REVIEW
Clinical Spectrum of Impulse Control Disorders in Parkinson’s Disease Daniel Weintraub, MD,1,2* Anthony S. David, FRCP, FRCPsych, MD, MSc,3 Andrew H. Evans, FRACP,4 Jon E. Grant, MD, MPH,5 and Mark Stacy, MD6 1
Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 2 Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA 3 Institute of Psychiatry, King’s College London, London, United Kingdom 4 Department of Neurology, the Royal Melbourne Hospital, Parkville, Australia 5 Department of Psychiatry, University of Chicago School of Medicine, Chicago, Illinois, USA 6 Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
ABSTRACT:
Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson’s disease (PD). Other impulsive-compulsive behaviors (ICBs) have been described in PD, including punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive PD medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apo-
Clinical Presentation ICDs are defined as behaviors that are performed repetitively, excessively, and compulsively to an extent that interferes in major areas of life functioning.1 ICDs have been conceptualized as “behavioral” addictions2,3 because of their similarities to drug addiction, with which they share many of the same risk factors, clinical features, cognitive changes, neurobiological substrates, and treatment approaches. In recognition of this shift in thinking, gambling disorder was moved from the category of “Impulse Control Disorders” to the new category of “Substance-Related and Addictive
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*Correspondence to: Dr. Daniel Weintraub, Perelman School of Medicine, University of Pennsylvania, 3615 Chestnut Street, #330, Philadelphia, PA 19104-2676, USA; [email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 12 May 2014; Revised: 16 July 2014; Accepted: 11 August 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26016
morphine and levodopa. Possible risk factors for ICDs include male sex, younger age and younger age at PD onset, a pre-PD history of ICDs, and a personal or family history of substance abuse, bipolar disorder, or gambling problems. Given the paucity of treatment options and potentially serious consequences, it is critical for PD patients to be monitored closely for development of ICDs C 2014 International Paras part of routine clinical care. V kinson and Movement Disorder Society
K e y W o r d s : Parkinson’s disease; impulse control disorder; dopamine agonists
Disorders” in the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).4 Others have argued for a broader conceptual framework, which places ICDs and related behaviors within “disinhibitory psychopathologies.”5 In recent years, there has been increasing evidence and awareness that PD patients are at increased risk of developing one or more of four major ICDs, which are compulsive or pathological gambling, buying, sexual, and eating behaviors.6 These behaviors range widely in severity, but can lead to devastating consequences, including financial ruin, divorce, loss of employment, and increased health risks. In general, ICDs are associated with greater functional impairment,7 decreased quality of life,8 and increased caregiver burden,9 Other ICBs have been linked to the use of dopamine replacement therapy (DRT) in PD. One is DDS (previously referred to as hedonic homeostatic dysregulation),10 a drug addiction-like state marked by self-medication with inappropriately high doses of dopaminergic medications, particularly L-dopa and high-potency, short-acting DAs (e.g., subcutaneous
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apomorphine). Several closely related phenomena have also been identified in PD, including: (1) punding— repetitive, purposeless behaviors, characterized by an intense preoccupation with specific items or activities (e.g., collecting, arranging, or taking apart objects)11; (2) hobbyism—similar, but higher-level repetitive behaviors (e.g., excessive exercise, Internet use, reading, art work, and work on projects); (3) walkabouts—consisting of excessive, aimless wandering10; and (4) hoarding—the acquisition of, and failure to discard, a large number of items with little or no objective value, which, in some cases, can lead to unsafe or unsanitary living conditions.12 It is not fully understood how these other behaviors are similar versus different in terms of their neural substrate compared with ICDs. Of these disorders, gambling disorder, binge eating disorder (BED), and hoarding disorder are included in DSM-5, but there are no formal DSM-5 criteria for compulsive buying or sexual behavior. For convenience, the term ICD has been broadly applied to cover the four major ICDs that have been reported to occur in PD patients. Multiple descriptive terms have been used to describe the clinical presentation of impulsive and compulsive behaviors in PD. The behaviors have both impulsive (lack of forethought or consideration of consequences) and compulsive (repetitious behaviors with a lack of self-control) aspects. In DSM-5, gambling disorder and related disorders are defined as a failure to resist an impulse, drive, or temptation to perform a typically pleasurable activity that is ultimately harmful to the person or to others because of its excessive nature. Although not the focus of formal research to date, it has been reported that the increased drive and motivation to engage in goaldirected behaviors can be beneficial for some PD patients with disease-related impairments (e.g., an increased interest in sex for a PD patient who previously had a decreased sex drive or an increased appetite in a PD patient who had lost weight). These behaviors only become a disorder when they become harmful to the patient in some way or interfere with daily functioning or social relationships. In such cases, there is also usually a deviation from premorbid behavior.
Frequency Despite high prevalence rates in the general population13 and in psychiatric cohorts,14 ICDs have been relatively understudied from an epidemiological viewpoint. Arguably, the best data on the prevalence of ICDs exist for gambling disorder. Prevalence rates for gambling disorder in the general population from national surveys vary worldwide. For example, past 12-month rates of problem gambling range from
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0.2% in Norway to 5.3% in Hong Kong. Reported rates of gambling disorder in the United States range from 0.4% to 1.1% of adults.15 The prevalence rates of the other ICDs in the general population remain unclear. A national study in the United States estimated the prevalence of compulsive buying at 5.8%.16 Although limited information is available on the true prevalence of compulsive sexual behavior (CSB), it is estimated to affect 3% to 6% of adults.17 BED, also referred to in the literature as pathological overeating, occurs in approximately 2% of the general U.S. population.18 The few studies done to date suggest that ICDs may be more common, overall, in treated PD patients, compared to healthy controls (HCs),19,20 or similarly disabled non-PD patients,21,22 although one recent study suggested otherwise.23 Determining the frequency of impulse control symptoms in de novo, untreated PD patients would help answer the question of whether PD itself confers an increased (or indeed decreased) risk for experiencing such symptoms. In the first published study assessing newly diagnosed, untreated PD patients, 18% screened positive for impulse control symptoms, a number similar to HCs.24 In a subsequent study analyzing data from the Parkinson’s Progression Markers Initiative of 311 newly, untreated PD patients and HCs, PD patients were not more likely to report symptoms of any ICD or related behavior. Thus, it appears, from these studies, that PD itself does not confer an increased risk for development of impulse control or related behavior symptoms in the absence of treatment. Given that approximately 20% of newly diagnosed PD patients report some symptoms, long-term follow-up is needed to determine whether such patients are at increased risk for ICD development, in relation to appropriately matched controls. An allied question is whether there is a typical “PD personality” that predates the disorder.25 One large, prospective study from the Mayo Clinic followed a cohort of 7,216 subjects rated on a self-report personality inventory from the 1960s.26 Those who screened positive for PD 40 years later were found to show no differences from the remainder on any traits. However, those with more broadly defined parkinsonism showed a slight increase in introverted personality (i.e., constraint; odds ratio: 1.39; 95% confidence interval: 1.06-1.84; P 5 0.02). For PD patients, initial cross-sectional studies that used formal assessments of ICDs reported an estimated prevalence of 1.7% to 7.0% for compulsive gambling, 3.5% for CSB,27 and 0.4% to 3.0% for compulsive buying.28-31 Compulsive or binge eating was also reported in PD, but its prevalence was not initially reported.10,32 In the DOMINION study,33 which included 3,090 medicated PD patients from 46 movement disorder centers in the United States and
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FIG. 1. Correlates and potential risk factors for ICDs and related behaviors.
Canada, one or more ICD was identified in 13.6% of patients (gambling in 5.0%, CSB in 3.5%, compulsive buying in 5.7%, and BED in 4.3%); 3.9% of participants had two or more ICDs. Recent research has suggested that up to 25% of patients treated with a minimally therapeutic dose of a DA may experience an ICD.34 Cultural factors may influence prevalence of ICDs in PD, but various studies lack uniformity. In four Asian studies, similar or high prevalence findings were reported in two (South Korea and Malaysia),35,36 and two others (Taiwan and China) reported lower overall prevalence rates than that reported in the DOMINION study.37,38 Other studies have suggested similar PD ICD frequencies in Finland,39 Denmark,40 Brazil,41 India,42 Germany,43 Spain,44 Russia,45 Australia,8 the UK,46 and Mexico.47 DDS and other ICBs in PD have not been as well studied as ICDs. Fifteen cases were reported in the original description of DDS in PD,10 but a crosssectional or cumulative prevalence rate was not reported. Regarding punding, in one series examining PD patients on higher L-dopa equivalent daily dosages, 14% met criteria for punding11; in contrast, another larger study of unselected PD patients reported a prev-
alence rate of only 1.4%.48 It is important to note that there are no universally accepted diagnostic criteria for punding, as well as for certain ICDs (e.g., hypersexuality), which may help explain the variation in prevalence rates reported for many of these disorders. Nearly all research to date examining the frequency and correlates of ICDs and similar behaviors in PD has been cross-sectional, so prospective studies are needed to determine incidence rates. In a recent prospective cohort study of DA-treated patients, 39% without an ICD at baseline developed an ICD over a 4-year period, with a median duration of ICD onset from initiation of DA of 23 months.49 Presence of motor complications, caffeine use, lifetime cigarette smoking, and higher peak DA doses were predictors of future ICD development.
Correlates and risk factors (Figure 1) Early case reports and cross-sectional studies suggested an association between the use of DRT, and DAs in particular, with the development of ICDs in PD. In the DOMINION study, ICDs were more
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common in patients treated with a DA (17.1%) than in patients not taking a DA (6.9%). DA treatment in PD was associated with 2- to 3.5-fold increased odds of having an ICD. The prevalence of ICDs was comparable in subjects treated with pramipexole and ropinirole, the two most commonly used DAs (17.7% and 15.5%, respectively), and there is no clear evidence for differential risk within the DA class. Use of Ldopa,33 especially at higher dosages, and of amantadine (used in PD mainly for the treatment of dyskinesias)50 were also associated with ICDs in this study, but to a lesser extent than DA treatment. Though some reports have shown a dose response between DA use and ICDs, such a relationship was not observed in this study. The association between DA use and ICDs is also supported by case reporting of ICDs occurring with DA treatment in other clinical populations (e.g., restless legs syndrome51 and fibromyalgia52). There has not been any systematic research to see how alternate formulations or delivery systems for DAs (e.g., long-acting agents delivered orally or transdermally) or other medications that enhance dopaminergic function (e.g., catechol O-methyltransferase inhibitors) modify ICD risk. In recent preliminary research, rasagiline treatment in PD has also been associated with a 2.12- to 3.74-fold increased odds of having an ICD on uni-44 or multivariate analysis.21 Prospective research examining incident ICD cases has been very limited. In a recent study, 46 DAtreated PD patients without an ICD at baseline were followed longitudinally (for variable time periods), and 39% of patients developed an ICD over time.49 The median time from DA initiation to onset of ICD symptoms was 23 months (range, 3-114). Patients who developed an ICD had great prevalence of motor complications and caffeine use at baseline, higher lifetime prevalence of cigarette smoking, and higher peak DA doses. Additional variables associated with ICDs in different studies include: (1) a personal or familial history of alcoholism or gambling; (2) impulsive or noveltyseeking traits; (3) younger age; (4) male sex; (5) early onset of PD; (6) being unmarried; and (7) past or current cigarette smoking.6;33,41 In the DOMINION study, another correlate of having an ICD was living in the United States compared with Canada, suggesting that environmental factors may play a role in ICD development or reporting in PD. Though total ICD frequency was similar for men and women, there were notable sex differences in the frequency of specific ICDs, with CSB more common in males and both compulsive buying and binge eating were more prevalent in women. The gender differences in prevalence rates for the various ICDs in PD mirror what is reported for the general population. ICDs have been reported to be less common in PD patients with
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dementia,53 but this may be an artifact of DA prescribing practices. Although DDS has been closely associated with the use of high-potency, shorter-acting dopaminergic medications, such as L-dopa and injectable apomorphine, the relationship between punding and specific dopaminergic medications remains unclear.
Neuropsychiatric Abnormalities Other psychiatric disorders or behaviors that share features of ICDs have been reported to occur in PD. For instance, obsessive-compulsive disorder (OCD), an anxiety disorder characterized by the repetition of nonpleasurable, nonharmful behaviors (e.g., checking or counting) to reduce anxiety, may occur at an increased frequency in PD, although it has not been reported in association with PD medications.54 It is important to note that the types of impulsive and compulsive behaviors previously described also do not occur in the context of obsessive-compulsive personality disorder, a lifelong personality-style characterized by preoccupation with orderliness, perfectionism, and control that may be linked to PD independently of disease duration and medications.55 For PD patients with an ICD, a large case-control study found that ICD patients drawn from the DOMINION study reported significantly more depression, state and trait anxiety, OCD, novelty seeking, and impulsivity symptoms.7 Other studies have also reported an association between ICD and depression symptoms8,28,39,40 and anxiety.46 ICD patients report an increased prevalence of sleep disturbances, including worse sleep efficiency, daytime sleepiness, and RLS symptoms,56,57 and another found increased anhedonia in ICD patients.58 It has been argued that apathy and ICDs are at opposite ends of a hypodopaminergic-hyperdopaminergic behavioral continuum,59,60 with experimental evidence coming from a DBS study in which ICD patients experienced improvement in ICD behaviors, but worsening in apathy symptoms when DA treatment was discontinued post-DBS.61 The apathy and other behavioral symptoms experienced by these patients has been conceptualized as a stereotyped dopamine agonist withdrawal syndrome, experienced by many PD ICD patients who discontinue DA treatment, and which shares the psychiatric and physical features of the withdrawal symptoms experience in the context of some substance abuse disorders.62 However, both impulsivity and apathy can be conceptualized as dysexecutive symptoms and frequently co-occur in other neuropsychiatric disorders. Similarly, what may appear to be apathy may be a behavioral response to an ICD or a facet of depression or cognitive impairment. Thus, ICDs in PD are associated with multiple
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psychiatric symptoms, including affective and anxiety symptoms, and elevated obsessionality, novelty seeking, impulsivity, and sleep disturbances, although the direction of causality behind these associations is not always clear. Patients with DDS typically develop cyclical mood disorders (i.e., mood elevation or hypomania secondary to DRT use, followed by a dysphoric affective state when medications are withdrawn or reduced).10,63 When in an elevated state, patients may be excessively involved in pleasurable activities that have a high potential for painful consequences.10 This syndrome is distinct from ICDs in some ways, given that few PD patients with an ICD are reported either to compulsively use their PD medications or to experience mood elevation, and many patients with DDS do not have a comorbid ICD.64 However, disentangling reckless behavior in the context of elevated mood and actual ICD symptoms requires skilled neuropsychiatric evaluation.
Assessment There is evidence that ICD behaviors in PD patients continue to be under-recognized and undermanaged in clinical practicel.8,30,65 Ongoing under-recognition could be, in part, a result of the fact that routine screening is not common; in addition, patients may not report symptoms either because of embarrassment, limited awareness of their behaviors, or not suspecting a possible association with their PD medications. Interestingly, a recent study found that ICD severity in PD patients was correlated with alexithymia, specifically, difficulty describing feelings, as opposed to externally oriented thinking,66 which might help explain under-reporting of ICD symptoms by patients. An ongoing issue is that the agreement between patient and informant reporting of symptoms is not high,36 with no clear direction for the mismatches in reporting,67 although patient under-reporting is likely more common.68 Several screening instruments have been used to assess for ICD symptoms in PD. One is the Minnesota Impulsive Disorders Interview,69 which queries for some of the ICDs reported to occur in PD. Another is the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP),70 and a rating scale version of this instrument exists (QUIP-RS),71 both of which can be self- or rater-administered and have been translated into numerous languages. In addition, the Dopamine Dysregulation Syndrome-Patient and Caregiver Inventory (DDS-PC) was developed as a screening questionnaire to assess the presence of a range of ICBs in PD.72 The Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDSUPDRS) includes a single item for DDS, which covers
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excessive gambling, sexual behaviors, hobbyism, punding, and DDS,73 although research suggests that this single question is not valid as an assessment tool for ICDs.74 The Structured Clinical Interview for Obsessive-Compulsive Spectrum Disorders (SCIDOCSD)75 is a structured interview constructed on the basis of the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I) and has been used in PD to determine the presence of a range of ICBs.8 The Ardouin scale, administered as a semistructured interview, includes 21 items that assess general psychological state, including depressive mood, hypomanic or manic mood, anxiety, irritability, hyperemotivity, psychotic symptoms, apathy, nonmotor fluctuations, and ICD and related behavior symptoms. These are thought to represent the spectrum of hyper- and hypodopaminergic behaviors and be sensitive to dopaminergic medication in PD.59 The scale is sensitive to change in symptom severity.76 Finally, the Parkinson’s Impulse Control Scale for the rating of severity of ICD behaviors in PD is a new, clinician-rated severity scale for the assessment of syndromal and subsyndromal forms of these behaviors, which has good test-retest reliability and sensitivity to change.77 The scale is interview based and requires a degree of clinical knowledge/ training for reliable administration and scoring. A manual will be available to accompany the scale.
Conclusions Mounting data suggest that PD medications, and DAs in particular, are associated with the development of ICDs in PD patients. Susceptibility to ICDs has also been associated with specific demographic and clinical characteristics. As in the general population, ICDs and other addictive behaviors can have serious personal, familial, psychosocial, financial, and medical consequences. In addition, ICDs in PD may become permanent, often because affected patients may be unable to discontinue DA therapy as a result of motor worsening or DAWS, and even DBS as a treatment option may not be free of risk. Given the numerous adverse consequences of ICDs and related behaviors, patient and caregiver education is crucial, as is routine monitoring for their development.
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Christenson GA, Faber RJ, deZwaan M. Compulsive buying: descriptive characteristics and psychiatric comorbidity. J Clin Psychiatry 1994;55:5-11.
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Pettorruso M, Martinotti G, Fasano A, et al. Anhedonia in Parkinson’s disease patients with and without pathological gambling: a case-control study. Psychiatry Res 2014;215:448-452.
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Weintraub D, Stewart S, Shea JA, et al. Validation of the Questionnaire for Impulsive-Compulsive Behaviors in Parkinson’s Disease (QUIP). Mov Disord 2009;24:1461-1467.
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Ardouin C, Chereau I, Llorca P, et al. Assessment of hyper- and hypodopaminergic behaviors in Parkinson’s disease. Rev Neurol 2009;175:845-856.
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Weintraub D, Mamikonyan E, Papay K, et al. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale. Mov Disord 2012;27:242-247.
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Leroi I, Andrews M, McDonald K, et al. Apathy and impulse control disorders in Parkinson’s disease: a direct comparison. Parkinsonism Relat Disord 2012;18:198-203.
72.
Cabrini S, Baratti M, Bonf a F, Cabri G, Uber E, Avanzi M. Preliminary evaluation of the DDS-PC inventory: a new tool to assess impulsive-compulsive behaviours associated to dopamine replacement therapy in Parkinson’s disease. Neurol Sci 2009;30:307-313.
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Thobois S, Ardouin C, Lhommee E, et al. Non-motor dopamine withdrawal syndrome after surgery for Parkinson’s disease: predictors and underlying mesolimbic denervation. Brain 2010;133:11111127.
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Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and climimetric testing results. Mov Disord 2008;23:2129-2170.
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Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010;67:58-63.
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Goetz CG, Tilley BC, Stebbins GT. Dopamine dysregulation syndrome item from the MDS-UPDRS. Mov Disord 2012;27:166.
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Maier F, Merkl J, Ellereit A, et al. Hypomania and mania related to dopamine replacement therapy in Parkinson’s disease. Parkinsonism Relat Disord 2014;20:421-427.
75.
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Gallagher DA, O’Sullivan SS, Evans AH, Lees AJ, Schrag A. Pathological gambling in Parkinson’s disease: risk factors and differences from dopamine dysregulation. An analysis of published case series. Mov Disord 2007;22:1757-1763.
du Toit P, van Kradenburg J, Niehaus D, et al. Comparison of obsessive-compulsive disorder patients with and without comorbid putative obsessive-compulsive spectrum disorders using a structured clinical interview. Compr Psychiatry 2001;42:291-300.
76.
Lhommee E, Klinger H, Thobois S, et al. Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviors. Brain 2012;135:1463-1477.
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Okai D, Askey-Jones S, Mack J, et al. Parkinson’s Impulse Control Scale (PICS) for the rating of severity of impulsive compulsive behaviors in Parkinson’s disease. Mov Disord 2014 (in press).
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Avila A, Cardona X, Martin-Baranera M, et al. Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol 2003;23:509-513.
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Clinical Spectrum of Impulse Control Disorders in Parkinson’s Disease Daniel Weintraub, MD,1,2* Anthony S. David, FRCP, FRCPsych, MD, MSc,3 Andrew H. Evans, FRACP,4 Jon E. Grant, MD, MPH,5 and Mark Stacy, MD6 1
Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 2 Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA 3 Institute of Psychiatry, King’s College London, London, United Kingdom 4 Department of Neurology, the Royal Melbourne Hospital, Parkville, Australia 5 Department of Psychiatry, University of Chicago School of Medicine, Chicago, Illinois, USA 6 Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA
ABSTRACT:
Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson’s disease (PD). Other impulsive-compulsive behaviors (ICBs) have been described in PD, including punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive PD medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apo-
Clinical Presentation ICDs are defined as behaviors that are performed repetitively, excessively, and compulsively to an extent that interferes in major areas of life functioning.1 ICDs have been conceptualized as “behavioral” addictions2,3 because of their similarities to drug addiction, with which they share many of the same risk factors, clinical features, cognitive changes, neurobiological substrates, and treatment approaches. In recognition of this shift in thinking, gambling disorder was moved from the category of “Impulse Control Disorders” to the new category of “Substance-Related and Addictive
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*Correspondence to: Dr. Daniel Weintraub, Perelman School of Medicine, University of Pennsylvania, 3615 Chestnut Street, #330, Philadelphia, PA 19104-2676, USA; [email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 12 May 2014; Revised: 16 July 2014; Accepted: 11 August 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26016
morphine and levodopa. Possible risk factors for ICDs include male sex, younger age and younger age at PD onset, a pre-PD history of ICDs, and a personal or family history of substance abuse, bipolar disorder, or gambling problems. Given the paucity of treatment options and potentially serious consequences, it is critical for PD patients to be monitored closely for development of ICDs C 2014 International Paras part of routine clinical care. V kinson and Movement Disorder Society
K e y W o r d s : Parkinson’s disease; impulse control disorder; dopamine agonists
Disorders” in the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).4 Others have argued for a broader conceptual framework, which places ICDs and related behaviors within “disinhibitory psychopathologies.”5 In recent years, there has been increasing evidence and awareness that PD patients are at increased risk of developing one or more of four major ICDs, which are compulsive or pathological gambling, buying, sexual, and eating behaviors.6 These behaviors range widely in severity, but can lead to devastating consequences, including financial ruin, divorce, loss of employment, and increased health risks. In general, ICDs are associated with greater functional impairment,7 decreased quality of life,8 and increased caregiver burden,9 Other ICBs have been linked to the use of dopamine replacement therapy (DRT) in PD. One is DDS (previously referred to as hedonic homeostatic dysregulation),10 a drug addiction-like state marked by self-medication with inappropriately high doses of dopaminergic medications, particularly L-dopa and high-potency, short-acting DAs (e.g., subcutaneous
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apomorphine). Several closely related phenomena have also been identified in PD, including: (1) punding— repetitive, purposeless behaviors, characterized by an intense preoccupation with specific items or activities (e.g., collecting, arranging, or taking apart objects)11; (2) hobbyism—similar, but higher-level repetitive behaviors (e.g., excessive exercise, Internet use, reading, art work, and work on projects); (3) walkabouts—consisting of excessive, aimless wandering10; and (4) hoarding—the acquisition of, and failure to discard, a large number of items with little or no objective value, which, in some cases, can lead to unsafe or unsanitary living conditions.12 It is not fully understood how these other behaviors are similar versus different in terms of their neural substrate compared with ICDs. Of these disorders, gambling disorder, binge eating disorder (BED), and hoarding disorder are included in DSM-5, but there are no formal DSM-5 criteria for compulsive buying or sexual behavior. For convenience, the term ICD has been broadly applied to cover the four major ICDs that have been reported to occur in PD patients. Multiple descriptive terms have been used to describe the clinical presentation of impulsive and compulsive behaviors in PD. The behaviors have both impulsive (lack of forethought or consideration of consequences) and compulsive (repetitious behaviors with a lack of self-control) aspects. In DSM-5, gambling disorder and related disorders are defined as a failure to resist an impulse, drive, or temptation to perform a typically pleasurable activity that is ultimately harmful to the person or to others because of its excessive nature. Although not the focus of formal research to date, it has been reported that the increased drive and motivation to engage in goaldirected behaviors can be beneficial for some PD patients with disease-related impairments (e.g., an increased interest in sex for a PD patient who previously had a decreased sex drive or an increased appetite in a PD patient who had lost weight). These behaviors only become a disorder when they become harmful to the patient in some way or interfere with daily functioning or social relationships. In such cases, there is also usually a deviation from premorbid behavior.
Frequency Despite high prevalence rates in the general population13 and in psychiatric cohorts,14 ICDs have been relatively understudied from an epidemiological viewpoint. Arguably, the best data on the prevalence of ICDs exist for gambling disorder. Prevalence rates for gambling disorder in the general population from national surveys vary worldwide. For example, past 12-month rates of problem gambling range from
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0.2% in Norway to 5.3% in Hong Kong. Reported rates of gambling disorder in the United States range from 0.4% to 1.1% of adults.15 The prevalence rates of the other ICDs in the general population remain unclear. A national study in the United States estimated the prevalence of compulsive buying at 5.8%.16 Although limited information is available on the true prevalence of compulsive sexual behavior (CSB), it is estimated to affect 3% to 6% of adults.17 BED, also referred to in the literature as pathological overeating, occurs in approximately 2% of the general U.S. population.18 The few studies done to date suggest that ICDs may be more common, overall, in treated PD patients, compared to healthy controls (HCs),19,20 or similarly disabled non-PD patients,21,22 although one recent study suggested otherwise.23 Determining the frequency of impulse control symptoms in de novo, untreated PD patients would help answer the question of whether PD itself confers an increased (or indeed decreased) risk for experiencing such symptoms. In the first published study assessing newly diagnosed, untreated PD patients, 18% screened positive for impulse control symptoms, a number similar to HCs.24 In a subsequent study analyzing data from the Parkinson’s Progression Markers Initiative of 311 newly, untreated PD patients and HCs, PD patients were not more likely to report symptoms of any ICD or related behavior. Thus, it appears, from these studies, that PD itself does not confer an increased risk for development of impulse control or related behavior symptoms in the absence of treatment. Given that approximately 20% of newly diagnosed PD patients report some symptoms, long-term follow-up is needed to determine whether such patients are at increased risk for ICD development, in relation to appropriately matched controls. An allied question is whether there is a typical “PD personality” that predates the disorder.25 One large, prospective study from the Mayo Clinic followed a cohort of 7,216 subjects rated on a self-report personality inventory from the 1960s.26 Those who screened positive for PD 40 years later were found to show no differences from the remainder on any traits. However, those with more broadly defined parkinsonism showed a slight increase in introverted personality (i.e., constraint; odds ratio: 1.39; 95% confidence interval: 1.06-1.84; P 5 0.02). For PD patients, initial cross-sectional studies that used formal assessments of ICDs reported an estimated prevalence of 1.7% to 7.0% for compulsive gambling, 3.5% for CSB,27 and 0.4% to 3.0% for compulsive buying.28-31 Compulsive or binge eating was also reported in PD, but its prevalence was not initially reported.10,32 In the DOMINION study,33 which included 3,090 medicated PD patients from 46 movement disorder centers in the United States and
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FIG. 1. Correlates and potential risk factors for ICDs and related behaviors.
Canada, one or more ICD was identified in 13.6% of patients (gambling in 5.0%, CSB in 3.5%, compulsive buying in 5.7%, and BED in 4.3%); 3.9% of participants had two or more ICDs. Recent research has suggested that up to 25% of patients treated with a minimally therapeutic dose of a DA may experience an ICD.34 Cultural factors may influence prevalence of ICDs in PD, but various studies lack uniformity. In four Asian studies, similar or high prevalence findings were reported in two (South Korea and Malaysia),35,36 and two others (Taiwan and China) reported lower overall prevalence rates than that reported in the DOMINION study.37,38 Other studies have suggested similar PD ICD frequencies in Finland,39 Denmark,40 Brazil,41 India,42 Germany,43 Spain,44 Russia,45 Australia,8 the UK,46 and Mexico.47 DDS and other ICBs in PD have not been as well studied as ICDs. Fifteen cases were reported in the original description of DDS in PD,10 but a crosssectional or cumulative prevalence rate was not reported. Regarding punding, in one series examining PD patients on higher L-dopa equivalent daily dosages, 14% met criteria for punding11; in contrast, another larger study of unselected PD patients reported a prev-
alence rate of only 1.4%.48 It is important to note that there are no universally accepted diagnostic criteria for punding, as well as for certain ICDs (e.g., hypersexuality), which may help explain the variation in prevalence rates reported for many of these disorders. Nearly all research to date examining the frequency and correlates of ICDs and similar behaviors in PD has been cross-sectional, so prospective studies are needed to determine incidence rates. In a recent prospective cohort study of DA-treated patients, 39% without an ICD at baseline developed an ICD over a 4-year period, with a median duration of ICD onset from initiation of DA of 23 months.49 Presence of motor complications, caffeine use, lifetime cigarette smoking, and higher peak DA doses were predictors of future ICD development.
Correlates and risk factors (Figure 1) Early case reports and cross-sectional studies suggested an association between the use of DRT, and DAs in particular, with the development of ICDs in PD. In the DOMINION study, ICDs were more
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common in patients treated with a DA (17.1%) than in patients not taking a DA (6.9%). DA treatment in PD was associated with 2- to 3.5-fold increased odds of having an ICD. The prevalence of ICDs was comparable in subjects treated with pramipexole and ropinirole, the two most commonly used DAs (17.7% and 15.5%, respectively), and there is no clear evidence for differential risk within the DA class. Use of Ldopa,33 especially at higher dosages, and of amantadine (used in PD mainly for the treatment of dyskinesias)50 were also associated with ICDs in this study, but to a lesser extent than DA treatment. Though some reports have shown a dose response between DA use and ICDs, such a relationship was not observed in this study. The association between DA use and ICDs is also supported by case reporting of ICDs occurring with DA treatment in other clinical populations (e.g., restless legs syndrome51 and fibromyalgia52). There has not been any systematic research to see how alternate formulations or delivery systems for DAs (e.g., long-acting agents delivered orally or transdermally) or other medications that enhance dopaminergic function (e.g., catechol O-methyltransferase inhibitors) modify ICD risk. In recent preliminary research, rasagiline treatment in PD has also been associated with a 2.12- to 3.74-fold increased odds of having an ICD on uni-44 or multivariate analysis.21 Prospective research examining incident ICD cases has been very limited. In a recent study, 46 DAtreated PD patients without an ICD at baseline were followed longitudinally (for variable time periods), and 39% of patients developed an ICD over time.49 The median time from DA initiation to onset of ICD symptoms was 23 months (range, 3-114). Patients who developed an ICD had great prevalence of motor complications and caffeine use at baseline, higher lifetime prevalence of cigarette smoking, and higher peak DA doses. Additional variables associated with ICDs in different studies include: (1) a personal or familial history of alcoholism or gambling; (2) impulsive or noveltyseeking traits; (3) younger age; (4) male sex; (5) early onset of PD; (6) being unmarried; and (7) past or current cigarette smoking.6;33,41 In the DOMINION study, another correlate of having an ICD was living in the United States compared with Canada, suggesting that environmental factors may play a role in ICD development or reporting in PD. Though total ICD frequency was similar for men and women, there were notable sex differences in the frequency of specific ICDs, with CSB more common in males and both compulsive buying and binge eating were more prevalent in women. The gender differences in prevalence rates for the various ICDs in PD mirror what is reported for the general population. ICDs have been reported to be less common in PD patients with
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dementia,53 but this may be an artifact of DA prescribing practices. Although DDS has been closely associated with the use of high-potency, shorter-acting dopaminergic medications, such as L-dopa and injectable apomorphine, the relationship between punding and specific dopaminergic medications remains unclear.
Neuropsychiatric Abnormalities Other psychiatric disorders or behaviors that share features of ICDs have been reported to occur in PD. For instance, obsessive-compulsive disorder (OCD), an anxiety disorder characterized by the repetition of nonpleasurable, nonharmful behaviors (e.g., checking or counting) to reduce anxiety, may occur at an increased frequency in PD, although it has not been reported in association with PD medications.54 It is important to note that the types of impulsive and compulsive behaviors previously described also do not occur in the context of obsessive-compulsive personality disorder, a lifelong personality-style characterized by preoccupation with orderliness, perfectionism, and control that may be linked to PD independently of disease duration and medications.55 For PD patients with an ICD, a large case-control study found that ICD patients drawn from the DOMINION study reported significantly more depression, state and trait anxiety, OCD, novelty seeking, and impulsivity symptoms.7 Other studies have also reported an association between ICD and depression symptoms8,28,39,40 and anxiety.46 ICD patients report an increased prevalence of sleep disturbances, including worse sleep efficiency, daytime sleepiness, and RLS symptoms,56,57 and another found increased anhedonia in ICD patients.58 It has been argued that apathy and ICDs are at opposite ends of a hypodopaminergic-hyperdopaminergic behavioral continuum,59,60 with experimental evidence coming from a DBS study in which ICD patients experienced improvement in ICD behaviors, but worsening in apathy symptoms when DA treatment was discontinued post-DBS.61 The apathy and other behavioral symptoms experienced by these patients has been conceptualized as a stereotyped dopamine agonist withdrawal syndrome, experienced by many PD ICD patients who discontinue DA treatment, and which shares the psychiatric and physical features of the withdrawal symptoms experience in the context of some substance abuse disorders.62 However, both impulsivity and apathy can be conceptualized as dysexecutive symptoms and frequently co-occur in other neuropsychiatric disorders. Similarly, what may appear to be apathy may be a behavioral response to an ICD or a facet of depression or cognitive impairment. Thus, ICDs in PD are associated with multiple
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psychiatric symptoms, including affective and anxiety symptoms, and elevated obsessionality, novelty seeking, impulsivity, and sleep disturbances, although the direction of causality behind these associations is not always clear. Patients with DDS typically develop cyclical mood disorders (i.e., mood elevation or hypomania secondary to DRT use, followed by a dysphoric affective state when medications are withdrawn or reduced).10,63 When in an elevated state, patients may be excessively involved in pleasurable activities that have a high potential for painful consequences.10 This syndrome is distinct from ICDs in some ways, given that few PD patients with an ICD are reported either to compulsively use their PD medications or to experience mood elevation, and many patients with DDS do not have a comorbid ICD.64 However, disentangling reckless behavior in the context of elevated mood and actual ICD symptoms requires skilled neuropsychiatric evaluation.
Assessment There is evidence that ICD behaviors in PD patients continue to be under-recognized and undermanaged in clinical practicel.8,30,65 Ongoing under-recognition could be, in part, a result of the fact that routine screening is not common; in addition, patients may not report symptoms either because of embarrassment, limited awareness of their behaviors, or not suspecting a possible association with their PD medications. Interestingly, a recent study found that ICD severity in PD patients was correlated with alexithymia, specifically, difficulty describing feelings, as opposed to externally oriented thinking,66 which might help explain under-reporting of ICD symptoms by patients. An ongoing issue is that the agreement between patient and informant reporting of symptoms is not high,36 with no clear direction for the mismatches in reporting,67 although patient under-reporting is likely more common.68 Several screening instruments have been used to assess for ICD symptoms in PD. One is the Minnesota Impulsive Disorders Interview,69 which queries for some of the ICDs reported to occur in PD. Another is the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP),70 and a rating scale version of this instrument exists (QUIP-RS),71 both of which can be self- or rater-administered and have been translated into numerous languages. In addition, the Dopamine Dysregulation Syndrome-Patient and Caregiver Inventory (DDS-PC) was developed as a screening questionnaire to assess the presence of a range of ICBs in PD.72 The Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDSUPDRS) includes a single item for DDS, which covers
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excessive gambling, sexual behaviors, hobbyism, punding, and DDS,73 although research suggests that this single question is not valid as an assessment tool for ICDs.74 The Structured Clinical Interview for Obsessive-Compulsive Spectrum Disorders (SCIDOCSD)75 is a structured interview constructed on the basis of the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I) and has been used in PD to determine the presence of a range of ICBs.8 The Ardouin scale, administered as a semistructured interview, includes 21 items that assess general psychological state, including depressive mood, hypomanic or manic mood, anxiety, irritability, hyperemotivity, psychotic symptoms, apathy, nonmotor fluctuations, and ICD and related behavior symptoms. These are thought to represent the spectrum of hyper- and hypodopaminergic behaviors and be sensitive to dopaminergic medication in PD.59 The scale is sensitive to change in symptom severity.76 Finally, the Parkinson’s Impulse Control Scale for the rating of severity of ICD behaviors in PD is a new, clinician-rated severity scale for the assessment of syndromal and subsyndromal forms of these behaviors, which has good test-retest reliability and sensitivity to change.77 The scale is interview based and requires a degree of clinical knowledge/ training for reliable administration and scoring. A manual will be available to accompany the scale.
Conclusions Mounting data suggest that PD medications, and DAs in particular, are associated with the development of ICDs in PD patients. Susceptibility to ICDs has also been associated with specific demographic and clinical characteristics. As in the general population, ICDs and other addictive behaviors can have serious personal, familial, psychosocial, financial, and medical consequences. In addition, ICDs in PD may become permanent, often because affected patients may be unable to discontinue DA therapy as a result of motor worsening or DAWS, and even DBS as a treatment option may not be free of risk. Given the numerous adverse consequences of ICDs and related behaviors, patient and caregiver education is crucial, as is routine monitoring for their development.
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