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Impulse control disorders in Parkinson's disease
Parkinsonism and Related Disorders 18S1 (2012) S80–S84
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Impulse control disorders in Parkinson’s disease Dolores Vilas, Claustre Pont-Sunyer, Eduardo Tolosa* Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Cl´ınic de Neuroci`encies, Hospital Cl´ınic de Barcelona, Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigaci´ on Biom´edica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain
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summary
Keywords: Parkinson’s disease Impulse control disorders Pathological gambling Binge eating Hypersexuality Dopamine agonists Compulsive behavior
Impulse control disorders (ICDs), a group of complex behavioral disorders, occur more commonly in Parkinson’s disease (PD) patients than in the general population, with a reported prevalence up to 13.6% in some studies. The most common ICDs reported are pathological gambling (PG), hypersexuality (HS), compulsive shopping and compulsive eating. More than a quarter of the patients with ICDs have 2 or more behavioral addictions. These abnormal behaviors impair activities of daily living and have a negative impact on quality of life of patients and their families. As with many other non motor symptoms in PD, ICDs are frequently under-reported by patients and caregivers and may be under-recognized by the treating physicians. Treatment with dopamine agonists (DA) is the main risk factor for developing ICDs, and stimulation of mesolimbic D3 receptors by DA is thought to underlie their development. The DA effect seems to be a class effect and not specific for any DA. Levodopa can also induce ICDs but much less so than the DAs. The management of ICDs in PD is complex. Modifications in dopaminergic drug treatment are frequently necessary. In some cases alternative therapies such as atypical antipsychotics, antidepressants or deep brain stimulation if motor symptoms become incapacitating after adjustment of dopamine replacement therapy should be considered. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction The term impulse control disorders (ICDs), defines a group of complex behavioral disorders characterized by failure to resist an impulse or temptation to perform an act that is harmful to the individual or to others. ICDs are thought to occur more commonly in PD patients than in the general population [1]. They have recently been the focus of considerable interest because of their association with the use of dopaminergic treatment, in particular dopamine agonists (DA), also because their presence has a significant negative impact on the quality of life of patients and their families. As with many other non motor symptoms in PD, ICDs are frequently under-reported by patients and caregivers and may be under-recognized by the treating physician. Other neuropsychiatric problems occurring in PD that may be related to ICD include dopamine dysregulation syndrome, an addictionlike state marked by excessive dopaminergic medication use; punding, a fascination with meaningless movements or activities and walkabout, characterized by excessive wandering [2,3]. 2. Epidemiology and risk factors Reported prevalence rates of ICDs in PD vary considerably ranging from 6% in PD patients not receiving DA and 17% among * Corresponding author. Eduardo Tolosa. Hospital Cl´ınic de Barcelona, Universitat de Barcelona, C/Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 932275785; fax: +34 932275783. E-mail address: [email protected] (E. Tolosa.) 1353-8020/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
those on DA treatment [4]. In one study assessing ICDs in 3090 PD patients, the DOMINION (Impulse Control Disorders in Parkinson’s Patients Treated With Pramipexole and Other Agents) cross-sectional study [5], the 6-month ICD prevalence was 13.6%. The most common ICDs reported were pathological gambling (PG), with a prevalence of 5%, hypersexuality (HS) (3.6%), compulsive shopping (5.7%) and compulsive eating (4.3%). More than a quarter of the patients with ICDs had 2 or more other behavioral addictions [5]. DA treatment is the primary risk factor for ICD development in PD. Several studies support this association [6,7] and it is also clear from a number of studies and everyday clinical practice that withdrawal of the offending DA typically results in marked improvement in the ICD. In the above mentioned DOMINION study DA treatment was associated with a 2- to 3.5-fold increased odds of having an ICD. ICDs frequency was similar for pramipexole and ropinirole (17.7% vs 15.5%), suggesting that the association between DA and ICDs is a drug class relationship. Additional variables independently associated with ICDs include male sex, mainly in HS and PG, younger age [5,8], being unmarried, current cigarette smoking, prior personal/family history of alcohol addiction or gambling problems, higher novelty seeking scores and impulse traits [8], a greater incidence of medication-induced hypomania/mania [8], an impaired planning [8], levodopa use [5], and amantadine (PG, HS and buying) [9]. An independent association between levodopa treatment and ICDs has been found [5]. In patients taking a DA, concurrent
D. Vilas et al. / Parkinsonism and Related Disorders 18S1 (2012) S80–S84
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Table 1 Diagnostic criteria for pathological gambling (PG) a A. Persistent and recurrent maladaptive gambling behavior as indicated by five or more of the following: 1.
Is preoccupied with gambling (eg preoccupied with reliving past gambling experiences, handicapping or planning the next venture, or thinking of ways to get money with which to gamble)
2.
Needs to gamble with increasing amounts of money in order to achieve the desired excitement
3.
Has repeated unsuccessful efforts to control, cut back or stop gambling
4.
Is restless or irritable when attempting to cut down or stop gambling
5.
Gambles as a way of escaping from problems or of relieving a dysphoric mood (e.g., feelings of helplessness, guilt, anxiety, depression)
6.
After losing money gambling, often returns another day to get even (“chasing” one’s losses)
7.
Lies to family members, therapist or others to conceal the extent of involvement with gambling
8.
Has committed illegal acts such as forgery, fraud, theft, or embezzlement to finance gambling
9.
Has jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling
10. Relies on others to provide money to relieve a desperate financial situation caused by gambling B. The gambling behavior is not better accounted for by a manic episode a
American Psychiatric Association, American Psychiatric Association Task Force on DSM-IV [11]. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed. Washington, DC: American Psychiatric Association; 2000.
levodopa use increased the odds of an ICD by approximately 50%. While the relation between ICDs and DA therapy is not dose-related, in the case of levodopa only high dosages were also associated with ICDs [5]. 3. Clinical manifestations ICDs are under-recognized in clinical practice. Most patients do not spontaneously offer information about ICD behaviors, either because of shame or because they do not understand that it is related to PD and its treatment. Most common ICDs in PD are PG, HS, compulsive shopping and compulsive eating. Early detection of ICDs is crucial and all patients should be questioned directly about such behavior. A useful tool to detect ICDs can be the Questionnaire for Impulsive-Compulsive Disorders I Parkinson’s Disease (QUIPCurrent-Short), a validated quick screening questionnaire that when positive should be followed by a clinical directed interview [10]. Pathological gambling (PG): PG is defined as an inability to resist gambling impulses despite severe repercussion on personal, family or professional life. PG is persistent and recurrent maladaptive gambling with tolerance or withdrawal, maladaptive behaviors and consequences (risking significant relationships or employment, turning to others for financial assistance) (Table 1). The more frequent PG modes are slot machines, lottery scratch cards and bingo. PG occurs more frequently during the “on” period [12]. Cultural differences are thought to have a significant impact on prevalence rates and in Far Eastern countries PG prevalence is higher than in Asia [13]. Voon et al. [8] studied the factors associated with dopaminergic drug-related PG in PD. When compared with patients without, those with PG had younger age of onset, higher novelty seeking, a greater incidence of medicationinduced hypomania/mania, an impaired planning and personal/ family history of alcohol use disorders. Hypersexual behavior (HS): HS typically entails an increase in premorbid sexual activities as well as an increase in the variety of sexual behaviors. In patients with HS the need for sexual behavior consumes so much money, time, concentration and energy that the patient describes himself as out of control. Intrusive unwanted paraphiliac thoughts prevent concentration on other life demands and are the source of anxiety. Orgasm does not produce satiety in the way it typically does for age mates [14]. HS occurs predominantly in males with relatively early-onset PD, patients with prior history of tobacco or alcohol addiction, and can be associated to other inappropriate behavior or psychotic
symptoms [9,14]. HS is associated to treatment with DA alone (including apomorphine) or adjunctive to levodopa, selegiline and amantadine [9] although this last relation is controversial, as discussed below. Compulsive shopping: This is defined as a maladaptive preoccupation with buying or shopping, or maladaptive buying or shopping impulses, frequent buying of more than can be afforded, items that are not needed, or shopping for longer periods of time than intended. The buying impulses cause marked distress, are time-consuming, interfere significantly with social or occupational functioning or result in financial problems [15]. Compulsive eating: Most frequent clinical presentations are an increase in the food intake dramatically in the setting of new-onset food cravings for carbohydrates, sweets, and/or salty foods; a newonset binge eating, compulsively eating both larger portions of food at mealtimes and more frequent snacks throughout the day and tendency to compulsively snack or binge in the middle of the night. The consequence of this is an unintentional and undesired increase in the weight and body mass index [16]. Compulsive shopping and binge eating are more common in female PD patients whereas compulsive sexual behaviors have been more frequently reported in males [4,5] (Table 2). Other symptoms associated with ICDs: Other neuropsychological disturbances such as novelty seeking and impulsivity have been associated with ICDs in PD. Their presence may vary depending on ICD type. Pathological gambling and compulsive shopping, for example, share similarities in higher novelty seeking and impulsive choice as compared with hypersexuality and binge eating. In another study, high scores in depression, anxiety and obsessivecompulsive symptoms have been reported in ICD PD patients [18]. Motor fluctuations are more common in patients with ICDs, and early and severe dyskinesias (within the first 12–24 months) have been considered a warning sign for the development of dopamine dysregulation syndrome or ICDs [13]. 4. Pathophysiology of ICDs A role for dopaminergic stimulation in the development of ICDs has been confirmed by several lines of evidence. Underlying pathological changes occurring in PD probably do not play a major role since ICDs are known to occur in other conditions treated with DA such as restless legs syndrome [19]. While dopaminergic mechanisms are important, not all patients taking dopaminergic drugs develop these behaviors and ICDs probably
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Table 2 Proposed criteria for compulsive buying and pathological hypersexuality Proposed criteria for compulsive buying a A.
Maladaptive preoccupation with buying or shopping, or maladaptive buying or shopping impulses or behavior, as indicated by at least one of the following: 1. Frequent preoccupation with buying or impulses to buy that is/are experienced as irresistible, intrusive and/or senseless 2. Frequent buying of more than can be afforded, frequent buying of items that are not needed, or shopping for longer periods of time than intended
B.
The buying preoccupations, impulses, or behaviors cause marked distress, are time-consuming, significantly interfere with social or occupational functioning or result in financial problems (eg, indebtedness or bankruptcy)
C.
The excessive buying or shopping behavior does not occur exclusively during periods of hypomania or mania
Proposed diagnostic criteria for pathological hypersexuality b A
The sexual thoughts or behaviors are excessive or an atypical change from baseline marked by one or more of the following: 1. Maladaptive preoccupation with sexual thoughts 2. Inappropriately or excessively requesting sex from spouse or partner 3. Habitual promiscuity 4. Compulsive masturbation 5. Telephone sex lines or pornography 6. Paraphilias
B.
The behavior must have persisted for at least one month
C.
The behavior causes at least one of the following: 1. Marked distress 2. Attempts to control thoughts or behavior are unsuccessful or result in marked anxiety or distress 3. Are time consuming 4. Interfere significantly with social or occupational functioning
D. The behavior does not occur exclusively during periods of hypomania or mania E. a b
If all criteria except C are fulfilled, the disorder is subsyndromal McElroy SL, Keck Jr PE, Pope Jr HG, Smith JM, Strakowski SM [17]. Compulsive buying: a report of 20 cases. J Clin Psychiatry 1994;55:242–8. Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. [4] Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006;67:1254–7.
arise from a complex interaction between pharmacologic and nonpharmacologic predisposing factors like young age, male sex and certain personality traits [20]. It has been hypothesized that treating the motor symptoms associated to the dorsal motor striatal dopaminergic deficiency, may result in an “overdose” in the cognitive and limbic pathways of the ventral corticostriatal circuitry resulting in ICDs [20]. These central dopaminergic pathways (mesolimbic and mesocortical) are intricately linked to the brain’s reward system and are implicated in various states of addiction. Activation of these systems is thought to be mediated by stimulation of D3 receptors which are predominantly expressed in ventral striatum and mediate reward, emotional and cognitive processes. Non-ergot DA currently used in PD has a high affinity for the D2/D3 receptors compared to D1 receptors. Several functional imaging studies strengthen the links between the ICDs in PD and addiction in general, where abnormalities of the reward pathways including the ventral striatum, the cingulate gyrus and the orbitofrontal cortex. Steeves et al. [21] for example, have described results of a [11 C]raclopride positron emission tomography (PET) study assessing dopaminergic function during gambling in PD patients. Patients with PG demonstrated greater decreases in binding potential in the ventral striatum during gambling than controls, likely reflecting greater dopaminergic release. Findings are similar to those reported in subjects with chemical addictions. The presences of ICDs in some patients receiving low doses of dopaminergic drugs suggests that a genetic predisposition may
play a role in some cases, and genetic polymorphisms have been reported as possible contributors to ICD susceptibility in PD. Such genetic polymorphisms include the D3 dopamine receptor p.S9G and GRIN2B c.366C>G [22]. Recently, a variant of the serotonin 2A receptor gene (HTR2A) has been reported to be associated with ICDs in PD patients receiving dopamine replacement therapy, mainly those taking low doses of dopaminergic drugs [23]. For a review of potential mechanisms involved in ICDs in PD see recent reviews by Voon et al. and Djamshidian et al. [13,20]. 5. Management of ICDs in PD Minimizing the risk of developing ICDs through preventive strategies is an important first step. ICDs, analogous to dyskinesias, once fully developed can be difficult to manage. Accordingly, before starting or modifying dopaminergic treatment potential risk factors such as male sex, young age and a history of drug abuse should be taken into consideration. The management of ICDs in PD is complex and there are limited data to support any particular therapeutic strategy for the management of ICDs in PD. It is first important to identify subjects with ICDs. Brief screening tests may be employed. It is also important to involve the spouse or other family members in the management of ICDs and a psychiatric consultation may be indicated. The association of dopamine replacement therapy and ICDs suggests that modifications in dopaminergic treatment may be an effective strategy. Several reports, and everyday practice in
D. Vilas et al. / Parkinsonism and Related Disorders 18S1 (2012) S80–S84
the clinic, have documented improvement or ICDs resolution with discontinuation of DA therapy, reduction of DA dose or switching to a different DA [6,7]. Still long-term outcomes are not fully known, only one study suggests that reducing the dose of dopamine agonists is associated with improvement in ICD symptoms over time in PD patients [24]. The effectiveness of changing agonists is not entirely clear. Furthermore some patients do not experience remission of ICD symptoms with these strategies, suggesting a multifactorial etiology in some cases. In these cases long-acting dopaminergic drugs instead of short-acting ones have been suggested since they provide more continuous stimulation of DA receptors which may involve less risk than rapid, intermittent or pulsatile stimulation. There is no proof though that such strategy is effective. When tapering DA medications a stereotyped withdrawal syndrome (DAWS) that can lead to profound disability can occur in a subset of patients. Physicians should monitor patients closely. The symptoms of DAWS resemble those of other drug withdrawal syndromes and include anxiety, panic attacks, dysphoria, diaphoresis, fatigue, pain, orthostatic hypotension, and drug cravings. In a retrospective cohort study of 93 non-demented patients with PD, 19% developed DAWS. All subjects with DAWS had baseline DA-related ICDs [25]. When these recommendations fail, the clinical management of ICDs patients can be complicated. Atypical antipsychotics, antidepressants, mood stabilizers and various psychosocial interventions have been recommended [6,9]. The role of these various agents in the management of ICDs is not well established as the data are primarily case reports [13]. A recent controlled study of 17 PD patients suggested that amantadine may be efficacious for the treatment of PG in patients with PD [26]. Amantadine 200 mg/day abolished or reduced PG in all patients. However, in the DOMINION study amantadine use was associated with the presence of 1 or more ICDs and at an individual ICD level this association was observed for compulsive gambling, sexual behavior, and shopping [5]. This association also was present in multivariable analysis after controlling for possible confounding clinical variables, including DA use and levodopa dosage. Zonisamide (ZNS) has also been evaluated in PD patients with ICDs in an open non-randomized trial [27]. There was a marked reduction in the severity of impulsive behaviors and global impulsiveness and the drug was generally well tolerated. Adequately designed studies are needed to confirm these results. In addition to pharmacological treatment, psychosocial interventions also may have a role in the management of ICDs. Counseling and limiting access to money and medications in conjunction with alterations in dopaminergic treatment have benefited some patients but long-term follow-up data are needed. The efficacy of subthalamic nucleus (STN) stimulation for ICDs in PD has not been fully clarified. Published reports are contradictory. Some case series suggest that deep brain stimulation (DBS) of STN could improve ICDs by decreasing levodopa dose or discontinuation of DA [28]. However, caution should be emphasized as symptoms may worsen in the early postoperative period associated with hypomania/mania, and new-onset postoperative PG has been reported [29]. ICDs should not be considered an indication for DBS. 6. Conclusions ICDs are not uncommon neuropsychiatric disturbances in PD with a reported prevalence of up to 13.6% in some studies. These abnormal behaviors impair activities of daily living and have a negative impact on quality of life of patients and their families. Treatment with DAs is the main risk factor for developing ICDs. Stimulation of mesolimbic D3 receptors by DA is thought to underlie
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the development of these disorders. The DA effect seems to be a class effect and not specific for any particular DA. Levodopa can also induce ICDs but much less so than DAs. The management of ICDs in PD is complex. On the base of the documented association between dopaminergic treatments and ICDs, modifications in dopaminergic drug treatment are frequently necessary. Emerging data suggest that reducing the dose of dopamine agonists is associated with improvement in ICD symptoms over time in PD patients. Other possible approaches to altering dopamine replacement therapies in PD patients with ICDs include discontinuing or switching dopamine agonist therapies, reducing levodopa dose, and considering alternative therapies such as atypical antipsychotics or deep brain stimulation if motor symptoms become incapacitating after alteration of dopamine replacement therapy. Conflict of interests Eduardo Tolosa has received honoraria for lectures from Boehringer Ingelheim, Novartis, UCB, GSK, Solvay, Teva and Lundbeck and participated in advisory boards for Boehringer Ingelheim, Novartis, Teva and Solvay. Dolores Vila and Claustre Pont declare no conflicts of interest. References 1. Avanzi M, Baratti M, Cabrini S, Uber E, Brighetti G, Bonfa F. Prevalence of pathological gambling in patients with Parkinson’s disease. Mov Disord 2006;21:2068–72. 2. Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000;68:423–8. 3. Evans AH, Katzenschlager R, Paviour D, O’Sullivan JD, Appel S, Lawrence AD, et al. Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004;19:397–405. 4. Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006; 67:1254–7. 5. Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010;67:589–95. 6. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003;61:422–3. 7. Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahlskog JE. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005;62:1377–81. 8. Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 2007;64:1089–96. 9. Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson’s disease and multiple system atrophy. Parkinsonism Relat Disord 2005;11:381–6. 10. Weintraub D, Hoops S, Shea JA, Lyons KE, Pahwa R, Driver-Dunckley ED, et al. Validation of the questionnaire for impulsive-compulsive disorders in Parkinson’s disease. Mov Disord 2009;24:1461–7. 11. American Psychiatric Association, American Psychiatric Association Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV-TR, 4th edn. Washington, DC: American Psychiatric Association; 2000. 12. Molina JA, Sainz-Artiga MJ, Fraile A, Jimenez-Jimenez FJ, Villanueva C, OrtiPareja M, et al. Pathologic gambling in Parkinson’s disease: a behavioral manifestation of pharmacologic treatment? Mov Disord 2000;15:869–72. 13. Djamshidian A, Averbeck BB, Lees AJ, O’Sullivan SS. Clinical aspects of impulsive compulsive behaviours in Parkinson’s disease. J Neurol Sci 2011;310:183–8. 14. Kaplan HI SB, Grebb JA. Synopsis of Psychiatry, 7th edn. Baltimore: Williams & Wilkins; 1994. 15. Ferrara JM, Stacy M. Impulse-control disorders in Parkinson’s disease. CNS Spectr 2008;13:690–8. 16. Nirenberg MJ, Waters C. Compulsive eating and weight gain related to dopamine agonist use. Mov Disord 2006;21:524–9. 17. McElroy SL, Keck Jr PE, Pope Jr HG, Smith JM, Strakowski SM. Compulsive buying: a report of 20 cases. J Clin Psychiatry 1994;55:242–8. 18. Voon V, Sohr M, Lang AE, Potenza MN, Siderowf AD, Whetteckey J, et al. Impulse control disorders in Parkinson disease: a multicenter case–control study. Ann Neurol 2011;69:986–96. 19. Cornelius JR, Tippmann-Peikert M, Slocumb NL, Frerichs CF, Silber MH. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case–control study. Sleep 2010;33:81–7.
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20. Voon V, Mehta AR, Hallett M. Impulse control disorders in Parkinson’s disease: recent advances. Curr Opin Neurol 2011;24:324–30. 21. Steeves TD, Miyasaki J, Zurowski M, Lang AE, Pellecchia G, Van Eimeren T, et al. Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study. Brain 2009;132:1376–85. 22. Lee JY, Lee EK, Park SS, Lim JY, Kim HJ, Kim JS, et al. Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson’s disease. Mov Disord 2009;24:1803–10. 23. Lee JY, Jeon BS, Kim HJ, Park SS. Genetic variant of HTR2A associates with risk of impulse control and repetitive behaviors in Parkinson’s disease. Parkinsonism Relat Disord 2011 Sep 5 [Epub ahead of print]. doi: 10.1016/ j.parkreldis.2011.08.009. 24. Mamikonyan E, Siderowf AD, Duda JE, Potenza MN, Horn S, Stern MB, et al. Long-term follow-up of impulse control disorders in Parkinson’s disease. Mov Disord 2008;23:75–80.
25. Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010;67:58–63. 26. Thomas A, Bonanni L, Gambi F, Di Iorio A, Onofrj M. Pathological gambling in Parkinson disease is reduced by amantadine. Ann Neurol 2010;68:400–4. 27. Bermejo PE, Ruiz-Huete C, Anciones B. Zonisamide in managing impulse control disorders in Parkinson’s disease. J Neurol 2010;257:1682–5. 28. Ardouin C, Voon V, Worbe Y, Abouazar N, Czernecki V, Hosseini H, et al. Pathological gambling in Parkinson’s disease improves on chronic subthalamic nucleus stimulation. Mov Disord 2006;21:1941–6. 29. Lim SY, O’Sullivan SS, Kotschet K, Gallagher DA, Lacey C, Lawrence AD, et al. Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson’s disease. J Clin Neurosci 2009;16: 1148–52.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Impulse control disorders in Parkinson’s disease Dolores Vilas, Claustre Pont-Sunyer, Eduardo Tolosa* Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Institut Cl´ınic de Neuroci`encies, Hospital Cl´ınic de Barcelona, Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigaci´ on Biom´edica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain
article info
summary
Keywords: Parkinson’s disease Impulse control disorders Pathological gambling Binge eating Hypersexuality Dopamine agonists Compulsive behavior
Impulse control disorders (ICDs), a group of complex behavioral disorders, occur more commonly in Parkinson’s disease (PD) patients than in the general population, with a reported prevalence up to 13.6% in some studies. The most common ICDs reported are pathological gambling (PG), hypersexuality (HS), compulsive shopping and compulsive eating. More than a quarter of the patients with ICDs have 2 or more behavioral addictions. These abnormal behaviors impair activities of daily living and have a negative impact on quality of life of patients and their families. As with many other non motor symptoms in PD, ICDs are frequently under-reported by patients and caregivers and may be under-recognized by the treating physicians. Treatment with dopamine agonists (DA) is the main risk factor for developing ICDs, and stimulation of mesolimbic D3 receptors by DA is thought to underlie their development. The DA effect seems to be a class effect and not specific for any DA. Levodopa can also induce ICDs but much less so than the DAs. The management of ICDs in PD is complex. Modifications in dopaminergic drug treatment are frequently necessary. In some cases alternative therapies such as atypical antipsychotics, antidepressants or deep brain stimulation if motor symptoms become incapacitating after adjustment of dopamine replacement therapy should be considered. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction The term impulse control disorders (ICDs), defines a group of complex behavioral disorders characterized by failure to resist an impulse or temptation to perform an act that is harmful to the individual or to others. ICDs are thought to occur more commonly in PD patients than in the general population [1]. They have recently been the focus of considerable interest because of their association with the use of dopaminergic treatment, in particular dopamine agonists (DA), also because their presence has a significant negative impact on the quality of life of patients and their families. As with many other non motor symptoms in PD, ICDs are frequently under-reported by patients and caregivers and may be under-recognized by the treating physician. Other neuropsychiatric problems occurring in PD that may be related to ICD include dopamine dysregulation syndrome, an addictionlike state marked by excessive dopaminergic medication use; punding, a fascination with meaningless movements or activities and walkabout, characterized by excessive wandering [2,3]. 2. Epidemiology and risk factors Reported prevalence rates of ICDs in PD vary considerably ranging from 6% in PD patients not receiving DA and 17% among * Corresponding author. Eduardo Tolosa. Hospital Cl´ınic de Barcelona, Universitat de Barcelona, C/Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 932275785; fax: +34 932275783. E-mail address: [email protected] (E. Tolosa.) 1353-8020/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
those on DA treatment [4]. In one study assessing ICDs in 3090 PD patients, the DOMINION (Impulse Control Disorders in Parkinson’s Patients Treated With Pramipexole and Other Agents) cross-sectional study [5], the 6-month ICD prevalence was 13.6%. The most common ICDs reported were pathological gambling (PG), with a prevalence of 5%, hypersexuality (HS) (3.6%), compulsive shopping (5.7%) and compulsive eating (4.3%). More than a quarter of the patients with ICDs had 2 or more other behavioral addictions [5]. DA treatment is the primary risk factor for ICD development in PD. Several studies support this association [6,7] and it is also clear from a number of studies and everyday clinical practice that withdrawal of the offending DA typically results in marked improvement in the ICD. In the above mentioned DOMINION study DA treatment was associated with a 2- to 3.5-fold increased odds of having an ICD. ICDs frequency was similar for pramipexole and ropinirole (17.7% vs 15.5%), suggesting that the association between DA and ICDs is a drug class relationship. Additional variables independently associated with ICDs include male sex, mainly in HS and PG, younger age [5,8], being unmarried, current cigarette smoking, prior personal/family history of alcohol addiction or gambling problems, higher novelty seeking scores and impulse traits [8], a greater incidence of medication-induced hypomania/mania [8], an impaired planning [8], levodopa use [5], and amantadine (PG, HS and buying) [9]. An independent association between levodopa treatment and ICDs has been found [5]. In patients taking a DA, concurrent
D. Vilas et al. / Parkinsonism and Related Disorders 18S1 (2012) S80–S84
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Table 1 Diagnostic criteria for pathological gambling (PG) a A. Persistent and recurrent maladaptive gambling behavior as indicated by five or more of the following: 1.
Is preoccupied with gambling (eg preoccupied with reliving past gambling experiences, handicapping or planning the next venture, or thinking of ways to get money with which to gamble)
2.
Needs to gamble with increasing amounts of money in order to achieve the desired excitement
3.
Has repeated unsuccessful efforts to control, cut back or stop gambling
4.
Is restless or irritable when attempting to cut down or stop gambling
5.
Gambles as a way of escaping from problems or of relieving a dysphoric mood (e.g., feelings of helplessness, guilt, anxiety, depression)
6.
After losing money gambling, often returns another day to get even (“chasing” one’s losses)
7.
Lies to family members, therapist or others to conceal the extent of involvement with gambling
8.
Has committed illegal acts such as forgery, fraud, theft, or embezzlement to finance gambling
9.
Has jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling
10. Relies on others to provide money to relieve a desperate financial situation caused by gambling B. The gambling behavior is not better accounted for by a manic episode a
American Psychiatric Association, American Psychiatric Association Task Force on DSM-IV [11]. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed. Washington, DC: American Psychiatric Association; 2000.
levodopa use increased the odds of an ICD by approximately 50%. While the relation between ICDs and DA therapy is not dose-related, in the case of levodopa only high dosages were also associated with ICDs [5]. 3. Clinical manifestations ICDs are under-recognized in clinical practice. Most patients do not spontaneously offer information about ICD behaviors, either because of shame or because they do not understand that it is related to PD and its treatment. Most common ICDs in PD are PG, HS, compulsive shopping and compulsive eating. Early detection of ICDs is crucial and all patients should be questioned directly about such behavior. A useful tool to detect ICDs can be the Questionnaire for Impulsive-Compulsive Disorders I Parkinson’s Disease (QUIPCurrent-Short), a validated quick screening questionnaire that when positive should be followed by a clinical directed interview [10]. Pathological gambling (PG): PG is defined as an inability to resist gambling impulses despite severe repercussion on personal, family or professional life. PG is persistent and recurrent maladaptive gambling with tolerance or withdrawal, maladaptive behaviors and consequences (risking significant relationships or employment, turning to others for financial assistance) (Table 1). The more frequent PG modes are slot machines, lottery scratch cards and bingo. PG occurs more frequently during the “on” period [12]. Cultural differences are thought to have a significant impact on prevalence rates and in Far Eastern countries PG prevalence is higher than in Asia [13]. Voon et al. [8] studied the factors associated with dopaminergic drug-related PG in PD. When compared with patients without, those with PG had younger age of onset, higher novelty seeking, a greater incidence of medicationinduced hypomania/mania, an impaired planning and personal/ family history of alcohol use disorders. Hypersexual behavior (HS): HS typically entails an increase in premorbid sexual activities as well as an increase in the variety of sexual behaviors. In patients with HS the need for sexual behavior consumes so much money, time, concentration and energy that the patient describes himself as out of control. Intrusive unwanted paraphiliac thoughts prevent concentration on other life demands and are the source of anxiety. Orgasm does not produce satiety in the way it typically does for age mates [14]. HS occurs predominantly in males with relatively early-onset PD, patients with prior history of tobacco or alcohol addiction, and can be associated to other inappropriate behavior or psychotic
symptoms [9,14]. HS is associated to treatment with DA alone (including apomorphine) or adjunctive to levodopa, selegiline and amantadine [9] although this last relation is controversial, as discussed below. Compulsive shopping: This is defined as a maladaptive preoccupation with buying or shopping, or maladaptive buying or shopping impulses, frequent buying of more than can be afforded, items that are not needed, or shopping for longer periods of time than intended. The buying impulses cause marked distress, are time-consuming, interfere significantly with social or occupational functioning or result in financial problems [15]. Compulsive eating: Most frequent clinical presentations are an increase in the food intake dramatically in the setting of new-onset food cravings for carbohydrates, sweets, and/or salty foods; a newonset binge eating, compulsively eating both larger portions of food at mealtimes and more frequent snacks throughout the day and tendency to compulsively snack or binge in the middle of the night. The consequence of this is an unintentional and undesired increase in the weight and body mass index [16]. Compulsive shopping and binge eating are more common in female PD patients whereas compulsive sexual behaviors have been more frequently reported in males [4,5] (Table 2). Other symptoms associated with ICDs: Other neuropsychological disturbances such as novelty seeking and impulsivity have been associated with ICDs in PD. Their presence may vary depending on ICD type. Pathological gambling and compulsive shopping, for example, share similarities in higher novelty seeking and impulsive choice as compared with hypersexuality and binge eating. In another study, high scores in depression, anxiety and obsessivecompulsive symptoms have been reported in ICD PD patients [18]. Motor fluctuations are more common in patients with ICDs, and early and severe dyskinesias (within the first 12–24 months) have been considered a warning sign for the development of dopamine dysregulation syndrome or ICDs [13]. 4. Pathophysiology of ICDs A role for dopaminergic stimulation in the development of ICDs has been confirmed by several lines of evidence. Underlying pathological changes occurring in PD probably do not play a major role since ICDs are known to occur in other conditions treated with DA such as restless legs syndrome [19]. While dopaminergic mechanisms are important, not all patients taking dopaminergic drugs develop these behaviors and ICDs probably
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Table 2 Proposed criteria for compulsive buying and pathological hypersexuality Proposed criteria for compulsive buying a A.
Maladaptive preoccupation with buying or shopping, or maladaptive buying or shopping impulses or behavior, as indicated by at least one of the following: 1. Frequent preoccupation with buying or impulses to buy that is/are experienced as irresistible, intrusive and/or senseless 2. Frequent buying of more than can be afforded, frequent buying of items that are not needed, or shopping for longer periods of time than intended
B.
The buying preoccupations, impulses, or behaviors cause marked distress, are time-consuming, significantly interfere with social or occupational functioning or result in financial problems (eg, indebtedness or bankruptcy)
C.
The excessive buying or shopping behavior does not occur exclusively during periods of hypomania or mania
Proposed diagnostic criteria for pathological hypersexuality b A
The sexual thoughts or behaviors are excessive or an atypical change from baseline marked by one or more of the following: 1. Maladaptive preoccupation with sexual thoughts 2. Inappropriately or excessively requesting sex from spouse or partner 3. Habitual promiscuity 4. Compulsive masturbation 5. Telephone sex lines or pornography 6. Paraphilias
B.
The behavior must have persisted for at least one month
C.
The behavior causes at least one of the following: 1. Marked distress 2. Attempts to control thoughts or behavior are unsuccessful or result in marked anxiety or distress 3. Are time consuming 4. Interfere significantly with social or occupational functioning
D. The behavior does not occur exclusively during periods of hypomania or mania E. a b
If all criteria except C are fulfilled, the disorder is subsyndromal McElroy SL, Keck Jr PE, Pope Jr HG, Smith JM, Strakowski SM [17]. Compulsive buying: a report of 20 cases. J Clin Psychiatry 1994;55:242–8. Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. [4] Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006;67:1254–7.
arise from a complex interaction between pharmacologic and nonpharmacologic predisposing factors like young age, male sex and certain personality traits [20]. It has been hypothesized that treating the motor symptoms associated to the dorsal motor striatal dopaminergic deficiency, may result in an “overdose” in the cognitive and limbic pathways of the ventral corticostriatal circuitry resulting in ICDs [20]. These central dopaminergic pathways (mesolimbic and mesocortical) are intricately linked to the brain’s reward system and are implicated in various states of addiction. Activation of these systems is thought to be mediated by stimulation of D3 receptors which are predominantly expressed in ventral striatum and mediate reward, emotional and cognitive processes. Non-ergot DA currently used in PD has a high affinity for the D2/D3 receptors compared to D1 receptors. Several functional imaging studies strengthen the links between the ICDs in PD and addiction in general, where abnormalities of the reward pathways including the ventral striatum, the cingulate gyrus and the orbitofrontal cortex. Steeves et al. [21] for example, have described results of a [11 C]raclopride positron emission tomography (PET) study assessing dopaminergic function during gambling in PD patients. Patients with PG demonstrated greater decreases in binding potential in the ventral striatum during gambling than controls, likely reflecting greater dopaminergic release. Findings are similar to those reported in subjects with chemical addictions. The presences of ICDs in some patients receiving low doses of dopaminergic drugs suggests that a genetic predisposition may
play a role in some cases, and genetic polymorphisms have been reported as possible contributors to ICD susceptibility in PD. Such genetic polymorphisms include the D3 dopamine receptor p.S9G and GRIN2B c.366C>G [22]. Recently, a variant of the serotonin 2A receptor gene (HTR2A) has been reported to be associated with ICDs in PD patients receiving dopamine replacement therapy, mainly those taking low doses of dopaminergic drugs [23]. For a review of potential mechanisms involved in ICDs in PD see recent reviews by Voon et al. and Djamshidian et al. [13,20]. 5. Management of ICDs in PD Minimizing the risk of developing ICDs through preventive strategies is an important first step. ICDs, analogous to dyskinesias, once fully developed can be difficult to manage. Accordingly, before starting or modifying dopaminergic treatment potential risk factors such as male sex, young age and a history of drug abuse should be taken into consideration. The management of ICDs in PD is complex and there are limited data to support any particular therapeutic strategy for the management of ICDs in PD. It is first important to identify subjects with ICDs. Brief screening tests may be employed. It is also important to involve the spouse or other family members in the management of ICDs and a psychiatric consultation may be indicated. The association of dopamine replacement therapy and ICDs suggests that modifications in dopaminergic treatment may be an effective strategy. Several reports, and everyday practice in
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the clinic, have documented improvement or ICDs resolution with discontinuation of DA therapy, reduction of DA dose or switching to a different DA [6,7]. Still long-term outcomes are not fully known, only one study suggests that reducing the dose of dopamine agonists is associated with improvement in ICD symptoms over time in PD patients [24]. The effectiveness of changing agonists is not entirely clear. Furthermore some patients do not experience remission of ICD symptoms with these strategies, suggesting a multifactorial etiology in some cases. In these cases long-acting dopaminergic drugs instead of short-acting ones have been suggested since they provide more continuous stimulation of DA receptors which may involve less risk than rapid, intermittent or pulsatile stimulation. There is no proof though that such strategy is effective. When tapering DA medications a stereotyped withdrawal syndrome (DAWS) that can lead to profound disability can occur in a subset of patients. Physicians should monitor patients closely. The symptoms of DAWS resemble those of other drug withdrawal syndromes and include anxiety, panic attacks, dysphoria, diaphoresis, fatigue, pain, orthostatic hypotension, and drug cravings. In a retrospective cohort study of 93 non-demented patients with PD, 19% developed DAWS. All subjects with DAWS had baseline DA-related ICDs [25]. When these recommendations fail, the clinical management of ICDs patients can be complicated. Atypical antipsychotics, antidepressants, mood stabilizers and various psychosocial interventions have been recommended [6,9]. The role of these various agents in the management of ICDs is not well established as the data are primarily case reports [13]. A recent controlled study of 17 PD patients suggested that amantadine may be efficacious for the treatment of PG in patients with PD [26]. Amantadine 200 mg/day abolished or reduced PG in all patients. However, in the DOMINION study amantadine use was associated with the presence of 1 or more ICDs and at an individual ICD level this association was observed for compulsive gambling, sexual behavior, and shopping [5]. This association also was present in multivariable analysis after controlling for possible confounding clinical variables, including DA use and levodopa dosage. Zonisamide (ZNS) has also been evaluated in PD patients with ICDs in an open non-randomized trial [27]. There was a marked reduction in the severity of impulsive behaviors and global impulsiveness and the drug was generally well tolerated. Adequately designed studies are needed to confirm these results. In addition to pharmacological treatment, psychosocial interventions also may have a role in the management of ICDs. Counseling and limiting access to money and medications in conjunction with alterations in dopaminergic treatment have benefited some patients but long-term follow-up data are needed. The efficacy of subthalamic nucleus (STN) stimulation for ICDs in PD has not been fully clarified. Published reports are contradictory. Some case series suggest that deep brain stimulation (DBS) of STN could improve ICDs by decreasing levodopa dose or discontinuation of DA [28]. However, caution should be emphasized as symptoms may worsen in the early postoperative period associated with hypomania/mania, and new-onset postoperative PG has been reported [29]. ICDs should not be considered an indication for DBS. 6. Conclusions ICDs are not uncommon neuropsychiatric disturbances in PD with a reported prevalence of up to 13.6% in some studies. These abnormal behaviors impair activities of daily living and have a negative impact on quality of life of patients and their families. Treatment with DAs is the main risk factor for developing ICDs. Stimulation of mesolimbic D3 receptors by DA is thought to underlie
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the development of these disorders. The DA effect seems to be a class effect and not specific for any particular DA. Levodopa can also induce ICDs but much less so than DAs. The management of ICDs in PD is complex. On the base of the documented association between dopaminergic treatments and ICDs, modifications in dopaminergic drug treatment are frequently necessary. Emerging data suggest that reducing the dose of dopamine agonists is associated with improvement in ICD symptoms over time in PD patients. Other possible approaches to altering dopamine replacement therapies in PD patients with ICDs include discontinuing or switching dopamine agonist therapies, reducing levodopa dose, and considering alternative therapies such as atypical antipsychotics or deep brain stimulation if motor symptoms become incapacitating after alteration of dopamine replacement therapy. Conflict of interests Eduardo Tolosa has received honoraria for lectures from Boehringer Ingelheim, Novartis, UCB, GSK, Solvay, Teva and Lundbeck and participated in advisory boards for Boehringer Ingelheim, Novartis, Teva and Solvay. Dolores Vila and Claustre Pont declare no conflicts of interest. References 1. Avanzi M, Baratti M, Cabrini S, Uber E, Brighetti G, Bonfa F. Prevalence of pathological gambling in patients with Parkinson’s disease. Mov Disord 2006;21:2068–72. 2. Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000;68:423–8. 3. Evans AH, Katzenschlager R, Paviour D, O’Sullivan JD, Appel S, Lawrence AD, et al. Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord 2004;19:397–405. 4. Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology 2006; 67:1254–7. 5. Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010;67:589–95. 6. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003;61:422–3. 7. Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahlskog JE. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005;62:1377–81. 8. Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol 2007;64:1089–96. 9. Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson’s disease and multiple system atrophy. Parkinsonism Relat Disord 2005;11:381–6. 10. Weintraub D, Hoops S, Shea JA, Lyons KE, Pahwa R, Driver-Dunckley ED, et al. Validation of the questionnaire for impulsive-compulsive disorders in Parkinson’s disease. Mov Disord 2009;24:1461–7. 11. American Psychiatric Association, American Psychiatric Association Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV-TR, 4th edn. Washington, DC: American Psychiatric Association; 2000. 12. Molina JA, Sainz-Artiga MJ, Fraile A, Jimenez-Jimenez FJ, Villanueva C, OrtiPareja M, et al. Pathologic gambling in Parkinson’s disease: a behavioral manifestation of pharmacologic treatment? Mov Disord 2000;15:869–72. 13. Djamshidian A, Averbeck BB, Lees AJ, O’Sullivan SS. Clinical aspects of impulsive compulsive behaviours in Parkinson’s disease. J Neurol Sci 2011;310:183–8. 14. Kaplan HI SB, Grebb JA. Synopsis of Psychiatry, 7th edn. Baltimore: Williams & Wilkins; 1994. 15. Ferrara JM, Stacy M. Impulse-control disorders in Parkinson’s disease. CNS Spectr 2008;13:690–8. 16. Nirenberg MJ, Waters C. Compulsive eating and weight gain related to dopamine agonist use. Mov Disord 2006;21:524–9. 17. McElroy SL, Keck Jr PE, Pope Jr HG, Smith JM, Strakowski SM. Compulsive buying: a report of 20 cases. J Clin Psychiatry 1994;55:242–8. 18. Voon V, Sohr M, Lang AE, Potenza MN, Siderowf AD, Whetteckey J, et al. Impulse control disorders in Parkinson disease: a multicenter case–control study. Ann Neurol 2011;69:986–96. 19. Cornelius JR, Tippmann-Peikert M, Slocumb NL, Frerichs CF, Silber MH. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case–control study. Sleep 2010;33:81–7.
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D. Vilas et al. / Parkinsonism and Related Disorders 18S1 (2012) S80–S84
20. Voon V, Mehta AR, Hallett M. Impulse control disorders in Parkinson’s disease: recent advances. Curr Opin Neurol 2011;24:324–30. 21. Steeves TD, Miyasaki J, Zurowski M, Lang AE, Pellecchia G, Van Eimeren T, et al. Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study. Brain 2009;132:1376–85. 22. Lee JY, Lee EK, Park SS, Lim JY, Kim HJ, Kim JS, et al. Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson’s disease. Mov Disord 2009;24:1803–10. 23. Lee JY, Jeon BS, Kim HJ, Park SS. Genetic variant of HTR2A associates with risk of impulse control and repetitive behaviors in Parkinson’s disease. Parkinsonism Relat Disord 2011 Sep 5 [Epub ahead of print]. doi: 10.1016/ j.parkreldis.2011.08.009. 24. Mamikonyan E, Siderowf AD, Duda JE, Potenza MN, Horn S, Stern MB, et al. Long-term follow-up of impulse control disorders in Parkinson’s disease. Mov Disord 2008;23:75–80.
25. Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010;67:58–63. 26. Thomas A, Bonanni L, Gambi F, Di Iorio A, Onofrj M. Pathological gambling in Parkinson disease is reduced by amantadine. Ann Neurol 2010;68:400–4. 27. Bermejo PE, Ruiz-Huete C, Anciones B. Zonisamide in managing impulse control disorders in Parkinson’s disease. J Neurol 2010;257:1682–5. 28. Ardouin C, Voon V, Worbe Y, Abouazar N, Czernecki V, Hosseini H, et al. Pathological gambling in Parkinson’s disease improves on chronic subthalamic nucleus stimulation. Mov Disord 2006;21:1941–6. 29. Lim SY, O’Sullivan SS, Kotschet K, Gallagher DA, Lacey C, Lawrence AD, et al. Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson’s disease. J Clin Neurosci 2009;16: 1148–52.