J Neurol (2008) 255 [Suppl 5]:51–59DOI 10.1007/s00415-008-5010-5

Journal of Neurology-S (JON-Supplement) Ms. No. JON 5010Steinkopff Verlag, Heidelberg/ottomedien, Darmstadt 1. runProvisional page numbers 51–59 Date 00.00.0000

JON

5010

Eric C. WoltersYsbrand D. van der WerfOdette A. van den Heuvel

Parkinson’s disease-related disorders in the impulsive-compulsive spectrum

■ Abstract In Parkinson’s disease (PD), there is increasing evidence for disorders in the impulsive- compulsive spectrum, related to the disease itself, to the pharmacologi-cal management of this disease or to both. These disorders comprise dopamine deficiency syndrome (with immediate reward seeking behaviour), dopamine dependency syndrome (with addictive behav-iour), dopamine dysregulation syn-drome (with both addictive behav-iour and stereotyped behaviour) and impulse control disorders

(such as pathological gambling, compulsive shopping, binge eating and hypersexuality). These disor-ders are especially seen in PD pa-tients with young age of onset, higher doses of antiparkinsonian drugs, pre-existent or current depression, pre-existing recrea-tional drug or alcohol use, and high novelty seeking personality traits. Dopamine is not only impli-cated in voluntary movement con-trol but also plays a significant role in the brain’s reward system and the modulation of behaviours. Therefore, most if not all drug-naïve PD patients will suffer dys-phoria, leading to mild immediate reward seeking behaviour as a con-sequence of the striatal dopamin-ergic denervation. In some of these patients, during treatment, this may even lead to the intake of in-creasing quantities of levodopa, above those required to adequately treat motor parkinsonism, with all characteristics of a dopamine dependence syndrome. These pa-tients may develop plastic changes in the striatal matrix leading to hyperkinesia, caused by extracellu-lar striatal dopaminergic fluctua-tions due to pulsatile dopamine replacement therapy. As soon as these changes are also seen in the striatal striosomes, in the frame-work of a dopamine dysregulation syndrome, stereotyped behaviours

(punding) may occur (supposedly due to dorsal versus ventral striatal overactivity). Finally, impulse control disorders are suggested as being pure adverse side-effects of dopamine replacement therapy. Obsessive-compulsive behaviour (caused by ventral to dorsal over-activity) so far has not been described in PD patients. Treatment of impulse control disorders is related to the underly-ing pathology. In the case of an intrinsic dopamine deficiency syn-drome, treatment with dopamine replacement therapy, especially levodopa, will help. In the multi-factorial (intrinsic and extrinsic) dopamine dependency and dysreg-ulation syndromes, addictive be-haviour might best be helped by psychosocial strategies, and pund-ing by continuous dopaminergic receptor stimulation (or amanta-dine), hypothesized to reduce the plastic changes-induced hypersen-sitization. The extrinsic impulse control disorders might be best treated by reducing or replacing dopamine receptor agonists.

■ Key words dopamine deficiency syndrome · dopamine dependency syndrome · dopamine dysregulation syndrome · impulse control disorders · obsessive compulsive behaviour · impulsive-compulsive spectrum disorders

E. C. Wolters (Y)Dept. of NeurologyVU University Medical CenterP. O. Box 70571007 MB Amsterdam, The NetherlandsE-Mail: E.Wolters@vumc.nl

Y. D. van der WerfDept. of Medical PsychologyVU University Medical Center P. O. Box 7057 1007 MB Amsterdam, The Netherlands

and

Dept. Sleep and Cognition Netherlands Institute for Neurosciencean Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam, The Netherlands

O. A. van den HeuvelDept. of Psychiatry and Anatomy & NeurosciencesVU University Medical CenterP. O. Box 7057 1007 MB Amsterdam, The Netherlands

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Introduction

Parkinson’s disease (PD) is a clinical syndrome, mani-festing characteristically with motor parkinsonism: bra-dykinesia, hypo-/akinesia, rigidity, tremor, and postural instability, caused by significant striatal dopaminergic denervation due to nigral degeneration. In the past de-cade it has become more and more recognized that be-sides signs of motor parkinsonism, many patients also suffer non-motor pathology due to both nigral (apathy, dysphoria, mild cognitive impairment) and extra-nigral degeneration (hyposmia, pain, fatigue, autonomic dys-functions, sleep disorders, mood disorders, cognitive deficits and/or dementia as well as delusions and hallu-cinations) (Table 1) [61, 63]. Due to adverse effects of do-pamine replacement therapy, PD patients also may suf-fer motor (hyperkinesia) and non-motor (mood swings, stereotyped behaviour (punding), impulse control dis-orders and psychosis.

Thanks to new insight into the pathological process, PD is now suggested to be the clinical manifestation of a multi-system degenerative process, comprising not only the dopaminergic but also the noradrenergic, serotoninergic, cholinergic, and other central neuro-transmitter systems [11, 62]. This interpretation seems more robust since single photon emission computed tomography (SPECT) and positron emission tomogra-phy (PET) studies confirmed the loss of integrity of these neurotransmitters [9, 12, 14, 39, 45]. For instance, 123I-2β-carboxymethoxy-3β-(4-iodophenyl) tropane (β-

CIT) SPECT studies showed reduced striatal and dorsal midbrain binding ratios (reflecting regional dopamine and serotonin transporter densities respectively) corre-lating with the severity of motor parkinsonism and pathological behaviour and mood [9, 12]. PET studies also established noradrenergic and cholinergic dener-vation in PD patients [7, 12, 14, 39, 45]. In PD, due to the clinical heterogeneity and the extreme variability in the progression of this disease, at least two different clinical phenotypes are suggested: tremulous PD and akinetic-rigid PD [52]. In this respect, non-motor symptoms, especially neuropsychiatric symptoms such as mood and cognitive disorders, are mainly seen in the akinetic-rigid PD patients. These non-motor symptoms, however, can be more disabling than the motor dysfunctions, both to the patients and their care-givers. More than 60 % of PD patients report one or more neuropsychiat-ric symptom, initially mostly depression and anxiety, symptoms which may antedate motor symptoms by several years [1, 49]. Later, apathy, disorders of the im-pulsive-compulsive spectrum such as immediate reward seeking behaviour and/or stereotyped behaviour as well as impulse control disorders such as pathological internet use, compulsive skin picking, pathological (compulsive) gambling, compulsive buying, binge eat-ing and hypersexuality, and also cognitive impairment, dementia and psychosis [10] may emerge. It is suggested that some of these neuropsychiatric disturbances, especially the impulse control disorders and psychotic manifestations, may be triggered by extrinsic factors such as the pharmacological treatment of motor Parkin-sonism.

Symptomatology in PD might be both intrinsic and extrinsic

Motor and non-motor symptoms in PD might be the manifestation of purely intrinsic disease-related condi-tions, purely extrinsic (mainly pharmacotherapy-re-lated) factors, or the specific combination of both intrin-sic and extrinsic factors (Table 2). Purely intrinsic symptoms are considered the result of the specific PD-related disintegration of the various neurotransmitter systems in the peripheral and central nervous system, whether or not in combination with Lewy bodies within cortical and subcortical structures and/or aging [62]. Purely extrinsic symptoms are the consequence of (ad-verse) effects of dopamine replacement therapy. Im-pulse control disorders such as compulsive eating, gam-bling or shopping, as well as hypersexuality (satyriasis) are hypothesized to be induced by purely extrinsic fac-tors, especially by dopamine replacement therapy [15].

Many symptoms, and especially therapeutic response fluctuations with hyperkinetic and neuropsychiatric symptoms, though, might be multifactorial, supposedly

Table 1 Major non-motor symptoms in Parkinson disease

Autonomic dysfunction Orthostatic hypotension Urogenital dysfunction ConstipationHeat or cold intolerance Hypo- or hyperhidrosis

Sleep disorders Sleep fragmentationInsomniaExcessive daytime somnolence (EDS)Sleep attacksREM sleep behaviour disorder (RBD)Periodic limb movements in sleep (PLMS)Restless legs syndrome (RLS)

Neuropsychiatric disorders Fatigue ApathyAnhedoniaDepression and anxietyImpulsive-compulsive disordersMild cognitive impairment (frontal executive dysfunction)DementiaPsychosis

Sensory disorders HyposmiaColourvision deficitsVestibular deficitsAbnormal sensationsPain

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triggered by exogenous conditions such as social depri-vation, infections and pharmacotherapeutic interven-tions in this specific disease. Dopamine replacement therapy, for instance, even during de-novo monother-apy, may induce predictive (wearing-off fluctuations) or unpredicitive (on-off fluctuations), acute and or sub-acute/persisting motor and non-motor response fluctu-ations, limiting therapeutic control. Acute, short-lived fluctuations comprise acute akinesia or hyperkinesia as well as mood swings with acute depressive episodes, ap-athy, anxiety, panic attacks and suicidal ideation, as well as pain, hallucinations and delusions. Subacute and/or persisting fluctuations may manifest with addictive be-haviour, hyperkinesia and stereotyped behaviour (pund-ing) in the framework of the dopamine dependency/dysregulation syndrome, with mood disorders, vivid dreams, delusional disorders and/or visual hallucina-tions.

In daily practice, many PD-related neuropsychiatric symptoms might thus be the result of both intrinsic and extrinsic factors. Addictve behaviour, for instance, might result from dopamine deficiency-related dysphoria in combination with the euphoric effects of levodopa; and also psychotogenic factors comprise both intrinsic (cho-linergic denervation due to PD-related and/or aging-re-lated pathology) and extrinsic (dopaminomimetic, anti-cholinergic, infectious, sociopsychological) conditions [10].

Management of these symptoms depends on the causative factor and before deciding on a management approach to an individual patient with advanced PD, it is necessary to ascertain if the symptoms are provoked by pure intrinsic or extrinsic factors or by a combination of both. In contrast to many other conditions where the dosage of medications is increased to alleviate disabling symptoms, many patients with advanced PD are sensi-tive to small changes in plasma levodopa levels and may suffer fluctuating adverse reactions to dopamine re-placement therapy. Therefore, the management of pa-tients with advanced PD should be individualized and directed toward decreasing the dose of the offending drug while raising or initiating the dose of alternative medication, with the goal of maintaining symptom con-trol.

Impulsive-compulsive disorders

Impulsive-compulsive disorders are considered the con-sequence of a person’s inability to resist an impulse, drive or temptation to perform an act out of character for that person that may ultimately cause harm to them-selves or others. These disorders sometimes involve pleasurable and/or hedonic behaviours, which interfere in major areas of life functioning due to the fact that they are performed repetitively, excessively or compulsively. Many patients, however, perform the compulsive behav-iours without enjoying the experience [36]. Due to over-lap with obsessive-compulsive disorders as well as drug abuse (addiction), the extent to which these disorders constitute a homogenous group is unclear. Therefore, these disorders are described as behavioural addictions, lying along an impulsive-compulsive spectrum with mild dopamine deficiency-related behavioural disor-ders at one end and obsessive-compulsive disorders at the other [25, 26]. Prevalence studies in PD investigating the occurrence of obsessive-compulsive symptoms and OCD have shown inconsistent results so far. The incon-sistency may be explained by differences in psychiatric diagnostic instruments used to measure the obsessive-compulsive symptoms. Alegret [2], for instance, showed increased ratings on the Maudsley Obsessive-Compul-sive Inventory (MOCI) and the Leyton Obsessive Inven-tory (LOI) in severe PD patients compared to control subjects and mild PD patients. These symptoms were mainly in the checking, doubting and cleaning dimen-sions. Others, though, found increased obsessive-com-pulsive symptoms only in a subgroup of PD patients (with left or bilateral motor symptoms) [35], or (using the Yale-Brown Obsessive-Compulsive Scale) not at all [24]. In a recent survey, PD patients had higher scores than controls for both impulsivity and compulsivity, but these scores did not correlate and only the higher impul-sivity score was associated with an increased probabil-ity of impulse control disorders [27]. The phenomeno-logical overlap between impulse control disorders and OCD needs further investigation, since better under-standing of the overlapping and differentiating charac-teristics will contribute to our understanding of the pathophysiology of the disturbances and treatment al-ternatives. In this perspective, it is important to investi-gate the influence of the dopaminergic striatal denerva-tion to other neurotransmitter systems (for instance

Dopamine Deficiency Syndrome (DDS-1) Intrinsic: PD Immediate reward-seeking behaviour

Dopamine Dependency Syndrome (DDS-2)Dopamine Dysregulation Syndrome (DDS-3)

Multifactorial: PD/DRT Multifactorial: PD/DRT

Addictive behaviourStereotyped behaviour (punding)

Impulse Control Disorders Extrinsic: DRT Pathological internet use/skin pickingCompulsive gambling/shoppingbinge eating, hypersexuality

Table 2 Survey of PD- and/or dopa-mine replacement therapy (DRT)-re-lated impulsive-compulsive disorders, with underlying causative factors and symptoms

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serotonin) and to understand the balance between the dorsal frontal-striatal circuits and the mesolimbic or ventral frontal-striatal circuits. Although the clinical presentation of repetitive behaviours is not always sim-ilar in PD and OCD patients, the disorders seem to have overlapping neuronal disturbances [28].

Although these disorders are quite common in the normal population, they are even more frequent in PD patients, where they are recognized to occur in 5–10 % of patients at some point during the course of this dis-ease [60].

In PD, the spectrum of these impulsive/compulsive disturbances, characterized by excessive or poorly con-trolled preoccupations, urges or behaviours, includes the intrinsic dopamine deficiency syndrome, the multi-factorial dopamine dependency and dysregulation syn-dromes as well as the hypothesized pure extrinsic, (iso-lated) impulse control disorders [51].

Dopamine deficiency syndrome (DDS-1)

Due to PD-related degeneration of the dopamine pro-ducing cells in the nigral substance, both motor and non-motor symptoms may arise as a consequence of the striatal denervation. Denervation of the dorsal striatum, at a certain level, will manifest with motor parkinsonism (bradykinesia, hypokinesia, rigidity and tremor), whereas ventral striatal denervation might come with loss of initiative, apathy, dysphoria, anxiety, fear and de-pressive mood. Indeed, dopamine replacement therapy, and especially levodopa, is the most effective treatment for Parkinson’s disease (PD). This medication provides substantial benefit for most patients: it not only im-proves motor Parkinsonism, but also stabilizes mood, extends independence, and increases survival. There-fore, in many drug-naïve PD patients subtle, mild reward seeking and immediate gratification (delayed discount-ing) behaviour might be seen [41], as a direct manifesta-tion of the dopamine deficiency syndrome.

Dopamine dependency syndrome (DDS-2)

As dopamine is implicated in the brain’s reward system and has been the focus of addiction research [18], in PD, the dopamine dependency syndrome in itself is sup-posed to be caused by dopamine replacement therapy in the PD-related striatal dopamine deficiency. In an effort to control dysphoric “withdrawal” symptoms in the “off” state, some patients will take increasing quantities of le-vodopa, far beyond those required to treat their motor disabilities. These patients demand rapid drug escala-tion and continue to request more levodopa despite the eventual emergence of increasingly severe drug-induced motor complications and harmful behavioural conse-

quences [32]. Using a semi-structured questionnaire, these patients were found to suffer maladaptive thera-peutic dependence on dopamine replacement therapy, fulfilling operational criteria of substance dependence [5]. Indeed, this syndrome closely resembles addiction to psychostimulants, with psychomotor agitation and euphoria, strong resistance to dose reduction, and with-drawal symptoms characterized by depression, dyspho-ria, irritability, anxiety, and impairment in occupational and social functioning [20, 32]. The dopamine depen-dency syndrome is thus characterized by a hypermoti-vation to take dopamine replacement drugs, supposedly due to increasing tolerance to the beneficial motor ef-fects of L-dopa, leading to compulsive use and a depen-dence condition comparable to addiction. Indeed, pa-tients suffering this syndrome report ‘wanting’ but not ‘liking’ levodopa. They not only experience invalidating hyperkinesia but eventually also a diminishing degree of pleasure by tolerance to the pleasurable effects of le-vodopa. Other attributes of addictive behaviour might also be seen, including an increased reaction to mone-tary reward [15].

Dopamine dysregulation syndrome (DDS-3)

In case of any association of pathological stereotyped behaviour (punding) with the overuse of dopamine replacement therapy (in the dopamine dependency syndrome), this behaviour is referred to as the manifes-tation of a homeostatic hedonic dysregulation: the do-pamine dysregulation syndrome [20].

Friedman in 1994 was the first who reported levo-dopa-induced motor stereotypy, resembling ampheta-mine-induced punding behaviour [19]. Since then, punding behaviour, a repetitive and mindless behav-ioural response elicited by repeated exposure to levo-dopa induced by behavioural sensitization, was ob-served in a minority of PD patients with an supposedly underestimated prevalence of 1.4 % in an unselected PD population [37] and 14 % in patients with higher levo-dopa doses [16].

■ Stereotyped behaviour (punding)

Punding behaviour is characterized as ‘compulsive hob-byism’: an intense inappropriate and unproductive fas-cination for common objects with repetitive meaning-less movements such as endless computer use, cleaning and tidying, gardening, collecting, repairing and/or dis-mantling (watches and radios) and sorting of common objects (rocks) [42]. Patients often completely lack in-sight into the disruptive nature of their behaviour. The nosology of repetitive behaviours observed in punding is unclear. Punding may share some clinical and possi-

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bly pathogenetic features with OCD: the purposeless of the compulsions and the calming effect and relief by performing them [15, 33]. As a rule, however, the obses-sive thought appears absent in punding. In OCD, though, obsessions are also not always present and compulsive behaviour may be driven by the feeling that ‘it just has to be like that’. The fact that PD patients often become anx-ious, stressed or frustrated when stopped in their com-pulsive behaviours, suggests that emotional/motiva-tional factors are also involved in punding to a certain degree.

As punding PD patients were found to take higher doses of (various) dopamine replacement therapy and to endure more severe dyskinesia than patients who do not pund [50], it is considered part of the dopamine dys-regulation syndrome. Currently punding is underdiag-nosed, and special attention should be given to dyski-netic patients frequently requiring larger doses or rescue doses of dopamine replacement therapy. Most of them will improve with reduction of their dopaminomimetic medication or by treating them with antipsychotic drugs or selective serotonergic reuptake inhibitors [40].

Impulse control disorders (ICD)

In the extrinsic impulse control disorders, it is suggested that the primary risk factor implies the use of dopamine replacement therapies, dopamine agonists rather than levodopa [59, 60], though its role is complex and less central than generally believed [43]. Other factors in-clude (male) gender, impulsivity and depression [27], the (younger) age of onset and pre-existing impulse con-trol disorders and/or substance use disorders [59] as well as a, in PD patients unusual, novelty-seeking per-sonality [17], though this is disputed by Bonci and Singh [8].

■ Pathological gambling

Pathological gambling, a failure to resist gambling im-pulses despite severe personal or family consequences, is associated with earlier PD onset, higher novelty seek-ing traits, personal or family history of alcoholism, and dopamine agonists adjunctive but not monotherapy [56, 59]. The association with dopamine agonists is still de-batable [13, 59], though reduction or stopping of these drugs improves this pathological behaviour [59]. Patho-logical or problem gambling in the general population is found in 1 % and 3 % respectively; in PD 2–4 % of all pa-tients met the criteria for pathological gambling [56, 57, 60].

■ Hypersexuality

Hypersexuality, a preoccupation with sexual feelings and thoughts, and manifesting with nymphomania or satyriasis may occur in 2–4 % of the patients [30, 56, 57, 60] during treatment with dopamine agonists, but is also described during high frequency subthalamic deep brain stimulation [46].

This condition easily disrupts normal social and/or marital life, and often necessitates treatment. Hypersex-uality, however, is rather refractory and therefore diffi-cult to treat. Usually, it will not wane after stopping the dopamine agonist or adding an atypical antipsychotic drug. Treatment with the antihormone cyproteron sometimes will bring relief [51].

■ Compulsive shopping

A compulsive buying disorder is characterized by exces-sive or poorly controlled preoccupations, urges, or be-haviours regarding shopping and spending that lead to subjective distress or impaired functioning [6]. Compul-sive buying disorder is estimated to have a lifetime prev-alence of 5.8 % in the United States general adult popu-lation, mostly women [31], and it tends to run in families with mood disorders and substance abuse. In Parkin-son’s disease, compulsive buying may be induced by treatment with dopamine agonists or with high fre-quency deep brain stimulation of the subthalamic nu-cleus. When stopping the agonists and/or deep brain stimulation is not an option, psychopharmacologic treatment and/or financial counselling might be help-ful.

■ Binge eating

Binge eating, also an impulse control disorder, is occa-sionally seen in PD patients, supposedly induced by treatment with dopamine agonists. It is defined by both eating an amount of food that is definitely larger than most people would eat during the same period of time under similar circumstances and a lack of control over eating (the feeling that one cannot stop eating or control what or how much one is eating) [4].

Neuroanatomy of stereotyped behaviour (punding) in PD

Normal goal-directed behaviour is orchestrated by the basal ganglia, through parallel circuits that interconnect [3]. These circuits divide the basal ganglia into a ventral, ‘limbic’ part and a dorsal, ‘sensorimotor’ part [21]. The ventral part receives input from, amongst others, the

56

amygdala, hippocampal formation and anterior cingu-late cortex, whereas the dorsal part is associated more with motor circuits in the brain (Fig. 1). Under normal circumstances, appropriate behaviours are selected in a motivational or mnemonic context; this means that in-formation flow needs to occur from the ventral to the dorsal part of the striatum. Intrastriatal connections are thought to underlie the orderly progression of ventral striatal information to dorsal striatal structures [55]. This transfer of information whereby limbic, i.e. incen-tive, emotional or motivational, input is transferred to motor output, is under the influence of dopamine input to the striatum [23]. Overactivation of the ventral part of the striatum is suggested to be associated with a dys-functionally increased emotional control over behav-iour, as seen in for example obsessive compulsive disor-der (OCD) and Tourette’s syndrome [22, 44, 54]. Although the stereotyped behaviour seen in the dopamine dysreg-ulation syndrome, partially overlaps with that seen in those conditions [58], here rather a dorsal striatal over-activation is thought to underlie the stereotyped behav-iour. In PD, striatal dopamine deficiency initially will re-sult indeed in a general striatal dysregulation, with both motor (dorsal striatum) as non-motor (ventral stria-tum) symptoms (the dopamine deficiency syndrome), at that time possibly with reward seeking behaviour due to a ventral to dorsal overactivity. Due to pulsatile stim-ulation of especially the dorsal striatal dopaminergic re-ceptors, neuroplastic changes (glutamatergic hypersen-sitivity) will subsequently arise. When occurring in the matrix this will manifest itself with hyperkinesia; in the striosomes, on the other hand, the dorsal striatal overac-

tivation to ventrally mediated emotional/motivational factors will lead to stereotyped, non-adaptive, rigid be-haviour. Indeed, in an animal model for PD, dopaminer-gic treatment primes the dorsal striatal system to re-spond to a subsequent dopaminergic challenge both with hyperkinesia and stereotyped behaviour [53], and in monkeys, repeated cocaine administration leads to stereotyped behaviour linked to dorsal striatal activa-tion [47]. In accordance with the report of amantadine being effective to reduce punding in a PD patient [29], a glutamate receptor antagonist was able to reduce the dorsal striatal overactivation and the associated behav-iour abnormalities in the animal PD-model [53]. The dorsal striatal overactivation in response to ventrally mediated incentive factors has yet to be investigated but supposedly results from a disruption of the normal and controlled flow of information from ventral to dorsal striatal structures, probably caused by glutamatergic hy-persensitivity. Based on the available evidence, we spec-ulate that the dopamine dysregulation syndrome-re-lated stereotyped behaviour seen in some PD patients is related to an exaggerated dorsal striosomal striatal acti-vation to ventral striatal incentive factors.

Treatment of impulse control disorders

The treatment of the PD-related impulsive-compulsive spectrum depends on the underlying condition. In the dopamine dependency syndrome, the best results will be obtained by giving the patient dopamine replace-ment therapy, especially levodopa. In the case of dopa-

Associationcortices

Sensorimotorcortices

Motor output

Intrastriatal connections

Normal

DDS-3

OCDEmotional/Motivationaldrive

Limbic corticesAmygdala

Acb

Caud

Put

Fig. 1 Schema of hypothetical intrastriatal information transfer underlying stereotyped behaviour in the dopamine dysregulation syndrome and obsessive compulsive disorder. The striatum can be divided into separate regions, characterized by their different inputs (left). Under normal circumstances, motor output based on incentive fac-tors is mediated by flow of information from the ventral to the dorsal striatum (top right; arrows indicate flow of information, not monosynaptic contacts). In the dopamine dysregulation syndrome, a normal limbic input into the ventral striatum becomes amplified into exaggerated and stereotyped motor output through sensitization of the dorsal striatum (middle right). The behaviour might appear comparable to certain types of behaviours seen in obsessive compulsive disorder (e.g. compulsive washing). In obsessive compulsive disorder, however, an exaggerated limbic input results in a strong ventral striatal activation, resulting in stereotyped motor output (lower right). Acb Nucleus Accumbens; Caud Caudate nucleus; DDS-3 dopamine dysregulation syndrome; Put putamen; OCD obsessive compulsive disorder

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mine dependency syndrome, psychosocial strategies will be needed. In these cases, gradual, carefully super-vised reduction in dopaminergic medications with ac-tive involvement of the patient’s family will be needed. In refractory cases quetiapine may be required [42]. In analogy with hyperkinesia, stereotyped behaviour, punding, is supposedly caused by striatal dopamine re-ceptor hypersensitization. Therefore, strategies must be selected to desensitize these receptors: continuous do-pamine receptor stimulation and/or amantadine. In-deed, recently, amantadine has been reported to reverse disabling punding in a PD patient, without aggravating motor parkinsonism [29]. As this molecule is known to suppress levodopa-induced hyperkinesia, these authors could not resist speculating that amantadine might block the glutamate NMDA receptors in the striatal patches [47].

In the past, case reports suggested good results in the treatment of impulse control disorders in PD patients with subthalamic deep brain stimulation, atypical antip-sychotics, antidepressants, mood stabilizers and psy-chosocial interventions [30, 38, 48], though often in combination with changes in the actual dopamine re-placement therapy (decreasing the doses of dopamine agonists). Recently, the treatment of a small series of PD patients suffering impulse control disorders (compul-sive gambling, compulsive shopping and/or hypersexu-ality) with a reduction of the actual dose of these drugs was reported [34]. In all cases, open discontinuation and/or significant decrease of dopamine agonists (with a congruent increase of the daily levodopa dose) re-sulted in a full or partial remission of the impulse con-trol disorder. Unfortunately, in this study, due to its de-

sign, there are many limitations, and caution must therefore be taken when interpreting these findings. As deep brain stimulation and other factors may also play an essential role in the occurrence of these behavioural disorders [46, 51], and especially in hypersexuality, dis-continuation and/or decreasing the dose of dopamine agonists will often fail to control this disorder [46].

■ Disclosure The authors have no conflicts of interest do declare.

■ Acknowledgement This article is part of Journal of Neurology (J Neurol, 2008, 255,Suppl 5). Publication of this supplement has been funded by an unrestricted grant from GlaxoSmithKline. GlaxoS-mithKline has had no editorial control with respect to the articles contained in this publication. The opinions and views expressed in this publication are those of the authors and do not necessarily constitute the opinions or recom-mendations of the publisher or GlaxoSmithKline. Dosages, indicati-ons and methods of use for medicinal products referred to in this pu-blication by the authors may reflect their research or clinical experience, or may be derived from professional literature or other sources. Such dosages, indications and methods of use may not reflect the prescribing information for such medicinal products and are not recommended by the publisher or GlaxoSmithKline. Prescribers should consult the prescribing information approved for use in their country before the prescription of any medicinal product. Whilst effort is made by the publisher and editorial board to see that no inaccurate or misleading data, opinion or statement appear in this publication, they wish to make it clear that the data and opinions appearing in the articles herein are the sole responsibility of the con-tributor concerned. Accordingly, the publishers, the editor and editorial board, GlaxoS-mithKline, and their respective employees, officers and agents accept no liability whatsoever for the consequences of such inaccurate or misleading data, opinion or statement. Publication of this supplement has been funded by an unrestricted grant from GlaxoSmithKline.

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