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Original Investigation |

Reports of Pathological Gambling, Hypersexuality, and Compulsive Shopping Associated With Dopamine Receptor Agonist Drugs FREE

Thomas J. Moore, AB1,2; Joseph Glenmullen, MD3; Donald R. Mattison, MD, MS4
[+] Author Affiliations
1Institute for Safe Medication Practices, Alexandria, Virginia
2Department of Epidemiology and Biostatistics, The George Washington University Milken Institute School of Public Health, Washington, DC
3Department of Psychiatry, Cambridge Hospital, Harvard Medical School, Cambridge, Massachusetts
4McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, and Risk Sciences International, Ottawa, Ontario, Canada
JAMA Intern Med. 2014;174(12):1930-1933. doi:10.1001/jamainternmed.2014.5262.
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Importance  Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia.

Objectives  To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs.

Design, Setting, and Participants  We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System.

Main Outcomes and Measures  Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs.

Results  We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001).

Conclusions and Relevance  Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings.

Figures in this Article

The development of unusual but severe impulse control disorders has been reported for dopamine receptor agonist drugs used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia.1 The events typically involve behaviors such as pathological gambling, hypersexuality, compulsive shopping, and, less frequently, binge eating and punding (the compulsive fascination with and performance of repetitive mechanical tasks). They can have catastrophic effects on jobs, marriages, and family finances. Reports have indicated high prevalence rates, on the order of 6% to 24%.2,3 In numerous case reports, the abnormal behavior ceased on discontinuation of the dopamine receptor agonist drug, and in some case reports, it reappeared when therapy was resumed.4

The possibility that Parkinson disease might be the underlying cause of the impulse control disorders was discounted in part because the incidence was higher when dopamine receptor agonist drugs were used,5 and because the same pattern of aberrant behavior occurred in patients with 2 other disorders—restless leg syndrome3 and hyperprolactinemia.6 Most previous studies, however, were small case series or a cohort of a few dozen to a few hundred patients in a neurology practice.2,3

Dopamine receptor agonist drugs are commonly prescribed, accounting for 2.1 million dispensed outpatient prescriptions in the fourth quarter of 2012.7 Small surveys show that impulse control disorders may be unrecognized in more than 50% of cases,8 and some patients, even when asked, may minimize the disorder.2

To further characterize this association, we analyzed adverse drug event reports for the 6 dopamine receptor agonist drugs marketed in the United States. We used domestic and foreign reports extracted from the US Food and Drug Administration (FDA) database of reported adverse drug events to conduct a disproportionality analysis.

Because this study relied entirely on publicly available data previously reviewed for public release by the FDA, institutional review board approval was not sought. Our source data were computer excerpts of all domestic and foreign serious adverse drug event reports received by the FDA from 2003 to 2012. We excluded cases indicating they were from litigation or a clinical study, or that described an event with an outcome that was not serious under the FDA definition.9 The case population was also limited to unique reports with an identifiable therapeutic drug that accounted for 100 or more cases during the study period. In addition, to consider possible effects of the use of multiple medicines, the study event population was defined as a specific suspect drug–case report pair; if 2 suspect drugs were identified in the same case report, it was counted as 2 events. Impulse control disorder events were defined as reports that contained 1 or more of 10 descriptive terms selected from the Medical Dictionary for Regulatory Activities (MedDRA)10 as most consistent with the published reports (Table 1). The total study population totaled 2.7 million events of all types.

Table Graphic Jump LocationTable 1.  Frequency of Medical Dictionary for Regulatory Activities Preferred Terms Identifying Impulse Control Disorder Events

To assess the association between impulse control disorder cases and each specific suspect drug, we calculated the proportional reporting ratio (PRR), a ratio similar in concept to the relative risk ratio. To calculate the PRR, we compared the proportion of target events (impulse control events with drug A)/(all events with drug A) with an expected value (all other impulse control events)/(all other drug events). The null hypothesis for this study was that cases of impulse control disorders were attributed to the suspect drugs by pure chance; drugs with more total case reports might also accrue more target events. We calculated the binomial probability that the differences observed occurred by chance. This is the method of Evans et al,11 except that the large number of denominator events for all other drugs (2.7 million) compromised the value of the χ2 statistic, which was omitted.

We identified 1580 reports of pathological gambling, hypersexuality, compulsive shopping, and related impulse control disorders during the 10-year period for which we reviewed adverse drug event reports. Gambling was the most frequent impulse control behavior reported, with the term pathological gambling mentioned in 628 (39.7%) of the events, and gambling in 186 (11.8%). These were followed by hypersexuality, compulsive shopping, and poriomania (Table 1).

Table 2 shows the characteristics of the specific reported impulse control disorders for the dopamine receptor agonist drugs (710 [44.9%]) and for other drugs (870 [55.1%]). The reports related to dopamine receptor agonist drugs occurred in patients with a median age of 55 years (interquartile range, 46-63 years); 65.8% of the patients were male. Almost half the events associated with dopamine receptor agonist drugs occurred outside the United States, with 343 foreign reports (48.3%) from 21 countries. The drugs had been prescribed for Parkinson disease in 438 events (61.7%), restless leg syndrome in 169 events (23.8%), conditions associated with hyperprolactinemia in 25 events (3.5%), and other indications in 39 events (5.5%), or the information was missing in 39 events (5.5%). The number of reports for all drugs increased from 26 in 2003 to 303 in 2012 (Figure). The proportion of the reports associated with dopamine receptor agonist drugs was relatively stable during the 10-year period.

Table Graphic Jump LocationTable 2.  Characteristics of Reported Impulse Control Disorder Events for Dopamine Receptor Agonists and Other Drugs in the US Food and Drug Administration Database of Reported Adverse Drug Events, 2003-2012
Place holder to copy figure label and caption
Figure.
Trend Over Time for Reports of Pathological Gambling, Hypersexuality, and Related Impulse Control Disorders

Total domestic and foreign reports of serious injury received by the US Food and Drug Administration containing any of 10 terms in the Medical Dictionary for Regulatory Activities that characterize the impulse control disorder under study.

Graphic Jump Location

In the disproportionality analysis, the 6 dopamine receptor agonist drugs had a strong signal (PRR = 277.6, P < .001). Table 3 shows the results for the individual drugs; the PRR for each of the 6 drugs, analyzed individually, was high and statistically significant. Compared with dopamine receptor agonist drugs that were less selective, there was a stronger signal for agents with a preferential affinity for the dopamine D3 receptor, notably pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001). We also found a weaker signal for aripiprazole, an antipsychotic classified as partial agonist at the D3 receptor (n = 37; PRR = 8.6, P < .001).

Table Graphic Jump LocationTable 3.  Dopamine Receptor Agonist Drugs Associated With Impulse Control Disorder Events

We found signals for other drugs affecting dopamine availability that are not dopamine receptor agonist drugs, notably combinations of levodopa, carbidopa, entacapone, and benserazide (which is not approved in the United States). However, the dopamine agonist receptors were concomitant therapy drugs in 189 of 230 of these reports (82.2%). When cases of concomitant therapy with dopamine agonists were excluded, the signal for the other drugs affecting dopamine availability was attenuated, but still significant (n = 41; PRR = 43.9, P < .001).

We detected weaker signals for antidepressants (n = 146; PRR = 2.9, P < .001) and antipsychotics (n = 92; PRR = 2.0, P < .001), but not for antiepileptics (n = 46; PRR = 1.1, P = .05). Data for individual drugs in these categories are not shown.

Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with serious impulse control disorders; the associations were significant, the magnitude of the effects was large, and the effects were seen for all 6 dopamine receptor agonist drugs. It is unlikely that target events such as pathological gambling or hypersexuality were mistaken for a symptom of the underlying diseases such as restless leg syndrome. The signal for dopamine receptor agonist drugs with preferential affinity for the D3 receptor, a molecular target that is also under study for potential treatments of addiction,12 was markedly stronger than the signal for the less-selective agonists. Consistent with previous studies,2 we saw weaker signals for drugs that increase the availability of dopamine in the absence of concomitant therapy with dopamine receptor agonist drugs.

Our data share the limitations of spontaneous adverse event reports that are not collected systematically: an individual report does not itself prove a causal relationship, only that such a relationship was suspected; the number of reports does not provide useful information about incidence because of differences in exposure and variability in reporting rates; and the reporting rate for events is low, typically ranging from less than 1% to 10%, and up to 34% in unusual situations.13 Insufficient data were available to investigate dose or treatment duration.

We also considered whether our methods might have produced unintentionally biased results. We investigated whether some external event, media publicity, or litigation might have stimulated an unusual number of reports. The Figure indicates a steady growth of reports from both inside and outside of the United States for a decade; thus, it is unlikely that a spurt of publicity or specific events explained our findings. When we calculated the PRR for the dopamine agonist receptor drugs, we used as the comparison group all other drugs without restriction as to the type of drug. However, if the comparison group had been the other classes of psychotropic drugs described above, the PRR would have been reduced approximately by half but would have remained extremely high. As in other epidemiologic studies with very large total case populations, almost all comparisons were statistically significant, limiting the value of this statistical measure.

At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings about the potential for the development of severe impulse control disorders as part of their prescribing information. Our data, and data from prior studies, show the need for these prominent warnings. Physicians who prescribe dopamine agonists should also vigilantly monitor their patients, and ensure that patients, families, and caregivers are counseled about the risk of these serious adverse events.

Accepted for Publication: August 21, 2014.

Corresponding Author: Thomas J. Moore, AB, Institute for Safe Medication Practices, 101 N Columbus St, Ste 410, Alexandria, VA 22314 (tmoore@ismp.org).

Published Online: October 20, 2014. doi:10.1001/jamainternmed.2014.5262.

Author Contributions: Mr Moore had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: Moore, Mattison.

Drafting of the manuscript: Moore, Mattison.

Critical revision of the manuscript for important intellectual content: Glenmullen, Mattison.

Statistical analysis: Moore.

Administrative, technical, or material support: Mattison.

Conflict of Interest Disclosures: Mr Moore and Dr Glenmullen have been consultant or expert witnesses in civil and criminal litigation involving many psychiatric drugs and psychiatric adverse drug effects. None of this litigation has involved the 6 dopamine receptor agonist drugs that are primarily discussed in this article.

Disclaimer: This article is based in part on data obtained under license from the following IMS Health Incorporated information service: National Prescription Audit (September-December 2012). The statements, findings and conclusions, views, and opinions contained and expressed herein are not necessarily those of IMS Health Incorporated or any of its affiliated or subsidiary entities.

Kelley  BJ, Duker  AP, Chiu  P.  Dopamine agonists and pathologic behaviors. Parkinsons Dis. 2012;2012:603631. doi:10.1155/2012/603631.
Weiss  HD, Marsh  L.  Impulse control disorders and compulsive behaviors associated with dopaminergic therapies in Parkinson disease. Neurol Clin Pract. 2012;2(4):267-274. doi:10.1212/CPJ.0b013e318278be9b.
PubMed   |  Link to Article
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(1):81-87.
PubMed
Tippmann-Peikert  M, Park  JG, Boeve  BF, Shepard  JW, Silber  MH.  Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists. Neurology. 2007;68(4):301-303. doi:10.1212/01.wnl.0000252368.25106.b6.
PubMed   |  Link to Article
Voon  V, Hassan  K, Zurowski  M,  et al.  Prospective prevalence of pathologic gambling and medication association in Parkinson disease. Neurology. 2006;66(11):1750-1752. doi:10.1212/01.wnl.0000218206.20920.4d.
PubMed   |  Link to Article
Bancos  I, Nannenga  MR, Bostwick  JM, Silber  MH, Erickson  D, Nippoldt  TB.  Impulse control disorders in patients with dopamine agonist-treated prolactinomas and nonfunctioning pituitary adenomas: a case-control study. Clin Endocrinol (Oxf). 2014;80(6):863-868doi:10.1111/cen.12375.
PubMed   |  Link to Article
National Prescription Audit for 2012. Plymouth Meeting, PA: IMS Health Inc; 2012.
Weiss  HD, Hirsch  ES, Williams  JR, Swearengin  L, Marsh  L.  Detection of impulse control disorders in Parkinson disease patients. Neurologist. 2010;16(6):406-407. doi:10.1097/NRL.0b013e3181e8868b.
PubMed   |  Link to Article
Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines. (Draft Guidance). http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092257.pdf. Published 2001. Accessed September 4, 2014.
MedDRA MSSO. Introductory Guide MedDRA Version 16.1. Chantilly, VA: MedDRA Maintenance and Support Services Organization; 2013.
Evans  SJ, Waller  PC, Davis  S.  Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001;10(6):483-486. doi:10.1002/pds.677.
PubMed   |  Link to Article
Newman  AH, Blaylock  BL, Nader  MA, Bergman  J, Sibley  DR, Skolnick  P.  Medication discovery for addiction: translating the dopamine D3 receptor hypothesis. Biochem Pharmacol. 2012;84(7):882-890. doi:10.1016/j.bcp.2012.06.023.
PubMed   |  Link to Article
Moore  TJ, Bennett  CL.  Underreporting of hemorrhagic and thrombotic complications of pharmaceuticals to the U.S. Food and Drug Administration: empirical findings for warfarin, clopidogrel, ticlopidine, and thalidomide from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost. 2012;38(8):905-907. doi:10.1055/s-0032-1328890.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Trend Over Time for Reports of Pathological Gambling, Hypersexuality, and Related Impulse Control Disorders

Total domestic and foreign reports of serious injury received by the US Food and Drug Administration containing any of 10 terms in the Medical Dictionary for Regulatory Activities that characterize the impulse control disorder under study.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Frequency of Medical Dictionary for Regulatory Activities Preferred Terms Identifying Impulse Control Disorder Events
Table Graphic Jump LocationTable 2.  Characteristics of Reported Impulse Control Disorder Events for Dopamine Receptor Agonists and Other Drugs in the US Food and Drug Administration Database of Reported Adverse Drug Events, 2003-2012
Table Graphic Jump LocationTable 3.  Dopamine Receptor Agonist Drugs Associated With Impulse Control Disorder Events

References

Kelley  BJ, Duker  AP, Chiu  P.  Dopamine agonists and pathologic behaviors. Parkinsons Dis. 2012;2012:603631. doi:10.1155/2012/603631.
Weiss  HD, Marsh  L.  Impulse control disorders and compulsive behaviors associated with dopaminergic therapies in Parkinson disease. Neurol Clin Pract. 2012;2(4):267-274. doi:10.1212/CPJ.0b013e318278be9b.
PubMed   |  Link to Article
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(1):81-87.
PubMed
Tippmann-Peikert  M, Park  JG, Boeve  BF, Shepard  JW, Silber  MH.  Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists. Neurology. 2007;68(4):301-303. doi:10.1212/01.wnl.0000252368.25106.b6.
PubMed   |  Link to Article
Voon  V, Hassan  K, Zurowski  M,  et al.  Prospective prevalence of pathologic gambling and medication association in Parkinson disease. Neurology. 2006;66(11):1750-1752. doi:10.1212/01.wnl.0000218206.20920.4d.
PubMed   |  Link to Article
Bancos  I, Nannenga  MR, Bostwick  JM, Silber  MH, Erickson  D, Nippoldt  TB.  Impulse control disorders in patients with dopamine agonist-treated prolactinomas and nonfunctioning pituitary adenomas: a case-control study. Clin Endocrinol (Oxf). 2014;80(6):863-868doi:10.1111/cen.12375.
PubMed   |  Link to Article
National Prescription Audit for 2012. Plymouth Meeting, PA: IMS Health Inc; 2012.
Weiss  HD, Hirsch  ES, Williams  JR, Swearengin  L, Marsh  L.  Detection of impulse control disorders in Parkinson disease patients. Neurologist. 2010;16(6):406-407. doi:10.1097/NRL.0b013e3181e8868b.
PubMed   |  Link to Article
Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines. (Draft Guidance). http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092257.pdf. Published 2001. Accessed September 4, 2014.
MedDRA MSSO. Introductory Guide MedDRA Version 16.1. Chantilly, VA: MedDRA Maintenance and Support Services Organization; 2013.
Evans  SJ, Waller  PC, Davis  S.  Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001;10(6):483-486. doi:10.1002/pds.677.
PubMed   |  Link to Article
Newman  AH, Blaylock  BL, Nader  MA, Bergman  J, Sibley  DR, Skolnick  P.  Medication discovery for addiction: translating the dopamine D3 receptor hypothesis. Biochem Pharmacol. 2012;84(7):882-890. doi:10.1016/j.bcp.2012.06.023.
PubMed   |  Link to Article
Moore  TJ, Bennett  CL.  Underreporting of hemorrhagic and thrombotic complications of pharmaceuticals to the U.S. Food and Drug Administration: empirical findings for warfarin, clopidogrel, ticlopidine, and thalidomide from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost. 2012;38(8):905-907. doi:10.1055/s-0032-1328890.
PubMed   |  Link to Article

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