- Email: [email protected]
Risk factors for pathologic gambling and other compulsions among Parkinson’s disease patients taking dopamine agonists
Available online at www.sciencedirect.com
Journal of Clinical Neuroscience 14 (2007) 1178–1181 www.elsevier.com/locate/jocn
Clinical Study
Risk factors for pathologic gambling and other compulsions among Parkinson’s disease patients taking dopamine agonists Asha Singh, Geetha Kandimala, Richard B. Dewey Jr., Padraig O’Suilleabhain
*
Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9036, USA Received 12 September 2006; accepted 17 January 2007
Abstract Three hundred patients with Parkinson’s disease taking dopamine agonists were surveyed for the presence of compulsions. Fifty-eight reported active compulsions which had developed after initiation of dopamine agonists. These included 25 with sexual compulsions and 28 with self-described compulsive gambling, of whom 17 met criteria for pathologic gambling. Males were over-represented. Patients with any compulsion and those with pathologic gambling were about 6 years younger than those without compulsions. These behavioral problems were not associated with an individual dopamine agonist, nor dose or duration, nor concomitant levodopa. Follow-up of the pathologic gamblers 1 year after intervention, which was cessation of the dopamine agonist in most cases, found ongoing but controlled gambling in five and complete cessation within 4 months in the remainder. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Dopamine agonists; Gambling
1. Introduction Dopamine agonists improve the classic motor impairments of Parkinson’s disease (PD). In the past few years pathologic gambling has been reported as a side-effect, plausibly a result of action at limbic dopamine receptors.1 The non-ergot dopamine agonists ropinirole and particularly pramipexole have tropism for D3 receptors which are found in the nucleus accumbens and olfactory tubercle, and pathologic gambling and addictive and compulsive behaviors in other contexts are associated with dysfunction of these frontal subcortical regions. These two dopamine agonists are widely used in PD patients and in a rapidly expanding number of people with restless legs syndrome. The risk of pathologic gambling is primarily social, and patients may lack insight into the problem or may minimize it until serious damage to finances or relationships has oc*
Corresponding author. Tel.: +1 214 648 9243; fax: +1 214 648 8540. E-mail address: [email protected] (P. O’Suilleabhain). 0967-5868/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2007.01.009
curred. Therefore a responsibility falls on the prescribing physician to detect this iatrogenic complication at an early stage. Risk-factor identification should help such surveillance efforts. We surveyed our patients with PD taking dopamine agonists to assess risk factors for pathologic gambling and other compulsions. 2. Methods 2.1. Subject identification For an 8-month period the authors verbally surveyed every patient seen in the Clinical Center for Movement Disorders at the University of Texas Southwestern Medical Center, Dallas, Texas, USA, who was taking a dopamine agonist. Additionally, we queried our electronic database to identify all patients seen since early 2003 who had a dopamine agonist listed as a medication. Those patients identified in the database who were not seen in the clinic during the study period were mailed a letter and were telephoned by the treating physician or the practice nurse for a
A. Singh et al. / Journal of Clinical Neuroscience 14 (2007) 1178–1181
phone survey. Patients who had stopped their dopamine agonist before the survey because of side-effects, including gambling, were excluded. The study was approved by the institution’s review board. 2.2. Survey process The prescribing physician directly questioned the patient when reviewing current medications and screening for side-effects during the office visit or phone contact. Those patients confirmed to be taking a dopamine agonist were advised that concern has arisen that certain drugs used to treat PD can increase compulsive behaviors, including gambling. With that preamble, we inquired: ‘‘Have you gambled money recently?’’ defined as in the previous 6 months. Those answering in the affirmative were administered the 10-question Diagnostic and Statistical Manual (DSM) gambling questionnaire2 to assess whether they met criteria for pathologic gambling and to exclude bipolar symptomatology. They were also questioned if they subjectively considered their gambling as compulsive. If so, they were asked for how long they had compulsively gambled, what their estimated gambling losses were during that period, and whether their self-defined compulsive gambling began before or after starting the dopamine agonist. The patients were then questioned if they had increases in other compulsive behavior. They were asked: ‘‘Have you had higher than normal sexual interest or libido recently, for example, interest in sexual intercourse, masturbation or pornography?’’ Those answering in the affirmative were asked if they considered the drives compulsive, and if so, how long the compulsion had existed, and if the compulsiveness had followed or preceded agonist use. Subjects were also asked: ‘‘In recent times are you experiencing an excessive or abnormal impulse to shop or spend or engage in other activities?’’ Those responding ‘yes’ were asked if they considered the drives compulsive, and if so, for how long, and the temporal relationship to agonist use. 2.3. Statistics For statistical analysis, only subjects with a diagnosis of PD3 were included. Subjects with any self-reported compulsion were compared with those denying any compulsions. Student’s t-tests were used for continuous variables: age; duration of PD; daily dose and duration of levodopa; duration of dopamine agonist use; and equivalent daily dose of dopamine agonist (conversion factor: 1 mg pramipexole = 6 mg ropinirole4). Fisher’s exact test was used for categorical variables: agonist; sex; use of levodopa; use of catechol-O-methyl transferase inhibitor (COMTI); and subthalamic nucleus deep brain stimulation (DBS). Subjects meeting criteria for pathologic gambling were compared with the remainder, using the same 11 variables. Bonferroni corrected significance level was p = 0.005.
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3. Results 3.1. Subject characteristics Survey data was available for 320 subjects confirmed to be taking dopamine agonists. We were unable to contact or survey 68 patients identified as possibly eligible from the clinic database. Three hundred had PD of whom 18 had undergone bilateral subthalamic deep brain stimulation, one had a pallidotomy, and one a thalamotomy. PD duration ranged from 1 to 27 years (mean: 9). Subjects comprised 194 males and 106 females, with mean age 65 years (range: 38–85). The diagnoses of those excluded from statistical analyses were: restless legs syndrome (n = 12); progressive supranuclear palsy (3); multiple system atrophy (2); diffuse Lewy body disease (1); essential tremor (1); and vascular parkinsonism (1). The agonists used were ropinirole in 135 patients and pramipexole in 165 patients including one also using apomorphine. Mean equivalent agonist dose was 16 mg/day (range: 0.8–45.0). Subjects had used dopamine agonists for 4.6 years (range: 0.3–18.0). Fifty-six patients were taking agonist monotherapy while 244 were using this in combination with levodopa at a mean daily dose of 700 mg (range: 50–2400). Eighty-three were also using COMTI, almost exclusively entacapone. 3.2. Any compulsion In all, 58 patients taking dopamine agonists reported one or more compulsions they felt developed following the use of dopamine agonists. As a group, these patients were younger (61 vs. 66 years, p = 0.0006) and were more likely male (48/194 vs. 10/106, p = 0.001). There was a trend towards higher levodopa dose (p = 0.02) but less so for levodopa use (p = 0.09) and not at all for agonist dose (p = 0.9). 3.3. Sexual compulsivity Thirty-three responded that interest in sex was excessive following dopamine agonist use. Twenty-five of these decided it was compulsive, only one of whom felt the compulsion preceded agonist use. All 25 were male, none had DBS, all but two were taking levodopa in conjunction, and six were taking COMTI. 3.4. Non-sexual, non-gambling compulsions Twenty-three subjects responded affirmatively to the questions about heightened abnormal behaviors other than gambling and sexual compulsivity. All but one characterized the behaviors as compulsive. The most common self-reported ‘other’ compulsions were eating, spending, playing computer games, and cleaning. Of these, seven were women, and 11 had comorbid gambling or sexual compulsions.
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A. Singh et al. / Journal of Clinical Neuroscience 14 (2007) 1178–1181
3.5. Gambling Forty-three patients were categorized as having gambled recently. Of these 17 met criteria for pathologic gambling. All 17 felt their gambling was compulsive, as did an additional 11 who also felt their gambling was compulsive but scored fewer than five points on the DSM questionnaire. Duration of compulsive gambling ranged from 0.5 to 10.0 years, and 25 out of the 28 with self-described compulsion to gamble reported this compulsion followed initiation of a dopamine agonist. Compulsive gamblers’ estimated losses ranged from US$300 to US$3 000 000, with a median of US$10 000. Nine of the 28 patients had other compulsions: seven for hypersexuality and two for spending and eating. Sixteen of the 17 subjects with DSM-defined pathologic gambling were male (p = 0.008). Three had undergone DBS in the past (p = 0.07). Compared with the 283 patients who were not pathologic gamblers, they were younger (58 vs. 65 years, p = 0.003). Nine used ropinirole and the other eight used pramipexole (p = 0.6). Other non-significant variables were dose of agonist and duration of agonist use; concomitant levodopa, dose of levodopa, duration of levodopa use; concomitant COMTI; and duration of PD. Follow-up was available for 16 of the pathologic gamblers 13 months (range: 11–18) after identification of the problem and intervention. This consisted of counseling about the nature and severity of the problem, participation in an abstinence program in one case, and recommendation to discontinue dopamine agonist after rapid taper. Fourteen had stopped and remained off dopamine agonists, one remained on reduced dose, and one remained on full dose. Nine had experienced deterioration of motor function with these changes, and had initiated or increased levodopa to compensate for this, but three complained that even high-dose levodopa did not work as well as the agonist. Eleven had completely stopped gambling at latencies ranging from 1–4 months after intervention, but five reported ongoing episodes of gambling but denied it was compulsive or problematic. No patient required neuroleptic prescription. 4. Discussion Since 2000 when compulsive gambling in PD patients taking dopamine agonists was first described,5 estimates of prevalence have ranged from 1.5–4.0%6–10 and it is increasingly clear that compulsive gambling behavior is triggered in some patients with PD following initiation of dopamine agonists. The primary focus of our study was identification of risk factors rather than estimation of prevalence, thus our control group was agonist-using PD subjects who lacked compulsions. Our study has the advantages of size, as this is the largest cohort of PD users taking agonists studied for this purpose, and of a high response rate exceeding 82% of all patients in our practice who were taking agonists. Measures were taken to ensure
an accurate response: in most cases the treating physician with a therapeutic and presumably trusting relationship with the patient orally delivered the questions in the course of a clinical encounter. Limitations of our study include possible selection biases: patients for whom we had prescribed agonists but who were no longer taking them were ineligible, even if due to side-effects including pathologic behaviors identified prior to this study. Also the geographically localized sampling should be considered, as our practice is based in a metropolitan area of a state without legalized gambling other than the state lottery but only a hundred miles from casinos. A further limitation is the absence of cognitive, mood and prior psychiatric history which are all of interest in analyzing this phenomenon10 but collection of psychometric data from all our patients would have been impractical. We collected but did not statistically analyze survey data from our patients without PD who were taking dopamine agonists. Of note, none had pathologic gambling or sexual compulsions and only one reported another (shopping) compulsion. However, the number of our patients without PD taking agonists was small, and the underlying diagnoses were diverse and dopamine agonist dose in most cases in an order of magnitude lower than in PD patients, so no conclusions are drawn. We would not conclude for example that PD diagnosis per se contributes to the risk of agonist-induced compulsion. Additionally, our findings regarding agonist-induced compulsions should not be extrapolated to restless legs syndrome or other populations taking dopamine agonists. The psychopathologic basis for gambling may be a disinhibition of risk-taking which is an evolutionarily adaptive predisposition and therefore hardwired into prefrontal subcortical–cortical circuits. Criteria for pathologic gambling are quite well established, and because gambling is not a normal daily pastime it was easy for us to analyze. Pathologic gambling was reported by 6% of our agonist users and by 8% of our male patients with PD taking a dopamine agonist. This is far higher than the background risk of the general population estimated at about 1%.11 Affected individuals were on average a few years younger but there was broad age overlap between the groups. This age association was consistently seen across other compulsions, and previous reports found PD patients with agonist-induced gambling or other compulsions significantly or trending to be younger.8–10 The age difference could reflect differences in PD biology or an age-related susceptibility to compulsivity independent of PD or greater plasticity in the younger brain’s neurotransmitter response. Other variables were not significant predictors of pathologic gambling, though male sex and DBS were overrepresented. A male predisposition is seen in other reports and certainly for sexual compulsion in our cohort, so we believe there is a male vulnerability. Pathologic gambling in general is more common in males for reasons which may be social or biological.12 Agonist dose and duration were non-significant, and pramipexole,
A. Singh et al. / Journal of Clinical Neuroscience 14 (2007) 1178–1181
which has greater affinity for D3 receptors than ropinirole, did not differ in risk, and dose of agonist did not predict pathologic gambling. The meaning of the data regarding other compulsions is less definitive. What subjects meant by ‘compulsion’ for sexual, acquisitive and eating behaviors, which are features of normal daily life, was not defined using a validated or conventionally accepted measure because there is none. The survey’s open-ended question uncovered instances of repetitive behavior such as cleaning or gambling which arguably are forms of punding, a fascination with repetitive meaningless motions. Voon pointed out a relationship between punding (repetition of individually acquired or learned behaviors arguably residing in sensorimotor corticostriato-thalamic circuits) and compulsions (repetition of evolutionarily selected patterns arguably residing in prefrontal or limbic circuits).13 Interestingly, dopamine agonists more commonly amplify the more species-wide and ‘inborn’ activities as compared with the individually acquired ones. Although firm recommendations cannot be made, we plan to educate patients about the potential for these drugs to distort libidinal drives or behaviors generally, with sexual and shopping compulsivity as specific examples. Our medium-term follow-up data indicates that in most cases gambling ceases or becomes controlled after withdrawal of dopamine agonists. Acknowledgement This research was unfunded. POS has received speaking fees from Boehringer Ingelheim, Glaxo Smith Kline, Pfizer and Novartis and research support from Glaxo Smith Kline, Pfizer and Novartis. RBD has received speaking fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva, and Vernalis and research support from Elan and Schwarz Pharma.
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References 1. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005;62:1377–81. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV TR). Washington, DC: American Psychiatric Association; 2000. 3. Litvan I, Bhatia KP, Burn DJ, et al. Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003;18:467–86. 4. Thobois S. Proposed dose equivalence for rapid switch between dopamine receptor agonists in Parkinson’s disease: a review of the literature. Clin Ther 2006;28:1–12. 5. Seedat S, Kesler S, Niehaus DJ, et al. Pathological gambling behaviour: emergence secondary to treatment of Parkinson’s disease with dopaminergic agents. Depress Anxiety 2000;11:185–6. 6. Szarfman A, Doraiswamy PM, Tonning JM, et al. Association between pathologic gambling and parkinsonian therapy as detected in the Food and Drug Administration Adverse Event database. Arch Neurol 2006;63:299–300, author reply: 300. 7. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003;61:422–3. 8. Voon V, Hassan K, Zurowski M, et al. Prospective prevalence of pathologic gambling and medication association in Parkinson disease. Neurology 2006;66:1750–2. 9. Weintraub D, Siderowf AD, Potenza MN, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006;63:969–73. 10. Pontone G, Williams JR, Bassett SS, et al. Clinical features associated with impulse control disorders in Parkinson disease. Neurology 2006;67:1258–61. 11. Shaffer HJ, Hall MN, Vander Bilt J. Estimating the prevalence of disordered gambling behavior in the United States and Canada: a research synthesis. Am J Public Health 1999;89:1369–76. 12. Blanco C, Hasin DS, Petry N, et al. Sex differences in subclinical and DSM-IV pathological gambling: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Psychol Med 2006;36:943–53. 13. Voon V. Repetition, repetition, and repetition: compulsive and punding behaviors in Parkinson’s disease. Mov Disord 2004;19:367–70.
Journal of Clinical Neuroscience 14 (2007) 1178–1181 www.elsevier.com/locate/jocn
Clinical Study
Risk factors for pathologic gambling and other compulsions among Parkinson’s disease patients taking dopamine agonists Asha Singh, Geetha Kandimala, Richard B. Dewey Jr., Padraig O’Suilleabhain
*
Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9036, USA Received 12 September 2006; accepted 17 January 2007
Abstract Three hundred patients with Parkinson’s disease taking dopamine agonists were surveyed for the presence of compulsions. Fifty-eight reported active compulsions which had developed after initiation of dopamine agonists. These included 25 with sexual compulsions and 28 with self-described compulsive gambling, of whom 17 met criteria for pathologic gambling. Males were over-represented. Patients with any compulsion and those with pathologic gambling were about 6 years younger than those without compulsions. These behavioral problems were not associated with an individual dopamine agonist, nor dose or duration, nor concomitant levodopa. Follow-up of the pathologic gamblers 1 year after intervention, which was cessation of the dopamine agonist in most cases, found ongoing but controlled gambling in five and complete cessation within 4 months in the remainder. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Dopamine agonists; Gambling
1. Introduction Dopamine agonists improve the classic motor impairments of Parkinson’s disease (PD). In the past few years pathologic gambling has been reported as a side-effect, plausibly a result of action at limbic dopamine receptors.1 The non-ergot dopamine agonists ropinirole and particularly pramipexole have tropism for D3 receptors which are found in the nucleus accumbens and olfactory tubercle, and pathologic gambling and addictive and compulsive behaviors in other contexts are associated with dysfunction of these frontal subcortical regions. These two dopamine agonists are widely used in PD patients and in a rapidly expanding number of people with restless legs syndrome. The risk of pathologic gambling is primarily social, and patients may lack insight into the problem or may minimize it until serious damage to finances or relationships has oc*
Corresponding author. Tel.: +1 214 648 9243; fax: +1 214 648 8540. E-mail address: [email protected] (P. O’Suilleabhain). 0967-5868/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2007.01.009
curred. Therefore a responsibility falls on the prescribing physician to detect this iatrogenic complication at an early stage. Risk-factor identification should help such surveillance efforts. We surveyed our patients with PD taking dopamine agonists to assess risk factors for pathologic gambling and other compulsions. 2. Methods 2.1. Subject identification For an 8-month period the authors verbally surveyed every patient seen in the Clinical Center for Movement Disorders at the University of Texas Southwestern Medical Center, Dallas, Texas, USA, who was taking a dopamine agonist. Additionally, we queried our electronic database to identify all patients seen since early 2003 who had a dopamine agonist listed as a medication. Those patients identified in the database who were not seen in the clinic during the study period were mailed a letter and were telephoned by the treating physician or the practice nurse for a
A. Singh et al. / Journal of Clinical Neuroscience 14 (2007) 1178–1181
phone survey. Patients who had stopped their dopamine agonist before the survey because of side-effects, including gambling, were excluded. The study was approved by the institution’s review board. 2.2. Survey process The prescribing physician directly questioned the patient when reviewing current medications and screening for side-effects during the office visit or phone contact. Those patients confirmed to be taking a dopamine agonist were advised that concern has arisen that certain drugs used to treat PD can increase compulsive behaviors, including gambling. With that preamble, we inquired: ‘‘Have you gambled money recently?’’ defined as in the previous 6 months. Those answering in the affirmative were administered the 10-question Diagnostic and Statistical Manual (DSM) gambling questionnaire2 to assess whether they met criteria for pathologic gambling and to exclude bipolar symptomatology. They were also questioned if they subjectively considered their gambling as compulsive. If so, they were asked for how long they had compulsively gambled, what their estimated gambling losses were during that period, and whether their self-defined compulsive gambling began before or after starting the dopamine agonist. The patients were then questioned if they had increases in other compulsive behavior. They were asked: ‘‘Have you had higher than normal sexual interest or libido recently, for example, interest in sexual intercourse, masturbation or pornography?’’ Those answering in the affirmative were asked if they considered the drives compulsive, and if so, how long the compulsion had existed, and if the compulsiveness had followed or preceded agonist use. Subjects were also asked: ‘‘In recent times are you experiencing an excessive or abnormal impulse to shop or spend or engage in other activities?’’ Those responding ‘yes’ were asked if they considered the drives compulsive, and if so, for how long, and the temporal relationship to agonist use. 2.3. Statistics For statistical analysis, only subjects with a diagnosis of PD3 were included. Subjects with any self-reported compulsion were compared with those denying any compulsions. Student’s t-tests were used for continuous variables: age; duration of PD; daily dose and duration of levodopa; duration of dopamine agonist use; and equivalent daily dose of dopamine agonist (conversion factor: 1 mg pramipexole = 6 mg ropinirole4). Fisher’s exact test was used for categorical variables: agonist; sex; use of levodopa; use of catechol-O-methyl transferase inhibitor (COMTI); and subthalamic nucleus deep brain stimulation (DBS). Subjects meeting criteria for pathologic gambling were compared with the remainder, using the same 11 variables. Bonferroni corrected significance level was p = 0.005.
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3. Results 3.1. Subject characteristics Survey data was available for 320 subjects confirmed to be taking dopamine agonists. We were unable to contact or survey 68 patients identified as possibly eligible from the clinic database. Three hundred had PD of whom 18 had undergone bilateral subthalamic deep brain stimulation, one had a pallidotomy, and one a thalamotomy. PD duration ranged from 1 to 27 years (mean: 9). Subjects comprised 194 males and 106 females, with mean age 65 years (range: 38–85). The diagnoses of those excluded from statistical analyses were: restless legs syndrome (n = 12); progressive supranuclear palsy (3); multiple system atrophy (2); diffuse Lewy body disease (1); essential tremor (1); and vascular parkinsonism (1). The agonists used were ropinirole in 135 patients and pramipexole in 165 patients including one also using apomorphine. Mean equivalent agonist dose was 16 mg/day (range: 0.8–45.0). Subjects had used dopamine agonists for 4.6 years (range: 0.3–18.0). Fifty-six patients were taking agonist monotherapy while 244 were using this in combination with levodopa at a mean daily dose of 700 mg (range: 50–2400). Eighty-three were also using COMTI, almost exclusively entacapone. 3.2. Any compulsion In all, 58 patients taking dopamine agonists reported one or more compulsions they felt developed following the use of dopamine agonists. As a group, these patients were younger (61 vs. 66 years, p = 0.0006) and were more likely male (48/194 vs. 10/106, p = 0.001). There was a trend towards higher levodopa dose (p = 0.02) but less so for levodopa use (p = 0.09) and not at all for agonist dose (p = 0.9). 3.3. Sexual compulsivity Thirty-three responded that interest in sex was excessive following dopamine agonist use. Twenty-five of these decided it was compulsive, only one of whom felt the compulsion preceded agonist use. All 25 were male, none had DBS, all but two were taking levodopa in conjunction, and six were taking COMTI. 3.4. Non-sexual, non-gambling compulsions Twenty-three subjects responded affirmatively to the questions about heightened abnormal behaviors other than gambling and sexual compulsivity. All but one characterized the behaviors as compulsive. The most common self-reported ‘other’ compulsions were eating, spending, playing computer games, and cleaning. Of these, seven were women, and 11 had comorbid gambling or sexual compulsions.
1180
A. Singh et al. / Journal of Clinical Neuroscience 14 (2007) 1178–1181
3.5. Gambling Forty-three patients were categorized as having gambled recently. Of these 17 met criteria for pathologic gambling. All 17 felt their gambling was compulsive, as did an additional 11 who also felt their gambling was compulsive but scored fewer than five points on the DSM questionnaire. Duration of compulsive gambling ranged from 0.5 to 10.0 years, and 25 out of the 28 with self-described compulsion to gamble reported this compulsion followed initiation of a dopamine agonist. Compulsive gamblers’ estimated losses ranged from US$300 to US$3 000 000, with a median of US$10 000. Nine of the 28 patients had other compulsions: seven for hypersexuality and two for spending and eating. Sixteen of the 17 subjects with DSM-defined pathologic gambling were male (p = 0.008). Three had undergone DBS in the past (p = 0.07). Compared with the 283 patients who were not pathologic gamblers, they were younger (58 vs. 65 years, p = 0.003). Nine used ropinirole and the other eight used pramipexole (p = 0.6). Other non-significant variables were dose of agonist and duration of agonist use; concomitant levodopa, dose of levodopa, duration of levodopa use; concomitant COMTI; and duration of PD. Follow-up was available for 16 of the pathologic gamblers 13 months (range: 11–18) after identification of the problem and intervention. This consisted of counseling about the nature and severity of the problem, participation in an abstinence program in one case, and recommendation to discontinue dopamine agonist after rapid taper. Fourteen had stopped and remained off dopamine agonists, one remained on reduced dose, and one remained on full dose. Nine had experienced deterioration of motor function with these changes, and had initiated or increased levodopa to compensate for this, but three complained that even high-dose levodopa did not work as well as the agonist. Eleven had completely stopped gambling at latencies ranging from 1–4 months after intervention, but five reported ongoing episodes of gambling but denied it was compulsive or problematic. No patient required neuroleptic prescription. 4. Discussion Since 2000 when compulsive gambling in PD patients taking dopamine agonists was first described,5 estimates of prevalence have ranged from 1.5–4.0%6–10 and it is increasingly clear that compulsive gambling behavior is triggered in some patients with PD following initiation of dopamine agonists. The primary focus of our study was identification of risk factors rather than estimation of prevalence, thus our control group was agonist-using PD subjects who lacked compulsions. Our study has the advantages of size, as this is the largest cohort of PD users taking agonists studied for this purpose, and of a high response rate exceeding 82% of all patients in our practice who were taking agonists. Measures were taken to ensure
an accurate response: in most cases the treating physician with a therapeutic and presumably trusting relationship with the patient orally delivered the questions in the course of a clinical encounter. Limitations of our study include possible selection biases: patients for whom we had prescribed agonists but who were no longer taking them were ineligible, even if due to side-effects including pathologic behaviors identified prior to this study. Also the geographically localized sampling should be considered, as our practice is based in a metropolitan area of a state without legalized gambling other than the state lottery but only a hundred miles from casinos. A further limitation is the absence of cognitive, mood and prior psychiatric history which are all of interest in analyzing this phenomenon10 but collection of psychometric data from all our patients would have been impractical. We collected but did not statistically analyze survey data from our patients without PD who were taking dopamine agonists. Of note, none had pathologic gambling or sexual compulsions and only one reported another (shopping) compulsion. However, the number of our patients without PD taking agonists was small, and the underlying diagnoses were diverse and dopamine agonist dose in most cases in an order of magnitude lower than in PD patients, so no conclusions are drawn. We would not conclude for example that PD diagnosis per se contributes to the risk of agonist-induced compulsion. Additionally, our findings regarding agonist-induced compulsions should not be extrapolated to restless legs syndrome or other populations taking dopamine agonists. The psychopathologic basis for gambling may be a disinhibition of risk-taking which is an evolutionarily adaptive predisposition and therefore hardwired into prefrontal subcortical–cortical circuits. Criteria for pathologic gambling are quite well established, and because gambling is not a normal daily pastime it was easy for us to analyze. Pathologic gambling was reported by 6% of our agonist users and by 8% of our male patients with PD taking a dopamine agonist. This is far higher than the background risk of the general population estimated at about 1%.11 Affected individuals were on average a few years younger but there was broad age overlap between the groups. This age association was consistently seen across other compulsions, and previous reports found PD patients with agonist-induced gambling or other compulsions significantly or trending to be younger.8–10 The age difference could reflect differences in PD biology or an age-related susceptibility to compulsivity independent of PD or greater plasticity in the younger brain’s neurotransmitter response. Other variables were not significant predictors of pathologic gambling, though male sex and DBS were overrepresented. A male predisposition is seen in other reports and certainly for sexual compulsion in our cohort, so we believe there is a male vulnerability. Pathologic gambling in general is more common in males for reasons which may be social or biological.12 Agonist dose and duration were non-significant, and pramipexole,
A. Singh et al. / Journal of Clinical Neuroscience 14 (2007) 1178–1181
which has greater affinity for D3 receptors than ropinirole, did not differ in risk, and dose of agonist did not predict pathologic gambling. The meaning of the data regarding other compulsions is less definitive. What subjects meant by ‘compulsion’ for sexual, acquisitive and eating behaviors, which are features of normal daily life, was not defined using a validated or conventionally accepted measure because there is none. The survey’s open-ended question uncovered instances of repetitive behavior such as cleaning or gambling which arguably are forms of punding, a fascination with repetitive meaningless motions. Voon pointed out a relationship between punding (repetition of individually acquired or learned behaviors arguably residing in sensorimotor corticostriato-thalamic circuits) and compulsions (repetition of evolutionarily selected patterns arguably residing in prefrontal or limbic circuits).13 Interestingly, dopamine agonists more commonly amplify the more species-wide and ‘inborn’ activities as compared with the individually acquired ones. Although firm recommendations cannot be made, we plan to educate patients about the potential for these drugs to distort libidinal drives or behaviors generally, with sexual and shopping compulsivity as specific examples. Our medium-term follow-up data indicates that in most cases gambling ceases or becomes controlled after withdrawal of dopamine agonists. Acknowledgement This research was unfunded. POS has received speaking fees from Boehringer Ingelheim, Glaxo Smith Kline, Pfizer and Novartis and research support from Glaxo Smith Kline, Pfizer and Novartis. RBD has received speaking fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva, and Vernalis and research support from Elan and Schwarz Pharma.
1181
References 1. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 2005;62:1377–81. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV TR). Washington, DC: American Psychiatric Association; 2000. 3. Litvan I, Bhatia KP, Burn DJ, et al. Movement Disorders Society Scientific Issues Committee report: SIC Task Force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 2003;18:467–86. 4. Thobois S. Proposed dose equivalence for rapid switch between dopamine receptor agonists in Parkinson’s disease: a review of the literature. Clin Ther 2006;28:1–12. 5. Seedat S, Kesler S, Niehaus DJ, et al. Pathological gambling behaviour: emergence secondary to treatment of Parkinson’s disease with dopaminergic agents. Depress Anxiety 2000;11:185–6. 6. Szarfman A, Doraiswamy PM, Tonning JM, et al. Association between pathologic gambling and parkinsonian therapy as detected in the Food and Drug Administration Adverse Event database. Arch Neurol 2006;63:299–300, author reply: 300. 7. Driver-Dunckley E, Samanta J, Stacy M. Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease. Neurology 2003;61:422–3. 8. Voon V, Hassan K, Zurowski M, et al. Prospective prevalence of pathologic gambling and medication association in Parkinson disease. Neurology 2006;66:1750–2. 9. Weintraub D, Siderowf AD, Potenza MN, et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006;63:969–73. 10. Pontone G, Williams JR, Bassett SS, et al. Clinical features associated with impulse control disorders in Parkinson disease. Neurology 2006;67:1258–61. 11. Shaffer HJ, Hall MN, Vander Bilt J. Estimating the prevalence of disordered gambling behavior in the United States and Canada: a research synthesis. Am J Public Health 1999;89:1369–76. 12. Blanco C, Hasin DS, Petry N, et al. Sex differences in subclinical and DSM-IV pathological gambling: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Psychol Med 2006;36:943–53. 13. Voon V. Repetition, repetition, and repetition: compulsive and punding behaviors in Parkinson’s disease. Mov Disord 2004;19:367–70.