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Impulse control disorders in Parkinson's disease in a Chinese population
Neuroscience Letters 465 (2009) 6–9
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Impulse control disorders in Parkinson’s disease in a Chinese population WenHui Fan, Hui Ding, JingHong Ma, Piu Chan ∗ Department of Neurology and Neurobiology, Key Laboratory of Neurodegenerative Disease of Ministry of Education, Beijing Institution of Geriatrics and Xuanwu Hospital of Capital Medical University, China
a r t i c l e
i n f o
Article history: Received 15 April 2009 Received in revised form 20 May 2009 Accepted 19 June 2009 Keywords: Parkinson’s disease Impulse control disorder Chinese
a b s t r a c t Background: Dopamine agonists have been used as first-line treatments for patients with Parkinson’s disease (PD) during its early stage, and several impulse control disorder (ICD) behaviors have been reported to be associated with their use. Objective: To investigate the association between ICD behaviors and the use of agonists in Chinese patients with PD and associated risk factors. Methods: Self-report screening questionnaires were mailed to 400 PD patients treated with anti-parkinsonian drugs in our clinical database and their spouses (served as control group). Those who screened positive for ICD behaviors by questionnaire were further interviewed over the telephone by a movement disorder specialist to confirm the diagnosis. Results: A total of 11 (3.53%) patients were diagnosed with ICD behaviors as follows: lifetime pathological gambling (1, 0.32%); subclinical or clinical hypersexuality (6, 1.92%); binge eating (1, 0.32%); dopamine dysregulation syndrome (2, 0.64%); and compulsive internet browsing (1, 0.32%). ICD behaviors were associated with an increased mean levodopa equivalent daily dosage and alcohol use (p = 0.005 and p = 0.002, respectively). Patients using dopamine agonists were significantly (p = 0.003) more likely to be diagnosed with an ICD (6.3%) as compared to those who were not (0.6%). Conclusion: PD patients who took dopamine agonists were more likely to report ICD behaviors in Chinese PD. © 2009 Published by Elsevier Ireland Ltd.
In recent years, dopamine agonists have been used as first-line treatments for Parkinson’s disease (PD), particularly in its early stage, because they attenuate motor symptoms and may postpone levodopa-induced dyskinesia [22]. In 2003, Driver-Dunckley et al. reported cases of pathological gambling associated with the use of dopamine agonists in PD patients [6]. Following this, compulsive shopping [26] and punding [13], pathological hypersexuality [26,30,8] and other behaviors [7] categorized as impulse control disorders (ICDs) were also reported in those using dopamine agonists. Several studies have investigated the frequency and risk factors for ICDs in PD patients in Canada [3], Israel [8], Italy [1], and America [26,30], but there is no such report for the Chinese population. The use of agonists in the past was not common in China with an average of 20–30% patients ever used in our survey. This is due to the limited availability and economics since most of the agonists were not covered by the insurance. In recent years, there are more agonists are available and economics is improved significantly which leads to more prescription to patients. In this preliminary study, we intended to investigate the association between anti-parkinsonian
∗ Corresponding author at: Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, #45 Changchun Street, Beijing 100053, China. Tel.: +86 10 83198677; fax: +86 10 83161294. E-mail address: [email protected] (P. Chan). 0304-3940/$ – see front matter © 2009 Published by Elsevier Ireland Ltd. doi:10.1016/j.neulet.2009.06.074
medication and lifestyle and ICD behaviors and its frequency in Chinese PD patients. Four-hundred patients with idiopathic PD and ever treated with anti-parkinsonian medication were selected from the clinical database of the center on neurodegenerative disorders at the Xuanwu Hospital. The PD diagnosis was made according to the United Kingdom Parkinson’s Disease Society Brain Bank Criteria [10]. Exclusion criteria included atypical parkinsonism, secondary parkinsonism, and cognitive abnormality that might interfere with the understanding of questionnaires. Two copies of the self-report screening questionnaires were mailed out to the subjects with instructions and consent forms. The spouses or caregivers of the subjects were also asked to fill the same questionnaire to serve as the control group and from them, we could acknowledge how the spouse would respond to the survey. All subjects were asked to send back the finished questionnaires in the postage-paid envelope. The study was approved by the hospital institutional review board. Written informed consent was obtained from all subjects and controls; strict measures were taken to ensure confidentiality. The questionnaires included a modified South Oaks Gambling Screen (SOGS), the Lejoyeux’s Compulsive Shopping questionnaire [12], and a specially designed hypersexuality questionnaire [26]. There were also items to detect binge eating, drug addiction, dopamine dysregulation syndrome, and internet addiction based on DSM-IV definitions [25,2] of these compulsive behaviors and their characteristics. Most items were relatively straightforward to
W. Fan et al. / Neuroscience Letters 465 (2009) 6–9 Table 1 Clinical characteristics of PD patients and controls.
Number of case Male, n (%) Age, year Disease duration, year Medication Levodopa, n (%) Levodopa + agonist, n (%) Levodopa + amantadine, n (%) Agonist only, n (%) Levodopa + agonist + (artane or amantadine), n (%) Others
PD patients
Controls
312 193 (61.9%) 65.77 (10.49) 5.67 (2.92)
132 49 (37.1%) 61.93 (13.52) –
86 (27.56%) 71 (22.76%) 41 (13.14%) 3 (0.96%) 56 (17.95%)
– – – – –
55 (17.63%)
–
be best understood by the subjects. Patients who screened positive for ICDs by the questionnaire were further interviewed over the telephone by a neurologist, who used DSM-IV diagnostic criteria for pathological gambling, drug addiction, internet addiction and compulsive binge eating to determine potential ICD and addiction behaviors. As defined by Voon et al. [26], hypersexuality, excessive sexual behaviors and thoughts, and atypical sexual changes must have persisted for more than one month, caused marked distress, or been time-consuming enough to interfere with social or occupational functions; unsuccessful control of these behaviors or thoughts and marked anxiety or distress (excluding episodes during mania or hypermania) are also included in Voon et al.’s description of ICD behaviors. If the above criteria were not met, the subject’s ICD behaviors were deemed subclinical. Detailed information including age, gender, disease duration, and presence/absence of spontaneous remission, daily dosage of medication, cigarette and alcohol consumption was also collected in the questionnaire. The spouses of all subjects screen positive were also interviewed by telephone to confirm the ICD behaviors provided by the positive subjects to help the diagnosis. The mean levodopa equivalent daily dose (LEDD) and total LEDD were calculated by formula noted in Table 3. Independent-sample t-tests and the Fisher’s exact test were used to compare age, gender, onset age, disease duration, and medication type and dosage of anti-parkinsonism drugs between PD patients with and without ICD behaviors at a two-sided significant level of p < 0.05. Logistic regression was used to investigate the interaction among the potential risk factors for ICD behaviors. A total of 312 patients (response rate 78%) and 132 (33%) controls mailed back their questionnaires (Table 1). Age, gender, and disease duration were not different between patients who returned questionnaires and those who did not (p = 0.223, 0.667, and 0.166, respectively). Among participants of the PD patients, 193 (61.9%)
7
were male, and 119 (38.1%) were female; the mean age was 65.77 years (range: 34–88) and mean disease duration was 5.67 years (range: 1–19). All PD patients were taking anti-parkinsonism drugs. For those taken levodopa, the average daily dose ranged from 50 to 1175 mg/d. Total 143 patients ever took dopamine agonists, with a LEDD ranging from 2.5 to 401.63 mg/d. Among control group who filled and mailed back questionnaire, there were 49 males and 83 females, with a mean age of 61.93 years. Forty-two PD patients had screened positive for ICD behaviors, and 12 of these patients refused telephone interview, and 30 were interviewed by a neurologist. Among PD patients interviewed, 11 (3.53%) fulfilled criteria for lifetime or concurrent ICDs; and their behaviors and medications are listed in Table 2. A total of 10/11 patients with ICD behaviors were taking piribedil. None of the control subjects has screened positive for ICD behaviors. The age, PD onset age, disease duration and gender of the 12 PD subjects who refused further interview did not differ from that of the 30 patients who responded (data not shown). Overall, 6 (1.92%) PD patients were diagnosed with hypersexuality according to the hypersexuality diagnostic criteria [26]. Two described excessive sexual thoughts, use of pornography, or increased libido that decreased or disappeared after stopping use of the agonist or changing to another drug. In addition, three patients who denied hypersexuality had spouses who noted excessive sexual behavior. One patient had excessive sexual thoughts but denied distress or interference with his daily life and was diagnosed as subclinical. One patient described binge eating after taking agonist and anti-depression drugs and gained 10 kg in 6 months; another spent up to 8 h internet browsing every day in average. One patient yelled and threw items at family members after taking dopamine agonist medication and was diagnosed as having an intermittent explosive disorder. There was one patient with a lifetime history of pathological gambling before PD onset. There were no patients who reported compulsive shopping or a compulsive hobby addiction. Ten (6.3%) out of 143 patients taking dopamine agonists and 1/169 (0.6%) patients not taking dopamine agonists developed ICD behaviors (p = 0.003). Patients who had ever used two or more agonists (5/29, 17.2%) had a much higher frequency of ICD behaviors compared to those who had used only a single agonist (5/114, 4.4%) (p = 0.029). Clinical characteristics of patients with and without ICD behaviors are shown in Table 3. Although the mean ages and disease-onset ages of PD patients with ICD behaviors were younger than those without ICDs, the differences were not statistically significant. Ten out of 11 PD patients with ICD behaviors were males (90.91%), compared with 193/301 without (61.90%) (p = 0.059). In patients with ICD behaviors, LEDD and total LEDD were higher as compared to those without; however, only the difference in LEDD alone
Table 2 ICD behaviors in patients with Parkinson’s disease. Case
Gender
Age, year
PD duration, year
Concurrent medication
Previously used agonist
Total LEDD (mg/d)
Possible ICD behaviors
1 2 3
M F M
62 53 71
7 9 5
Levodopa + piribedil Levodopa + piribedil Levodopa + piribedil
625 1000 460
4 5
M M
64 61
7 5
Levodopa + piribedil + pramipexole Piribedil
Pergolide – Ergocriptine, bromocriptine Ergocriptine –
6 7 8 9
M M M M
71 56 60 75
4 3 3 9
Levodopa + piribedil Levodopa + amantadine Levodopa + amantadine + piribedil Levodopa + piribedil
300 300 600 681.94
PG (before PD onset) Binge eating, DA addiction Compulsive internet browsing Pornography Intermittent explosive disorder Sexual orgasm DA addiction Subclinical hypersexuality Hypersexuality
10 11
M M
68 63
7 3
Levodopa + amantadine + piribedil Amantadine + artane + piribedil
400 50
Hypersexuality Hypersexuality
Bromocriptine – – Pergolide, ergocriptine pramipexole – –
Note: DA = dopamine; PG = pathological gambling; ICD = impulsive control disorder; LEDD = levodopa equivalent daily dose.
801.63 100
8
W. Fan et al. / Neuroscience Letters 465 (2009) 6–9
Table 3 Comparison between patients with and without ICD behaviors.
Number of case Age, year, mean (SD) Male, n (%) Disease duration (year), mean (SD) Onset age (year), mean (SD) Daily levodopa dose (mg/d), mean (SD) LEDD (mg/d), mean (SD) Total LEDD (mg/d), mean (SD) Cigarette consumption (pack year), mean (SD) Current smoker, n (%) Alcohol user, n (%) Alcohol addiction, n (%) Daily alcohol consumption, drink/day (1 drink = 1.25 oz hard liquor, 12 oz beer, 4–5 oz wine) mean (SD) Coffer user, n (%) PD family history Diazepam use, n (%) Exercise time, h/day, mean (SD) Onset side, n (%)
Without ICD
ICD
p value
301 65.86 (10.55) 193/301 (61.9%) 5.70 (2.94) 60.08 (10.61) 357.01 (211.89) 35.45 (49.96) 392.46 (224.71) 39.75 (149.59) 34 (11.4%) 40 (13.4%) 10 (3.3%) 0.54 (2.01)
11 64.15 (6.84) 10/11 (90.91%) 5.36 (2.54) 58.73 (6.72) 345.45 (242.34) 142.37 (100.61) 487.82 (289.04) 158.18 (279.21) 3 (27.3%) 6 (54.5%) 1 (9.1%) 5.00 (14.95)
0.595 0.059 0.709 0.675 0.860 0.005 0.172 0.191 0.132 0.002 0.332 0.345
14 (4.7%) 12/82 (4%) 57 (19.1%) 1.30 (1.12) Right side: 150 (50.2%) Left side: 129 (43.1%) Both sides: 20 (6.7%)
0 (0%) 2/2 (100%) 3 (27.3%) 1.13 (0.63) Right side: 4 (36.4%) Left side: 7 (63.6%)
– – 0.451 0.765 0.541 0.222
Note: LEDD (mg/d) = piribedil (mg/d) × 1 + pramipexole (mg/d) × 67.75 + pergolide (mg/d) × 100 + ropinirole (mg/d) × 16.67 + bromocriptine (mg/d) × 10 + ergocriptine (mg/d) × 2.5. Total LEDD (mg/d) = regular levodopa dose (mg/d) × 1 + levodopa CR dose (mg/d) × 0.75 + LEDD, and plus [regular levodopa dose (mg/d) + CR levodopa dose (mg/d) × 0.75] × 0.25 if taking COMT-I.
was significant (142.37 mg vs. 35.45 mg, p = 0.005). Mean levodopa equivalent daily dose was comparable between patients with and without ICD behaviors. There was lower frequency of alcohol (13.4% vs. 54.5%, p = 0.002) and cigarette consumption (11.4% vs. 27.3%, p = 0.132) and prescribed sedatives such as diazepam (19.1% vs. 27.3%, p = 0.451) in those without ICD behaviors. There was no difference in frequency of ICD behaviors between PD patients who used amantadine (5/125, 4.1%) and those who had not (6/187, 3.2%) (p = 0.760). With logistic analysis, it was found that the use of agonists (OR 5.968, 95% CI: 2.714–13.125) and alcohol daily consumption (OR 1.115, 95% CI: 1.010–1.231) were independent risk factors for ICD behavior, respectively, but not LEDD (OR 1.007, 95% CI: 0.996–1.019). We here reported an association between use of levedopa and agonists and ICD behaviors, with a dose-dependent relationship in Chinese patients. The frequency of ICD behavior (3.53%) in Chinese PD patients was lower than in previous studies in non-Chinese populations (6.3–14%) [26,30,8]. In our study, use of agonists (particularly D3 agonists), and alcohol consumption were risk factors for ICD behaviors. Pathological gambling, though common in Caucasian PD patients, was rare in our Chinese population. A lower frequency of ICD behaviors was found in our study. It is generally believed that the questionnaire-based survey underestimated the prevalence of ICD. Partly questionnaires were firstly used in Chinese population may also under-ascertain the frequency. However, the lower frequency of ICD behaviors in our Chinese population may reflect a lower dosage of levodopa use (average levodopa dosage in our study was 357 mg/d) and lower ever use of agonists (45.83% in our population compared to a range of 50.4–68.0% in Western countries [6,30,18]). This is further supported by the fact that a higher rate of use of agonists in our center as a movement disorder referral center as compared to the national level in China. In addition, social and economic differences between China and Western countries may play a role. Indeed, the D3 agonist, pramipexole, has only been available in China since 2007. Whether or not genetic background may also be a consideration warrants further investigation since Chinese and Caucasian populations may have different distributions of dopamine receptor polymorphisms [29].
Interestingly, 10/11 PD patients with ICD behaviors were taking piribedil since it has been available in China for more than 10 years in China, while most other studies have related pramipexole use to ICDs in Western countries [11,21,16,5]. Piribedil activates postsynaptic D2 receptors in the substantia-striatal pathway, as well as D2 and D3 receptors in mesencephal-cortical and mesencephal-limbic pathways, which are involved in the control of motion and mental states. Although pergolide, a D2 agonist, was also quite commonly used in China before 2008, we did not find any PD patients with ICD behaviors associated with its use. Our results may support the idea that overactivation of D3 receptors plays an important role in inducing ICD behaviors in PD patients. A prospective follow-up study of ICD behaviors in Chinese PD patients taking pramipexole is warranted. A higher pathological gambling incidence (7.2–8%) in patients taking dopamine agonists has been reported in previous studies in Caucasian populations [30,3,27,20] but has not necessarily been linked to the dose [27,20], treatment duration, or agonist subtype [30,27,20]. Although most of PD or restless leg syndrome (RLS) patients with pathological gambling behaviors were taking pramipexole [13,30], other medications including bromocriptine [15] and levodopa [14] have also been linked to these behaviors. However, in our study, only one patient reported a lifetime history of pathological gambling, and it manifested before the onset of PD which is not consistent with behaviors seen in previous studies [30,8,3,1,14,27,20,9,28]. The prevalence of pathological gambling has been reported as 0.4–4.2% in the general Caucasian population [3,17,4,24] and 2.6–9.3% in PD patients with anti-parkinsonsim medications [30,3,1,27,20,9]. The fact that gambling is forbidden in the mainland China and is more easily accessible in other countries may be related to these differences. Similar to other reports, hypersexuality was the most common ICD behavior identified in our study. Approximately 2.2–8.33% of PD patients taking pramipexole, levodopa, or selegiline reported hypersexuality in other studies [26,30,16,20,23,19], and 1.92% of our PD patients fulfilled the criteria for pathological hypersexuality. All these patients were taking piribedil; five of them were also taking levodopa, and one was taking pramipexole. Pathologi-
W. Fan et al. / Neuroscience Letters 465 (2009) 6–9
cal hypersexuality disappeared in two patients following piribedil cessation (n = 1) or a change to pergolide (n = 1). There was no difference in mean age, age at disease onset, disease duration, mean and total LEDD, cigarette consumption, or diazepam between patients with and without ICD behaviors. In other studies, however, younger onset age of motor symptoms was associated with development of ICD behaviors [26,8]. Gender difference was almost statistically significant (90.91% vs. 61.9%, p = 0.059) between patients with and without ICD behaviors, suggesting the possibility that male patients taking medication may be more likely to develop ICD behaviors. Compulsive shopping or hobbyism was not found in our study. Our results indicate that differences in lifestyle and anti-parkinsonism drug use as compared to other studies make it difficult to compare with other populations. The limitations of our study include that it was conducted by mail and telephone interview, and we could not assess conditions such as depression, anxiety, and diminished cognitive function that may have confounded the results. Additionally, self-report, questionnaire-based methods as well as 12 PD patients screened positive refused to be interviewed may limit accurate determination of the frequency of ICD behaviors. More rigorous investigation in a cohort of randomized PD patients and age, gender-matched normal controls is warranted. In conclusion, ICD behaviors were not uncommon in PD patients in China, especially in those treated with D3 agonists and used alcohol. Although there are similarities in ICD behaviors among PD patients in different countries, variations in cultural background, social economics, genetic makeup, and the behavior of use of anti-parkinsonism drugs may confound comparisons across populations. Acknowledgements We thank Dr. Sam Goldman for reviewing the manuscript. This study was supported by grants from the Ministry of Sciences and Technology of China (2004BA702B02, 2006AA02A408, 2008ZX09312-014), and Beijing Natural Science Foundation (7031002). References [1] M. Avanzi, M. Baratti, S. Cabrini, E. Uber, G. Brighetti, F. Bonfa, Prevalence of pathological gambling in patients with Parkinson’s disease, Mov. Disord. 21 (12) (2006) 2068–2072. [2] K.W. Beard, E.M. Wolf, Modification in the proposed diagnostic criteria for Internet addiction, Cyberpsychol. Behav. 4 (3) (2001) 377–383. [3] D. Crockford, J. Quickfall, S. Currie, S. Furtado, O. Suchowersky, N. El-Guebaly, Prevalence of problem and pathological gambling in Parkinson’s disease, J. Gambl. Stud. 24 (4) (2008) 411–422. [4] R.M. Cunningham-Williams, R.A. Grucza, L.B. Cottler, S.B. Womack, S.J. Books, T.R. Przybeck, E.L. Spitznagel, C.R. Cloninger, Prevalence and predictors of pathological gambling: results from the St. Louis personality, health and lifestyle (SLPHL) study, J Psychiatr Res 39 (2005) 377–390. [5] M.L. Dodd, K.J. Klos, J.H. Bower, Y.E. Geda, K.A. Josephs, J.E. Ahlskog, Pathological gambling caused by drugs used to treat Parkinson disease, Arch. Neurol. 62 (9) (2005) 1377–1381. [6] E. Driver-Dunckley, J. Samanta, M. Stacy, Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease, Neurology 61 (3) (2003) 422–423.
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Impulse control disorders in Parkinson’s disease in a Chinese population WenHui Fan, Hui Ding, JingHong Ma, Piu Chan ∗ Department of Neurology and Neurobiology, Key Laboratory of Neurodegenerative Disease of Ministry of Education, Beijing Institution of Geriatrics and Xuanwu Hospital of Capital Medical University, China
a r t i c l e
i n f o
Article history: Received 15 April 2009 Received in revised form 20 May 2009 Accepted 19 June 2009 Keywords: Parkinson’s disease Impulse control disorder Chinese
a b s t r a c t Background: Dopamine agonists have been used as first-line treatments for patients with Parkinson’s disease (PD) during its early stage, and several impulse control disorder (ICD) behaviors have been reported to be associated with their use. Objective: To investigate the association between ICD behaviors and the use of agonists in Chinese patients with PD and associated risk factors. Methods: Self-report screening questionnaires were mailed to 400 PD patients treated with anti-parkinsonian drugs in our clinical database and their spouses (served as control group). Those who screened positive for ICD behaviors by questionnaire were further interviewed over the telephone by a movement disorder specialist to confirm the diagnosis. Results: A total of 11 (3.53%) patients were diagnosed with ICD behaviors as follows: lifetime pathological gambling (1, 0.32%); subclinical or clinical hypersexuality (6, 1.92%); binge eating (1, 0.32%); dopamine dysregulation syndrome (2, 0.64%); and compulsive internet browsing (1, 0.32%). ICD behaviors were associated with an increased mean levodopa equivalent daily dosage and alcohol use (p = 0.005 and p = 0.002, respectively). Patients using dopamine agonists were significantly (p = 0.003) more likely to be diagnosed with an ICD (6.3%) as compared to those who were not (0.6%). Conclusion: PD patients who took dopamine agonists were more likely to report ICD behaviors in Chinese PD. © 2009 Published by Elsevier Ireland Ltd.
In recent years, dopamine agonists have been used as first-line treatments for Parkinson’s disease (PD), particularly in its early stage, because they attenuate motor symptoms and may postpone levodopa-induced dyskinesia [22]. In 2003, Driver-Dunckley et al. reported cases of pathological gambling associated with the use of dopamine agonists in PD patients [6]. Following this, compulsive shopping [26] and punding [13], pathological hypersexuality [26,30,8] and other behaviors [7] categorized as impulse control disorders (ICDs) were also reported in those using dopamine agonists. Several studies have investigated the frequency and risk factors for ICDs in PD patients in Canada [3], Israel [8], Italy [1], and America [26,30], but there is no such report for the Chinese population. The use of agonists in the past was not common in China with an average of 20–30% patients ever used in our survey. This is due to the limited availability and economics since most of the agonists were not covered by the insurance. In recent years, there are more agonists are available and economics is improved significantly which leads to more prescription to patients. In this preliminary study, we intended to investigate the association between anti-parkinsonian
∗ Corresponding author at: Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, #45 Changchun Street, Beijing 100053, China. Tel.: +86 10 83198677; fax: +86 10 83161294. E-mail address: [email protected] (P. Chan). 0304-3940/$ – see front matter © 2009 Published by Elsevier Ireland Ltd. doi:10.1016/j.neulet.2009.06.074
medication and lifestyle and ICD behaviors and its frequency in Chinese PD patients. Four-hundred patients with idiopathic PD and ever treated with anti-parkinsonian medication were selected from the clinical database of the center on neurodegenerative disorders at the Xuanwu Hospital. The PD diagnosis was made according to the United Kingdom Parkinson’s Disease Society Brain Bank Criteria [10]. Exclusion criteria included atypical parkinsonism, secondary parkinsonism, and cognitive abnormality that might interfere with the understanding of questionnaires. Two copies of the self-report screening questionnaires were mailed out to the subjects with instructions and consent forms. The spouses or caregivers of the subjects were also asked to fill the same questionnaire to serve as the control group and from them, we could acknowledge how the spouse would respond to the survey. All subjects were asked to send back the finished questionnaires in the postage-paid envelope. The study was approved by the hospital institutional review board. Written informed consent was obtained from all subjects and controls; strict measures were taken to ensure confidentiality. The questionnaires included a modified South Oaks Gambling Screen (SOGS), the Lejoyeux’s Compulsive Shopping questionnaire [12], and a specially designed hypersexuality questionnaire [26]. There were also items to detect binge eating, drug addiction, dopamine dysregulation syndrome, and internet addiction based on DSM-IV definitions [25,2] of these compulsive behaviors and their characteristics. Most items were relatively straightforward to
W. Fan et al. / Neuroscience Letters 465 (2009) 6–9 Table 1 Clinical characteristics of PD patients and controls.
Number of case Male, n (%) Age, year Disease duration, year Medication Levodopa, n (%) Levodopa + agonist, n (%) Levodopa + amantadine, n (%) Agonist only, n (%) Levodopa + agonist + (artane or amantadine), n (%) Others
PD patients
Controls
312 193 (61.9%) 65.77 (10.49) 5.67 (2.92)
132 49 (37.1%) 61.93 (13.52) –
86 (27.56%) 71 (22.76%) 41 (13.14%) 3 (0.96%) 56 (17.95%)
– – – – –
55 (17.63%)
–
be best understood by the subjects. Patients who screened positive for ICDs by the questionnaire were further interviewed over the telephone by a neurologist, who used DSM-IV diagnostic criteria for pathological gambling, drug addiction, internet addiction and compulsive binge eating to determine potential ICD and addiction behaviors. As defined by Voon et al. [26], hypersexuality, excessive sexual behaviors and thoughts, and atypical sexual changes must have persisted for more than one month, caused marked distress, or been time-consuming enough to interfere with social or occupational functions; unsuccessful control of these behaviors or thoughts and marked anxiety or distress (excluding episodes during mania or hypermania) are also included in Voon et al.’s description of ICD behaviors. If the above criteria were not met, the subject’s ICD behaviors were deemed subclinical. Detailed information including age, gender, disease duration, and presence/absence of spontaneous remission, daily dosage of medication, cigarette and alcohol consumption was also collected in the questionnaire. The spouses of all subjects screen positive were also interviewed by telephone to confirm the ICD behaviors provided by the positive subjects to help the diagnosis. The mean levodopa equivalent daily dose (LEDD) and total LEDD were calculated by formula noted in Table 3. Independent-sample t-tests and the Fisher’s exact test were used to compare age, gender, onset age, disease duration, and medication type and dosage of anti-parkinsonism drugs between PD patients with and without ICD behaviors at a two-sided significant level of p < 0.05. Logistic regression was used to investigate the interaction among the potential risk factors for ICD behaviors. A total of 312 patients (response rate 78%) and 132 (33%) controls mailed back their questionnaires (Table 1). Age, gender, and disease duration were not different between patients who returned questionnaires and those who did not (p = 0.223, 0.667, and 0.166, respectively). Among participants of the PD patients, 193 (61.9%)
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were male, and 119 (38.1%) were female; the mean age was 65.77 years (range: 34–88) and mean disease duration was 5.67 years (range: 1–19). All PD patients were taking anti-parkinsonism drugs. For those taken levodopa, the average daily dose ranged from 50 to 1175 mg/d. Total 143 patients ever took dopamine agonists, with a LEDD ranging from 2.5 to 401.63 mg/d. Among control group who filled and mailed back questionnaire, there were 49 males and 83 females, with a mean age of 61.93 years. Forty-two PD patients had screened positive for ICD behaviors, and 12 of these patients refused telephone interview, and 30 were interviewed by a neurologist. Among PD patients interviewed, 11 (3.53%) fulfilled criteria for lifetime or concurrent ICDs; and their behaviors and medications are listed in Table 2. A total of 10/11 patients with ICD behaviors were taking piribedil. None of the control subjects has screened positive for ICD behaviors. The age, PD onset age, disease duration and gender of the 12 PD subjects who refused further interview did not differ from that of the 30 patients who responded (data not shown). Overall, 6 (1.92%) PD patients were diagnosed with hypersexuality according to the hypersexuality diagnostic criteria [26]. Two described excessive sexual thoughts, use of pornography, or increased libido that decreased or disappeared after stopping use of the agonist or changing to another drug. In addition, three patients who denied hypersexuality had spouses who noted excessive sexual behavior. One patient had excessive sexual thoughts but denied distress or interference with his daily life and was diagnosed as subclinical. One patient described binge eating after taking agonist and anti-depression drugs and gained 10 kg in 6 months; another spent up to 8 h internet browsing every day in average. One patient yelled and threw items at family members after taking dopamine agonist medication and was diagnosed as having an intermittent explosive disorder. There was one patient with a lifetime history of pathological gambling before PD onset. There were no patients who reported compulsive shopping or a compulsive hobby addiction. Ten (6.3%) out of 143 patients taking dopamine agonists and 1/169 (0.6%) patients not taking dopamine agonists developed ICD behaviors (p = 0.003). Patients who had ever used two or more agonists (5/29, 17.2%) had a much higher frequency of ICD behaviors compared to those who had used only a single agonist (5/114, 4.4%) (p = 0.029). Clinical characteristics of patients with and without ICD behaviors are shown in Table 3. Although the mean ages and disease-onset ages of PD patients with ICD behaviors were younger than those without ICDs, the differences were not statistically significant. Ten out of 11 PD patients with ICD behaviors were males (90.91%), compared with 193/301 without (61.90%) (p = 0.059). In patients with ICD behaviors, LEDD and total LEDD were higher as compared to those without; however, only the difference in LEDD alone
Table 2 ICD behaviors in patients with Parkinson’s disease. Case
Gender
Age, year
PD duration, year
Concurrent medication
Previously used agonist
Total LEDD (mg/d)
Possible ICD behaviors
1 2 3
M F M
62 53 71
7 9 5
Levodopa + piribedil Levodopa + piribedil Levodopa + piribedil
625 1000 460
4 5
M M
64 61
7 5
Levodopa + piribedil + pramipexole Piribedil
Pergolide – Ergocriptine, bromocriptine Ergocriptine –
6 7 8 9
M M M M
71 56 60 75
4 3 3 9
Levodopa + piribedil Levodopa + amantadine Levodopa + amantadine + piribedil Levodopa + piribedil
300 300 600 681.94
PG (before PD onset) Binge eating, DA addiction Compulsive internet browsing Pornography Intermittent explosive disorder Sexual orgasm DA addiction Subclinical hypersexuality Hypersexuality
10 11
M M
68 63
7 3
Levodopa + amantadine + piribedil Amantadine + artane + piribedil
400 50
Hypersexuality Hypersexuality
Bromocriptine – – Pergolide, ergocriptine pramipexole – –
Note: DA = dopamine; PG = pathological gambling; ICD = impulsive control disorder; LEDD = levodopa equivalent daily dose.
801.63 100
8
W. Fan et al. / Neuroscience Letters 465 (2009) 6–9
Table 3 Comparison between patients with and without ICD behaviors.
Number of case Age, year, mean (SD) Male, n (%) Disease duration (year), mean (SD) Onset age (year), mean (SD) Daily levodopa dose (mg/d), mean (SD) LEDD (mg/d), mean (SD) Total LEDD (mg/d), mean (SD) Cigarette consumption (pack year), mean (SD) Current smoker, n (%) Alcohol user, n (%) Alcohol addiction, n (%) Daily alcohol consumption, drink/day (1 drink = 1.25 oz hard liquor, 12 oz beer, 4–5 oz wine) mean (SD) Coffer user, n (%) PD family history Diazepam use, n (%) Exercise time, h/day, mean (SD) Onset side, n (%)
Without ICD
ICD
p value
301 65.86 (10.55) 193/301 (61.9%) 5.70 (2.94) 60.08 (10.61) 357.01 (211.89) 35.45 (49.96) 392.46 (224.71) 39.75 (149.59) 34 (11.4%) 40 (13.4%) 10 (3.3%) 0.54 (2.01)
11 64.15 (6.84) 10/11 (90.91%) 5.36 (2.54) 58.73 (6.72) 345.45 (242.34) 142.37 (100.61) 487.82 (289.04) 158.18 (279.21) 3 (27.3%) 6 (54.5%) 1 (9.1%) 5.00 (14.95)
0.595 0.059 0.709 0.675 0.860 0.005 0.172 0.191 0.132 0.002 0.332 0.345
14 (4.7%) 12/82 (4%) 57 (19.1%) 1.30 (1.12) Right side: 150 (50.2%) Left side: 129 (43.1%) Both sides: 20 (6.7%)
0 (0%) 2/2 (100%) 3 (27.3%) 1.13 (0.63) Right side: 4 (36.4%) Left side: 7 (63.6%)
– – 0.451 0.765 0.541 0.222
Note: LEDD (mg/d) = piribedil (mg/d) × 1 + pramipexole (mg/d) × 67.75 + pergolide (mg/d) × 100 + ropinirole (mg/d) × 16.67 + bromocriptine (mg/d) × 10 + ergocriptine (mg/d) × 2.5. Total LEDD (mg/d) = regular levodopa dose (mg/d) × 1 + levodopa CR dose (mg/d) × 0.75 + LEDD, and plus [regular levodopa dose (mg/d) + CR levodopa dose (mg/d) × 0.75] × 0.25 if taking COMT-I.
was significant (142.37 mg vs. 35.45 mg, p = 0.005). Mean levodopa equivalent daily dose was comparable between patients with and without ICD behaviors. There was lower frequency of alcohol (13.4% vs. 54.5%, p = 0.002) and cigarette consumption (11.4% vs. 27.3%, p = 0.132) and prescribed sedatives such as diazepam (19.1% vs. 27.3%, p = 0.451) in those without ICD behaviors. There was no difference in frequency of ICD behaviors between PD patients who used amantadine (5/125, 4.1%) and those who had not (6/187, 3.2%) (p = 0.760). With logistic analysis, it was found that the use of agonists (OR 5.968, 95% CI: 2.714–13.125) and alcohol daily consumption (OR 1.115, 95% CI: 1.010–1.231) were independent risk factors for ICD behavior, respectively, but not LEDD (OR 1.007, 95% CI: 0.996–1.019). We here reported an association between use of levedopa and agonists and ICD behaviors, with a dose-dependent relationship in Chinese patients. The frequency of ICD behavior (3.53%) in Chinese PD patients was lower than in previous studies in non-Chinese populations (6.3–14%) [26,30,8]. In our study, use of agonists (particularly D3 agonists), and alcohol consumption were risk factors for ICD behaviors. Pathological gambling, though common in Caucasian PD patients, was rare in our Chinese population. A lower frequency of ICD behaviors was found in our study. It is generally believed that the questionnaire-based survey underestimated the prevalence of ICD. Partly questionnaires were firstly used in Chinese population may also under-ascertain the frequency. However, the lower frequency of ICD behaviors in our Chinese population may reflect a lower dosage of levodopa use (average levodopa dosage in our study was 357 mg/d) and lower ever use of agonists (45.83% in our population compared to a range of 50.4–68.0% in Western countries [6,30,18]). This is further supported by the fact that a higher rate of use of agonists in our center as a movement disorder referral center as compared to the national level in China. In addition, social and economic differences between China and Western countries may play a role. Indeed, the D3 agonist, pramipexole, has only been available in China since 2007. Whether or not genetic background may also be a consideration warrants further investigation since Chinese and Caucasian populations may have different distributions of dopamine receptor polymorphisms [29].
Interestingly, 10/11 PD patients with ICD behaviors were taking piribedil since it has been available in China for more than 10 years in China, while most other studies have related pramipexole use to ICDs in Western countries [11,21,16,5]. Piribedil activates postsynaptic D2 receptors in the substantia-striatal pathway, as well as D2 and D3 receptors in mesencephal-cortical and mesencephal-limbic pathways, which are involved in the control of motion and mental states. Although pergolide, a D2 agonist, was also quite commonly used in China before 2008, we did not find any PD patients with ICD behaviors associated with its use. Our results may support the idea that overactivation of D3 receptors plays an important role in inducing ICD behaviors in PD patients. A prospective follow-up study of ICD behaviors in Chinese PD patients taking pramipexole is warranted. A higher pathological gambling incidence (7.2–8%) in patients taking dopamine agonists has been reported in previous studies in Caucasian populations [30,3,27,20] but has not necessarily been linked to the dose [27,20], treatment duration, or agonist subtype [30,27,20]. Although most of PD or restless leg syndrome (RLS) patients with pathological gambling behaviors were taking pramipexole [13,30], other medications including bromocriptine [15] and levodopa [14] have also been linked to these behaviors. However, in our study, only one patient reported a lifetime history of pathological gambling, and it manifested before the onset of PD which is not consistent with behaviors seen in previous studies [30,8,3,1,14,27,20,9,28]. The prevalence of pathological gambling has been reported as 0.4–4.2% in the general Caucasian population [3,17,4,24] and 2.6–9.3% in PD patients with anti-parkinsonsim medications [30,3,1,27,20,9]. The fact that gambling is forbidden in the mainland China and is more easily accessible in other countries may be related to these differences. Similar to other reports, hypersexuality was the most common ICD behavior identified in our study. Approximately 2.2–8.33% of PD patients taking pramipexole, levodopa, or selegiline reported hypersexuality in other studies [26,30,16,20,23,19], and 1.92% of our PD patients fulfilled the criteria for pathological hypersexuality. All these patients were taking piribedil; five of them were also taking levodopa, and one was taking pramipexole. Pathologi-
W. Fan et al. / Neuroscience Letters 465 (2009) 6–9
cal hypersexuality disappeared in two patients following piribedil cessation (n = 1) or a change to pergolide (n = 1). There was no difference in mean age, age at disease onset, disease duration, mean and total LEDD, cigarette consumption, or diazepam between patients with and without ICD behaviors. In other studies, however, younger onset age of motor symptoms was associated with development of ICD behaviors [26,8]. Gender difference was almost statistically significant (90.91% vs. 61.9%, p = 0.059) between patients with and without ICD behaviors, suggesting the possibility that male patients taking medication may be more likely to develop ICD behaviors. Compulsive shopping or hobbyism was not found in our study. Our results indicate that differences in lifestyle and anti-parkinsonism drug use as compared to other studies make it difficult to compare with other populations. The limitations of our study include that it was conducted by mail and telephone interview, and we could not assess conditions such as depression, anxiety, and diminished cognitive function that may have confounded the results. Additionally, self-report, questionnaire-based methods as well as 12 PD patients screened positive refused to be interviewed may limit accurate determination of the frequency of ICD behaviors. More rigorous investigation in a cohort of randomized PD patients and age, gender-matched normal controls is warranted. In conclusion, ICD behaviors were not uncommon in PD patients in China, especially in those treated with D3 agonists and used alcohol. Although there are similarities in ICD behaviors among PD patients in different countries, variations in cultural background, social economics, genetic makeup, and the behavior of use of anti-parkinsonism drugs may confound comparisons across populations. Acknowledgements We thank Dr. Sam Goldman for reviewing the manuscript. This study was supported by grants from the Ministry of Sciences and Technology of China (2004BA702B02, 2006AA02A408, 2008ZX09312-014), and Beijing Natural Science Foundation (7031002). References [1] M. Avanzi, M. Baratti, S. Cabrini, E. Uber, G. Brighetti, F. Bonfa, Prevalence of pathological gambling in patients with Parkinson’s disease, Mov. Disord. 21 (12) (2006) 2068–2072. [2] K.W. Beard, E.M. Wolf, Modification in the proposed diagnostic criteria for Internet addiction, Cyberpsychol. Behav. 4 (3) (2001) 377–383. [3] D. Crockford, J. Quickfall, S. Currie, S. Furtado, O. Suchowersky, N. El-Guebaly, Prevalence of problem and pathological gambling in Parkinson’s disease, J. Gambl. Stud. 24 (4) (2008) 411–422. [4] R.M. Cunningham-Williams, R.A. Grucza, L.B. Cottler, S.B. Womack, S.J. Books, T.R. Przybeck, E.L. Spitznagel, C.R. Cloninger, Prevalence and predictors of pathological gambling: results from the St. Louis personality, health and lifestyle (SLPHL) study, J Psychiatr Res 39 (2005) 377–390. [5] M.L. Dodd, K.J. Klos, J.H. Bower, Y.E. Geda, K.A. Josephs, J.E. Ahlskog, Pathological gambling caused by drugs used to treat Parkinson disease, Arch. Neurol. 62 (9) (2005) 1377–1381. [6] E. Driver-Dunckley, J. Samanta, M. Stacy, Pathological gambling associated with dopamine agonist therapy in Parkinson’s disease, Neurology 61 (3) (2003) 422–423.
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