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La depressione nelle malattie neurologiche
Roberto Ceravolo
Department of Clinical and Experimental MedicineUniversity of Pisa
Depressione
e
Malattie neurologiche
MALATTIA DI
ALZHEIMERDEMENZA FRONTO
TEMPORALE
MALATTIA DI
PARKINSON
Epilessia
Neuro-
miopatie
Cefalea
SM
Stroke
Sclerosi laterale
amiotrofica
Irritabilitagrave 46
Apatia 48
Ansia68
Depressione69
hanno almeno 1 sintomoneuropsichiatrico in unapopolazione con etagrave media di70 aa e una durata media dimalattia di 5 aa
87Kulisevsky et al 2008
Disinibizione 11
Comport Motori
aberranti 13
Allucinazioni16
Agitazione
22Euforia
12Deliri14
Depression in PD Unmet needs
Depression is the factor most significantly associated with QoL and isan important contributor to caregiver distress (Hobson et al 1999Schrag et al 2000)
In general practice registries 64 of PD patients reported clinicallysignificant depression on GDS scale but only 7 were treated withADs (Meara et al Age Ageing 19992838)
In a movement disorder clinic 34 of patients met diagnostic criteriafor depressive disorder but 65 were not treated with ADs(Weintraub J Geriatr Psych Neurol 200316178-83)
Over 1000 PD patients in 6 countries 50 had significant depressionas measured by BDI however only 1 of patients had revealeddepressive symptoms to the clinicians (GPDS Mov Disord 20021760-67)
Inclusion criteria Antidepressanttreatment in PD reporting outcomemeasure
27 studies from 1965 to 2003 total patient population=772 subjects
1627 were specifically designed fordepression in PD
Only 1127 studies suitable formeta-analysis
Only 2 studies with Double Blindversus placebo design
Depression in PD
Under recognized
Misdiagnosed
Under treated
Depression NICE criteria
Depressive syndrome
AFFECTIVEdomain
COGNITIVE domain
PHYSICAL
domainBEHAVIORAL
domain
Low mood
Pessimism
Desperation
Guilty feeling
Suicide ideation
Weight change
Insomnia
Loss of libido
Somatic symptoms
Aches and pain
Anhedonia
Slowness
Hypomimia
Irritability
Anxiety
Modified from NICE National Institute of Clinical Excellence
Slowness of thinking
Attention memoryreduction
Guilty ideas
Self reproching
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depressione
e
Malattie neurologiche
MALATTIA DI
ALZHEIMERDEMENZA FRONTO
TEMPORALE
MALATTIA DI
PARKINSON
Epilessia
Neuro-
miopatie
Cefalea
SM
Stroke
Sclerosi laterale
amiotrofica
Irritabilitagrave 46
Apatia 48
Ansia68
Depressione69
hanno almeno 1 sintomoneuropsichiatrico in unapopolazione con etagrave media di70 aa e una durata media dimalattia di 5 aa
87Kulisevsky et al 2008
Disinibizione 11
Comport Motori
aberranti 13
Allucinazioni16
Agitazione
22Euforia
12Deliri14
Depression in PD Unmet needs
Depression is the factor most significantly associated with QoL and isan important contributor to caregiver distress (Hobson et al 1999Schrag et al 2000)
In general practice registries 64 of PD patients reported clinicallysignificant depression on GDS scale but only 7 were treated withADs (Meara et al Age Ageing 19992838)
In a movement disorder clinic 34 of patients met diagnostic criteriafor depressive disorder but 65 were not treated with ADs(Weintraub J Geriatr Psych Neurol 200316178-83)
Over 1000 PD patients in 6 countries 50 had significant depressionas measured by BDI however only 1 of patients had revealeddepressive symptoms to the clinicians (GPDS Mov Disord 20021760-67)
Inclusion criteria Antidepressanttreatment in PD reporting outcomemeasure
27 studies from 1965 to 2003 total patient population=772 subjects
1627 were specifically designed fordepression in PD
Only 1127 studies suitable formeta-analysis
Only 2 studies with Double Blindversus placebo design
Depression in PD
Under recognized
Misdiagnosed
Under treated
Depression NICE criteria
Depressive syndrome
AFFECTIVEdomain
COGNITIVE domain
PHYSICAL
domainBEHAVIORAL
domain
Low mood
Pessimism
Desperation
Guilty feeling
Suicide ideation
Weight change
Insomnia
Loss of libido
Somatic symptoms
Aches and pain
Anhedonia
Slowness
Hypomimia
Irritability
Anxiety
Modified from NICE National Institute of Clinical Excellence
Slowness of thinking
Attention memoryreduction
Guilty ideas
Self reproching
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Irritabilitagrave 46
Apatia 48
Ansia68
Depressione69
hanno almeno 1 sintomoneuropsichiatrico in unapopolazione con etagrave media di70 aa e una durata media dimalattia di 5 aa
87Kulisevsky et al 2008
Disinibizione 11
Comport Motori
aberranti 13
Allucinazioni16
Agitazione
22Euforia
12Deliri14
Depression in PD Unmet needs
Depression is the factor most significantly associated with QoL and isan important contributor to caregiver distress (Hobson et al 1999Schrag et al 2000)
In general practice registries 64 of PD patients reported clinicallysignificant depression on GDS scale but only 7 were treated withADs (Meara et al Age Ageing 19992838)
In a movement disorder clinic 34 of patients met diagnostic criteriafor depressive disorder but 65 were not treated with ADs(Weintraub J Geriatr Psych Neurol 200316178-83)
Over 1000 PD patients in 6 countries 50 had significant depressionas measured by BDI however only 1 of patients had revealeddepressive symptoms to the clinicians (GPDS Mov Disord 20021760-67)
Inclusion criteria Antidepressanttreatment in PD reporting outcomemeasure
27 studies from 1965 to 2003 total patient population=772 subjects
1627 were specifically designed fordepression in PD
Only 1127 studies suitable formeta-analysis
Only 2 studies with Double Blindversus placebo design
Depression in PD
Under recognized
Misdiagnosed
Under treated
Depression NICE criteria
Depressive syndrome
AFFECTIVEdomain
COGNITIVE domain
PHYSICAL
domainBEHAVIORAL
domain
Low mood
Pessimism
Desperation
Guilty feeling
Suicide ideation
Weight change
Insomnia
Loss of libido
Somatic symptoms
Aches and pain
Anhedonia
Slowness
Hypomimia
Irritability
Anxiety
Modified from NICE National Institute of Clinical Excellence
Slowness of thinking
Attention memoryreduction
Guilty ideas
Self reproching
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depression in PD Unmet needs
Depression is the factor most significantly associated with QoL and isan important contributor to caregiver distress (Hobson et al 1999Schrag et al 2000)
In general practice registries 64 of PD patients reported clinicallysignificant depression on GDS scale but only 7 were treated withADs (Meara et al Age Ageing 19992838)
In a movement disorder clinic 34 of patients met diagnostic criteriafor depressive disorder but 65 were not treated with ADs(Weintraub J Geriatr Psych Neurol 200316178-83)
Over 1000 PD patients in 6 countries 50 had significant depressionas measured by BDI however only 1 of patients had revealeddepressive symptoms to the clinicians (GPDS Mov Disord 20021760-67)
Inclusion criteria Antidepressanttreatment in PD reporting outcomemeasure
27 studies from 1965 to 2003 total patient population=772 subjects
1627 were specifically designed fordepression in PD
Only 1127 studies suitable formeta-analysis
Only 2 studies with Double Blindversus placebo design
Depression in PD
Under recognized
Misdiagnosed
Under treated
Depression NICE criteria
Depressive syndrome
AFFECTIVEdomain
COGNITIVE domain
PHYSICAL
domainBEHAVIORAL
domain
Low mood
Pessimism
Desperation
Guilty feeling
Suicide ideation
Weight change
Insomnia
Loss of libido
Somatic symptoms
Aches and pain
Anhedonia
Slowness
Hypomimia
Irritability
Anxiety
Modified from NICE National Institute of Clinical Excellence
Slowness of thinking
Attention memoryreduction
Guilty ideas
Self reproching
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Inclusion criteria Antidepressanttreatment in PD reporting outcomemeasure
27 studies from 1965 to 2003 total patient population=772 subjects
1627 were specifically designed fordepression in PD
Only 1127 studies suitable formeta-analysis
Only 2 studies with Double Blindversus placebo design
Depression in PD
Under recognized
Misdiagnosed
Under treated
Depression NICE criteria
Depressive syndrome
AFFECTIVEdomain
COGNITIVE domain
PHYSICAL
domainBEHAVIORAL
domain
Low mood
Pessimism
Desperation
Guilty feeling
Suicide ideation
Weight change
Insomnia
Loss of libido
Somatic symptoms
Aches and pain
Anhedonia
Slowness
Hypomimia
Irritability
Anxiety
Modified from NICE National Institute of Clinical Excellence
Slowness of thinking
Attention memoryreduction
Guilty ideas
Self reproching
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depression in PD
Under recognized
Misdiagnosed
Under treated
Depression NICE criteria
Depressive syndrome
AFFECTIVEdomain
COGNITIVE domain
PHYSICAL
domainBEHAVIORAL
domain
Low mood
Pessimism
Desperation
Guilty feeling
Suicide ideation
Weight change
Insomnia
Loss of libido
Somatic symptoms
Aches and pain
Anhedonia
Slowness
Hypomimia
Irritability
Anxiety
Modified from NICE National Institute of Clinical Excellence
Slowness of thinking
Attention memoryreduction
Guilty ideas
Self reproching
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depression NICE criteria
Depressive syndrome
AFFECTIVEdomain
COGNITIVE domain
PHYSICAL
domainBEHAVIORAL
domain
Low mood
Pessimism
Desperation
Guilty feeling
Suicide ideation
Weight change
Insomnia
Loss of libido
Somatic symptoms
Aches and pain
Anhedonia
Slowness
Hypomimia
Irritability
Anxiety
Modified from NICE National Institute of Clinical Excellence
Slowness of thinking
Attention memoryreduction
Guilty ideas
Self reproching
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Guilt thoughts Depression
Sleepchanges
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
DEPRESSION GALAXY
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Guilty thoughts Depression
Sleep changes
Anxiety
Anorexiabulimia
Fatigue
Tiredness
Reduced energy
Anhedonia
Aches and Pains
Suicidal ideation
Brooding
Loss of libido
Weight
change
Phobic
features
Hypochondria
Motor
slowness
PD DEPRESSION GALAXY
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Cheng-Che Shen Neurology 2013
Ris
chio
di M
P
Periodo di follow-up
4636 p con depressione
18544 controlli
Malattia di Pakinson 142 (plt 0001)
Rischio di MP aumenta quando crsquoegrave una
diagnosi di depressione HR=324
letagrave egrave piugrave alta nei pazienti con depressione e
PD rispetto ai pazienti depressi non PD
Depressione difficile da trattare egrave un fattore di
rischio per MP indipendente
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Alexander StorchNeurology 2013
Nonmotor fluctuations in Parkinson
diseaseSeverity and correlation with motor complications
Fluttuazioni non motorie (NMS) presenti nel 100 dei pz con fluttuazioni motorie tutti i SNM sono peggiori nelle fasi OFF
La gravitagrave dei NMS non correla con lrsquoentitagrave delle variazioni motorie
in circa 23 dei pzlrsquoansia e la depressione erano presenti solo in fase off
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Barone et al2009
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
bull La diagnosi dovrebbe essere fatta seguendo i criteri DSM-V
bull La depressione sub-sindromica dovrebbe essere inclusa come
categoria diagnostica negli studi
bull Il momento della valutazione dovrebbe essere (on o off)
bull Per i paziente con demenza dovrebbero essere interrogati i caregivers
bull Lrsquoanedonia dovrebbe essere considerata solo sulla base della perdita di
piacere
DepressioneMP
Mov Disord 2006
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
[
DepressioneMP
I sintomi di depressione in MP sono diversi
rispetto a quelli solitamente presenti nella
depressione primaria i pazienti con MP
hanno meno senso di colpa meno biasimo
ma maggiore irritabilitagrave tristezza che
correlano con lo stato di salute raro il
suicidioDepression in Parkinsons diseaseMust be properly diagnosed and treated to avoid serious morbidityBMJ VOLUME 320 13 MAY 2000
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Associata con aumento della disabilitagrave
Peggiora la qualitagrave della vita
Tende ad essere sottodiagnosticatasottotrattata
Solo 20-26 dei p con MP e depressione ricevono un trattamento
(Richard IH Neurology 1997 Oct)(Weintraub D J Geriatr Psyc Neurol 2003)
DepressioneMP
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Scale cliniche depressione in MP
screening monitoraggio
HAM-D
MADRSUPDRS
BDI I-IIGDS
Scala clinica Cut-off suggerito nella MP
Hamilton Depression (HAM-D) 9-10
Beck Depression Inventory (BDI) 13-14
Geriatric Depression Scale 30 (GDS 30) 9-10
Geriatric Depression Scale 15 (GDS 15) 4-5
Montgomery-Asberg Depression Rating Scale (MADRS) 14-15
+frequentemente utilizzate
breve autosomministrata risposte sino
DepressioneMP
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Prevalence of Depressive Disorder and
Depressive symptoms in PD
Major depression 17
Minor depression 22
Dysthymia 13
Reijnders et al Mov Disord 2007
Clinically significant
depressive symptoms 361
DepressionPD
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
22
ldquoDEPRESSIONrdquo in PDwhat should we treat
Depressive Disorder
(Major Minor Dysthimia)
Depressive Symptoms
DSM-V criteria for
Diagnosis of depression
screening for depressive
symptoms
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Low mood AnxietyDepression
Depression in PD not ONE disease
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
DEPRESSIONE E SEROTONINA
Pazienti con MP
Ridotti trasportatori SERT nella regione orbitofrontale corteccia del cingolo insula amigdala e ippocampo
(Kish S Brain 2008)
(Guttman Eur J Neurol 2007)
(Albin J Cereb Blood Flow Metab 2008)
Riduzione dei livelli di 5-HT e dei trasportatori SERT a livello striatale (soprattutto caudato)
Riduzione dei neuroni serotoninergici nucleo dorsale del rafe
Pazienti con MP e depressione
Ridotta ecogenicitagrave nel rafe mesencefalico alla sonografia transcranica
(Pauls J Neuropathol Exp Neurol 1991)
(Berg J Neurol 1999)
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Natural history of degenerative parkinsonism
Department of Clinical and Experimental Medicine University of Pisa
Possible correlation anatomo-clinic
SALAT D et al Lancet Neurology 2016
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
11C-DASB11C-MADAM
Serotonintransporter
5-HT
Imaging
serotonin terminal function
AADC
TRYP
5-HTP
5-HT
TH
Serotonin
receptors
5-HT1A
1B1C
1E
1D1F5-HT2A
2B2C
5-HT4
67
5-HT5
5-HT1A
5-HT1B
5-HT3
18F-dopa
11C-AMT
123I-beta CIT 123I-FP-CIT
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
11C-DASB
Serotonin transporter
11C-WAY100635
Serotonin HT1A receptor
123I-FP-CIT
Serotonin and Dopamine
transporter
PETSPECT ligands
11C-AZ10419369
Serotonin HT1B receptor
18F-altanserin
Serotonin HT2A receptor
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
[11C]DASB binding positively correlated with
depression but not with disease severityduration
wide-spread increase in [11C]DASB in
PDdepression
1 dorsolateral cortices
2 prefrontal cortices
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Lower uptake in depressedvs non-depressed PD
bull 8 non depressedPD patients
bull 4 depressed PD patients
Ballanger et al 2011
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
x= 6 plt0001 y= 8 plt0001
y= -1 plt001z= 43 plt0001
z= 10 plt0001
Lower 11C-DASB uptake
in PD with depression
7 PD depr lt 7 PD without depression
amygdalacingulate
cingulate
thalamus
thalamus
striatum
Courtesy of Nicola Pavese
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Autore
annoCampione Disegno Farmaco
Scala
usata
Risultati(decremento punteggio
scala)
Follow up
Leentjens200333
6
6Doppio cieco
Sertralina
PlaceboMADRS
-9
-1110 settimane
Fregni200434
21
21Doppio cieco
Fluoxetina
TMS
HAM D
BDI
-9sect-8sect
-10sect-8sect8 settimane
Serrano Duenas200235
37
40Randomizzato
Fluoxetina
AmitriptilinaHAM D
Inefficace
Efficace 12 mesi
Avila200336
7
9Randomizzato
Fluoxetina
NefazodoneBDI
Ugualmente
efficaci sect12 settimane
Antonini200637
12
11Doppio cieco
Sertralina
AmitriptilinaHAM D
-12sect
-11sect3 mesi
Barone200638
33
34Doppio cieco
Pramipexole
SertralineHAM D
-10sect
-9sect12 settimane
Devos200823
16
15
17
Doppio cieco
Placebo
Citalopram
Desimipramina
MADRS
-9
-14
-20
4 settimane
Menza200921
17
18
17
Doppio cieco
Placebo
Paroxetina
Nortriptilina
HAM D
-4
-6
-11
8 settimane
Richard201224
39
42
34
Doppio cieco
Placebo
Paroxetina
Venlafaxina ER
HAM D
-68
-13
-11
12 settimane
differenza significativa rispetto al placebo
sect differenza significativa rispetto al basale
Studi sullrsquoutilizzo di SSRI nei pazienti con Malattia di Parkinson e depressione (2003-2013)
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Efficacy and Acceptability of selective serotoninreuptake inhibitors for the treatment of depression in Parkinsons disease
a systematic review andmeta-analysis of randomized controlled trials
Petros Skapinakis et all
BMC Neurology 2010 1049
bull Il 63 degli antidepressivi prescritti sono SSRI e nel 7 sono TCAbull Crsquoegrave ancora incertezza sullrsquoefficacia degli SSRI nella depressione in MPbull I risultati di questo studio mostrano che la pratica clinica attuale non
egrave supportata da forti evidenze
Trattamento della depressione in MP
DepressioneMP
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depression and PD clinical features
Anhedonia
Low mood and impaired interest or
ability to experience pleasure
Core symptomOther clinical features
1 Altered sleep patterns
2 Change in weight
3 Loss of libido
4 Psychomotor retardation
5 Reduced energy
Starkstein Mov Disord 2008
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Imaging del rilascio di dopamina
10 di riduzione
del 11C raclopride
BP riflette un
incremento di 5
volte del rilascio di
Dopamina
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Journal of Psychiatric Research 2006
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
DAergic
PRE -
SYNAPTIC
NEURON
DAT
Tracer
PET SPECTPOST -
SYNAPTIC
NEURON
DAT TRACER BINDING = Density of DAergic terminals
Healthy Control Parkinsonrsquos disease
11C-RTI 3218F-CFT123I-beta CIT 123I-FP-CIT123I-altropane99mTc-TroDAT
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depressive symptoms in Parkinsons disease are related to reduced [123I]FP-CIT binding in the caudate nucleus
Vriend 2014
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Frosini D et al 2015
Mesolimbic dopaminergic dysfunction in Parkinsonrsquos disease-depression evidence from a 123I-FP-CIT SPECT investigation
Pd-nd (35) PD-d (15)
MeanplusmnSD MeanplusmnSD
Age at onset (years) 683plusmn71 661plusmn55
Disease duration (years) 12plusmn10 10plusmn05
Age at scan (years) 671plusmn69 668plusmn54
UPDRS II 58plusmn36 70plusmn34
UPDRS III 156plusmn70 157plusmn53
MMSE 279plusmn17 275plusmn13
BDI 25plusmn09 168plusmn38
Left caudate FP-CIT uptake 32 plusmn12 34plusmn 11
Right caudate FP-CIT uptake 33plusmn11 34 plusmn11
Left putamen FP-CIT uptake 17plusmn 10 18 plusmn09
Right putamen FP-CIT uptake 18plusmn 08 12 plusmn08
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Pramipexole for the treatment of depressive symptomsin patients with Parkinsonrsquos disease a randomised
double-blind placebo-controlled trialPaolo Barone Werner Poewe Stefan Albrecht Catherine Debieuvre Dan Massey Olivier Rascol Eduardo Tolosa Daniel Weintraub
Lancet Neurol 2010 9 573ndash80
Miglioramento dello scoreBeck depression Inventory(BDI) Geriatric DepressionScale (GDS) UPDRS II e EQ-5D vs placebo
Lrsquoeffetto del trattamento sui sintomi depressivi egrave
stato per un 80 diretto sulla depressione
valutato con la BDI per un 20 indiretto legato ad un miglioramento dellrsquo UPDRS III
Trattamento della depressione in MP
DepressioneMP
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
PD (90)
HC (90)
Major Depression 211 33
Dysthymia 188 44
DAP 30 33
Anxiety 111 144
DOC 33 22
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Mov Disord 2010
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depressed compared to non depressed dopaminergic and noradrenergic denervation
Locus coeruleus
Medial thalamus
Left
Ventral
striatum
Right Amigdala
Remy et al Brain 2005
[11C]RTI 32 PET
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Biochemical Pharmacology 2007
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
0 20 40 60 80 100
SNc
DRN
LC
DVN
DPDNDPD
GLIOSIS
NEURONAL LOSS
DVN dorsal vagus nerveLC locus coeruleusDRN dorsal raphe nucleiSNc substantia nigra c
Frisina et al 2009 modified
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Mapping the norepinephrine transporter
NETSCAN
A Varrone et al 2010
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Weintraub et al 2010
Atomoxetine treatment was not efficacious for the treatment of clinically significantdepressive symptoms in PD but was associated with improvement in globalcognitive performance and daytime sleepiness
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
115pazientiDoppio cieco vs placeborandomizzato
venlafaxina
paroxetina
12 settimaneplacebo
weeks
SSRI e SNRI sono piugrave efficaci per il trattamento della depressione in MP del placebo
HAM-D
A randomized double-blind
placebo-controlled trial of antidepressants in
Parkinson disease Parkinson disease
IH RichardNeurology 2012
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
A non-comparative assessment of tolerabilityand efficacy of duloxetine in the treatment ofdepressed patients with Parkinsons disease
Trattamento della depressione in MP
Studio multicentrico non comparativo open-label (151 pazienti)
tollerabilitagrave
sicurezza
efficaciaDuloxetina 60mg 12 settimane
Pazienti con MP e depressione Maggiore
U Bonuccelli Expert Opin Pharmacolther 2012
Miglioramento significativoHAM-17 PDQ39
BDI CGI-S PGI-I
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depressive symptoms are associated whit cholinergic deficit in PD
(corrected for MMSe)
bull 18 PD (6 PDD)bull 10 HS
[11C]PMP PET (attivita Ach Esterasi)
Cornell Scale for Depression
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
2013
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
sadness anxiety anhedonia apathy
DEPRESSION
ACETHYLCOLINEDOPAMINENORADRENALINESEROTONIN
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Depression-Fatigue-PainAn unique syndrome
Pain
Fatigue
Depression
Apathy
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
NMS frequency () and PD severityPRIAMO STUDY
Disease severity as Hoehn amp Yahr score
N=1072
1 15ndash2 25ndash3 4ndash5
Pain 509 586 671 796
Urinary 431 517 683 898
Sleep dysfunction 479 606 754 816
Fatigue 377 565 689 816
Apathy 246 268 366 490
Attentionmemory 377 404 517 653
Skin 144 198 345 327
Psychiatric 611 633 732 837
Respiratory 96 155 228 306
Gastrointestinal 455 544 769 735
Adapted from Antonini A et al The PRIAMO study background methods and recruitment Neurol Sci 200829 (2)61ndash5 Barone P et al The PRIAMO study A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinsons disease MovDisorders 20091524(11)1641ndash9
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
8166 PD patients
46755 individualswithout PD
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
NON MOTOR SYMPTOMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls
bull Anhedonia apathy memory complaints and inattentionoccurred more frequently during the 2-year premotor period
bull Smell loss mood disturbances taste loss excessive sweatingfatigue and pain were more frequently reported in the 2- to10-year premotor period
bull Constipation dream-enacting behavior excessive daytimesleepiness and postprandial fullness were frequentlyperceived more than 10 years before motor symptoms
Mov Dis 2014
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Edgar Degas (1834-1917) Melancholy late 1860s French Oil on canvasCourtesy of The Phillips Collection Washington DC
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
bull A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean score of287 plusmn 099
bull 136 patients (338) reported distressing fatigue (PFS-16 mean score ge33)
bull Patients with distressing fatigue were olderand had a longer duration of PD than thosewithout distressing fatigue
bull Famale gender was a risk factor to developfatigue
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
bull The presence of distressing fatigue wasassociated with
bull Higher total Unified Parkinsonrsquos DiseaseRating Scale (UPDRS) scores
bull Poorer quality of life (39-item ParkinsonrsquosDisease Questionnaire [PDQ-39])
bull Worse social and psychological behaviorsbull Higher severity of depressive symptomsbull Higher prevalence of sleep disorders
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
ALL SUBJECTS - 349
PD WITHOUT FATIGUE AT BASELINE - 221
PD WITH FATIGUE AT BASELINE - 128STUDIO ELLDOPA
Fatigue is a frequent symptom in early untreated non-depressed patients with Parkinson disease
Fatigue was associated with the severity of PD and progressed less in patients treated with levodopa
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
- 10 healty subjects- 7 PD patients with fatigue- 8 PD patientswithout fatigue
Right cingulate and right thalamus
Right and left striatum and left
cingulate
Right and left striatum and right and left thalamus
Right and left cingulatus
Right and left striatum and left
amygdala
11C-DASB uptake
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
Take home message
bull La depressione nella MP egrave sindrome premotoria molto
frequente durante la malattia e fattore di peggioramento
della qualitagrave della vita
bull Il suo riconoscimento egrave cruciale spesso sottodiagnosticata e
sottotrattata
bull Piu che una diagnosi formale dovremo riconoscere I sintomi
depressivi e trattarli in relazione al loro differente substrato
neurochimico
bull Necessario conoscere la multidimensionalitagrave del quadro per
un precoce ed efficace trattamento
top related