al. Brain 2005;128: Locus coeruleus Medial thalamus Medial ventral thalamus Right amygdala Copyright © 2005 by the Guarantors of Brain.

156 156 Burden

157 157 Global Parkinson’s Disease Survey Steering Committee. Mov Disord 2002;17:60-7. Factors Predicting Poor Quality of Life in Parkinson’s Disease Depression Disease stage and medication Satisfaction with explanation given at diagnosis Current level of optimism Not explained

158 158 Determinants of Quality of Life in Parkinson’s Disease ReferenceStudy populationFactors associated with poor QoL Kuopio et al. (2000a)Population-basedDepression, disease severity (freezing, nocturnal akinesia, early morning akinesia, dystonia) Larsen et al. (2000)Population-basedDepression, insomnia, disability, disease severity Schrag et al. (2000a)Population-basedDepression, disability, postural instability, cognitive impairment (akinetic-rigid) Damiano et al. (2000)Clinic-basedDyskinesias, comorbidity Hobson et al. (1999)Clinic-basedDisease severity, depression, cognitive impairment Rubenstein et al. (1998)Clinic-basedDisease severity, off-periods, dyskinesias, dystonia, sleep disturbances Lyons et al. (1998)Parkinson’s disease registry Postural instability, gait abnormalities, bradykinesia, disease duration GPDSC* (2002)Clinic-basedDepression, disease severity and medication, satisfaction with explanation at diagnosis, current optimism Zach et al. (2004)Clinic-basedDepression, disease duration Chapuis et al. (2005)Clinic-basedLevodopa doses, disease severity, dyskinesias * Global Parkinson’s Disease Steering Committee study Copyright © 2002 Movement Disorder Society.

159 159 Complex Relationship between Depression and Parkinson’s Disease Symptoms Celesia GG, Wanamaker WM. Dis Nerv Syst 1972;33: Starkstein SE, et al. J Nerv Ment Dis 1990;178:27-31 Hoehn & Yahr Depression %

160 160 Correlates of Depression in Parkinson’s Disease No/poor relationship between : –Age –Age of onset –Gender –Disease duration –Disease severity Close relationship between: –Quality of life Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69: Lieberman A. Acta Neurol Scand 2006;113:1-8.

161 161 Treatment of Depression in Parkinson’s Disease Approximately 25% of patients with Parkinson’s disease diagnosed with depression receive treatment 1,2 Efficacy of antidepressants 3 –Large placebo effect, which may result in similar effect of antidepressants and placebo –Older patients appear to respond better –Minor depression and dysthymia less likely to respond 1. Richard IH, Kurlan R. Neurology 1997;49: Weintraub D, et al. J Geriatr Psychiatry Neurol 2003;16: Weintraub D, et al. Mov Disord 2005;20:

162 162 Depression May Precede Motor Symptoms in Parkinson’s Disease Diagnosis of depression is more common in patients with PD before the onset of the disease Patients with depression have a two- to threefold risk of developing PD Depression is not only a reaction to having PD Depression is either an early symptom in PD or a risk factor for developing PD Ishihara L, Brayne C. Acta Neurol Scand 2006;113: Lieberman A. Acta Neurol Scand 2006;113:1-8.

163 163 Impact and Treatment of Depression in Patients with Parkinson’s Disease Depression is the strongest predictor of poor quality of life in PD Depression may be more disabling than motor symptoms Treatment of depression is often insufficient in PD –Should become an important target in the management of the disease Schrag A, et al. Neurol Neurosurg Psychiatry 2000;69:

164 164 Diagnosis and Evaluation

165 165 Diagnosis of Depression – DSM-IV Criteria 1.Depressed mood 2.Decreased interest (apathy) or pleasure in activities (anhedonia) 3.Significant weight loss 4.Insomnia or excessive sleep 5.Psychomotor retardation or agitation 6.Loss of energy (anergia) 7.Feelings of inappropriate guilt 8.Recurrent thoughts of death Major depression is diagnosed if five or more of the following symptoms are present: Statistical Manual of Mental Disorders, 4 th ed

166 166 Difficulties in Diagnosing Depression in Parkinson’s Disease Overlap of Parkinson’s disease with DSM-IV criteria: –Psychomotor retardation (including hypomimia, hypophonia, slowed movement, fatigability and stooped posture) –Apathy –Insomnia –Anergia –Weight loss –Loss of libido DSM-IV criteria exclude concomitant disease Minor depression is more frequent than major depression Relative absence of traditional symptoms of depression: –Feelings of guilt –Shame –Sorrow Lieberman A. Acta Neurol Scand 2006;113:1-8.

167 167 Diagnosis of Depression in Parkinson’s Disease Feelings of emptiness and hopelessness Reduced reactivity to emotional stimuli Loss of the ability to enjoy and feel pleasure (anhedonia) Diagnosis of depression in PD is based on subjectively experienced depressive symptoms: Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.

168 168 Depression Scales in Parkinson’s Disease Observer-rated –Hamilton Depression Rating Scale 1 –Montgomery-Asberg Depression Rating Scale 1 Patient-rated –Beck Depression Inventory 2,3 1. Leentjens AF, et al. Int J Geriatr Psychiatry 2000;15: Leentjens AF, et al. Mov Disord 2000;15: Levin BE, et al. J Neurol Neurosurg Psychiatry 1988;51:

169 169 Treatment

170 170 Depression in Parkinson’s Disease – Treatment Options Off-period related depression –Adjustment of dopaminergic treatment Primary depression –Pharmacological treatment Dopamine agonists (e.g. pramipexole) Tricyclic or tetracylic antidepressants Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SSNRIs) Selective noradrenaline reuptake inhibitors (SNRIs) Other antidepressants –Selective MAO-A* inhibitors –Bupropion –Non-pharmacological treatment Cognitive behavioural therapy, counselling, coping strategies, sleep deprivation In therapy-resistant forms –Transcranial magnetic stimulation (TMS) –Electroconvulsive therapy (ECT) Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Miyasaki JM, et al. Neurology 2006;66: * Monoamine oxidase type-A

171 171 Treatment of Off-Period Related Depression in Parkinson’s Disease Anxiety and depression are increased during off-periods and can even precede akinetic states 1 Off-period related depression occurs particularly in patients with suboptimal medication: 2 –Switch to immediate-release levodopa –Shorten dosing intervals of levodopa or add a dopamine agonist –If wearing off: Add a dopamine agonist or a catechol-O-methyltransferase (COMT) inhibitor; or Amantadine In recently diagnosed patients with Parkinson’s disease who are depressed: –Start treatment with dopamine agonists (e.g. pramipexole) 1, 3 Delay the onset of dyskinesia and motor fluctuations Antidepressant effects of dopamine agonists (pramipexole) 1 1. Lemke MR, et al. J Neurol 2004;25(Suppl 6):VI/ Sawabini KA, et al. In: Principles of Treatment in Parkinson’s Disease; Lieberman A. Acta Neurol Scand 2006;113:1-8.

172 172 Treatment of Depression in Parkinson’s Disease – Dopamine Agonists First-generation ergot-derived agonists (bromocriptine, pergolide) –Non-blinded studies in depressed patients without Parkinson’s disease suggested an antidepressant effect –Subsequent double-blind studies did not give confirmation, or resulted in minimal or modest improvement Second-generation non-ergot agonists (pramipexole, ropinirole) –Pramipexole has been shown to have some antidepressant effects –Stimulation of D 3 receptors and preference for D 3 versus D 2 receptors seem to have antidepressant effect –Anxiolytic effects of dopamine agonists in laboratory-based studies –Antidepressant effects of dopamine agonists Not yet thoroughly studied Most available data relate to pramipexole Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Lieberman A. Acta Neurol Scand 2006;113:1-8.

173 173 ReferenceAgentDesignEffects Willner et al. 1994PramipexoleExperimentalAnti-anhedonic Maj et al. 1997PramipexoleExperimentalAntidepressive Corrigan et al. 2000PramipexoleDouble-blind, placebo- controlled, n = 174 Antidepressive better than placebo, comparable with fluoxetine in depression Perugi et al. 2001Pramipexole, Ropinirole Open, prospective, n = 18Antidepressive in refractory bipolar II depression, combination Rektorova et al. 2003Pramipexole Pergolide Open, randomised, controlled, n = 41 Antidepressive in Parkinson‘s Disease Reichmann et al. 2003PramipexoleOpen, prospective, n = 657Improvement of motor signs and depression in Parkinson’s disease Goldberg et al. 2004PramipexoleDouble-blind, randomised, placebo-controlled, n = 22 Antidepressive, refractory bipolar depression, add-on to mood stabilisers Zarate et al. 2004PramipexoleDouble-blind, randomised, placebo-controlled, n = 21 Antidepressive, refractory bipolar depression, add-on to mood stabilisers Lemke et al. 2005PramipexoleOpen, prospective, n = 657Antidepressive and anti-anhedonic in Parkinson‘s disease Barone et al. 2006Pramipexole vs. Sertraline Parallel-group, randomised, n = 67 Remission: pramipexole 60.6% vs. sertraline 27.3% Studies on Dopamine Agonists in the Treatment of Depression

174 Pramipexole 1.19 mg/d Placebo P < 0.05 % Responders (≥ 50% reduction in HAM-D † scores after 6 weeks) Double-blind, placebo-controlled, randomised study (n = 22) * carbamazepine, lithium, divalproex, lamotrigine, gabapentin † 17-item Hamilton Depression Rating Scale Pramipexole as Add-on Therapy to Existing Mood Stabilisers* in Treatment-Resistant Bipolar Depression (1) Goldberg JF, et al. Am J Psychiatry 2004;161:564-6.

175 175 Goldberg JF, et al. Am J Psychiatry 2004;161: Pramipexole as Add-on Therapy to Existing Mood Stabilisers* in Treatment-Resistant Bipolar Depression (2) * carbamazepine, lithium, divalproex, lamotrigine, gabapentin † Clinical Global Impression (CGI) – Severity of Illness score Pramipexole 1.19 mg/d Placebo CGI-SI † score Baseline6 weeks P = 0.02 Double-blind, placebo-controlled, randomised study (n = 22)

176 176 Pramipexole versus Pergolide in the Treatment of Depression in Patients with Parkinson’s Disease Rektorova I, et al. Eur J Neurol 2003;10: Open, multicentre, randomised study (n = 41) BaselineAfter 8 months Pramipexole (1.9 mg /day) Pergolide (3.0 mg /day) MADRS* NS P < 0.05 * Montgomery-Asberg Depression Rating Scale Copyright © 2003, Blackwell Publishing Ltd.

177 177 Lemke MR, et al. J Neuropsych Clin Neurosci 2005;17: * loss of pleasure † T1 = baseline ‡ T2 = at the end of a maintenance period of 9 weeks on average § SHAPS-D: Snaith-Hamilton Pleasure Scale (German version) Course of Anhedonia* during Treatment with Pramipexole in Parkinson’s Disease Anhedonia (Frequency): T1 † : n = 286 (45.7%)  T2 ‡ : n = 160 (25.5%) (  2 = 94.45, df = 1, P < 0.001) Anhedonia: SHAPS-D § (0–14) 3 6 T1T2 SHAPS-D (P < 0.001) © 2005 American Psychiatric Press, Inc. Blackwell Publishing Ltd.

178 178 Course of Depression during Treatment with Pramipexole in Parkinson’s Disease Lemke MR, et al. J Neuropsych Clin Neurosci 2005;17: * T1 = baseline † T2 = at the end of a maintenance period of 9 weeks on average ‡ SPES = Short Parkinson’s Evaluation Scale MildModerateSevereNone Depression (SPES ‡ ) Patients (n) T1* T2 † ** **P < 0.01 © 2005 American Psychiatric Press, Inc. Blackwell Publishing Ltd.

179 179 Pramipexole vs. Sertraline in the Treatment of Parkinson’s Disease (1) HAM-D* scores decreased in both groups throughout 12 weeks of treatment * 17-item Hamilton Depression Rating Scale Mean HAM-D score BaselineEndpoint *** P < versus baseline Pramipexole Sertraline *** Barone P, et al. J Neurol 2006;253: Copyright © 2006 Springer.

180 180 Pramipexole group: More remission/recovery † Improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscore None (0%) vs. 7 (14.7%) in the sertraline group withdrew for adverse events † as defined by HAM-D score  8 Conclusions: Pramipexole (1.5–4.5 mg/day) has comparable efficacy with sertraline (SSRI) (50 mg/day) on depressive symptoms Dopamine agonists may be an alternative to antidepressants in Parkinson’s disease Proportion of Patients who Recovered (%) PramipexoleSertraline P = Barone P, et al. J Neurol 2006;253: Pramipexole vs. Sertraline in the Treatment of Parkinson’s Disease (2)

181 181 Antidepressive Effects of Dopamine Agonists Reduction of off-periods Dopamine agonist Antidepressive effect Mesolimbic D 3 receptors + potential neuroprotective effects ? ? Lieberman A. Acta Neurol Scand 2006;113:1-8. Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.

182 182 Treatment of Depression in Parkinson’s Disease – Tricyclic Antidepressants Five randomised, controlled, double-blind studies in Parkinson’s disease 1,2 –Probably effective: amitriptyline, nortriptyline, imipramine and desipramine –Anticholinergic effects may also improve motor symptoms Worsen cognitive functions May be even more effective than SSRIs* 3 –Higher rates of side effects and withdrawals 1. Lemke MR, et al. J Neurol. 2004;251(Suppl 6):VI/ Miyasaki JM, et al. Neurology 2006;66: Serrano-Duenas M. Rev Neurol 2002;35: * selective serotonin reuptake inhibitors

183 183 Anticholinergic effects –Alternation of cognitive functions Sedation Confusion, delirium –Orthostatic hypotension  Poorly tolerated in cognitively impaired elderly patients –Cardiotoxicity Possible serotonin syndrome if associated with the MAO-B* inhibitors Tricyclic Antidepressants in Parkinson’s Disease – Side Effects Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Lieberman A. Acta Neurol Scand 2006;113:1-8. * monoamine oxidase type-B

184 184 Selective Serotonin and Noradrenaline Reuptake Inhibitors (SSRIs and SNRIs) in the Treatment of Depression in Parkinson’s Disease Similar efficacy with tricyclic antidepressants but different safety profile –Better tolerability in elderly patients Possibility of worsening of motor symptoms with SSRIs (fluoxetine, paroxetine and fluvoxamine) –Considered a rare phenomenon Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.

185 185 Sedation Insomnia Dry mouth Nausea Sexual dysfunction Weight gain or weight loss Increased risk of serotonin syndrome if concomitant treatment with MAO-B* inhibitors Selective Serotonin and Noradrenaline Reuptake Inhibitors (SSRIs and SNRIs) – Side Effects Lieberman A. Acta Neurol Scand 2006;113:1-8. * monoamine oxidase type-B

186 186 Non-Pharmacological Treatment of Depression in Parkinson’s Disease Psychotherapy –No controlled trials –Subjective experience of deficits determine quality of life (QoL) and subjective well-being Psychotherapy may be integrated into treatment programmes –Interpersonal psychotherapy –Cognitive therapy –Training of social functions –Relaxation therapies Sleep deprivation Transcranial magnetic stimulation (TMS) –Treatment-resistant depressed patients with Parkinson’s disease Insufficient evidence Electroconvulsive therapy (ECT) –Treatment-resistant depressed PD patients Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Miyasaki JM, et al. Neurology 2006;66:

187 187 Treatment of Anxiety Associated with Depression in Parkinson’s Disease SSRIs* and SNRIs † –If moderate depression and moderate anxiety –Not all have been approved for anxiety Benzodiazepines –May be required because of the frequent association of anxiety with depression in Parkinson’s disease –Cause multiple side effects Impair cognition Impair motor functions Cause falls  May be particularly detrimental in elderly PD patients –Potential addiction –Consider short-term use Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Lieberman A. Acta Neurol Scand 2006;113:1-8. * selective serotonin reuptake inhibitors † selective noradrenaline reuptake inhibitors

188 188 Psychotropic Agents to Avoid in Parkinson’s Disease Lithium Sodium Valproate can increase parkinsonism and tremor can increase extrapyramidal symptoms can increase parkinsonism Amoxapine Neuroleptic medication Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Miyasaki JM, et al. Neurology 2006;66:

189 189 Abbreviations: SSRI, selective serotonin reuptake inhibitors; SNRI, selective noradrenaline reuptake inhibitor; TCA, tricyclic antidepressants; TMS, transcranial magnetic stimulation; ECT, electroconvulsive therapy; MAO-B, monoamine oxidase B Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Sawabini KA, et al. In: Principles of Treatment in Parkinson’s Disease; Lieberman A. Acta Neurol Scand 2006;113:1-8. Schapira A. In: Neurology and Clinical Neuroscience; Depression in Parkinson’s disease Primary "Off-period" dysphoria Optimise existing antiparkinsonian therapy Improvement? Patient under levodopa Educational programme/ Psychotherapy Start treatment with second-generation dopamine agonists De novo Parkinson’s disease Educational programme/ Psychotherapy Start treatment with second-generation dopamine agonists Improvement? YesNo Start SSRI, SNRI, or moclobemide Change to TCA if no improvement Combine TCAs with SSRIs or SNRI TMS or ECT if resistant to medication Yes Continue and review COMT inhibitor No Apomorphine support Dopamine agonist MAO-B inhibitor Duodenal levodopa Surgery Optimise PD symptoms with additional/alternative drugs if not already used Levodopa Continue and review

190 190 Depression in Parkinson’s Disease – Conclusion (1) Depression is frequent in patients with PD and a major independent factor of poor quality of life Depression is difficult to recognise and measure in PD patients and its treatment is often insufficient Depression may precede the diagnosis of PD Dopaminergic, noradrenergic and, probably, serotonergic mechanisms are involved

191 191 Adjustment of antiparkinsonian treatment and patient education may be sufficient in patients with off-period related depression Main pharmacological treatment options in not off-period related depression: –Second-generation dopamine agonists Most available data support potential antidepressant properties of pramipexole Possible first-line therapy in many depressed patients with Parkinson’s disease  Offer a combined treatment approach to depression and motor symptoms and avoid polypharmacy –Tricyclics and newer selective antidepressants Probably effective; however, should not be considered as first-line therapy Consultation with a psychiatrist –Is mandatory for PD patients with severe depression or when depression is the leading symptom –Is mandatory for PD patients with depression resistant to pharmacological treatment –Recommended in PD patients with minor depression Depression in Parkinson’s Disease – Conclusion (2)

192 192 Supported by an educational grant from Boehringer Ingelheim International GmbH Scientific coordination: Armine Najand, MD Produced by: LMS Group 75 rue Guy Môquet Malakoff France Phone: Fax:


Download ppt "1 Current Concepts and Perspectives in Parkinson’s Disease Anthony H.V. Schapira, DSc, MD, FRCP, FMedSci Professor of Neurology University Department of."

Similar presentations


Ads by Google