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Impulse control disorders in Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management
Parkinsonism and Related Disorders 15S (2009) S111–S115
Impulse control disorders in Parkinson’s disease: definition, epidemiology, risk factors, neurobiology and management Roberto Ceravolo *, Daniela Frosini, Carlo Rossi, Ubaldo Bonuccelli Department of Neurosciences, University of Pisa, Pisa, Italy
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Keywords: Impulse control disorders Parkinson’s disease Dopamine receptor agonists
A B S T R A C T There is increasing awareness that impulse control disorders (ICDs), including pathological gambling, hypersexuality, compulsive eating and buying, can occur as a complication of Parkinson’s disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reports and prospective studies have reported an association between ICDs and the use of dopamine receptor agonists at higher doses, and DDS has been associated with L-dopa at higher doses or short-acting dopamine receptor agonists. Risk factors for ICDs include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, history of substance use or bipolar disorder, and a personality profile characterized by impulsiveness. The management of clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly dopamine receptor agonists, which is usually associated with an improvement of ICDs. There is no empirical evidence supporting the use of psychiatric drugs for ICDs in PD. Functional neuroimaging studies such as functional MRI and PET can investigate in vivo the neurobiological basis of these pathological behaviours. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction Impulse control disorders (ICDs) are characterized by the failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others. It is very important to recognize ICDs because they can cause considerable distress to patients and caregivers, and can have disastrous personal, financial and socio-familial consequences. They are certainly underreported due to patients’ embarrassment to admit to having them. The formal ICDs are grouped together in a category entitled “ICDs not elsewhere classified” and include intermittent explosive disorder, kleptomania, pyromania, pathological gambling (PG), trichotillomania, and ICD not otherwise specified (ICD-NOS). Different psychiatric disorders characterized by impaired impulse control (e.g. bipolar disorders, binge-eating disorder, and attention-deficit hyperactivity disorder) are classified elsewhere in the DSM. ICDNOS includes compulsive sexual behaviours, compulsive buying or shopping, problematic internet use, and compulsive skin picking [1]. Other psychiatric disorders or behaviours that share features of ICDs have been reported to occur in Parkinson’s disease (PD) in the context of dopamine replacement therapy (DRT). For instance, with excessive use of DRT, patients have been reported to develop (hypo)mania, a mood disorder that can imply excessive involvement in pleasurable activities that have a high potential for * Correspondence to: Roberto Ceravolo, Department of Neurosciences, University of Pisa, Pisa, Italy. Tel.: +39 050 992051; fax: +39 050 550563. E-mail address: [email protected] (Roberto Ceravolo). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
painful consequences. In addition, obsessive–compulsive disorder, an anxiety disorder characterized by the repetition of nonharmful behaviours to reduce anxiety, may occur at an increased frequency in PD, although it has not been reported in association with DRT. Punding and walkabout are characterized by repetitive behaviours and poor impulse control, but the behaviours are typically nonpleasurable or low in risk–reward characteristics when compared with ICD behaviours [2]. Thus, ICDs may represent the severe end of a spectrum of behavioural disturbances in PD that are characterized by poorly or uncontrolled repetitive behaviours [3]. Another compulsive disturbance is represented by the dopamine dysregulation syndrome (DDS), which is characterized by the use of dopaminergic drugs in doses excessive to those required to treat motor symptoms despite the development of disabling dyskinesias [4]. The clinical characteristics of these patients meet accepted criteria for addiction: compulsive drug taking in excess of clinical requirements; intoxication similar to that seen with drugs such as cocaine and characterized by hypomania and impulsivity; persistent use despite social and personal difficulties caused by the drugs; withdrawal symptoms such as dysphoria and anxiety following dosage reductions; and hoarding the drug or obtaining prescriptions from different physicians. The core features of ICDs include repetitive or compulsive engagement in a behaviour despite adverse consequences, diminished control over the problematic behaviour, an appetitive urge or craving state prior to engagement in the problematic behaviour, and a hedonic quality during the performance of the problematic behaviour. ICDs share a conceptual resemblance to drug addiction in
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that individuals pursue an activity in a compulsive manner despite harmful consequences, in particular the development of tolerance, the negative effect of withdrawal, repeated unsuccessful attempts to cut back or stop, and finally impairment in major areas of life functioning [5–8]. 2. Epidemiology of ICDs in PD Following anecdotal reports of ICDs in PD patients treated with dopamine receptor agonists, studies were conducted in recent years to ascertain the prevalence of ICDs in the PD population. The prevalence rates reported are quite variable, ranging from 6% to 25%, and this heterogeneity might be due to methodological differences such as the measures used for screening [9–18]. Nevertheless, even considering just the lowest prevalence rate reported, this rate is higher than that in the general population. We have recently carried out a study on a huge sample of PD patients (n = 607) who had been referred to two centres for PD (Pisa, Versilia) and were screened by telephone interview based on a modified Minnesota Impulsive Disorders Interview, which includes questions on the presence of clinically significant compulsive gambling, sexual, and buying behaviours in order to assess actual or lifetime ICDs. For people whose results were positive, i.e. scored more than one, the diagnosis was then confirmed in a clinical setting. Overall, we found a high prevalence of ICDs of 8.8%, consistent with previous data. The most common ICD was PG (4.2%), followed by compulsive sexual behaviour (3.7%); again in line with previous reports. Interestingly, 10 of 54 patients whose results were positive at the screening had not previously been identified in routine clinical practice [19]. PG is the most extensively studied ICD in PD and it is the only one with formal diagnostic criteria included in the DSM-IV. PG has been defined as an impulse control disorder in which the patient fails to resist gambling impulses despite severe personal, family or occupational consequences. After the first study by Driver-Dunckley and colleagues [9] who retrospectively identified 9 patients of 1,884 (0.5% of the sample) with documented PG, a subsequent prospective study using faceto-face interviews reported the prevalence of PG to be 7% [10]. In a recent prospective study [11], 4.4% (17/388) of patients at six movement disorders centres met the criteria for PG. The results of two large studies that prospectively screened for ICDs in PD were recently published. In the first study [12], 297 patients with PD were screened for PG with a modified version of the South Oaks Gambling Scale. Lifetime and current rates of PG were 3.4% and 1.7%, respectively. In the second study [13], 272 patients with PD at two movement disorders centres were screened for the presence of several ICDs (compulsive gambling, sexual behaviour, and buying). In that study, the rates of at least one active ICD or an ICD any time during PD were 4.0 and 6.6%, respectively. Among active cases, compulsive sexual behaviour was as common as problematic gambling (2.6 vs 2.2%, respectively), and the rate of compulsive buying was 0.4%. Hypersexuality is also common [14]. The first description was in patients on subcutaneous apomorphine but it can occur also with other dopamine receptor agonists or L -dopa [20–23]. In a recent case-control study, Voon and colleagues found a prevalence of hypersexuality of 7.2% in PD patients on dopamine receptor agonist therapy, whereas in the general population it is 1% [14]. It usually manifests itself as an increased libido but sometimes it can involve exhibitionism, excessive use of sex telephone lines, prostitution services, and sex shops. In a retrospective study, an association between hypersexuality, male gender and young onset of PD was found [24], suggesting a causative relationship between ICD and the use of dopamine receptor agonists. A prospective study
is, however, necessary to confirm this finding and to ascertain prevalence data. In summary, preliminary prevalence estimates (either current or anytime during the course of PD) for ICDs in PD patients overall are approximately 2.0–6.0% for pathological or problematic gambling, 2.0–10.0% for compulsive sexual behaviour [15], and 0.4–2.0% for compulsive buying [16]. These studies also suggested that these ICDs may be more common in PD than in the general population or in assessed healthy controls. However, the true prevalence of ICDs in PD is not known, probably because most studies have focused only on gambling disorders, and so other ICDs may be just as common as PG in PD. It should also be taken into account that patients may be reluctant to admit ICD behaviours. 3. Risk factors Patients with PD who develop ICDs (especially PG) are usually male, have younger age at PD onset and therefore probably a drug prescribing pattern in favour of dopamine receptor agonists, have a personal or immediate family history of alcohol use disorders, or a prior history of ICD [25–30]. In addition, the psychological profile may have a role as a risk factor since PD patients with ICDs have higher novelty-seeking trait scores, as well as impaired planning on an impulsivity scale [15]. Depressive mood [30] is also considered a powerful risk factor, and low performance in cognitive tasks exploring frontal function has recently been reported [31] in association with PG. Other risk factors have been described in relation to PD features such as longer duration of PD [13] as well as early disease onset [12]. However, the strongest risk factor is exposure to dopaminergic drugs. In a very exhaustive and rigorous article, Weintraub et al. [13] reported that although age, PD duration, history of ICD symptomatology prior to development of PD, dopamine receptor agonist or amantadine use, and total L -dopa equivalent daily dose met strict criteria to be considered as risk factors in a univariate model, dopamine receptor agonist use and history of ICD symptomatology prior to PD were the only significant predictors of an active ICD with a multivariate model. Retrospective reports suggest a different role of specific dopamine receptor agonists considering their different dopamine receptor affinity [9,32]. In particular, some investigators found an increase in the prevalence of PG in PD patients treated with pramipexole, a dopamine receptor agonist with a specific affinity for the dopamine D3 receptor, compared with the others dopamine receptor agonists. Driver-Dunckley and colleagues found 9 PG cases, 8 of whom had been treated with pramipexole and 1 with pergolide. All their patients improved after switching to ropinirole or reducing the pramipexole dose [9]. Dodd and colleagues identified 11 PG cases from their practice, 9 of whom were on pramipexole and 2 on ropinirole therapy [32]. The authors concluded that pramipexole may result in gambling to a higher degree compared with other agonists, suggesting that PG in PD could be due to disproportionate stimulation of D3 receptors, which are represented more in limbic areas. Unfortunately, the total number of patients who were treated with the various agonists was not reported, so we cannot estimate the exact incidence of PG with a specific dopamine receptor agonist. Other authors have also reported a similar risk of developing PG with ropinirole, pergolide, and pramipexole [10]. In their prospective study, Voon and colleagues [14] did not find significant differences between specific dopamine receptor agonists, or at least non-ergot dopamine receptor agonists, which have greater affinity for the D3 receptors [11,31]. In an exhaustive analysis of published case series, Gallagher et al. [25] reported that 174 of 177 patients were on dopamine receptor agonist therapy, only 2 were on L -dopa monotherapy, and 1 was on
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selegiline in combination with L -dopa. Of the patients on dopamine receptor agonist treatment, only 17 were on monotherapy. With regard to risk factors for PG (odds ratios), no significant differences have been observed between ergot and non-ergot derivatives, or between pramipexole and ropinirole. Most cases reported in the literature were with combination therapy (dopamine receptor agonist plus L -dopa), suggesting a cross-sensitization phenomenon of brain systems mediating reward. The role of dopamine receptor agonist dose in increasing the risk of developing ICDs is controversial. In their meta-analysis, Gallagher et al. [25] reported that half of the PD patients with PG were on the maximum recommended dose or more of pramipexole and ropinirole. In contrast to this, other reports did not find any association between the risk of PG and the dose administered, and recent papers have described the occurrence of ICDs also in patients treated with low doses of dopamine receptor agonists for restless legs syndrome [33]. Genes provide the first contribution to the susceptibility to develop ICDs. Dopaminergic function-related genes such as the D2A1 allele of D2 receptors have been implicated in drug abuse, compulsive eating, smoking and PG [34]. Moreover, D4 receptor polymorphism has been associated with PG [35,36]. Genetic predisposition could even be considered an important risk factor for ICDs in PD, as suggested by the evidence of an association between a family history of PG or alcohol abuse and the development of PG during dopaminergic treatment. Recently, dopaminergic and glutamatergic receptors and serotonin transporter gene polymorphism have been evaluated in PD patients with ICDs. After controlling for clinical variables, D3 receptor p.S9G and GRIN2B c.366C>G were identified as risk factors for ICDs [37]. 4. Neurobiology of ICDs in PD patients The pathophysiology of ICDs has been reported to involve specific neurotransmitter systems, brain regions and neural circuitries. The crucial neural network appears to be the cortico-striatothalamo-cortical pathway and, with regard to the neurotransmitter dopamine system, seems to be critical mainly within the mesocorticolimbic pathway for reward and reinforcement processes. The brain areas mostly involved include the prefrontal cortex, mainly ventromedial and orbitofrontal areas, which are involved in planning and judgement; ventral striatum, in particular the nucleus accumbens, which is crucial for the reward system; and amygdala, known to be involved in emotions and conditioned response. To date, only a few studies with functional imaging have been performed to investigate in vivo the pathophysiology of ICDs. In 2005, Reuter and colleagues published the results of a brilliant study [38] conducted in 12 pathological gamblers and 12 healthy matched controls, using functional MRI and a gambling task based on a card game known to robustly activate the ventral striatum. They observed that, during the simulated gambling task, compared with the controls, the pathological gamblers had decreased activation of the ventromedial prefrontal cortex and ventral striatum, areas involved in the reward process. These findings were intriguing and the authors speculated that there is a sort of basal hypofunction of such areas in PG, and that the pathological behaviour could be a compensatory phenomenon similar to the mechanism underlying drug addiction. From this perspective, PG might be considered as a non-substance-related addictive disorder or behavioural addiction. In 2006, Evans and colleagues [39] investigated small groups of PD patients with and without DDS, using PET with a specific D2 ligand, raclopride. They reported no significant difference between patients with and without DDS in the percentage decrease in raclopride binding after an L -dopa challenge in the dorsal striatum. In fact, in the ventral striatum, a significant decrease in raclopride binding after L -dopa was observed only in patients with DDS,
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implying a good dopamine reserve at the ventral-striatal level. This finding could suggest that compulsive medication use in PD and perhaps ICD-related disorders might be associated with sensitization of ventral-striatal circuitry. A very recent study by Cilia et al. [40] had similar findings using a different approach. The investigators studied 11 PD patients with active PG by means of brain perfusion SPECT, compared with matched PD and healthy controls. They found that PD patients with PG showed resting overactivity in brain areas involved in reward and reward-based learning, motivation, impulse control, decision making and memory processing such as the basal ganglia, orbitofrontal cortex, hippocampus, amygdala, and insula, suggesting specific functional abnormalities in the mesocorticolimbic network. These findings might suggest that the predisposition to develop PG could be related to a relative preservation of the mesocorticolimbic pathway despite the pathological changes in the dorsal nigrostriatal pathway. Thus, PG may develop as a consequence of an abnormal druginduced overstimulation in PD patients with a relatively spared mesocorticolimbic network. In a recent paper [41], Steeves et al. reported the results of a study on striatal dopamine release by PET and [11 C]raclopride in PD patients with PG compared with PD patients without PG during a gambling task and a control task. In PD patients with PG, they observed a greater decrease in raclopride binding potential in the ventral striatum during the gambling task compared with PD patients without PG, reflecting greater dopaminergic release, consistent with previous studies. Interestingly, they reported that ventral striatal binding during the control task was also lower in PD patients with PG, and this finding could be interpreted to reflect lower baseline levels of D2 /D3 receptors. Since several studies suggest that low dopamine binding may mediate vulnerability to addiction, this finding might support the similarity between PD patients with PG and patients with chemical addictions, and the classification of PG in PD within the spectrum of behavioural addictions. 5. Management Management of ICDs consists of patient and caregiver education, modification of DRT, and, in some cases, psychoactive drugs. It is essential to identify individuals with active ICDs by an active screening. Clinicians should discuss current understanding of the risks and benefits of and alternatives to drug treatment, and they should highlight the importance of honest reporting. They should always involve the spouse or other family members and ensure medical compliance, including guarding against hoarding and overuse of medications. All patients with ICDs should be thoroughly assessed for comorbid neuropsychiatric problems. For those patients whose ICD occurs in the context of dopamine receptor agonist treatment, the behaviours often resolve or improve with dose reduction, switching to a different agonist, or discontinuing agonist treatment entirely [32,42]. In a recent observational follow-up study [42] of PD patients with an agonist-induced ICD, only patients who discontinued or significantly decreased agonist exposure experienced remission or significant reduction of ICD behaviours. Thus, when tolerated, withdrawal of medication to the lowest effective daily dose of DRT should be considered the initial treatment of choice. Clinicians should discourage patients from taking nocturnal or “rescue” does of short-acting dopaminergic agents. When a reduced DRT dosage causes worsening motor function, there is little evidence and no prospective data to guide subsequent medication adjustments. Agonist dose reduction can be offset by increases in L -dopa treatment [42]. However, this intervention is not always successful; some patients are reluctant to discontinue
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or decrease dopamine receptor agonist treatment due to the motor or nonmotor benefits they experience when on the medication, and not all ICDs occur in the context of dopamine receptor agonist treatment. When the aforementioned measures are not tolerated or prove ineffective, psychoactive drugs and psychotherapy provide a secondary course of treatment. Counselling and cognitive-behavioural therapy can be useful as an adjunctive approach, but several reports describe disappointing results [9,43]. Limiting a patient’s access to money or the internet may help in reducing PG and compulsive buying when such controls are feasible. ICDs may improve with treatment of concomitant depression [12]. Selective serotonin reuptake inhibitors, however, though effective in obsessive–compulsive disorders are of questionable benefit in DRT [44,45], since they may facilitate dopaminergic transmission and could worsen ICDs. The atypical neuroleptics clozapine [46], risperidone [47] and quetiapine [4] have been reported to help control ICDs; however, one controlled study of olanzapine has been negative [48]. In addition, valproate and lithium have been reported to help individual patients with ICDs [49]. In non-PD populations with PG, nalmefene, an opioid antagonist, has been found to be efficacious [50]. However, any use of psychoactive drugs should be closely monitored in patients with ICDs.
[8] [9] [10] [11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
6. Conclusions Current estimates suggest that ICDs are exhibited by approximately 10–14% of patients with PD. ICDs typically identified in PD fall into the domains of gambling, sex, shopping and eating. Risk factors for ICDs in PD include young age, impulsive or novelty-seeking personality, personal or family history of alcoholism, prior history of ICDs, and dopamine receptor agonist therapy. The role of genetic predisposition should be investigated to optimize prevention. ICDs can be challenging to recognize because the behaviours are typically hedonic and excessive engagement in these behaviours might be associated with guilt or embarrassment. ICDs after DRT might be considered a behavioural addiction due to a dysfunction in the meso(cortical)-limbic pathway. Treatments can involve switching dopaminergic therapies, applying behavioural and drug treatments used for ICDs in non-PD, engaging spouses or other family members, and psychiatric consultation. Conflict of interest Roberto Ceravolo, Daniela Frosini and Carlo Rossi have nothing to declare. Ubaldo Bonuccelli has received consulting/lecture fees from GlaxoSmithKline, Novartis, Boehringer Ingelheim, Eli Lilly and Teva.
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Impulse control disorders in Parkinson’s disease: definition, epidemiology, risk factors, neurobiology and management Roberto Ceravolo *, Daniela Frosini, Carlo Rossi, Ubaldo Bonuccelli Department of Neurosciences, University of Pisa, Pisa, Italy
A R T I C L E
I N F O
Keywords: Impulse control disorders Parkinson’s disease Dopamine receptor agonists
A B S T R A C T There is increasing awareness that impulse control disorders (ICDs), including pathological gambling, hypersexuality, compulsive eating and buying, can occur as a complication of Parkinson’s disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reports and prospective studies have reported an association between ICDs and the use of dopamine receptor agonists at higher doses, and DDS has been associated with L-dopa at higher doses or short-acting dopamine receptor agonists. Risk factors for ICDs include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, history of substance use or bipolar disorder, and a personality profile characterized by impulsiveness. The management of clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly dopamine receptor agonists, which is usually associated with an improvement of ICDs. There is no empirical evidence supporting the use of psychiatric drugs for ICDs in PD. Functional neuroimaging studies such as functional MRI and PET can investigate in vivo the neurobiological basis of these pathological behaviours. © 2009 Elsevier Ltd. All rights reserved.
1. Introduction Impulse control disorders (ICDs) are characterized by the failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others. It is very important to recognize ICDs because they can cause considerable distress to patients and caregivers, and can have disastrous personal, financial and socio-familial consequences. They are certainly underreported due to patients’ embarrassment to admit to having them. The formal ICDs are grouped together in a category entitled “ICDs not elsewhere classified” and include intermittent explosive disorder, kleptomania, pyromania, pathological gambling (PG), trichotillomania, and ICD not otherwise specified (ICD-NOS). Different psychiatric disorders characterized by impaired impulse control (e.g. bipolar disorders, binge-eating disorder, and attention-deficit hyperactivity disorder) are classified elsewhere in the DSM. ICDNOS includes compulsive sexual behaviours, compulsive buying or shopping, problematic internet use, and compulsive skin picking [1]. Other psychiatric disorders or behaviours that share features of ICDs have been reported to occur in Parkinson’s disease (PD) in the context of dopamine replacement therapy (DRT). For instance, with excessive use of DRT, patients have been reported to develop (hypo)mania, a mood disorder that can imply excessive involvement in pleasurable activities that have a high potential for * Correspondence to: Roberto Ceravolo, Department of Neurosciences, University of Pisa, Pisa, Italy. Tel.: +39 050 992051; fax: +39 050 550563. E-mail address: [email protected] (Roberto Ceravolo). 1353-8020/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
painful consequences. In addition, obsessive–compulsive disorder, an anxiety disorder characterized by the repetition of nonharmful behaviours to reduce anxiety, may occur at an increased frequency in PD, although it has not been reported in association with DRT. Punding and walkabout are characterized by repetitive behaviours and poor impulse control, but the behaviours are typically nonpleasurable or low in risk–reward characteristics when compared with ICD behaviours [2]. Thus, ICDs may represent the severe end of a spectrum of behavioural disturbances in PD that are characterized by poorly or uncontrolled repetitive behaviours [3]. Another compulsive disturbance is represented by the dopamine dysregulation syndrome (DDS), which is characterized by the use of dopaminergic drugs in doses excessive to those required to treat motor symptoms despite the development of disabling dyskinesias [4]. The clinical characteristics of these patients meet accepted criteria for addiction: compulsive drug taking in excess of clinical requirements; intoxication similar to that seen with drugs such as cocaine and characterized by hypomania and impulsivity; persistent use despite social and personal difficulties caused by the drugs; withdrawal symptoms such as dysphoria and anxiety following dosage reductions; and hoarding the drug or obtaining prescriptions from different physicians. The core features of ICDs include repetitive or compulsive engagement in a behaviour despite adverse consequences, diminished control over the problematic behaviour, an appetitive urge or craving state prior to engagement in the problematic behaviour, and a hedonic quality during the performance of the problematic behaviour. ICDs share a conceptual resemblance to drug addiction in
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that individuals pursue an activity in a compulsive manner despite harmful consequences, in particular the development of tolerance, the negative effect of withdrawal, repeated unsuccessful attempts to cut back or stop, and finally impairment in major areas of life functioning [5–8]. 2. Epidemiology of ICDs in PD Following anecdotal reports of ICDs in PD patients treated with dopamine receptor agonists, studies were conducted in recent years to ascertain the prevalence of ICDs in the PD population. The prevalence rates reported are quite variable, ranging from 6% to 25%, and this heterogeneity might be due to methodological differences such as the measures used for screening [9–18]. Nevertheless, even considering just the lowest prevalence rate reported, this rate is higher than that in the general population. We have recently carried out a study on a huge sample of PD patients (n = 607) who had been referred to two centres for PD (Pisa, Versilia) and were screened by telephone interview based on a modified Minnesota Impulsive Disorders Interview, which includes questions on the presence of clinically significant compulsive gambling, sexual, and buying behaviours in order to assess actual or lifetime ICDs. For people whose results were positive, i.e. scored more than one, the diagnosis was then confirmed in a clinical setting. Overall, we found a high prevalence of ICDs of 8.8%, consistent with previous data. The most common ICD was PG (4.2%), followed by compulsive sexual behaviour (3.7%); again in line with previous reports. Interestingly, 10 of 54 patients whose results were positive at the screening had not previously been identified in routine clinical practice [19]. PG is the most extensively studied ICD in PD and it is the only one with formal diagnostic criteria included in the DSM-IV. PG has been defined as an impulse control disorder in which the patient fails to resist gambling impulses despite severe personal, family or occupational consequences. After the first study by Driver-Dunckley and colleagues [9] who retrospectively identified 9 patients of 1,884 (0.5% of the sample) with documented PG, a subsequent prospective study using faceto-face interviews reported the prevalence of PG to be 7% [10]. In a recent prospective study [11], 4.4% (17/388) of patients at six movement disorders centres met the criteria for PG. The results of two large studies that prospectively screened for ICDs in PD were recently published. In the first study [12], 297 patients with PD were screened for PG with a modified version of the South Oaks Gambling Scale. Lifetime and current rates of PG were 3.4% and 1.7%, respectively. In the second study [13], 272 patients with PD at two movement disorders centres were screened for the presence of several ICDs (compulsive gambling, sexual behaviour, and buying). In that study, the rates of at least one active ICD or an ICD any time during PD were 4.0 and 6.6%, respectively. Among active cases, compulsive sexual behaviour was as common as problematic gambling (2.6 vs 2.2%, respectively), and the rate of compulsive buying was 0.4%. Hypersexuality is also common [14]. The first description was in patients on subcutaneous apomorphine but it can occur also with other dopamine receptor agonists or L -dopa [20–23]. In a recent case-control study, Voon and colleagues found a prevalence of hypersexuality of 7.2% in PD patients on dopamine receptor agonist therapy, whereas in the general population it is 1% [14]. It usually manifests itself as an increased libido but sometimes it can involve exhibitionism, excessive use of sex telephone lines, prostitution services, and sex shops. In a retrospective study, an association between hypersexuality, male gender and young onset of PD was found [24], suggesting a causative relationship between ICD and the use of dopamine receptor agonists. A prospective study
is, however, necessary to confirm this finding and to ascertain prevalence data. In summary, preliminary prevalence estimates (either current or anytime during the course of PD) for ICDs in PD patients overall are approximately 2.0–6.0% for pathological or problematic gambling, 2.0–10.0% for compulsive sexual behaviour [15], and 0.4–2.0% for compulsive buying [16]. These studies also suggested that these ICDs may be more common in PD than in the general population or in assessed healthy controls. However, the true prevalence of ICDs in PD is not known, probably because most studies have focused only on gambling disorders, and so other ICDs may be just as common as PG in PD. It should also be taken into account that patients may be reluctant to admit ICD behaviours. 3. Risk factors Patients with PD who develop ICDs (especially PG) are usually male, have younger age at PD onset and therefore probably a drug prescribing pattern in favour of dopamine receptor agonists, have a personal or immediate family history of alcohol use disorders, or a prior history of ICD [25–30]. In addition, the psychological profile may have a role as a risk factor since PD patients with ICDs have higher novelty-seeking trait scores, as well as impaired planning on an impulsivity scale [15]. Depressive mood [30] is also considered a powerful risk factor, and low performance in cognitive tasks exploring frontal function has recently been reported [31] in association with PG. Other risk factors have been described in relation to PD features such as longer duration of PD [13] as well as early disease onset [12]. However, the strongest risk factor is exposure to dopaminergic drugs. In a very exhaustive and rigorous article, Weintraub et al. [13] reported that although age, PD duration, history of ICD symptomatology prior to development of PD, dopamine receptor agonist or amantadine use, and total L -dopa equivalent daily dose met strict criteria to be considered as risk factors in a univariate model, dopamine receptor agonist use and history of ICD symptomatology prior to PD were the only significant predictors of an active ICD with a multivariate model. Retrospective reports suggest a different role of specific dopamine receptor agonists considering their different dopamine receptor affinity [9,32]. In particular, some investigators found an increase in the prevalence of PG in PD patients treated with pramipexole, a dopamine receptor agonist with a specific affinity for the dopamine D3 receptor, compared with the others dopamine receptor agonists. Driver-Dunckley and colleagues found 9 PG cases, 8 of whom had been treated with pramipexole and 1 with pergolide. All their patients improved after switching to ropinirole or reducing the pramipexole dose [9]. Dodd and colleagues identified 11 PG cases from their practice, 9 of whom were on pramipexole and 2 on ropinirole therapy [32]. The authors concluded that pramipexole may result in gambling to a higher degree compared with other agonists, suggesting that PG in PD could be due to disproportionate stimulation of D3 receptors, which are represented more in limbic areas. Unfortunately, the total number of patients who were treated with the various agonists was not reported, so we cannot estimate the exact incidence of PG with a specific dopamine receptor agonist. Other authors have also reported a similar risk of developing PG with ropinirole, pergolide, and pramipexole [10]. In their prospective study, Voon and colleagues [14] did not find significant differences between specific dopamine receptor agonists, or at least non-ergot dopamine receptor agonists, which have greater affinity for the D3 receptors [11,31]. In an exhaustive analysis of published case series, Gallagher et al. [25] reported that 174 of 177 patients were on dopamine receptor agonist therapy, only 2 were on L -dopa monotherapy, and 1 was on
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selegiline in combination with L -dopa. Of the patients on dopamine receptor agonist treatment, only 17 were on monotherapy. With regard to risk factors for PG (odds ratios), no significant differences have been observed between ergot and non-ergot derivatives, or between pramipexole and ropinirole. Most cases reported in the literature were with combination therapy (dopamine receptor agonist plus L -dopa), suggesting a cross-sensitization phenomenon of brain systems mediating reward. The role of dopamine receptor agonist dose in increasing the risk of developing ICDs is controversial. In their meta-analysis, Gallagher et al. [25] reported that half of the PD patients with PG were on the maximum recommended dose or more of pramipexole and ropinirole. In contrast to this, other reports did not find any association between the risk of PG and the dose administered, and recent papers have described the occurrence of ICDs also in patients treated with low doses of dopamine receptor agonists for restless legs syndrome [33]. Genes provide the first contribution to the susceptibility to develop ICDs. Dopaminergic function-related genes such as the D2A1 allele of D2 receptors have been implicated in drug abuse, compulsive eating, smoking and PG [34]. Moreover, D4 receptor polymorphism has been associated with PG [35,36]. Genetic predisposition could even be considered an important risk factor for ICDs in PD, as suggested by the evidence of an association between a family history of PG or alcohol abuse and the development of PG during dopaminergic treatment. Recently, dopaminergic and glutamatergic receptors and serotonin transporter gene polymorphism have been evaluated in PD patients with ICDs. After controlling for clinical variables, D3 receptor p.S9G and GRIN2B c.366C>G were identified as risk factors for ICDs [37]. 4. Neurobiology of ICDs in PD patients The pathophysiology of ICDs has been reported to involve specific neurotransmitter systems, brain regions and neural circuitries. The crucial neural network appears to be the cortico-striatothalamo-cortical pathway and, with regard to the neurotransmitter dopamine system, seems to be critical mainly within the mesocorticolimbic pathway for reward and reinforcement processes. The brain areas mostly involved include the prefrontal cortex, mainly ventromedial and orbitofrontal areas, which are involved in planning and judgement; ventral striatum, in particular the nucleus accumbens, which is crucial for the reward system; and amygdala, known to be involved in emotions and conditioned response. To date, only a few studies with functional imaging have been performed to investigate in vivo the pathophysiology of ICDs. In 2005, Reuter and colleagues published the results of a brilliant study [38] conducted in 12 pathological gamblers and 12 healthy matched controls, using functional MRI and a gambling task based on a card game known to robustly activate the ventral striatum. They observed that, during the simulated gambling task, compared with the controls, the pathological gamblers had decreased activation of the ventromedial prefrontal cortex and ventral striatum, areas involved in the reward process. These findings were intriguing and the authors speculated that there is a sort of basal hypofunction of such areas in PG, and that the pathological behaviour could be a compensatory phenomenon similar to the mechanism underlying drug addiction. From this perspective, PG might be considered as a non-substance-related addictive disorder or behavioural addiction. In 2006, Evans and colleagues [39] investigated small groups of PD patients with and without DDS, using PET with a specific D2 ligand, raclopride. They reported no significant difference between patients with and without DDS in the percentage decrease in raclopride binding after an L -dopa challenge in the dorsal striatum. In fact, in the ventral striatum, a significant decrease in raclopride binding after L -dopa was observed only in patients with DDS,
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implying a good dopamine reserve at the ventral-striatal level. This finding could suggest that compulsive medication use in PD and perhaps ICD-related disorders might be associated with sensitization of ventral-striatal circuitry. A very recent study by Cilia et al. [40] had similar findings using a different approach. The investigators studied 11 PD patients with active PG by means of brain perfusion SPECT, compared with matched PD and healthy controls. They found that PD patients with PG showed resting overactivity in brain areas involved in reward and reward-based learning, motivation, impulse control, decision making and memory processing such as the basal ganglia, orbitofrontal cortex, hippocampus, amygdala, and insula, suggesting specific functional abnormalities in the mesocorticolimbic network. These findings might suggest that the predisposition to develop PG could be related to a relative preservation of the mesocorticolimbic pathway despite the pathological changes in the dorsal nigrostriatal pathway. Thus, PG may develop as a consequence of an abnormal druginduced overstimulation in PD patients with a relatively spared mesocorticolimbic network. In a recent paper [41], Steeves et al. reported the results of a study on striatal dopamine release by PET and [11 C]raclopride in PD patients with PG compared with PD patients without PG during a gambling task and a control task. In PD patients with PG, they observed a greater decrease in raclopride binding potential in the ventral striatum during the gambling task compared with PD patients without PG, reflecting greater dopaminergic release, consistent with previous studies. Interestingly, they reported that ventral striatal binding during the control task was also lower in PD patients with PG, and this finding could be interpreted to reflect lower baseline levels of D2 /D3 receptors. Since several studies suggest that low dopamine binding may mediate vulnerability to addiction, this finding might support the similarity between PD patients with PG and patients with chemical addictions, and the classification of PG in PD within the spectrum of behavioural addictions. 5. Management Management of ICDs consists of patient and caregiver education, modification of DRT, and, in some cases, psychoactive drugs. It is essential to identify individuals with active ICDs by an active screening. Clinicians should discuss current understanding of the risks and benefits of and alternatives to drug treatment, and they should highlight the importance of honest reporting. They should always involve the spouse or other family members and ensure medical compliance, including guarding against hoarding and overuse of medications. All patients with ICDs should be thoroughly assessed for comorbid neuropsychiatric problems. For those patients whose ICD occurs in the context of dopamine receptor agonist treatment, the behaviours often resolve or improve with dose reduction, switching to a different agonist, or discontinuing agonist treatment entirely [32,42]. In a recent observational follow-up study [42] of PD patients with an agonist-induced ICD, only patients who discontinued or significantly decreased agonist exposure experienced remission or significant reduction of ICD behaviours. Thus, when tolerated, withdrawal of medication to the lowest effective daily dose of DRT should be considered the initial treatment of choice. Clinicians should discourage patients from taking nocturnal or “rescue” does of short-acting dopaminergic agents. When a reduced DRT dosage causes worsening motor function, there is little evidence and no prospective data to guide subsequent medication adjustments. Agonist dose reduction can be offset by increases in L -dopa treatment [42]. However, this intervention is not always successful; some patients are reluctant to discontinue
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or decrease dopamine receptor agonist treatment due to the motor or nonmotor benefits they experience when on the medication, and not all ICDs occur in the context of dopamine receptor agonist treatment. When the aforementioned measures are not tolerated or prove ineffective, psychoactive drugs and psychotherapy provide a secondary course of treatment. Counselling and cognitive-behavioural therapy can be useful as an adjunctive approach, but several reports describe disappointing results [9,43]. Limiting a patient’s access to money or the internet may help in reducing PG and compulsive buying when such controls are feasible. ICDs may improve with treatment of concomitant depression [12]. Selective serotonin reuptake inhibitors, however, though effective in obsessive–compulsive disorders are of questionable benefit in DRT [44,45], since they may facilitate dopaminergic transmission and could worsen ICDs. The atypical neuroleptics clozapine [46], risperidone [47] and quetiapine [4] have been reported to help control ICDs; however, one controlled study of olanzapine has been negative [48]. In addition, valproate and lithium have been reported to help individual patients with ICDs [49]. In non-PD populations with PG, nalmefene, an opioid antagonist, has been found to be efficacious [50]. However, any use of psychoactive drugs should be closely monitored in patients with ICDs.
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6. Conclusions Current estimates suggest that ICDs are exhibited by approximately 10–14% of patients with PD. ICDs typically identified in PD fall into the domains of gambling, sex, shopping and eating. Risk factors for ICDs in PD include young age, impulsive or novelty-seeking personality, personal or family history of alcoholism, prior history of ICDs, and dopamine receptor agonist therapy. The role of genetic predisposition should be investigated to optimize prevention. ICDs can be challenging to recognize because the behaviours are typically hedonic and excessive engagement in these behaviours might be associated with guilt or embarrassment. ICDs after DRT might be considered a behavioural addiction due to a dysfunction in the meso(cortical)-limbic pathway. Treatments can involve switching dopaminergic therapies, applying behavioural and drug treatments used for ICDs in non-PD, engaging spouses or other family members, and psychiatric consultation. Conflict of interest Roberto Ceravolo, Daniela Frosini and Carlo Rossi have nothing to declare. Ubaldo Bonuccelli has received consulting/lecture fees from GlaxoSmithKline, Novartis, Boehringer Ingelheim, Eli Lilly and Teva.
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