Journal of Parkinson’s Disease 3 (2013) 105–138DOI 10.3233/JPD-120165IOS Press

105

Review

A Systematic Review of Impulse ControlDisorders in Parkinson’s Disease

Mette Buhl Callesena,b, Jørgen Scheel-Krugerb, Morten L. Kringelbachb,c and Arne Møllera,b

aDepartment of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, DenmarkbCenter of Functionally Integrative Neuroscience, Aarhus University, Aarhus, DenmarkcDepartment of Psychiatry, Oxford University, UK

Abstract. Throughout the past decade it has been recognized that dopaminergic medication administered to remedy motorsymptoms in Parkinson’s disease is associated with an enhanced risk for impulse control disorders and related compulsivebehaviors such as hobbyism, punding, and the dopamine dysregulation syndrome. These complications are relatively frequent,affecting 6–15.5% of patients, and they most often appear, or worsen, after initiation of dopaminergic therapy or dosage increase.Recently, impulse control disorders have also been associated with subthalamic nucleus deep brain stimulation. Here we presenta systematic overview of literature published between 2000 and January 2013 reporting impulse control disorders in Parkinson’sdisease. We consider prevalence rates and discuss the functional neuroanatomy, the impact of dopamine-serotonin interactions,and the cognitive symptomatology associated with impulse control disorders in Parkinson’s disease. Finally, perspectives forfuture research and management of impulse control disorders in Parkinson’s disease are discussed.

Keywords: Impulse control disorders, Parkinson disease, dopamine, serotonin, neuroanatomy, decision making

INTRODUCTION

Parkinson’s disease (PD) is a progressive neu-rodegenerative disorder associated with a dopaminedeficiency in the substantia nigra zona compacta andthe ventral tegmental area in the midbrain causingabnormalities in movement, behavior, cognition, andemotion. Based on observations, James Parkinson firstdescribed the disorder as the “shaking palsy” in 1817.At that time, the senses and intellect of patients suf-fering from PD were believed to be unaffected by thedisease [1]. Half a century later this assumption wasrevised by “the father of modern neurology” the Frenchneurologist, Jean-Martin Charcot (1825–93), who

∗Correspondence to: Mette Buhl Callesen, Department ofNuclear Medicine and PET-Centre, Aarhus University Hospital,Noerrebrogade 44, Building 10 G, 8000 Aarhus C, Denmark. Tel.:+45 78464405; E-mail: buhl@pet.auh.dk.

suggested that the patients’ state of mind is alteredas the disease progresses. Nevertheless, in the generalclinic, PD is still largely considered to be a movementdisorder characterized by cardinal motor symptoms.According to the UK Brain Bank criteria for PD, pres-ence of bradykinesia accompanied by at least one ofthe following: resting tremor, muscular rigidity, or pos-tural instability, are required for a diagnosis of PD.Furthermore, at least three supportive criteria includ-ing: unilateral onset, excellent response to levodopa,resting tremor, severe levodopa-induced chorea, pro-gressive disorder, levodopa response for over 5 years,persistent asymmetry affecting the side of onset most,or clinical course of over 10 years, must be present fora definite diagnosis.

Recently it has been established that even at earlydisease stages, PD is associated with cognitive impair-ments involving executive functions, working memory,

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106 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

impulse control, reversal learning, and decision-making, as well as emotional disturbances includingdepression, apathy, and anxiety causing a generallydecreased quality of life [2–9]. These non-motor mani-festations of PD are to a great extent considered toresult from a deficient dopaminergic innervation oflimbic and prefrontal cortical brain regions followingdisease progression and are thus more pronounced atlater disease stages. The syndromes may be furtherdeteriorated by additional degeneration of the choliner-gic, noradrenergic, and serotonergic neurotransmittersystems [10–13]. Moreover, the medical and surgicaltreatments administered to relieve motor symptomsplay complex roles via their indirect influence on un-affected brain regions potentially inducing cognitiveand emotional dysfunctions. Weintraub and Nirenberg[8] , Crossman [14], and Cools et al. [3, 4] recently dis-cussed and presented results supporting the hypothesisthat the behavioral syndromes depend on disturbancesin the balance between the depleted dorsal striatum andthe dominance of the relatively intact ventral striatum(including the nucleus accumbens) in early stages ofthe disease [3, 4, 6]. Though dopaminergic treatmentin early PD relatively successfully recovers the nor-mal function within the dorsal striatum involved in thesensory-motor circuit, the dopaminergic agents may“overdose” the ventral striatum, potentially resultingin affective disturbances and impulse control disorders(ICDs) [2–4].

In the DSM-IV [15], ICDs define a category ofbehavioral disorders characterized by recurrent mal-adaptive disinhibited behavior despite personal andrelational consequences. Among these are pathologi-cal gambling, compulsive buying, hypersexuality, andbinge eating. Since the early case report by Seedatet al. in 2000 [16], it has been well documented thatdopaminergic medication in a subgroup of PD patientsinduces ICDs and related compulsive disorders suchas hobbyism, punding (i.e. various behavioral stereo-typies), and the dopamine dysregulation syndrome(DDS) characterized by addiction-like self-medicationof high doses of levodopa and short-acting dopamineagonists [8, 17]. The behavioral complications mostoften appear, or worsen, after initiation of D2/D3dopamine agonist therapy or dosage increase. In addi-tion, symptoms tend to improve or disappear upondosage decrease or discontinuation of the dopamineagonist treatment [8, 18–22]. The various syndromesaffect 6–15.5% of PD patients [21, 23–28] comparedto a prevalence of ICDs of 1.1–1.6% in the generaladult population [23, 24, 29, 30]. Moreover, ICDs havebeen associated with subthalamic nucleus deep brain

stimulation (STN DBS) in subgroups of patients [23,31–42], where the results still present important con-troversies and disagreements [32, 42–44]. We return tothis discussion later.

The etiology and pathogenesis of treatment-inducedICDs in PD remain unknown, though altered activityof the mesolimbic dopamine system has been sug-gested to be responsible for the phenomenon [23,45]. Besides a high dose of dopamine agonists, addi-tional risk factors associated with ICDs in PD includeyoung age at PD onset (often in early forties), malegender, a novelty seeking personality, a personal orfamily history of addictive behaviors, and genetic fac-tors [25, 28, 45–53]. A recent study added depressivesymptoms to the list of important risk factors sug-gesting that the variance in the risk for developingICDs is more attributable to the presence of depres-sive symptoms than to the above-mentioned factors[54]. This gained further support through a follow-upstudy describing 22 PD patients without ICDs at base-line, who at follow-up displayed behavioral symptomssignificantly associated with an increase in depressivesymptoms [55]. This is very interesting since depres-sion is a major comorbidity in PD affecting 30–45%of patients, and in fact neuronal loss in the substantianigra is significantly more pronounced in PD patientswith comorbid depression compared to patients with-out depression [9]. Moreover, findings of improvedmood disorder symptoms subsequently to treatmentwith dopamine agonists such as pramipexole serveadditional backup to linking depression and ICDs inPD [9, 56]. For a further discussion of the epidemi-ology of ICDs in PD, we refer to a recent review byWeintraub and Nirenberg [8].

Here we present a systematic review of literaturepublished between 2000 and January 2013 reportingICDs in PD [16, 18–22, 26, 27, 32–39, 41, 42, 45,48, 51, 53–55, 57–132]. We consider prevalence ratesand discuss distinctive forms of cognitive impairmentsassociated with ICDs in PD. Furthermore, comple-menting the work of Weintraub and Nirenberg [8],we add a discussion of the functional neuroanatomyand the dopamine-serotonin interactions implicatedin ICDs in PD. Finally, we consider perspectives forfuture research and suggest possible implications forthe management of ICDs in PD.

The studies included in this review have been iden-tified through PubMed using the following searchwords: Parkinson’s disease, impulse control disor-ders, impulsivity, cognition, and decision-making.The initial search strategy, which combined thewords Parkinson’s disease + impulse control disorders,

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 107

identified 346 articles on January 18th 2013. We endedup including 98 empirical studies in the review amongwhich 64 reports examining both PD patients with andwithout ICDs are presented in Table 1 below. Inclusioncriteria were: Empirical studies examining PD patientswho developed ICDs or experienced a worsening ofICD symptoms subsequent to initiation of dopaminer-gic medication or dosage increase. Exclusion criteriawere: Reviews or other theoretical studies; studiesfocusing exclusively on other neurological diseasesthan PD such as multiple system atrophy or restlesslegs syndrome; studies on ICDs in unmedicated PDpatients; studies focusing solely on treatment of ICDsin PD. However, we will return to the latter topic inour final discussion. A more extensive overview of all98 studies is presented in the Supplementary Tables 1and 2.

SUMMARY AND DISCUSSION OF THELITERATURE REVIEW

Based on the 98 reviewed reports, we concludethat ICDs occur relatively frequently in PD secondaryto dopaminergic therapy. In total 17,286 PD patientswere examined during 2000 and January 2013, andin this material 2,455 (14.2%) displayed prior orcurrent symptoms of ICDs during dopamine replace-ment therapy. However, evaluating prevalence andcharacteristics of ICDs in PD, we only consideredepidemiological studies suitable for this purpose. Wereviewed 29 epidemiological studies describing a totalof 14,929 patients with PD, including 1,495 patientswith ICDs, which corresponds to a mean overall preva-lence of 10% across different cultures. Pathologicalgambling and hypersexuality appear to be the mostprevalent ICDs reported equally frequent in 518 (3.5%)and 524 (3.5%) of the 14,929 PD patients with ICDs,respectively. Binge eating was observed in 383 patients(2.6%) and compulsive buying in 374 patients (2.5%).Related compulsive conditions such as punding andhobbyism were reported in 549 patients (3.7%) andDDS in 53 (0.4%), see Fig. 1. In total 377 patientsreported symptoms of more than one ICD (2.5%).

The prevalence estimates are based on informa-tion available in the epidemiological studies in spiteof the fact that not all of them assess all types ofICDs and compulsive disorders. Particularly, informa-tion on DDS is often not reported, and some papers lackinformation on which specific types of ICDs patientsexperienced. Thus, the true prevalence rates might besomewhat higher, which is in fact what Cilia and vanEimeren [133] summarizes on the basis of the DOMIN-

ION study by Weintraub et al. [26]. Moreover, a veryrecent study in Finnish PD patients reports frequenciesof pathological gambling and hypersexuality amount-ing to 8.8% and 22.8%, respectively [54], whereaspathological gambling as deviant from other studieswas only prevalent in 0.7% of Turkish PD patients,since gambling is illegal in Turkey [125]. This sug-gests that cultural differences might exist. Interestinglythough, the prevalence rates in Asian samples werealmost similar to prevalences in Western samples. Limet al. [99] demonstrate that approximately 15% of PDpatients in Malaysia display symptoms of ICDs rela-tive to approximately 14% reported by Weintraub etal. on the basis of the largest cohort to date of 3,090North American and Canadian PD patients [26]. Thus,it seems that the overall prevalence of ICDs in Asianand Western PD populations are comparable. Insteadit seems that the most noticeable cultural differenceis the relatively lower doses of dopamine agonistsused in Asian samples compared to Western samples[99]. According to Lim et al. [99], piribedil, whichlike pramipexole and ropinirole is selective for D2/D3dopamine receptors, is the most available dopamineagonist in Asian countries and this compound hasalso been associated with ICDs [99]. Nevertheless,in the Malaysian sample where piribedil accountedfor approximately two thirds of the dopamine agonistusage, only ropinirole and pramipexole were signifi-cantly associated with ICD symptoms [99].

Almost all PD patients with ICDs were treated withdopaminergic medication at the time of examination.The majority received a combination of levodopa anddopamine agonists. The most frequently used directD2/D3 dopamine agonists were pramipexole, ropini-role, and pergolide, and generally, the daily dose ofdopaminergic medication was higher in patients withICDs. Based on the epidemiological studies, the meantotal levodopa equivalent daily dose (LEDD, levodopaand dopamine agonists) in PD patients with ICDs was1,030 mg/day compared to a total LEDD in PD patientswithout ICDs of only 679 mg/day. The mean dopamineagonist LEDD was 243 mg/day in PD patients withICDs compared to 132 mg/day in PD patients withoutICDs. It is important to note, however, that LEDDsare most likely calculated based on different formu-las, which complicates a direct comparison of LEDDsacross studies [134].

Overall, ICD symptoms predominantly occurredsubsequent to treatment initiation or dosage increase,and seemed particularly related to the effects of theD2/D3 dopamine agonists [20, 22, 59, 63, 65, 69,71, 72, 74, 84, 85, 88]. This tendency is reflected in

108 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

Ove

rvie

wof

64em

piri

cals

tudi

eson

ICD

sin

PDpu

blis

hed

betw

een

2000

–Jan

.201

3co

mpa

ring

PDpa

tient

sw

ithan

dw

ithou

tIC

Ds

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,

Mea

n(S

D)

mg/

day

Cas

e-co

ntro

lstu

dies

Mol

ina

etal

.(20

00)

[18]

250

12(1

:11)

PDI:

NA

56(9

)43

(9)

PG:1

2L

evod

opa:

12Pu

ndin

g:3

BE

:1R

omito

etal

.(20

02)

[33]

304

(1:3

)L

evod

opa

Pre-

DB

S:53

41H

S:4

Perg

olid

eL

evod

opa:

400–

1200

STN

DB

SPe

rgol

ide:

5–6

Eva

nset

al.(

2004

)[6

1]50

17(5

:12)

PDI:

PDI:

1,70

7PD

I:59

PDI:

44Pu

ndin

g:17

Lev

odop

a:16

PDC

:1,1

30,p

<0.

000

PDC

:63

PDC

:49

HS:

4Pe

rgol

ide:

2PG

:1B

rom

ocri

ptin

e:1

DD

S:10

PDC

:L

evod

opa:

33Pe

rgol

ide:

10B

rom

ocri

ptin

e:2

Ava

nzie

tal.

(200

6)[2

1]98

6(3

:3)

PDI:

PDI:

760

(208

)68

(6)

PDI:

60(2

)PG

:6L

evop

dopa

:6PD

C:7

17(4

63)

PDC

:63

(4)

DD

S:2

DA

:4V

oon

etal

.(20

07)

[25]

6321

(6:1

5)L

evod

opa

in20

PDI:

874

(496

)60

(9)

PDI:

51(9

)PG

:21

Pram

ipex

ole:

5D

AL

ED

D:2

68(1

94)

PDC

:58

(10)

Rop

inir

ole:

8PD

C:7

47(3

23)

Perg

olid

e:7

DA

LE

DD

:192

(105

)Is

aias

etal

.(20

08)

[91]

5014

(7:7

)PD

I:PD

I:65

6(2

52)

PDI:

60(9

)PD

I:51

CB

:5(4

:1)

Pram

ipex

ole:

8PD

C:6

22(2

94)

PDC

:65

(9)

PDC

:57

Inte

rmitt

ente

xplo

sive

diso

rder

:1(1

:0)

Rop

inir

ole:

1Pe

rgol

ide:

1H

S:2

(1:1

)PG

:1(1

:0)

Mul

tiple

ICD

s:5

(0:5

)

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 109Ta

ble

1(c

onti

nued

)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Cili

aet

al.(

2008

)[1

08]

5111

(1:1

0)PD

I:PD

I:81

2(2

29)

PDI:

57(6

)PD

I:50

(5)

PG:1

1L

evod

opa:

11D

AL

ED

D:2

89(5

8)PD

C:5

5(7

)PD

C:4

6(7

)H

S:5

Pram

ipex

ole:

6PD

C:8

77(2

89)

BE

:2R

opin

irol

e:2

DA

LE

DD

:340

(157

)C

B:2

Perg

olid

e:3

Hob

byis

m:1

PDC

:L

evod

opa:

40Pr

amip

exol

e:20

Rop

inir

ole:

7Pe

rgol

ide:

10C

aber

golin

e:3

Imam

ura

etal

.(20

08)

[122

]48

11(0

:11)

PDI:

PDI:

573

(548

)PD

I:60

(7)

PDI:

50(1

3)PG

:11

Lev

odop

a:7

Pram

ipex

ole:

4(2

)PD

C:6

2(1

)PD

C:5

4(1

2)Pr

amip

exol

e:7

PDC

:879

(558

)R

opin

irol

e:1

Pram

ipex

ole:

3(2

),p

<0.

001

PDC

:L

evod

opa:

32Pr

amip

exol

e:12

Rop

inio

rle:

3H

albi

get

al.(

2009

)[4

2]53

6(N

A)

Lev

odop

a:44

PDw

ithD

BS:

682

(427

)PD

with

DB

S:64

(10)

PDw

ithD

BS:

52PD

with

DB

S:3

DA

:21

PDw

ithou

tDB

S:58

2(4

60)

PDw

ithou

tDB

S:66

(11)

PDw

ithou

tDB

S:60

PG:1

STN

DB

S:16

CB

:2PD

with

outD

BS:

3PG

:1C

B:2

HS:

1T

rich

otill

oman

ia:1

Mul

tiple

ICD

s:2

110 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Sant

ange

loet

al.(

2009

)[1

23]

3015

(4:1

1)PD

I:PD

I:77

4(3

20)

PDI:

62(1

0)PD

I:53

(10)

PG:1

5L

evod

opa:

13D

AL

ED

D:2

80(2

09)

PDC

:62

(9)

PDC

:55

(9)

DA

:12

PDC

:651

(284

)(P

ram

ipex

ole:

10)

DA

LE

DD

:293

(180

)PD

C:

Lev

odop

a:12

DA

:14

(Pra

mip

exol

e:9;

Rop

inir

iole

:2)

Siri

etal

.(20

10)

[114

]63

21(3

:18)

Lev

odop

aPD

I:73

1(2

84)

PDI:

60(8

)PD

I:53

(9)

PG:2

1D

AD

AL

ED

D:2

68(1

14)

PDC

:65

(6),

p=

0.01

PDC

:57

(7)

PDC

:787

(284

)D

AL

ED

D:2

39(1

31)

Voo

net

al.(

2010

)[7

5]28

14(4

:10)

Lev

odop

a:20

PDI:

589

(301

)PD

I:52

(8)

NA

PG:9

Pram

ipex

ole:

18D

AL

ED

D:1

62(4

3)PD

C:5

5(1

3)C

B:5

Rop

inir

ole:

10PD

C:6

10(2

98)

DA

LE

DD

:156

(57)

Vita

leet

al.(

2011

)[7

8]63

49L

evod

opa:

54PD

I:71

9PD

I:65

PDI:

57PG

:14

(4:1

0)Pr

amip

exol

e:41

DA

LE

DD

:243

PDC

:61

PDC

:53

HS:

13(0

:13)

Rop

inir

ole:

11PD

C:6

30(3

12)

BE

:12

(6:6

)D

AL

ED

D:2

67(2

01)

Mul

tiple

ICD

s:10

(1:9

)Z

ahod

neet

al.(

2011

)[3

6]96

36D

A:4

2%PD

BE

:563

(251

)PD

BE

:68

(5)

PDB

E:5

8(8

)B

E:9

(3:6

)D

BS:

22PD

with

outB

E:6

81(4

90)

PDw

ithou

tBE

:66

(10)

PDw

ithou

tBE

:PG

:17

STN

DB

S:16

56(1

3)C

B:1

1G

PiD

BS:

6H

S:1

STN

DB

S:4

PDB

E(4

4%)

Pund

ing:

8M

ultip

leIC

Ds:

67%

ofPD

BE

Mul

tiple

ICD

s:29

%PD

with

outB

E

STN

DB

S:14

%of

PDw

ithou

tBE

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 111

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Ler

oiet

al.(

2011

)[8

6]99

35(N

A)

Lev

odop

a14

2(1

65)

63(1

1)55

(12)

PG:1

2D

AL

ED

Dra

nge:

0–61

0m

g/d

HS:

9C

B:5

BE

:3D

DS:

3Pu

ndin

g:3

Biu

ndo

etal

.(20

11)

[87]

5935

(NA

)L

evod

opa

PDI:

557

(305

)PD

I:61

(10)

PDI:

53(1

1)PG

:2D

AD

AL

ED

D:1

87(1

49)

PDC

:70.

4(6

.8),

p<

0.00

1PD

C:6

1(1

0),p

=0.

012

HS:

16PD

C:4

97(3

41)

CB

:17

DA

LE

DD

:166

(109

)B

E:1

Pund

ing:

3H

obby

ism

:7M

ultip

leIC

Ds:

12V

oon

etal

.(20

11)

[80]

564

282

(91:

191)

Lev

odop

aPD

I:94

6(3

6)PD

I:61

(1)

PDI:

54(1

)PG

:54

(14:

40)

DA

DA

LE

DD

:266

(14)

PDC

:61

(1)

PDC

:54

(1)

CB

:59

(28:

31)

PDC

:809

(36)

HS:

47(1

:46)

DA

LE

DD

:265

(14)

BE

:41

(20:

21)

Cili

aet

al.(

2011

)[9

4]30

15(1

:14)

Lev

odop

aPD

I:84

8(2

53)

PDI:

59(8

)PD

dura

tion:

PG:1

5D

AD

AL

ED

D:2

96(1

48)

PDC

:59

(7)

PDI:

9(3

)PD

C:8

80(2

45)

PDC

:9(2

)D

AL

ED

D:3

17(1

16)

Cha

zero

net

al.(

2011

)[1

09]

115

PG:1

Lev

odop

am

onot

hera

py:4

0A

llpa

tient

s:A

llpa

tient

s:A

llpa

tient

s,PD

dura

tion:

7(4

)Pr

oble

mga

mbl

ing:

14D

Am

onot

hera

py:4

Lev

odop

aL

ED

D:6

31(4

36)

67(6

)H

S:2

Lev

odop

a+

DA

:61

DA

LE

DD

:130

(168

)N

ole

vodo

paor

DA

:10

112 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,

Mea

n(S

D)

mg/

day

Ben

tivog

lioet

al.(

2012

)[9

7]34

17(3

:14)

Lev

odop

aPD

I:60

6(3

19)

PDI:

62(1

0)PD

dura

tion:

HS:

8D

AD

AL

ED

D:1

73(1

12)

PDC

:64

(9)

PDI:

7(4

)C

B:2

PDC

:616

(368

)PD

C:7

(4)

PG:1

0D

AL

ED

D:1

93(8

9)B

E:6

Mul

tiple

ICD

s:7

Dja

msh

idia

net

al.(

2012

)[1

13]

4326

(4:2

2)L

evod

opa

PDI:

934

(407

)PD

I:59

(10)

PDI:

48(1

0)H

S:12

PDI:

PDC

:740

(369

)PD

C:6

5(5

),p

<0.

001

PDC

:55

(7),

p=

0.00

2PG

:13

DA

:13

CB

:5PD

C:

Pund

ing:

7D

A:2

1E

xper

imen

tals

tudi

esE

vans

etal

.(20

06)

[79]

168

(NA

)L

evod

opa

PDI:

1,51

7PD

I:51

PDI:

39D

DS:

8D

APD

C:8

48PD

C:6

0PD

C:4

8Pu

ndin

g:8

Stee

ves

etal

.(20

09)

[74]

147

(2:5

)L

evod

opa:

14PD

I:85

6(4

07)

PDI:

47–7

2PD

dura

tion:

PG:7

DA

:14

DA

LE

DD

:138

(172

)PD

C:5

1–74

PDI:

7(3

)PD

I:PD

C:7

56(4

00)

PDC

:6(3

)Pr

amip

exol

e:5

DA

LE

DD

:167

(113

)R

opin

irol

e:2

Rao

etal

.(20

10)

[92]

189

(2:7

)L

evod

opa:

16PD

I:41

8(3

06)

PDI:

56(1

1)PD

I:49

BE

:5D

A:1

7D

AL

ED

D:2

78(1

16)

PDC

:54

(10)

PDC

:47

PG:4

PDC

:309

(171

)C

B:3

DA

LE

DD

:319

(187

)H

S:4

Mul

tiple

ICD

s:4

Cili

aet

al.(

2010

)[9

5]29

8(1

:7)

Lev

odop

a:29

PDI:

831

(294

)PD

I:61

(8)

PDdu

ratio

n:PG

:8D

A:2

9D

AL

ED

D:2

41(1

18)

PDC

:60

(9)

PDI:

6(2

)H

S:5

PDC

:852

(301

)PD

C:6

(2)

BE

:3D

AL

ED

D:2

52(1

21)

CB

:2M

ultip

leIC

Ds:

6

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 113

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Voo

net

al.(

2010

)[9

6]28

14(4

:10)

PDI:

PDI:

508

(301

)PD

I:52

(8)

NA

PG:9

Lev

odop

a:10

DA

LE

DD

:162

(43)

PDC

:55

(13)

CB

:5Pr

amip

exol

e:9

PDC

:610

(298

)R

opin

irol

e:5

DA

LE

DD

:155

(57)

PDC

:L

evod

opa:

10Pr

amip

exol

e:9

Rop

inir

ole:

5W

uet

al.(

2010

)[1

10]

155

(NA

)L

evod

opa

NA

NA

NA

NA

Van

Eim

eren

etal

.(20

10)

[107

]14

7(N

A)

Lev

odop

aPD

I:77

2(3

18)

PDI:

60(1

0)PD

dura

tion:

PG:7

DA

DA

LE

DD

:143

(105

)PD

C:6

2(1

1)PD

I:7

(3)

PDI:

PDC

:700

(323

)PD

C:7

(3)

Pram

ipex

ole:

6D

AL

ED

D:1

22(8

5)R

opin

irol

e:1

Fros

inie

tal.

(201

0)[1

12]

147

(NA

)L

evod

opa

PDI:

520

(219

)PD

I:58

(11)

PDdu

ratio

n:PG

:7PD

I:D

AL

ED

D:4

08(1

56)

PDC

:58

(9)

PDI:

6(2

)B

E:1

Pram

ipex

ole:

4PD

C:4

62(2

29)

PDC

:7(4

)H

S:1

Rop

inir

ole:

3D

AL

ED

D:3

25(5

0)PD

C:

Pram

ipex

ole:

4R

opin

irol

e:3

Rod

rigu

ez-O

roz

etal

.(20

11)

[38]

2810

(1:9

)L

evod

opa

PDI:

1041

(689

)PD

I:53

(11)

PDI:

44PG

:5D

APD

dysk

ines

ia:1

170

(531

)PD

dysk

ines

ia:6

2(4

)PD

dysk

ines

ia:4

6H

S:5

STN

DB

S:28

PDC

:102

4(4

65)

PDC

:59

(5)

PDC

:48

CB

:5B

E:2

DD

S:5

Pund

ing:

5M

ultip

leIC

Ds:

7V

oon

etal

.(20

11)

[45]

2814

(4:1

0)PD

I:PD

I:58

9(3

01)

PDI:

52(8

)N

APG

:9Pr

amip

exol

e:9

DA

LE

DD

:162

(43)

PDC

:55

(13)

CB

:5R

opin

irol

e:5

PDC

:610

(298

)PD

C:

DA

LE

DD

:156

(57)

Pram

ipex

ole:

9R

opin

irol

e:5

114 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Cla

asse

net

al.(

2011

)[5

1]41

22(9

:13)

Lev

odop

a:26

PDI:

736

(451

)PD

I:61

(6)

PDdu

ratio

n:PG

:2D

A:4

1D

AL

ED

D:2

92(1

61)

PDC

:64

(8)

PDI:

10(7

)H

S:13

PDC

:613

(325

)PD

C:6

(4)

CB

:12

DA

LE

DD

:230

(124

)B

E:1

0H

obby

ism

:17

O’S

ulliv

anet

al.(

2011

)[1

11]

1811

(3:8

)L

evod

opa:

18PD

I:69

8(3

37)

PDI:

57(8

)PD

I:45

(11)

HS:

5D

AD

AL

ED

D:6

2(9

2)PD

C:5

8(1

1)PD

C:4

7(9

)B

E:5

PDC

:949

(253

)PG

:5D

AL

ED

D:2

41(1

43)

CB

:5D

DS:

5Pu

ndin

g:5

Mul

tiple

ICD

s:8

Ray

etal

.(20

12)

[82]

147

(NA

)L

evod

opa:

13PD

I:88

8(4

80)

PDI:

60(1

1)PD

dura

tion:

PG:7

DA

:12

PDC

:644

(338

)PD

C:6

1(1

0)PD

I:10

(6)

PDC

:8(5

)Jo

utsa

etal

.(20

12)

[105

]20

10(0

:10)

PDI:

PDI:

635

(ran

ge:2

50–8

76)

PDI:

62(r

ange

:45–

71)

PDI:

53(r

ange

:40–

64)

PG:5

Lev

odop

a:9

DA

LE

DD

:172

(ran

ge:0

–280

)PD

C:6

2(r

ange

:53–

70)

PDC

:57

(ran

ge:4

7–63

)H

S:4

DA

:9PD

C:8

26(r

ange

:210

–112

7)B

E:1

PDC

:D

AL

ED

D:2

00(r

ange

:0–3

20)

Lev

odop

a:9

DA

:9E

pide

mio

logi

cals

tudi

esD

rive

r-D

unck

ley

etal

.(20

03)

[59]

1,88

49

(2:7

)L

evod

opa:

9PD

IPD

I:57

46PG

:9Pr

amip

exol

e:52

9L

evod

opa

LE

DD

:883

Rop

inir

ole:

421

Pram

ipex

ole:

4Pe

rgol

ide:

331

Perg

olid

e:5

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 115Ta

ble

1(c

onti

nued

)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Pezz

ella

etal

.(20

05)

[98]

202

7(2

:5)

PDD

DS:

Lev

odop

a:6

PDD

DS:

961

(282

)PD

DD

S:59

(5)

PDD

DS:

51(3

)D

DS:

7D

A:7

PDw

ithou

tDD

S:67

5(3

72)

PDw

ithou

tDD

S:63

(5)

PDw

ithou

tDD

S:52

(3)

Com

puls

ive

beha

vior

:2

of7

PDw

ithou

tDD

S(n

=32

):H

S:1

of7

Lev

odop

a:12

Vio

lent

beha

vior

:3of

7D

A:2

0

Ard

ouin

etal

.(20

06)

[64]

598

7(1

:6)

PDI:

NA

<70

year

sN

APG

:7L

evod

opa:

7H

S:5

Bro

moc

ript

ine:

5C

B:2

Rop

inir

ole:

1B

E:2

DD

S:4

Gro

sset

etal

.(20

06)

[65]

388

17(6

:11)

PDI:

PDI:

PDI:

56(7

)PD

I:52

PG:1

7L

evod

opa:

9L

evod

opa

LE

DD

:430

PDC

:69

(10)

PDC

64Pr

amip

exol

e:9

Pram

ipex

ole:

5R

opin

irol

e:7

Rop

inir

ole:

12Pe

rgol

ide:

1Pe

rgol

ide:

1Im

amur

aet

al.(

2006

)[6

7]1,

411

6(0

:6)

PDI:

PDI:

61(r

ange

:53–

71)

51PG

:6L

evod

opa:

4L

evod

opa:

100–

1000

HS:

1Pr

amip

exol

e:4

Pram

ipex

ole:

3–6

Rop

inir

ole:

1R

opin

irol

e:5

Wei

ntra

ubet

al.(

2006

)[9

0]27

211

(1:1

0)PD

I:PD

I:92

6(5

35)

PDI:

60(9

)PD

I:48

HS:

7L

evod

opa:

11PD

C:5

69(3

69)

PDC

:67

(10)

,p=

0.00

6PD

C:

PG:6

Perg

olid

e:3

62(6

),p

=0.

04C

B:1

Pram

ipex

ole:

5R

opin

irol

e:3

Sing

het

al.(

2007

)[4

8]30

058

Lev

odop

a:24

4D

A:1

6PD

I:61

NA

HS:

25R

opin

irol

e:13

5PD

C:5

8PG

:0.5

–10

year

sPG

:17

(1:1

6)Pr

amip

exol

e:16

5

116 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Gila

diet

al.(

2007

)[6

9]19

327

(6:2

1)L

evod

opa:

24N

AN

APD

I:52

(12)

PG:6

Rop

inir

ole:

9PD

C:5

9(1

2)C

B:6

Perg

olid

e:4

BE

:7H

S:17

Mul

tiple

ICD

s:10

Ond

oet

al.(

2008

)[7

2]21

17

(3:4

)L

evod

opa:

148

Tota

lsam

ple:

Tota

lsam

ple:

64(1

0)To

tals

ampl

e:54

(12)

PG:7

Pram

ipex

ole:

141

Lev

odop

a:66

7(3

25)

PDI:

59(6

)PD

I:49

(11)

CB

:3R

opin

irol

e:57

DA

:3(1

)H

S:1

Perg

olid

e:12

PDI:

Bro

moc

ript

ine:

1D

A:4

(2)

Cro

ckfo

rdet

al.(

2008

)[7

3]14

013

(4:9

)L

evod

opa:

99%

PDI:

602

(355

)PD

I:62

(8)

NA

Prob

lem

gam

blin

gD

A:8

8%PD

C:7

75(4

72)

PDC

:66

(12)

Coo

per

etal

.(20

09)

[120

]14

16

(1:5

),4.

3%PD

I:N

ATo

tals

ampl

e:68

(10)

PDI:

50(3

)H

S:6

Lev

odop

a:4

PDI:

61(r

ange

:52–

74)

PDC

:62

(1),

p<

0.05

HS

sym

ptom

s:15

DA

:5W

icks

etal

.(20

09)

[127

]20

827

(13%

,NA

)PD

I:N

ATo

talP

Dsa

mpl

e:58

(10)

PDdu

ratio

n:PG

:13%

DA

:65%

Tota

lPD

sam

ple:

8(7

)PD

C:

DA

:59%

Fan

etal

.(20

09)

[128

]31

211

(1:1

0)PD

I:PD

I:48

8(2

89)

PDI:

64(7

)PD

I:59

(7)

PG:1

Lev

odop

a:9

DA

LE

DD

:142

(101

)PD

C:6

6(1

1)PD

C:6

0(1

1)H

S:6

Piri

bedi

l:10

PDC

:392

(225

)B

E:1

Pram

ipex

ole:

1D

AL

ED

D:3

5(5

0),p

=0.

005

DD

S:2

Am

anta

dine

:4Pu

ndin

g:1

Tota

lPD

sam

ple:

Lev

odop

a:25

4D

A:1

30A

man

tadi

ne:9

7

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 117

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Wei

ntra

ubet

al.(

2010

)[2

6]30

9042

0(1

53:2

67)

Lev

odop

ain

86.8

%Pr

amip

exol

eL

ED

D:3

07(1

68)

PDI:

60(8

)PD

I:m

edia

n=

53Pr

oble

mga

mbl

ing:

154

DA

in66

.0%

:R

opin

irol

eL

ED

D:2

78(1

65)

PDC

:64

(8),

p<

0.00

1.PD

C:m

edia

n=

58PG

:89

DB

S:Pe

rgol

ide

LE

DD

:287

(169

)H

S:10

8PD

I:36

CB

:177

PDC

:264

BE

:132

Mul

tiple

ICD

s:12

0W

eint

raub

etal

.(20

10)

[131

]30

8542

0(1

53:2

67)

PDon

aman

tadi

ne:I

CD

:128

(18%

)PD

onam

anta

dine

:PD

onam

anta

dine

:62

(8)

Med

ian

PDdu

ratio

n:PD

onam

anta

dine

:PG

:54

(7.4

%)

HS:

37(5

.1%

)C

B:5

8(8

%)

BE

:32

(4.4

%)

PDof

fam

anta

dine

:PG

:100

(4.2

%),

p<

0.00

1H

S:71

(3%

),p

<0.

01C

B:1

19(5

%),

p<

0.01

BE

:100

(4.2

%)

PDof

fam

anta

dine

:292

(12%

),p

<0.

001

Lev

odop

a:26

78D

A:2

038

DB

S:30

0

Med

ian

levo

dopa

LE

DD

:469

PDof

fam

anta

dine

:Med

ian

levo

dopa

LE

DD

:450

,P

<0.

001

DB

S:PD

onam

anta

dine

:94

(12.

9%)

PDof

fam

anta

dine

:206

(9%

),p

<0.

01

PDof

fam

anta

dine

:64

(8)

Age

<65

:PD

onam

anta

dine

:446

(61%

)PD

off

aman

tadi

ne:1

177

(50%

),p

<0.

0001

PDon

aman

tadi

ne:1

0PD

off

aman

tadi

ne:6

,p

<0.

0001

118 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Wei

sset

al.(

2010

)[5

3]25

032

(NA

)L

evod

opa

NA

Ons

etof

ICD

:PD

dura

tion

befo

reIC

Don

set:

7(5

)PG

:8Pr

amip

exol

e57

(9)

Prob

lem

gam

blin

g:5

Rop

inir

ole

HS:

16C

B:1

1B

E:6

Rec

kles

ssp

endi

ngan

ddr

ivin

g:1

Mul

tiple

ICD

s:12

Bha

rmal

etal

.(20

10)

[121

]14

66

(2:4

)PD

I:PD

I:PD

I:58

(7)

PDdu

ratio

n:PG

:6L

evod

opa

mon

othe

rapy

:012

26(r

ange

:600

–217

9)To

tals

ampl

e:68

(10)

,p<

0.05

PDI:

12Pr

amip

exol

e:5

Pram

ipex

ole:

5(r

ange

:2–8

)To

tals

ampl

e:M

ales

:9(7

)Pe

rgol

ide:

1Pe

rgol

ide:

3Fe

mal

es:1

0(5

)To

tals

ampl

e:To

tals

ampl

e:N

AL

evod

opa

mon

othe

rapy

:80

Pram

ipex

ole:

41Pe

rgol

ide:

11R

opin

irol

e:9

Bro

moc

ript

ine:

5K

enan

gile

tal.

(201

0)[1

25]

554

33(6

:27)

,5.9

%PD

I:PD

I:70

2(3

69)

PDI:

58(1

0)PD

I:49

(9)

Pund

ing:

19(5

7.5%

)L

evod

opa

DA

LE

DD

:368

(181

)PD

C:6

0(1

0)PD

C:5

2(1

1)H

S:14

(42.

4%)

Perg

olid

e:12

PDC

:640

(357

)B

E:9

(27.

2%)

Cab

ergo

line:

7D

AL

ED

D:3

19(2

08)

CB

:8(2

4.2%

)Pr

amip

exol

e:7

DD

S:7

(21.

1%)

Rop

inir

ole:

4PG

:4(1

2.1%

)Pi

ribe

dil:

10PD

C:

Lev

odop

aPe

rgol

ide:

9C

aber

golin

e:14

Pram

ipex

ole:

25R

opin

irol

e:1

Piri

bedi

l:15

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 119Ta

ble

1(c

onti

nued

)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Lee

etal

.(20

10)

[129

]11

6711

8(5

5:63

)To

tals

ampl

e:To

tals

ampl

e:65

9(3

87)

PDI:

61(1

2)PD

I:53

(11)

CB

:29

Lev

odop

a:10

94PD

I:PD

C:6

5(1

0)PD

C:5

9(1

0)PG

:15

DA

:850

DA

LE

DD

:145

(150

)H

S:33

PDI:

PDC

:B

E:4

0D

A:9

4D

AL

ED

D:9

9(1

23)

Pund

ing:

49PD

C:7

56M

ultip

leIC

Ds:

34A

uyeu

nget

al.(

2011

)[8

5]21

315

(2:1

3)PD

I:PD

I:12

15(6

36)

PDI:

60(6

)PD

I:46

(6)

Lev

odop

a:15

DA

LE

DD

:277

(148

)PD

C:6

8(1

0),p

<0.

001

PDC

:59

(11)

,p<

0.00

1D

A:1

4PD

C:6

34(3

31)

Bro

moc

ript

ine:

11D

AL

ED

D:8

5(9

9)L

imet

al.(

2011

)[9

9]20

048

Tota

lsam

ple:

Tota

lsam

ple:

528

(387

)To

tals

ampl

e:To

tals

ampl

e:A

nyIC

D:3

0L

evod

opa:

81%

DA

LE

DD

:74

(84)

63(1

0)56

(12)

BE

:17

DA

:53%

Am

anta

dine

:41

(106

)H

S:16

Piri

bedi

l:33

.5%

CB

:7Pr

amip

exol

e:11

.5%

PG:5

Rop

inir

ole:

8%Pu

ndin

g/ho

bbyi

sm:2

7B

rom

ocri

ptin

e:0.

5%D

DS:

4A

man

tadi

ne:1

5%M

ultip

leIC

D:1

9D

BS:

5.5%

Has

san

etal

.(20

11)

[130

]32

169

(20:

49)

Lev

odop

aPD

hobb

yism

:PD

hobb

yism

:56

(ran

ge:3

4–72

)PD

I:51

(10)

PG:2

5D

APr

amip

exol

e:2

(ran

ge:1

–5)

Oth

erw

ise

NA

PDC

:59

(10)

,p<

0.00

01H

S:24

PDI:

Rop

inir

ole:

14(r

ange

:8–2

5)B

E:1

2C

B:1

8H

obby

ism

:8Pu

ndin

g:12

The

rape

utic

DA

dose

(>6

mg

ropi

niro

leor

>2

mg

pram

ipex

ole)

:59

Targ

etD

Ado

se(>

12m

gro

pini

role

or>

4.5

mg

pram

ipex

ole)

:39

DB

S:9

Oth

erw

ise

NA

120 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

PDC

:T

hera

peut

icD

Ado

se(>

6mg

ropi

niro

leor

>2

mg

pram

ipex

ole)

:147

Targ

etD

Ado

se(>

12m

gro

pini

role

or>

4.5

mg

pram

ipex

ole)

:67

DB

S:12

Lim

otai

etal

.(20

12)

[83]

1040

97(N

A)

Lev

odop

aPD

I:11

22(6

44)

PDI:

64(1

0)PD

I:52

(10)

ICD

:89

DA

DA

LE

DD

:292

(184

)PD

C:7

1(1

0),p

<0.

001

PDC

:60

(12)

,p<

0.00

1D

DS:

14PD

C:7

79(5

43),

p<

0.00

1PD

DD

S:66

(12)

PDD

DS:

53(1

0)IC

D+

DD

S:6

DA

LE

DD

:142

(176

),p

<0.

001

PDC

:71

(11)

PDC

:59

(12)

Pund

ing:

11PD

DD

S:17

13(8

69)

DA

LE

DD

:309

(199

)PD

C:7

96(5

46),

p<

0.00

1D

AL

ED

D:1

52(1

81),

p<

0.00

3K

imet

al.(

2012

)[2

7]29

746

(19:

27)

PDI:

PDI:

844

(376

)PD

I:66

(11)

PDI:

60(1

2)PG

:4D

A:2

9D

AL

ED

D:1

71(1

87)

PDC

:71

(8)

PDC

:66

(9)

HS:

21PD

C:

PDC

:614

(348

),p

<0.

001

P<

0.00

9P

<0.

001

BE

:9D

A:1

10,p

<0.

016

DA

LE

DD

:90

(140

),p

<0.

002

CB

:3Pu

ndin

g:14

Hob

byis

m:5

Wal

kabo

ut:3

DD

S:7

Mul

tiple

ICD

s:15

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 121

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Mou

met

al.(

2012

)[3

2]15

9IC

D:2

4D

DS:

7Pr

e-D

BS

ICD

:6(3

:3)

Pre-

DB

SD

DS:

4(0

:4)

Pre-

DB

SIC

D+

DD

S:1

(0:1

)

DA

:4PD

I;0

PDD

DS;

1PD

I+

DD

S;81

PDC

DB

S:15

9(S

TN

orG

Pi)

STN

DB

S:3

PDD

DS;

4PD

IG

PiD

BS:

1PD

DD

S;2

PDI;

1PD

I+D

DS

Pre-

DB

S:PD

I:73

5(3

88)

PDD

DS:

1271

(744

)PD

I+D

DS:

2250

PDC

:877

(511

),p

<0.

03

NA

PDI:

44(7

)PD

DD

S:45

(1)

PDI+

DD

S:40

PDC

:49

(10)

Jout

saet

al.(

2012

)[5

4]57

519

2(4

8:14

4)M

ultip

leIC

Ds:

69PG

:48

HS:

124

CB

:55

BE

:64

Hob

byis

m:1

25Pu

ndin

g:87

Wal

kabo

ut:3

2

Lev

odop

a:45

1D

A:4

30M

edia

nL

ED

D:5

61(r

ange

:26

–323

0)M

edia

nD

AL

ED

D:1

60(r

ange

:105

–210

)

Med

ian

age:

64(r

ange

:43

–90)

Med

ian

PDdu

ratio

n:6

(ran

ge<

1–29

)

Pere

z-L

lore

teta

l.(2

012)

[104

]20

352

(14:

38)

PDI:

LE

DD

>10

50:

Age

<68

:PD

dura

tion:

HS:

20L

evod

opa:

48PD

I:PD

I:14

patie

nts

(26%

)PD

I:9

(1)

CB

:13

DA

:52

34pa

tient

s(6

3%)

PDC

:86

patie

nts

(56%

)PD

C:9

(1)

PG:5

Am

anta

dine

:2PD

C:

BE

:28

PDC

:63

patie

nts

(42%

)M

ultip

leIC

Ds:

11L

evod

opa:

130

DA

:109

Am

anta

dine

:7

122 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

Tabl

e1

(con

tinu

ed)

Ref

eren

ceTo

talN

N(f

:m),

PDpa

tient

sT

reat

men

t:N

Tota

lLE

DD

,Mea

nA

geA

geat

PDon

set

with

PDw

ithIC

Ds

(SD

)m

g/da

yM

ean

(SD

)ye

ars

Mea

n(S

D)

year

sD

AL

ED

D/D

Ado

se,M

ean

(SD

)m

g/da

y

Jout

saet

al.(

2012

)[5

5]29

0A

tba

selin

e:11

9A

tbas

elin

e:A

tbas

elin

e:A

tbas

elin

e:A

tbas

elin

e:M

ultip

leIC

Ds:

43PD

I:PD

with

stab

leIC

D(n

=82

):PD

with

stab

leIC

D(n

=82

):62

PDw

ithst

able

ICD

(n=

82):

56PG

:33

Lev

odop

a:88

Med

ian

LE

DD

:609

PDC

(n=

135)

:65

PDC

(n=

135)

:58

HS:

73D

A:9

2M

edia

nD

AL

ED

D:2

10C

B:3

6A

man

tadi

ne:6

PDC

(n=

135)

:B

E:4

0PD

C:

Med

ian

LE

DD

:508

Hob

byis

m:7

3L

evod

opa:

118

Med

ian

DA

LE

DD

:160

Pund

ing:

48D

A:1

23W

alka

bout

:17

Am

anta

dine

:9B

astia

ens

etal

.(20

13)

[100

]16

418

of46

(9:9

)PD

I:PD

I:PD

I:62

(10)

PDI:

57(1

0)B

E:1

6(7

:9)

Lev

odop

a:7

Med

ian

LE

DD

:150

(ran

ge:0

–2,3

20)

PDC

:62

(11)

PDC

:57

(9)

HS:

6(1

:5)

DA

:10

Med

ian

DA

LE

DD

:106

(ran

ge:0

–450

)C

B:5

(3:2

)A

man

tadi

ne:3

PDC

:PG

:1(1

:0)

PDC

:M

edia

nL

ED

D:1

50(r

ange

:0–1

,510

)Pu

ndin

g:12

Lev

odop

a:13

Med

ian

DA

LE

DD

:0(r

ange

:0–4

50)

Mul

tiple

ICD

s:8

DA

:11

Am

anta

dine

:0

N=

num

bero

fpat

ient

s(f

:m=

fem

ales

:mal

es).

PD=

Park

inso

n’s

dise

ase.

ICD

s=im

puls

eco

ntro

ldis

orde

rs.P

G=

path

olog

ical

gam

blin

g.H

S=

hype

rsex

ualit

y.C

B=

com

puls

ive

buyi

ng.B

E=

bing

e-ea

ting.

DD

S=

dopa

min

edy

sreg

ulat

ion

synd

rom

e.PD

I=PD

patie

ntsw

ithIC

Ds.

PDC

=PD

cont

rols

.DA

=do

pam

ine

agon

ist.

DB

S=

deep

brai

nst

imul

atio

n.ST

N=

subt

hala

mic

nucl

eus.

GPi

=gl

obus

palli

dus

pars

inte

rna.

LE

DD

=le

vodo

paeq

uiva

lent

daily

dose

.NA

=no

tapp

licab

le.p

-val

ues

indi

cate

sign

ifica

ntdi

ffer

ence

sbe

twee

nPD

Ian

dPD

C.

M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism 123

Fig. 1. Illustrates the number of PD patients with ICDs across the specific kinds of ICDs: pathological gambling; hypersexuality; binge eating;compulsive buying; punding; and dopamine dysregulation syndrome. In total 377 patients reported having more than one ICD (2.5%). Hence,the sum of patients across ICDs (2,289) is larger than the total number of patients (1,495) in the in the epidemiological studies reporting ICDs,since those with multiple ICDs are counted in all respective specific ICDs. Furthermore, the prevalence of DDS is probably underestimated,since information on DDS was unavailable in many of the reviewed report.

a higher frequency of ICDs of up to 17.1% amongPD patients treated with dopamine agonists relative to6.9% in patients not treated with dopamine agonists[26]. Generally, ICD symptoms improved or resolvedafter reduction or discontinuation of dopamine ago-nist therapy [18–22, 38, 48, 58, 62, 66, 67, 70–72,84, 88, 89], even when increasing levodopa dose ascompensation for the lacking agonist treatment [81,88]. Nevertheless, in most cases described it remainsunclear whether ICD onset is a direct result of treat-ment initiation (or increase) or a consequence ofprolonged dopaminergic therapy. Furthermore, mostlikely individual differences in PD symptomatology,age at disease onset, gender, personality, and psychi-atric history influence the treatment-induced ICDs toan unknown degree. In addition, ICDs were alreadypresent prior to PD onset or treatment initiation in atleast 28 patients (1.1%), a frequency correspondingto the prevalence of ICDs in the general population.These patients reported a worsening of symptoms fol-lowing medication. Moreover, at least 58 (2.4%) PDpatients with ICDs had a prior history of substanceuse disorders, while at least 179 (7.3%) and 79 (3.2%)patients with comorbid ICDs reported current or priorsymptoms of a mood disorder or anxiety, respectively.Unfortunately, such details of information are simplynot available in all included reports. Hopefully, thenew screening instruments discussed by Weintraub andNirenberg [8] may contribute to solving some of theseissues in the future.

The presented findings support the concept oftreatment-induced ICDs in PD, which we will discuss

in a neuro-cognitive perspective taking distinct brainregions, dopamine-serotonin interactions, and cogni-tive impairments into account.

THE FUNCTIONAL ROLE OF THESUBTHALAMIC NUCLEUS IN ICDS IN PD

In the reviewed literature, it has been reported thata minimum of 86 patients with DBS in STN experi-enced occurrence, worsening, or no improvement ofICD symptoms following surgery [32, 33, 36, 37, 39,42, 93, 118], which corresponds to 3.5% of patientswith ICDs. In contrast, ICD symptoms declined or werefully alleviated in at least 36 other cases (correspond-ing to 1.5% of patients with ICDs) upon DBS in STN,an effect, which is most likely related to the markedreduction in dopaminergic medication following DBS[32, 35, 37, 38, 40, 41, 64]. These deviating resultsstrongly suggest that STN DBS influences both motorand non-motor functioning in PD in complex waysvia its neuronal network connections. It remains opento speculation whether the discrepancies relate to thecoordinates of stimulation or alternatively result fromchanges of the basal tonus of endogenous or exogenousdopamine in the basal ganglia-cortical loops [135]. Oneassumption might be that stimulation of the ventrome-dial STN through its close connection to the nucleusaccumbens via the ventral pallido-medial STN neu-ronal loop potentially induces ICD symptoms, sincethe ventral striatum, and the nucleus accumbens inparticular, is crucial in impulse control, motivational

124 M.B. Callesen et al. / Impulse Control Disorders and Parkinsonism

processes, and addictive behaviors [38]. Understandingthe underlying mechanisms behind these issues isfurther complicated by different frequencies of stim-ulations leading to very different outcomes probablyinfluencing both the ventromedial and lateral STN.Contrasting incidences have been reported where STNDBS has not only been linked to increased impulsivityand ICDs [44, 136], but also to lack of motivation andeven severe apathy and anhedonia [9, 137]. Accordingto Tang and Strafella [9] and Volkmann et al. [138], apa-thy, often co-occurring with depression, is one of themostcommonadverseeffectsofSTNDBSdocumentedin 24.6% of PD patients three years after surgery. How-ever, a decrease in apathy severity within 3–6 monthsafter surgery has been observed, indicating that perhapsapathy is only related to medication withdrawal or DBSitself in the immediate postoperative period. This sug-gests, that apathy could be a consequence of diseaseprogression as well, that might be relieved by dopaminereplacement therapy [9, 56, 138, 139]. Thus it appearsthat ICDs and apathy in PD, though representing oppo-site extremes of a continuum, are somehow related tothe same brain structures and networks mediated bydopaminergic therapy [138, 140, 141].

It remains a current hypothesis that DBS applied tothe lateral STN region supports sensory-motor loops,whereas DBS applied to the medial STN influencesventral mesolimbic-nucleus accumbens-frontostriatalcircuitry. Rodriguez-Oroz et al. [38] demonstrated thatPD patients with ICDs and PD patients with severemotor dyskinesia secondary to STN DBS both displaytheta-alpha (4–10 Hz) activity, but at different frequen-cies. PD patients with ICDs thus display activity (meanpeak at 6.71 Hz) 2–8 mm below the intercommissuralline, whereas PD patients with dyskinesia displaytheta-alpha activity (mean peak at 8.38 Hz) 0–2 mmbelow the intercommissural line [38]. In PD patientswith ICDs, cortico-subthalamic coherence was mostfrequent at 4–7.5 Hz in scalp electrodes placed atfrontal regions anterior to the primary motor cortex.This indicates that activity stems from associative-prefrontal and emotional loops involved in cognitiveand motivational processes mediated via frontal cor-tical innervations of the STN. However, it remainsuncertain whether the activity upon STN stimulationrelates to a reversed STN activation of the cortexor relates to the subcortical loops. In contrast, inPD patients with dyskinesia the cortico-subthalamiccoherence was most frequent at 7.5–10 Hz in elec-trodes placed over the primary and supplementarymotor areas. This suggests that the recorded activityin this group of patients stems from sensory-motor

circuits regulating motor control and coordination[38].

It seems obvious that the role of the STN in PD,on both a motor and cognitive level, still needs furtherinvestigations. Nevertheless, the STN clearly appearsto be situated at an essential position within the basalganglia playing a central role in not only sensory-motor loops, but also in associative-prefrontal andemotional circuits [14, 31, 38]. A relatively new tar-get for DBS alleviating motor symptoms of PD, whichhas received increased attention in recent years, is thepedunculopontine nucleus (PPN) [142–144]. The PPNis a tegmental mesopontine nucleus composed of bothcholinergic and non-cholinergic neurons with strongreciprocal connections to key output stations of thedorsal and ventral mesolimbic systems of the basalganglia [142]. The subregions of the PPN are thusinvolved in the modulation and control of motor perfor-mance, attention, procedural learning, reinforcement,and reward processing [142, 145, 146]. Interestingly,deep brain stimulation in PPN, unlike STN DBS, hasso far only been associated with the development ofICDs in PD in a single case [118], making it a relevanttarget for future research.

THE ROLE OF THE NUCLEUSACCUMBENS AND FRONTAL CORTEX INICDS IN PD

The ventral striatum, and in particular the nucleusaccumbens, plays a pivotal role in ICDs and in emo-tional, cognitive, and addictive processes [147, 148].It represents a crucial anatomical substrate within theneural networks involving the prefrontal, orbitofrontal,and associative-prefrontal cortical loops, which influ-ence the essential dysfunctional elements present in PDpatients with ICDs such as reward evaluation, reversallearning, impulsivity, and temporal discounting [94,149, 150]. In the following we discuss the impact ofthese neuronal networks in relation to ICDs in PDbased on different neuroimaging techniques.

Using functional magnetic resonance imaging(fMRI), Voon et al. [45] showed a decreased activ-ity within the orbitofrontal cortex and the anteriorcingulate cortex during risky decision-making in PDpatients with ICDs. They demonstrated an associationbetween dopamine agonists and increased sensitivitytowards risk in PD patients with ICDs accompaniedby a decreased activity in the ventral striatum. Like-wise, Rao et al. [92] observed that PD patients withICDs had a significantly reduced blood oxygenationlevel dependent (BOLD) activity in the right ventral

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striatum during risk taking compared to PD patientswithout ICDs. These results point at a bias towardsrisky choices in PD patients with ICDs, which mightbe the behavioral consequence of an impaired risk eval-uation following dopamine agonist therapy [45]. Incontrast, Voon et al. [96] demonstrated a dopamineagonist-induced increase in ventral striatum activityrelated to positive prediction error signifying a “bet-ter than expected” outcome in PD patients with ICDspotentially resulting in a reward bias. This effect wasnot seen in PD patients without ICDs. Additionally, PDpatients with ICDs had an overall greater orbitofrontalcortex activity to gains and loss omissions and loweractivity to losses than PD patients without ICDs [96].Similarly, Frosini et al. [112] showed an increasedBOLD response upon gambling cues bilaterally in theanterior cingulate cortex and in the left ventral striatumin PD patients with pathological gambling comparedto PD patients without pathological gambling. In addi-tion, this finding was associated with a cue-inducedcraving, which resembles that in individuals sufferingfrom addiction [112].

These discrepancies might be explained by differ-ences in the used paradigms. Graef et al. [150], recentlyshowed that while levodopa improved PD patients’performance on an instrumental learning task withconstant stimulus-reward contingencies depending ondorsal striato-frontal circuits, treatment impaired per-formance on a reversal learning task with varyingreward contingencies relying on ventral striato-frontalloops. The findings by Graef et al. [150] support the“overdose hypothesis” assuming harmful effects ofdopaminergic medication on reward evaluation andother cognitive functions depending on less affectedbrain regions in PD, such as the ventral striatum,and in particular the nucleus accumbens, in earlydisease stages [2–4, 150]. This hypothesis is fur-ther supported by van Eimeren et al.s [107] positronemission tomography (PET) findings of increasedactivity in the lateral orbitofrontal cortex, the ros-tral cingulate zone, the amygdala, and the externalpallidum upon apomorphine intake in PD patientswithout pathological gambling while performing aprobabilistic card game. In contrast, PD patients withpathological gambling showed the opposite reactionof apomorphine-induced deactivation of these brainregions resulting in impaired impulse control andresponse inhibition [107]. Moreover, using single-photon emission computed tomography (SPECT),Cilia et al. [108] reported hyperactivity during rest inthe orbitofrontal cortex, the hippocampus, the amyg-dala, the insula, and the ventral pallidum in PD patients

with ICDs. They argued, that the abnormal restingstate in the mesocorticolimbic circuit in this subgroupof patients provided additional support to the “over-dose hypothesis” by suggesting a medication-inducedoverstimulation of the relatively intact reward-relatedneuronal networks [108].

FunctionalPETstudiesofaddictionandpathologicalgambling, have shown an abnormally enhanced pha-sic dopamine release in the ventral striatum in addictedindividuals when confronted with cues of their addic-tion [20, 61, 62, 147, 151–155]. A similar dysfunctionaldopaminergic response upon gambling has been shownin PD patients with comorbid pathological gambling[74]. Steeves and colleagues [74], reported a lowerbaseline binding potential for the dopamine D2/D3radioligand [11C]-raclopride in the ventral striatum ofPD patients with pathological gambling compared toPD patients without pathological gambling and a rel-atively greater decrease in [11C]-raclopride bindingduring gambling. This finding may suggest a relativelyhigher endogenous ventral striatal dopamine releaseupon gambling in PD patients with pathological gam-bling than in the PD control group. Similar findings ofdecreased [11C]-raclopride binding in the ventral stria-tumandthecaudatenucleuswhenexposed to rewardingversus neutral visual stimuli were reported by the teamof O‘Sullivan and Wu in PD patients with ICDs com-pared to PD controls [110, 111] indicating an enhancedendogenous dopamine release. In a SPECT study usingthe radiotracer FP-CIT, Cilia et al. [95] showed thatPD patients with pathological gambling had a lowertracer binding in the ventral striatum compared to PDpatientswithoutgamblingproblems.AccordingtoCiliaet al. [95], these results might reflect either a reduc-tion of mesolimbic projections, or a lower dopaminetransporter density combined with increased synapticdopamine levels as previously suggested [74, 108].

The findings in PD patients with ICDs translate tofindings in both human and animal studies of addictionsuggesting low baseline dopamine receptor availabil-ity to be associated with vulnerability of addiction[156–158]. Interestingly, low striatal dopamine recep-tor availability has also recently been demonstrated inindividuals suffering from morbid obesity due to bingeeating [159, 160]. Following this line of arguments,individuals with ICDs and other types of addictions, arelikely to seek more potential rewarding events, e.g. thepossible gains related to gambling, in order to compen-sate for a reward deficiency syndrome characterizedby a chronic dopamine craving [74, 161]. However,Joutsa et al. [162] very recently argued that a striataldopamine release during gambling irrespective of out-

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come in fact challenges this hypothesis, which predictsblunted mesolimbic dopamine responses to gamblingin pathological gamblers. Thus according to this argu-ment, the findings by Voon et al. [45] and Rao et al.[92] support the reward deficiency hypothesis, whereasthe findings by Voon et al. [96], Frosini et al. [112]and Steeves et al. [74] contradict the hypothesis. Theexpectation of receiving a reward seems to be enough toinduce a striatal dopamine release in PD patients withpathological gambling, which is also seen in patholog-ical gamblers without PD [151, 152, 162]. Moreover,the experience of wanting or craving induced merely byvisual gambling cues or following loss might serve asanother hypothesis for explaining the observed striataldopamine release [112].

The processing of reward involves aspects of moti-vation, prediction, and pleasure, also referred to as thepsychological components of “wanting”, “learning”,and “liking” [163, 164]. In addictive behaviors, want-ing to a great extent equals craving. Recent studies haveshown that even though individuals suffering fromaddiction do potentially get a dopaminergic enhance-ment from engaging in the addictive behavior, theymight not feel any hedonic impact from the reward ofthe action. Exactly this is seen in a group of PD patientswith DDS [79]. Using PET imaging, Evans et al. [79]demonstrated an increased dopamine release in theventral striatum upon levodopa intake in PD patientswith DDS, which correlated with the patients’ subjec-tive feelings of drug wanting (craving) but not liking[79]. This finding hints at liking and wanting com-ponents involving different neurotransmitter systems,where wanting seems closely related to the dopamin-ergic system, and liking seems associated with theopiate system [164]. In fact, the ability to learn toseek reward remains intact in rats lacking up to 99%of dopamine in the nucleus accumbens, they merelylack the motivation to use the skills they have learned[164]. Thus, consistent with the findings by Graef etal. [150], one could argue that the reward system isnot only a dopamine-driven system rather it includes acombination of a dopaminergic motivational part andan opioid dependent pleasure part.

In summary, the nucleus accumbens certainly seemsto play a key role during the acquisition phase ofaddictive behaviors, whereas the dorsal striatum is par-ticularly important in maintaining an addiction [147,150, 165]. This transition seems to be facilitated bythe direct D2/D3 dopamine agonists on hypersensi-tive postsynaptic dorsal striatal dopamine receptors.Anatomically, the shift from initiation to consolidationof an addiction might reflect an equivalent shift from

limbic to associative-prefrontal and sensory-motorcircuits via the ventral tegmental area and the sub-stantia nigra zona compacta dopaminergic ascendingloops innervating the dorsal striatum [150, 165, 166].The discussed findings highlight the importance ofthe orbitofrontal cortex, the anterior cingulate cortex,and the ventral striatum in risk evaluation, which ismediated by dopamine agonists in ICDs in PD. Thus,these findings might explain why dopamine agonistsare important risk factors for developing ICDs in PD[45, 51, 167]. Furthermore, several studies show analtered dopaminergic activity within the ventral stria-tum in PD patients with concomitant ICDs resemblingthe dopaminergic activity observed in non-PD individ-uals suffering from other kinds of addiction. However,these issues are still not sufficiently investigated, andresearch suggests that dopamine and dopaminergictherapy are not the only agents that may impact thecourse of the disease. Other neurotransmitters aredepleted in PD as well, and in the following we discussthe influence of serotonin in ICDs in PD.

THE ROLE OF SEROTONIN IN IMPULSECONTROL DISORDERS IN PARKINSON’SDISEASE

It is obvious that dopamine agonists are not ableto fully compensate for the natural physiologicaltonic/phasic release of dopamine or the inactivationby the re-uptake transporter following its release,since the dopaminergic nerve terminals are degener-ated in PD. Among other important neurotransmittersdepleted in PD is serotonin, whose impact on non-motor manifestations of the disease is still subject tomuch debate [9–12]. Furthermore, the possible role ofa decrease in serotonergic activity in PD patients withICDs with regard to impulsivity, response inhibition,and temporal discounting remains to be established.The serotonin innervations originating from the dor-sal raphe nucleus supplies approximately 80% of theserotonergic innervation to the prefrontal and motorcortices as well as to the subcortical structures involvedin PD (striatum, pallidum, STN, substantia nigra,and PPN) [168]. In PD, the role of serotonin isvery important in relation to both ICDs and emo-tional disturbances associated with the disease, suchas depression, apathy, and anxiety [10]. It is beyondthe scope of this review to discuss the complex detailsregarding the interactions between dopamine and sero-tonin, since this topic has already been covered byexcellent reviews [169–171]. Consequently, only a few

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highlights from the published literature will be dis-cussed.

In conjunction with dopamine, serotonin seems toplay an essential role in the modulation of impulsecontrol, risk taking, and decision-making, and theactivity of serotonin has been associated with enhancedreversal learning and attentional shifting, increasedresponse inhibition, and decreased delay discounting[158, 170, 172–176]. Moreover, Campbell-Meiklejohnet al. [177] recently found that serotonin and dopaminecomplement each other in loss chasing (i.e. gambling torecover losses) in pathological gamblers. While sero-tonin activity seems related to persistent loss chasing,dopamine activity appears to regulate the magnitudeof the losses being chased [177]. In addition, Longet al. [178] demonstrated that serotonin depletionshapes risky decision-making in macaque monkeystrained to perform a simple gambling task for rewards.Reducing serotonin synthesis resulted in a decreasedpreference for more conservative options in the gam-bling task, resulting in riskier decision-making in themonkeys. These findings introduce an important issueconcerning the balance between high and low levelsof serotonin leading to different, sometimes almostopposite, neural network activations and behavioraloutcomes. Macoveanu et al. [175] recently demon-strated that high and low levels of serotonin hadopposite effects on activity in the dorsomedial pre-frontal cortex and the amygdala related to negativeoutcomes following low-risk decisions in a gamblingtask. In the dorsomedial prefrontal cortex, low levels ofserotonin increased the negative outcome-related neu-ral activity, whereas high levels of serotonin resulted ina decreased activity [175]. The opposite neural reac-tion to negative outcomes in the gambling task waspresent in the left amygdala, where high levels of sero-tonin led to increased activity relative to a decreasedactivity associated with low levels of serotonin [175].

The balance between high and low levels ofserotonin is furthermore implicated in impulsivity.Miyazaki et al. [176] demonstrated the importanceof serotonin in temporal discounting through findingsof increased serotonergic firing facilitating waitingbehavior towards future rewards. These results sug-gest that in addition to the implications of dopaminedepletion, low levels of serotonin, e.g. as a result ofserotonergic degeneration in PD, might be essentialin explaining the inability in PD patients with ICDsto wait for a reward and hence contributing to theirmaladaptive behavior.

To summarize, the presented results suggest thatboth the dopaminergic and the serotonergic systems are

implicated in temporal discounting and risk-sensitivedecision-making in general as well as in pathologicalgambling and other ICDs. Furthermore, the findingscautiously hint at potential dose-dependent pharmaco-logical therapies for ICDs and addiction. Consistentwith preclinical findings, a case study demonstrateda positive treatment response in a patient admin-istered fluvoxamine to treat pathological gambling[179]. Whether similar selective serotonin reuptakeinhibitors, or perhaps direct serotonergic agonists aim-ing at specific receptor subtypes, might amelioratepathological gambling and other ICDs in early PD,perhaps at least in patients with comorbid depression,remains an open question for future research to address[49, 180]. In addition, it appears highly clinically rele-vant to further investigate how ICDs in PD impact thepatients’ daily functioning. In the following, we dis-cuss cognitive impairments associated with ICDs inPD.

COGNITIVE SYMPTOMATOLOGY INIMPULSE CONTROL DISORDERS INPARKINSON’S DISEASE

Cognitive processes such as attention, planning, andanticipation are of ultimate importance in social inter-action, learning, and decision-making [3, 4, 6, 181,182]. It is well known that PD patients without ICDsexperience cognitive difficulties in domains relatedto the fronto-striatal loops as their disease progresses[11–13, 28, 183, 184]. According to Hirano et al. [13],the mesocortical dopamine system affected in PD isassociated with executive functions and is mediatedvia levodopa medication and dopamine metabolism.Cholinergic impairment in PD is also implicated inattention and working memory and the role of acetyl-choline in development of dementia is supported byacetylcholinesterase PET imaging [13]. Furthermore,research indicates that despite relatively preservedfunctions of the orbital and ventromedial prefrontalcortex in early disease stages, cognitive impairmentsmight even occur in early PD, though most likely asa consequence of dopaminergic treatment [185, 186].Below, we discuss findings based on a selection ofcognitive tasks dependent on frontal cortical functionscomparing PD patients with and without ICDs.

Executive functioning

The Stroop test and the Wisconsin Card Sorting Testrepresent two widely used tasks to evaluate executivefunctions. The Stroop test, which measures selective

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attention, cognitive flexibility, and speed of cognitiveprocessing, has been associated with activation in theanterior cingulate cortex and the dorsolateral prefrontalcortex [187]. Similarly, the Wisconsin Card SortingTest is a test of set shifting measuring cognitive flexi-bility. This test has been associated with activation ofthe dorsolateral prefrontal cortex as well as the ventro-lateral prefrontal cortex and the caudate nucleus, whichalso modulate working memory functions [188–190].Various studies have shown that PD patients performpoorly on both of these tests revealing a deficit in alter-ation or maintenance of a learned strategy based ontask-dependent feedback and impaired impulse controlregulation [183, 184, 191–195]. However, findings ofpreserved executive functions in PD exist as well, atleast in early PD [196].

In PD patients with concurrent ICDs, Vitale et al.[78] recently demonstrated deficits on executive tasksexploring cognitive flexibility and spatial planning. Inaddition, they noticed that the cognitive difficultiesassociated with ICDs in PD differed depending on thespecific kind of ICD patients presented. PD patientswith hypersexuality and multiple ICDs performedworse on verbal learning and memory tests com-pared to PD patients with pathological gambling [78].Particularly, the PD patients with comorbid hypersex-uality revealed more general cognitive deficits, poorerinhibitory control, and reduced immediate and delayedmemory compared to PD patients with pathologicalgambling [78]. These findings suggest that hyper-sexuality in PD is associated with a more profounddeficiency in the balance of the associative-prefrontaland emotional-limbic circuits than pathological gam-bling in PD. Additionally, compared to PD patientswithout pathological gambling, Santangelo et al. [123]reported impaired performance in PD patients withpathological gambling on cognitive tasks evaluat-ing long-term memory and frontal lobe functions,including the Frontal Assessment Battery, phonologi-cal fluency, and the Trail Making Test. In contrast, Siriet al. [114] demonstrated preserved executive functionsin PD patients with pathological gambling. Comparedto PD patients without pathological gambling, patientswith gambling problems revealed higher general cog-nitive abilities and performed better on attention andverbal fluency [114].

Reversal and reinforcement learning

Closely related to cognitive flexibility is reinforce-ment and reversal learning, which has also been foundto be compromised in PD, at least in medicated patients

[186, 197]. Reversal learning impairments appear tobe particularly pronounced following treatment withthe dopamine D2/D3 receptor agonist pramipexole [3,198, 199]. In line with our previous discussion of thefunctional neuroanatomy of ICDs in PD, the resultson cognitive impairments in PD might be explainedby a treatment-induced disruption of functional activ-ity within the nucleus accumbens, which is involved inalteration of behavioral strategy. Interestingly, Cools etal. [148] demonstrated that reversal learning was in factaccompanied by increased nucleus accumbens activityonly in medicated PD patients. Current neuroanatom-ical studies strongly suggest that the modulatoryinfluence on cognition via the nucleus accumbensappears to be mediated by its upstream neuronallooping through the ventral pallidum and thalamic pro-jections to the frontal cortex [166, 200]. Furthermore,the aforementioned fMRI study by Voon et al. [96]demonstrated that dopamine agonists increase the rateof learning from gain and enhanced ventral striatalactivity to positive prediction error in PD patients withICDs, an effect that was not present in PD patientswithout ICDs. In contrast, dopamine agonists induceda decrease in learning from loss in PD patients withoutICDs but not in PD patients with ICDs [96]. Lastly,PD patients with ICDs had greater orbitofrontal cortexactivation upon gains relative to lower activation uponlosses compared to PD patients without ICDs both onand off medication [96]. However as previously dis-cussed, Graef et al. [150] showed that dopaminergictreatment affects tasks implicating diverse neuronalnetworks differently.

Decision-making under ambiguity

A wide range of cognitive tasks is designed toexamine decision-making. Among these are the IowaGambling Task, the Cambridge Gambling Task, theGame of Dice Task, the Balloon Analogue Risk Task,and the Beads Task, which are all associated withthe limbic-orbitofrontal-striatal loop [201]. The IowaGambling Task is most often used to measure decision-making under ambiguous scenarios with implicit rulesand it is known that patients with deficits in theorbitofrontal and ventromedial prefrontal cortex andthe amygdala perform poorly on this task [201–203].Also, PD patients have revealed impaired performanceon the Iowa Gambling Task [97, 194, 196, 204–208]and this has even been found in early disease stagesdespite preserved executive functions [196]. In con-trast, Euteneuer et al. [201] observed intact IowaGambling Task performance in PD patients without

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ICDs in spite of impaired performance on the Game ofDice Task and executive dysfunctions. Furthermore,Bentivoglio et al. [97] recently reported that com-pared to PD patients without ICDs, PD patients withICDs tend to lose more money and make more riskydecisions on the task resembling the performance ofpathological gamblers without PD [151, 152].

Djamshidian et al. [113] investigated decision-making under ambiguity in PD patients with andwithout ICDs using the Beads Task, which assessesreflective impulsivity under ambiguous conditions[209]. Overall, PD patients made more impulsive deci-sions than controls, reflecting a tendency in PD patientsto make rapid decisions based on insufficient informa-tion [113]. A similar trend has been associated withDBS in STN. Frank et al. [44] showed that STN DBSinterferes with the normal capacity to slow decision-making processes down when faced with ambiguousdecision-making scenarios. In fact, they found that PDpatients with DBS made more hasty decisions underhigh-conflict conditions [44].

Decision-making under risk

Decision-making under risk requires intact dorso-lateral prefrontal cortex activity [6, 201] and can beassessed using the Game of Dice Task and the Cam-bridge Gambling Task, on which PD patients haveshown poor performance [5, 201, 210, 211]. In partic-ular, medicated patients seem to be impaired on thesetasks, as suggested by Torta et al. [211] who found thatpatients receiving higher doses of dopaminergic medi-cation performed worse and were more impulsive thanpatients receiving lower treatment doses.

Another way of measuring risky decision-makingis by using the Balloon Analogue Risk Task [212], inwhich loss aversion has been associated with increasedanterior cingulate cortex activity, whereas increasedventromedial prefrontal cortex activity has been asso-ciated with reward seeking [213]. In PD patients,this task seems to be modulated by dopaminergicmedication, at least in PD patients with concurrentICDs. Claassen et al. [51] recently demonstrated thatdopamine agonists increased risk taking in PD patientswith ICDs on this task, whereas no effect of dopamineagonists on risk taking was observed in PD patientswithout ICDs.

Temporal discounting

Temporal discounting refers to a preference towardsmore immediate rewards and a parallel devaluation of

delayed rewards, a clinical finding very common inindividuals suffering from ICDs and addictions. Justa few years ago, Voon et al. [75] linked dopamineagonist medication to an elevated delay discountingin PD patients with pathological gambling and com-pulsive buying relative to PD patients without ICDs.Furthermore, PD patients with ICDs revealed moreworking memory deficits than PD controls [75]. Inter-estingly, in another study Voon et al. [80] demonstratedincreased impulsive decision-making in PD patientswith compulsive buying and pathological gambling,but not in patients with binge eating or hypersexuality.Housden et al. [214] presented a similar finding in PDpatients with comorbid ICDs indicating an inability towait for a reward despite intact reward learning [149,214]. Overall, these findings suggest that a tendency inPD patients with ICDs towards devaluation of delayedrewards, though differences across ICDs might exist.Furthermore, the disinhibited behavior appears to beenhanced by dopamine agonists and strongly associ-ated with an elevated preference for immediate overfuture rewards [75, 80, 149, 214].

In summary, the aspects of cognition discussedabove are highly relevant in PD since patients oftensuffer significant impairments as the disease progressesand following prolonged treatment. The issue of execu-tive and decision-making dysfunctions associated withICDs in PD is far from resolved, but it appears that acommon feature for cognitive deficits associated withICDs in PD involve disturbances in impulsivity, tempo-ral discounting, cognitive flexibility, and reinforcementand reversal learning that is particularly related to theventral striatum and the frontal cortex [13]. Never-theless, inconsistent findings reinforce the need foradditional studies to determine whether ICDs in PD areaccompanied by further cognitive deficits and whetherdifferent ICDs are associated with different behavioraland cognitive profiles in PD.

CONCLUSIONS AND PERSPECTIVES

We have reviewed the literature from the past 12years reporting ICDs in PD and conclude that a contin-uously growing number of studies support the conceptof treatment-induced ICDs in PD. Both pharmacolo-gical and surgical therapies have been associated withthe development of ICDs. Particularly, the direct D2/D3dopamine agonists appear to be linked to this behav-ioral complication. Furthermore, we have argued thatboth the subthalamic nucleus and the nucleus accum-bens play key roles in ICDs, potentially leading to

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serious consequences for the individual on financial,interpersonal, and cognitive levels. However, to fullyunderstand why ICDs affect up to 15.5% of PDpatients, it is not enough to consider the contributionsof the dopaminergic system. Additional neurotransmit-ters need to be taken into account. We highlighted theimpact of serotonin in the non-motor manifestationsof PD and touched upon the role of opioids in addic-tive behaviors, since both neurotransmitters seem tobe important mediators in reward processing and riskevaluation.

Despite an increasing interest in the field, we lacksufficient knowledge regarding therapy in ICD symp-tomatology in PD. Thus, there is a great need for futureresearch to take a closer look at the functional neu-roanatomy of ICDs and related cognitive deficits asevaluated by PET [74, 79, 82, 105, 107, 110, 111],SPECT [94, 95, 108], fMRI [45, 92, 96, 112], orMEG studies [215] in order to fully understand whyPD patients appear to be at greater risk of develop-ing ICDs than the general population. We have arguedthat both the orbitofrontal and anterior cingulate cor-tices and the ventral striatum are linked to impairedrisk evaluation, which is mediated by dopamine ago-nists in PD patients suffering from comorbid ICDs.This serves as just one possible explanation of whydopamine agonists are among important risk factorsfor developing ICDs in PD [45, 51]. Another possi-ble explanation is related to the “overdose hypothesis”and attributes the cognitive deficits in PD patientswith ICDs to the depleted caudate nucleus, and thedorsal striatum in general, altering the cognitive func-tions associated with the prefrontal cortex. This is thenfurther compromised as the relatively intact ventralstriatum in early PD is overdosed by dopaminergictreatment.

Likewise, an important step for future researchis to assess how ICDs and other non-motor man-ifestations of PD affect the daily functioning andpsychological well-being of the patients. Potentially,this could lead to faster identification of PD patientsat risk for developing ICDs and improved manage-ment of adverse effects of treatment. A recent studydemonstrated that in PD patients with ICDs symptomseverity and related psychiatric disturbance improvedfollowing cognitive-behavioral therapy, unfortunatelywithout relieving caregiver distress or burden markedly[216, 217]. It is important in this regard to empha-size that the detection of ICDs relies very much oncaregivers, who play an important role in the dailymedical care and supervision of psychiatric symptomsfollowing withdrawal of dopamine agonists [53, 98,

216, 218]. Still, reduction of dopamine agonists isthe primary strategy in managing ICDs in PD, butit is often associated with the development or wors-ening of depression, anxiety, or apathy, which havebeen found to occur in up to 19% of patient duringdopamine agonist withdrawal [219]. Pharmacologicalmanagement of ICDs in PD has received increasingattention in recent years and several different com-pounds have been scientifically tested. Among theseare zonisamide [220] and donepezil [221], which areused to treat cognitive impairments and dementia inPD [222]. Also valproate, which is traditionally used totreat e.g. epilepsy, anorexia nervosa, anxiety, and bipo-lar disorders, has been shown effective in treating bothpathological gambling in non-PD patients and ICDsin PD [34, 223]. Other possible candidates includeselective serotonin reuptake inhibitors, at least in thesubgroup of patients with ICD who displays comor-bid depressive symptoms, the noradrenaline reuptakeinhibitor atomoxetine, which is sometimes prescribedto patients with ADHD, since this compound leavesthe ventral striatal dopamine system intact; and theopioid antagonist nalmefene [224, 225]. Undoubtedly,it is an important topic for future studies to investi-gate this in more detail, since mixed results have beenreported so far [226, 227]. Additionally, future researchshould investigate whether dopamine agonist with anextended release are associated with ICDs as well, orwhether these compounds could serve as an alternativeto the more short-acting dopamine agonists in pre-venting the increased risk of developing ICDs in PD[226].

SUPPLEMENTARY MATERIAL

Supplementary Table 1: Extensive overview of98 reports on ICDs in PD published between2000–January 2013 including case reports, case series,case-control studies, experimental studies, and epi-demiological studies. The table provides informationon sample size, gender distribution, treatment, age, andPD duration.

Supplementary Table 2: Extensive overview of98 reports on ICDs in PD published between2000–January 2013 including case reports, case series,case-control studies, experimental studies, and epi-demiological studies. The table provides informationon prior history of ICDs, psychiatric symptoms, Hoehn& Yahr, UPDRS, and additional information. The sup-plementary tables can be found here: http://iospress.metapress.com/content/e83v319qq21204m1/

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ACKNOWLEDGMENTS

We thank Malene Flensborg Damholdt, TrineGjerløff, and Anne Landau for commenting on aprevious version of this review. We thank the DanishAgency for Science, Technology and Innovation forfinancial support, grant number 2102-07-0005.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

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