Abstract
Impulse control disorders in Parkinson’s disease are relatively common drug-induced addictive behaviours that are usually triggered by the dopamine agonists pramipexole, ropinirole and rotigotine. This narrative review aimed to provide a comprehensive overview of the current knowledge of impulse control disorders in Parkinson’s disease. We summarised the prevalence, clinical features, risk factors and potential underlying mechanisms of impulse control disorders in Parkinson’s disease. Moreover, recent advances in behavioural and imaging characteristics and management strategies are discussed. Early detection as well as a tailored multidisciplinary approach, which typically includes careful adjustment of the dopaminergic therapy and the treatment of associated neuropsychiatric symptoms, are necessary. In some cases, a continuous delivery of levodopa via a pump or the dopamine D1 receptor agonist, apomorphine, can be considered. In selected patients without cognitive or speech impairment, deep brain stimulation of the subthalamic nucleus can also improve addictions. Finding the right balance of tapering dopaminergic dose (usually dopamine agonists) without worsening motor symptoms is essential for a beneficial long-term outcome.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Impulse control disorders are a relatively common side effect of dopamine receptor agonists in patients with Parkinson’s disease. |
Additional neuropsychiatric comorbidities are common in those with impulse control disorders, which further negatively impacts the quality of life of patients and their families. |
The underlying mechanisms involved are not entirely clear, although a relatively preserved nucleus accumbens causing a dopaminergic over-stimulation of the ventral striatum seems to play a pivotal role. |
Management of impulse control disorders is challenging and requires a reduction and often cessation of dopamine agonists. |
1 Introduction
Impulse control disorders (ICDs) are defined as a “failure to resist an impulse, temptation, or drive to perform an act that is harmful to the person or others” [1]. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) includes oppositional defiant disorder, intermittent explosive disorder, conduct disorder, kleptomania and pyromania as ICDs [2]. The DSM-V also lists nine types of substance addictions that include alcohol, caffeine, cannabis, hallucinogens, inhalants (such as nitrous oxide, amyl nitrite and volatile solvents including paint removers and cleaning products), opioids, sedatives, hypnotics, anxiolytics, stimulants and tobacco. Moreover, gambling disorder is now included in the chapter on Substance-Related and Addictive Disorders [2]. This change was performed to highlight the similarities between gambling disorder and drug addiction: in both conditions, an anticipatory craving, a decrease of anxiety, and the feeling of euphoria following gambling or intake of the drug may occur. Additionally, both gambling disorder as well as drug addiction frequently co-occur [3]. According to the DSM-V criteria, ICDs occur in five stages. Typically, ICDs begin with an increased sense of tension, followed by a failure to resist an urge to act. During the act, the arousal peaks and as the act is completed a sense of relief or release is felt. Finally, patients may feel remorse or guilt for their behaviour [2].
Impulse control disorders and related disorders are seen as comorbidities in neurodegenerative diseases, such as progressive supranuclear palsy [4, 5], multiple system atrophy [6, 7] and frontotemporal dementia [8], and are most common in patients with idiopathic Parkinson’s disease (PD) [9]. Moreover, addictive behaviours can also occur in patients without clear evidence of neuronal/nigrostriatal degeneration as a direct consequence of dopamine agonist therapy in patients with fibromyalgia [10], patients with restless legs syndrome (particularly in those who have in addition augmentation) [11] and in patients with endocrine diseases (such as pituitary adenomas) [12]. Furthermore, ICDs and related disorders have been described in patients with frontal lobe dysfunction such as Gilles de la Tourette syndrome [13], and in patients with attention-deficit hyperactivity syndrome [14]. In the majority of patients diagnosed with PD, these addictive behaviours emerge following the start of dopaminergic therapy, mainly dopamine agonists.
Regardless of the underlying comorbidity, patients with ICDs and related disorders typically continue their addiction despite negative consequences. Any attempt to discontinue the behaviour frequently leads to dysphoria, anxiety and depression, similar to withdrawal symptoms after drug abuse [15].
Compulsive sexual disorder (see Table 1), gambling disorder (see Table 2), compulsive shopping (see Table 3) and compulsive eating are the most commonly described ICDs in PD [9]. Other related addictions in patients with PD include dopamine dysregulation syndrome (DDS, sometimes also called Lees syndrome), where patients hoard drugs, self-medicate with a larger amount of levodopa against the physician’s advice to avoid off-periods (for diagnostic criteria, see Table 4) and exhibit punding, which is the urge to perform senseless activities repeatedly (such as assembling and disassembling, collecting or sorting objects in brackets) [16,17,18]. Other phenomena include hobbyism (a pathological pursuit in common hobbies, such as excessive fishing, writing or Internet use) reckless generosity [19], excessive hoarding [20], walkabouts [21] and drug addiction [22]. Although the name ICD implies an inability to resist an urge, these heterogeneous behaviours are sometimes complex, sometimes habitual, non-goal oriented and stereotyped. Therefore, ICDs also have impulsive and compulsive aspects that have been mentioned in several studies [23,24,25]. Similar to the general population, it is believed that the impulsive component, together with the feeling of joy and gratification may be responsible for the initiation of the addiction, while a more habitual and compulsive component may be the culprit of persistence [26].
In line with this, patients with PD with ICDs and DDS often report a feeling of euphoria, mania or pleasure; while punding is a more peculiar addictive behaviour in PD, not driven by pleasure [27]. Previously, it was thought that a gambling disorder was the most frequent ICD and increased libido would occur less frequently [9] but results of several studies suggest that compulsive sexual behaviour (for proposed diagnostic criteria see Table 2) is one of the most, if not the most common addiction in male patients with PD [28, 29]. Multiple addictions are also common if an ICD or related disorder has been detected [9], particularly in those with compulsive sexual disorder [29].
While ICDs in PD have been described more thoroughly within the last few decades, these side effects of dopaminergic medication are not new and had been reported in the 1960s and 1970s, a few years after the introduction of levodopa [30,31,32]. The true prevalence of these behaviours in PD is unknown, as patients likely conceal or under-report these side effects because of shame or denial. The general consensus is that ICDs and related addictions occur somewhere between 14% and 30% [9, 28] and are likely much higher in patients with a younger disease onset [33] with a 5-year cumulative incidence of 46% [34]. Because of the increased awareness and change in prescribing dopaminergic therapy, ICDs and related addictions are currently possibly declining again, although some suggest that the COVID-19-induced lockdowns and thus an increase in environmental stress may have caused again a rise of these addictive behaviours [35]. The objective of this narrative review is to provide a comprehensive overview of risk factors, potential mechanisms, diagnosis and the management of ICDs and related disorders in patients with PD.
2 Behavioural Aspects of Patients with PD with ICDs and Related Disorders
Not surprisingly, studies found that patients with PD with addictive disorders report higher impulsivity scores, had higher levels of neuroticism, lower levels of agreeableness and conscientiousness, as well as lower working memory capacity than patients with PD without ICDs and related disorders [38,39,40]. Furthermore, these patients have higher schizotypy scores (which measures the risk of psychosis) compared with controls [41].
Several studies have assessed the acute behavioural changes following dopaminergic administration in PD so far. Unmedicated patients with PD showed enhanced learning from negative feedback while medicated patients learned better from positive feedback [42,43,44]. This has been shown in drug-naïve patients with PD (n = 26) who were treated for 12 weeks with an oral dopamine agonist (pramipexole n = 14, ropinirole n = 12) and tested on feedback learning. This was done using a computer-based probabilistic classification task, where a reward-learning task, a punishment-learning task and a no-feedback outcome were inter-mixed. Untreated patients had intact negative feedback learning but impaired positive feedback learning whereas this behaviour changed to impairment of negative outcomes with normal reward learning following 12 weeks of dopamine agonist therapy [45]. These studies led us to the hypothesis that patients with PD with ICDs have increased positive feedback learning and/or diminished negative feedback learning, which may then facilitate the development of addictive behaviours in PD. However, several studies prior to and following dopaminergic therapy did not show differences in feedback learning in a two-choice probabilistic discrimination task in patients with PD with ICDs and related disorders compared to healthy volunteers [40, 41, 46]. In contrast, one other study with a two-choice probabilistic discrimination task with three conditions (gain, loss, neutral) showed that patients with PD with ICDs and related disorders (n = 14) had better reward learning [47], in another study, patients with PD with ICDs and related disorders (n = 16) were worse in negative feedback learning [48]. Furthermore, patients with PD with ICDs and related disorders had a heightened reward sensitivity to reward-related cues measured by pupillary dilatation both in the “off” as well as in the “on” state, whereas patients with PD without ICDs and related disorders only had this reward sensitivity after dopaminergic medication [49]. Other factors that may likely contribute to the development of ICDs and related disorders include risk taking. Two studies observed patients with PD prior to and after dopaminergic therapy; patients were tested with a forward and backward digit span test, an instrumental learning task, a gambling task in one study [40] and with the Balloon Analogue Risk Task (a computerised decision-making task used to assess risk-taking behaviour) in the other study. Both studies found increased risk-taking behaviour in patients with PD with ICDs following medication intake [40], particularly dopamine agonists (either pramipexole or ropinorole) [50].
Mixed results have been also reported on inhibitory control. In one study, patients with PD (n = 52) were worse than healthy controls in the Stroop task prior to dopaminergic medication intake, with no difference between patients with PD with addictive behaviours (n = 28) and those without (n = 24). After dopaminergic medication, both patients performed as well as healthy volunteers with no group differences [51]. In line with this, patients with PD with addictions did not perform worse on the Simon task (a task to assess impulsive choice) than PD controls following dopamine agonist intake. In fact, those with ICDs and related behaviours made fewer fast impulsive response errors than PD controls, which suggests that addictive behaviours in PD are less related to motor impulsivity [52]. However, preliminary results from an eye-tracking study showed increased error rates on the anti-saccade task [53]. In the anti-saccade task, participants are asked to fixate a central cross on a screen. As soon as it disappears, a peripheral cue appears on the horizontal plane randomly on the right or left; here participants are asked to not perform a saccade towards the cue, but rather in the opposite direction. Successful inhibitory control depends on intact frontal cortical function as well as an intact frontal eye field and normal function within the thalamo-cortico-cerebellar network [54]. In line with this, a functional magnetic resonance imaging (MRI) study with a double-blind, randomised, crossover design on male volunteers (n = 16) receiving placebo and pramipexole has shown that pramipexole reduces striatal interaction with the prefrontal cortex [55]. These data further dovetail with the hypothesis of a dysfunction of prefrontal cortical inhibition in patients with PD with ICDs and related disorders.
Impulsivity has several facets and it is likely that in contrast to motor impulsivity, temporal discounting (the preference of a smaller immediate reward rather than a larger delayed reward) and reflection impulsivity (tendency to make decisions without considering available information) may play a bigger role in the development of addictive behaviours in PD. Patients with PD with ICDs and related disorders (n = 35) had a steeper discounting of future rewards on medication compared with their off state [56] and had increased temporal discounting in their on medication state compared with non-impulsive patients with PD (n = 55) [41, 43, 57]. In particular, patients with PD with a gambling disorder and those with compulsive shopping seem to have greater temporal discounting than patients with PD with other ICDs, such as compulsive sexual behaviour and binge eating disorder [38]. The orbitofrontal cortex seems to play a critical role in encoding temporal discounting. For example, lesions to the medial part due to a stroke caused increased discounting for money, suggesting that the orbitofrontal cortex is necessary for optimal weighting of future outcomes during decision making [58].
Furthermore, patients with PD with ICDs and related disorders made premature decisions and jumped to conclusions with little evidence in a study comparing patients with PD with ICDs (n = 6), patients with PD without ICDs (n = 27), patients with a gambling disorder (n = 23) and patients with substance abuse (n = 13) using the bead task [59]. This poor information sampling is sometimes also called “reflection impulsivity” and is likely caused by dopamine agonist medication but not levodopa or deep brain stimulation (DBS) [60].
Another typical feature of patients with PD with ICDs and related disorders is enhanced novelty seeking [38], which could also be shown in a probabilistic learning task [61].
Taken together, these studies show that ICDs and related disorders likely affect impulsivity in the decisional domain, with impairment in temporal discounting, poor information sampling, novelty seeking and increased risk taking, and less difficulties in the motor domain, such as response inhibition.
3 Differences of ICDs and Related Disorders Within Patients with PD
Comparative studies and large studies with differences between the single addictive behaviours are rare. This is likely because of the multiple addictions that frequently co-occur [9]. One large study, however, compared patients with PD with gambling disorders (n = 54), compulsive sexual behaviour disorders (n = 47), compulsive shopping (n = 54) and those with binge eating disorders (n = 42). All these patients only had one addictive behaviour. As expected, all patients with PD with ICDs and related disorders had greater depression and all but the binge eating group had higher anxiety scores compared with PD controls (n = 282). Interestingly, only patients with PD with compulsive shopping had increased temporal discounting (assessed with the delayed discounting task, a self-report scale used to observe choice impulsivity) compared with PD controls. Novelty seeking was significantly different to PD controls (18.7 on the self-report Temperament and Character Inventory) in patients with compulsive shopping (25.1) with a trend in those with a gambling disorder (22.3) but not in patients with PD with a compulsive sexual disorder (19.1) and patients diagnosed with a binge eating disorder (18.9) [38]. Moreover, patients with PD with single or multiple ICDs had higher levodopa doses (679.9 vs 544 mg/day), were functionally more impaired and had higher scores on depression (Geriatric Depression Scale-15, 4.9 vs 2.8), anxiety (State Trait Anxiety Inventory, 39.9 vs 33.6), obsessive-compulsive (Obsessive Compulsive Inventory, 13.7 vs 8.8), novelty seeking (Temperament and Character Inventory, 21.8 vs 18.7) and impulsivity (Barratt Impulsiveness Scale, 66.6 vs 57.5) compared with PD controls. However, there was no difference between patients with PD with single and with multiple ICDs [38].
There are some characteristics that are probably more commonly seen in patients with PD with compulsive sexual disorders than in patients with PD with other types of addictions. For example, one albeit small study (n = 111) reported that multiple ICDs are particularly common in young male patients with PD with a compulsive sexual disorder [29]. Furthermore, psychotic symptoms such as paranoid delusional jealousy (Othello syndrome) have also been more commonly described in those with a compulsive sexual disorder. These patients have the false certainty of the infidelity of their partners [62]. In line with this, one study also found that patients with PD with a compulsive sexual disorder are less agreeable than patients with PD with other ICDs or PD controls using the Neuroticism-Extroversion-Openness Five Factor Inventory [63]. In the Parkinson Progression Markers Initiative cohort, punding behaviours could be predicted by current or antecedent attentional dysfunction in de novo patients with PD and by impairments in activities of daily living [64].
4 Burden of ICDs and Related Disorders in PD
Patients with PD with ICDs and related disorders experience more non-motor symptoms (particularly neuropsychiatric problems) than patients with PD without addictive behaviours. More specifically, depression, a poorer quality of life [28], a reduction in social well-being [65], apathy [66] worse sleep, more anxiety as well as higher mania scores [67], psychosis [68] and a higher frequency of rapid eye movement-sleep behaviour disturbances [69] are frequently seen in these patients. Higher aggressiveness, irritability, disinhibition, poorer insight and denial also occur regularly [70]. Moreover, urinary dysfunction, fatigue, cardiovascular problems [71] as well as poorer working memory [40] negatively impact the quality of life of patients with PD and ICDs.
In addition, patients with PD who develop addictive behaviours have a longer disease duration (i.e. data from the National Danish Patient Registry show a mean disease duration of 9.3 years in patients with ICDs compared with 7.5 years in those without), have more motor complications, and take larger amounts of dopaminergic medication than those without ICDs and related disorders [38, 39, 68, 72, 73].
Apart from the patients’ personal disease burden, the burden of relatives caring for patients with PD is already high because of mental, physical and socioeconomic problems [74]. Carers of patients with PD without ICDs and related problems report a far greater burden from mental rather than physical stress, which significantly reduces their quality of life [75]; this strain on the quality of life is even more pronounced in carers of patients with PD with ICDs and related disorders [76]. More specifically, depressive symptoms, apathy and disinhibition in patients with PD with ICDs result in the high caregiver burden [77].
4.1 Illustrative Case
4.1.1 Non-Pharmacological Risk Factors for ICDs and Related Disorders in PD
It is unclear why some patients with PD develop addictive disorders and others do not. It is therefore unlikely that a single mechanism is causative for the development of ICDs. However, it has now been widely accepted that the use of dopaminergic medications (particularly dopamine agonists) in susceptible patients is responsible for the development of an addiction in PD [78] [79]. Several non-pharmacological risk factors have been identified in recent years. The individual vulnerability may consist of striatal density or genetic factors or a combination of both [72]. In line with this, a recent genome-wide association study identified four loci (DAB1, PRKAG2, MEFV and PRKCE) associated with ICDs in a large cohort of 5770 patients with PD, which can distinguish patients with PD at high versus low risk for developing addictions [80].
Other factors include a younger age, younger onset of PD, being single and experiencing more non-motor symptoms than patients with PD without addictions (see Table 5) [38, 68, 72, 73]. Furthermore, higher anxiety scores as well as autonomic and cognitive dysfunction seem to also be risk factors [81]. Sex differences also play a role but are not specific for PD. Compulsive sexual behaviour has been more frequently reported in male patients with PD (n = 3090, 5.2% prevalence in men vs 0.5% prevalence in women [9]), while compulsive shopping and binge eating disorders (same study cohort, respectively, 4.5% in men vs 7.8% in women and 3.4% in men vs 5.8% in women) seem to occur more often in female patients with PD [9, 36].
Other risk factors include a higher novelty-seeking personality trait, a history of alcohol or smoking, depression, anxiety, insomnia, higher caffeine consumption, and a personal or family history of addictive behaviour [23, 82,83,84]. Depression and anxiety seem to play an important role, as both of these symptoms occur significantly more often in the off-state and on-state in patients with ICDs compared with those without (depression, 23% vs 13%; anxiety, 9% vs 4%). Moreover, larger changes in depressive symptoms from the off to the on state (identified as the change in the Hamilton Depression Rating Scale) were also observed in the ICD group compared with the PD control group; this was assessed in a cross-sectional study including 159 patients without ICDs and 41 patients with ICDs [85]. Alexithymia, the difficulty to express, define or identify emotions, has been also linked with increased impulsivity in drug-naïve patients with PD [86] and has been proposed as a risk factor for ICDs [86, 87]. In line with this, apathy, a reduction in emotions, interests and motivation which is common in PD, frequently also co-occurs in patients with ICDs [88]. It has been therefore speculated that the hypodopaminergic behaviours, such as depression, anxiety and apathy, which lie on the opposite spectrum of hyperdopaminergic behaviours (ICDs) [89], may share a common behavioural continuum [90, 91].
4.1.2 Pharmacological Risk factors for ICDs and Related Disorders in PD
It is currently accepted that dopaminergic medication can trigger addiction in PD, as PD itself is not associated with an increased prevalence of ICDs and related disorders. In fact, a case-control study in drug-naïve patients with PD (n = 168) showed a similar frequency of ICDs and related disorders (18.5% PD vs 20.3% controls) compared to healthy controls (n = 143) [92].
By far the biggest risk factor for developing compulsive sexual behaviour, compulsive shopping, and gambling disorder in PD is the use of dopamine agonist therapy [23]. Gambling disorder in patients with PD has almost always been triggered by dopamine agonists and has been only rarely associated with levodopa monotherapy [93].
Although craving for sweets is common in PD, particularly in those who have ICDs [94], the association of binge eating and dopamine agonist therapy remains unclear. Counterintuitively, dopamine agonist use seems not to be associated with binge eating and food addiction in PD [95]. In fact, a small (n = 96 patients with PD) cross-sectional study identified eight patients with binge eating with DBS being the only predictor for overeating [96].
There have been conflicting reports on whether ICDs correlate with the dopamine agonist dose but the dopamine agonist plasma concentration was similar between those with compared to those without ICDs [97]. However, the lifetime average dose as well as the duration of dopamine agonist therapy seem to be associated with ICDs [34]. Moreover, the combination of a dopamine agonist with levodopa seems to increase the risk of ICDs and related disorders even further possibly owing to an increase of mesolimbic dopamine levels and the synergic effect on dopamine receptors [9, 25, 98,99,100]. In line with this, dyskinesias (resulting from higher dopaminergic therapy) are significantly more often seen in patients with PD with ICDs and related disorders than in those without [101].
Although addictive behaviours can be triggered with all available dopamine agonists, they are less often seen in patients with PD treated with the transdermal dopamine agonist rotigotine compared with pramipexole or ropinirole [102]. These results have been recently confirmed in a meta-analysis including more than 650 patients with PD. The rotigotine patch was three times less likely to induce addictive behaviours than pramipexole and ropinirole [103]. While rotigotine has high affinities to the dopamine D1, D2, D3, D4, and D5 receptors, ropinirole and pramipexole only have high affinities to the D2, D3 and D4 receptors. While these pharmacodynamics may play a role in triggering addictions, it is more likely that the drug delivery (oral vs transdermal) is more relevant. Transdermal drug application may lead to a more continuous drug delivery, avoiding peaks and troughs. While oral dopamine agonist plasma concentrations eventually drop after 6–12 h, plasma concentrations during rotigotine therapy remain stable for up to 24 h. Moreover, transdermal application of rotigotine provides direct access to the bloodstream avoiding the hepatic first-pass effect seen in oral dopamine agonists [103] (see Table 6).
The role of D3 agonism in inducing impulsivity has been further confirmed in a recent pharmacovigilance-pharmacodynamic study. Here, around 3000 ICD reports of impulsivity under dopamine agonists (pramipexole and pergolide) are presented, with data regarding receptor occupancy supporting the role of D3-induced ICDs [104]. Interestingly, however, there seems to be no difference between the extended-release and standard oral dopamine agonist formulation (pramipexole and ropinirole) [34].
Although much rarer, ICDs and related disorders have been also described with the use of monoamine oxidase B inhibitors [102] and amantadine [9]. Impulse control disorders under the therapy of catechol O methyltransferase inhibitors are rare. The exact frequency is unknown, mainly because most studies report levodopa equivalent daily doses. A post-hoc analysis on the pooled data from two large randomised, double-blind, placebo-controlled trials on opicapone (n = 517) shows a low incidence of addictive behaviours (between 0.2 and 0.5%) [105], but importantly the risk of ICDs does not appear to increase with long-term use of opicapone [106]. More recently, ICDs have also been observed with aripiprazole (n = 97), which acts as a partial D3 agonist, bupropion (n = 56), a dopaminergic antidepressant and the psychostimulant methylphenidate (n = 40) [107,108,109].
5 Management of ICDs in PD and Pragmatic Treatment
5.1 Experimental Drugs Currently Under Investigation
Naltrexone, an opioid receptor antagonist, which is effective in alcohol addiction, failed to improve ICDs in PD [133]. However, it has been argued that some ICDs such as hobbyism may be more responsive to naltrexone than other ICDs, but further studies are warranted [134]. Clonidine, an α2-adrenergic agonist, has been shown to significantly reduce impulsivity in a gambling task in abstinent heroin addicts (n = 53) [135]. A recent randomised, controlled, double-blind, phase IIb trial in patients with PD with ICDs (n = 39) showed, however, that administration of clonidine for 8 weeks resulted only in a non-significant reduction of impulsivity compared with placebo [136]. Although in this study clonidine (75 µg twice daily) was well tolerated, common side effects include low blood pressure as well as dizziness and depression, which may further reduce the quality of life in PD. Nevertheless, the results of this study warrant a longer treatment duration and a larger sample size in a further phase III trial. A crossover, double-blind, placebo-controlled study using atomoxetine (40 mg orally), a noradrenalin reuptake inhibitor, showed reduced motor and reflection impulsivity as well as risk taking. Although this study is promising, the sample size was rather small and none of the patients with PD had ICDs (n = 33) [137]. However, evidence from functional MRI shows that atomoxetine may enhance prefrontal cortex connectivity and possibly have a restoring effect on executive functions; this may hold interest in future trials [138].
Currently, a randomised, placebo-controlled, phase II trial (NCT03947216) assessing the effect of pimavanserin, a selective serotonin 5-HT2A inverse agonist, on ICDs is underway and results are expected in 2025. In this trial, patients with PD will be treated with pimavanserin 17 mg or placebo daily for 8 weeks, with the primary outcome measure being the change in ICDs (measured with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease [QUIP]) after treatment.
Management of ICDs and related disorders in PD is challenging. Thus, the phrase “prevention is better than cure” is particularly important, as there are no consensus guidelines available because of the paucity of randomised controlled trials. Therefore, all patients with PD should be advised about the potential risk of developing behavioural addictions especially following dopamine agonist therapy. This consultation should ideally take place together with family members, carers or close friends who are in regular contact with the patient. Long-term vigilance is required especially in younger patients, those who have a personal or family history of addictive behaviours, or who are single and experience more motor symptoms such as dyskinesias as well as non-motor symptoms [23]. It is also important to highlight that ICDs and related behaviours in PD almost always build up gradually and any change in behaviour, particularly increased irritability, disturbed night-time sleep or increased spending may be harbingers. In line with this, it has been reported that 24% of patients with subsyndromal ICDs (defined as subthreshold behaviours without reaching the formal diagnostic criteria) developed clinically significant ICDs after 1 year [88]. The severity of the addiction is important to take into consideration and sometimes an immediate hospital admission may be required. The QUIP [139] and the QUIP rating scale, which includes the severity of the addiction [24], can be useful to detect an ICD early on.
In contrast, there are rare circumstances where no change of treatment is required in patients with PD with addictive behaviours depending on the patients’ disability, financial and social circumstances. However, usually if an ICD or a related disorder is left untreated or ignored, it may have devastating financial and psychological consequences for the lives of patients and their families (see illustrative case).
Non-pharmacological approaches such as physical exercise, cognitive behavioural therapy or limiting access to credit cards, the Internet or gambling venues should be implemented but are usually not enough on their own [16, 23, 140]. Dopamine agonists should be reduced in patients with gambling disorders, compulsive sexual disorders and those with compulsive shopping and (if possible) completely weaned off. Patients are sometimes reluctant to reduce the dopamine agonist because of low insight but switching from a dopamine agonist to levodopa can improve impulsive behaviour within a few months [141]. However, patients must be informed that anxiety, panic attacks, depression, dysphoria, fatigue, pain and the feeling of being undertreated may occur. These symptoms are known as dopamine agonist withdrawal syndrome and may cause significant psychological distress that may be refractory to levodopa or any other PD medication [142]. Hospital admission may be necessary in these patients to alleviate dopamine agonist withdrawal syndrome.
In patients with DDS, a reduction in levodopa, or a fast-acting apomorphine pen injection is necessary, but these patients often do not tolerate the reduction because of worsening of motor fluctuations, ‘off’ dystonia or withdrawal symptoms. These heterogeneous non-motor as well as motor symptoms usually subside within a few days or weeks but can also last several months [72]. Again, in these patients, hospital admission and a multidisciplinary approach including a psychiatrist and psychologist may be necessary.
Treatment of the neuropsychiatric comorbidities, such as depression, anxiety and panic attacks, as well as an improvement of potential sleep disturbances may be frequently required regardless of the underlying addictive behaviour [23, 67, 143]. Trazodone and the alpha-2 adrenoreceptor antagonist mirtazapine may help to improve some neuropsychiatric symptoms as well as nocturnal sleep [144]. Additionally, considering that the pathophysiology of depression in PD likely involves several neurotransmitters (dopaminergic, serotoninergic, noradrenergic), depression should be treated with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or a tricyclic antidepressant. Although there are no official guidelines guiding the therapeutic choice, there is some evidence in favour of the aforementioned drugs, as well as for cognitive-behavioural therapy [145, 146]. If patients have additional psychosis, quetiapine or clozapine may be administered; however, regular blood counts because of the potential risk of agranulocytosis are limitations in those treated with clozapine [146].
The role of DBS of the subthalamic nucleus in patients with PD with ICDs and related disorders is controversial. However, in selected patients with PD who do not experience cognitive impairment, or have any other contraindication for functional surgery, DBS of the subthalamic nucleus can result in improvement of ICDs and related symptoms because of the reduction in dopaminergic therapy [147]. In some patients, however, de novo ICDs can occur, possibly due to misplacement of the electrode, or failure of a dopaminergic drug reduction [16]. Pre-operative but also post-operative psychiatric monitoring is mandatory in patients with PD who undergo DBS, given reports of the increased risk of post-surgical suicide attempts [143].
Dyskinesias have been linked with ICDs in PD [72] and thus, a reduction in dyskinesias by decreasing the overall dopaminergic therapy will often also lead to an improvement of addictive behaviours. In line with this, there is preliminary evidence that continuous delivery of levodopa/carbidopa or the D1 receptor agonist apomorphine can improve ICDs [148, 149].
Overall, a remission of ICDs and related disorders can be achieved in about 40–80% of patients. Not surprisingly, several studies have shown that a reduction in the dopamine agonist dose or ideally a complete discontinuation is linked with better outcomes [34, 150,151,152].
6 Potential Underlying Mechanisms
In PD, the dorsal striatum is primarily affected and neurodegeneration is more severe than in mesolimbic neurons, which are relatively unaffected [111]. Therefore, one hypothesis is that in patients with PD with ICDs and related behaviours, the nucleus accumbens may still be relatively intact and that the extra dopaminergic medication leads to a local dopamine overdose in the ventral striatum [112]. Importantly the nucleus accumbens shell has strong connections to limbic structures and is therefore believed to have an important role in motivation and addiction. Stimulation of the nucleus accumbens is believed to play a pivotal role in drug addiction, as the iatrogenic dopamine release in this nucleus shares similarities to natural rewards (such as food), but is missing the physiological adaptation (habituation and inhibition by predictive stimuli) [113, 114].
This “overdose hypothesis” has been recently confirmed in a post-mortem immunohistochemistry study in patients with PD with various addictive behaviours (n = 31) who were matched to patients with PD without addictions (n = 29). Patients with PD with ICDs and related disorders had significantly less alpha-synuclein pathology in the ventral striatum than patients without addictions. This further strengthens the hypothesis that the ventral striatum is indeed better preserved in these patients. Furthermore, and on the surface counterintuitively, patients with ICDs had also lower D3 receptors [115]. This may be due to downregulation of the receptors leading to a supersensitivity of the remaining D3 receptors or a premorbid personality trait making these patients more vulnerable for addictive behaviours [115, 116]. Alternatively, the lower D3 receptors could also reflect a smaller motor response to dopaminergic medication in patients, which would then lead to higher doses to achieve symptomatic control, causing a dopamine overdose of the ventral striatum [115]. However, as D1 and D2 but not D3 receptors are responsible for the overall best motor response [114], this hypothesis remains speculative.
Dopamine agonists may directly affect the cortico-striatal network. A study with 16 healthy male volunteers shows that pramipexole increases mesolimbic dopamine levels during anticipation of monetary rewards, but at the same time reduces the striatal interaction to the prefrontal cortex [55]. This dopamine agonist induced reduction in “top down control” in addition to the mesolimbic dopamine “overdose” is currently thought to play a key role for developing ICDs and related disorders in susceptible patients [110].
7 Imaging in Patients with PD with ICDs and Related Disorders
7.1 Structural MRI
The role of structural imaging in patients with PD with ICDs is inconclusive with some studies showing cortical thinning of the orbitofrontal cortex [117], while others reported an increased cortical thickness of the orbitofrontal cortex [118, 119], and others did not find structural differences compared to PD controls [81, 120]. There are only a few of these studies and they vary in the number of participants observed and their demographics; orbitofrontal cortex thinning has also been associated with other conditions, which may work as confounders when interpreting these results (depression, alcohol dependence). Thus, there is no clear evidence on whether cortical thickness does play a major role in patients with PD with ICDs and related behaviours.
7.2 Functional MRI
Resting-state MRI revealed that patients with PD with ICDs have an increased connectivity within the salience network (anterior insula and dorsal anterior cingulate cortex) and a decreased connectivity within the central executive network (dorsolateral prefrontal and lateral posterior parietal cortex). This altered connectivity of the neurocognitive networks, which is also found in patients with other addiction disorders, may be one neural correlate of ICDs in PD [121].
7.3 Positron Emission Tomography
One of the first positron emission tomography (PET) studies using [11C] raclopride assessed patients with PD with DDS (n = 8) and PD controls (n = 8) prior to and following the first levodopa dose. Patients with PD with DDS but not PD controls had elevated levodopa-induced ventral striatal dopamine release. This sensitised ventral striatal dopamine release was associated with self-reported compulsive drug “wanting” but not “liking” [122]. Sensitisation (an enhanced response to a stimulus) is — like tolerance, withdrawal and dependence — a hallmark of addiction [123]. In line with this, another PET study using [11C] raclopride showed a higher ventral striatal dopamine release in patients with PD with a gambling disorder during gambling but not in PD controls following dopamine agonist therapy (pramipexole n = 5, ropinirole n = 2) [124]. Moreover, patients with PD with a variety of different ICDs but not PD controls also exhibited an increased ventral striatal dopamine release following reward-related visual cues after levodopa intake (200/50 mg, scanning acquired 45 minutes after intake) [125]. Another H215O PET study revealed a reduction in the lateral orbitofrontal cortex, as well as in the amygdala and the rostral cingulum during a card selection game following apomorphine administration only in patients with PD with a gambling disorder (n = 7) [126].
A study using the PET radiotracer, [11C] FLB-457, with high affinity for extra-striatal D2/D3 receptors, found decreased binding in the midbrain during a gambling task in patients with PD with ICDs (n = 7) compared with PD controls (n = 7). These results hint towards a wider dopaminergic dysfunction with altered striatal and cortical dopamine homeostasis in patients with PD with ICDs [127]. In line with this, a study using cerebral 18F‐fluorodeoxyglucose PET showed that patients with PD with ICDs (n = 18) had a dysfunction of a large network including the mesocorticolimbic system, the caudate, the parahippocampus and the orbitofrontal cortex, but also with increased metabolism of the right middle and inferior temporal gyri [128]. It is therefore possible that these temporal regions are involved in the establishment of the mnemonic component of addiction [128].
Several studies have used the [123I] FP-CIT radioligand, which showed a reduction in dopamine transporter (DAT) levels in the ventral striatum of patients with PD with a gambling disorder (n = 8) [129] and patients with PD with a variety of different ICDs (n = 282) [130]. It is possible that the lower DAT binding reflects lower membrane DAT expression on presynaptic terminals, resulting in a functional reduction of presynaptic reuptake and thus increased dopamine levels within the ventral striatum [129]. In line with these results, a small preliminary study (n = 31) [131] and a large (n = 320 at baseline; n = 284 at year 1, n = 217 at year 2, n = 96 at year 3) longitudinal study using the data acquired in the Parkinson’s Progression Marker Initiative found an association between lower striatal DAT binding and an increased risk of developing ICDs [132]. Thus, these PET studies, combined with the neuropathological results, imply that increased and abnormal mesolimbic dopamine release, due to a relatively intact ventral striatum, in combination with prefrontal cortex dysfunction may trigger behavioural addictions [115, 124,125,126].
8 Conclusions
Impulse control disorders are relatively common non-motor symptoms that arise in patients with PD being treated with dopaminergic drugs, most commonly with dopamine agonist therapy. The variability on the amount of patients who develop ICDs and also the type of ICDs that may arise depends on several risk factors, which include younger age, higher anxiety traits and a history of addictive behaviours in the past. As ICDs may have devastating consequences in patients’ lives both socially and financially, patients being started on dopaminergic drugs should be properly informed of the possibility of ICDs arising, ideally in the presence of a family member or close friend. If an ICD is reported, early treatment is of paramount importance, as the patient’s cognition may already be impaired. Management of ICDs requires a reduction, and if possible, a complete discontinuation of dopamine agonist therapy. In patients with DDS, a reduction in fast-acting dopaminergic drugs is necessary. Often patients with PD have to be admitted to hospital to alleviate dopamine agonist withdrawal syndrome. New trials exploring additional therapeutic strategies need to take in account the diverse nature of all disorders falling under the term ICDs and if necessary tailor a therapy for each disorder.
References
Dell’Osso B, Altamura AC, Allen A, Marazziti D, Hollander E. Epidemiologic and clinical updates on impulse control disorders: a critical review. Eur Arch Psychiatry Clin Neurosci. 2006;256(8):464–75.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
Grant JE, Chamberlain SR. Expanding the definition of addiction: DSM-5 vs. ICD-11. CNS Spectr. 2016;21(4):300–3.
Kok ZQ, Murley AG, Rittman T, Rowe J, Passamonti L. Co-occurrence of apathy and impulsivity in progressive supranuclear palsy. Mov Disord Clin Pract. 2021;8(8):1225–33.
O’Sullivan SS, Djamshidian A, Ahmed Z, Evans AH, Lawrence AD, Holton JL, et al. Impulsive-compulsive spectrum behaviors in pathologically confirmed progressive supranuclear palsy. Mov Disord. 2010;25(5):638–42.
Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE. Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson’s disease and multiple system atrophy. Parkinsonism Relat Disord. 2005;11(6):381–6.
Cilia R, Siri C, Colombo A, Pezzoli G. Multiple compulsive behaviors in multiple system atrophy: the importance of predisposition to addiction. Parkinsonism Relat Disord. 2014;20(3):355–7.
Pompanin S, Jelcic N, Cecchin D, Cagnin A. Impulse control disorders in frontotemporal dementia: spectrum of symptoms and response to treatment. Gen Hosp Psychiatry. 2014;36(6):760.e5-7.
Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010;67(5):589–95.
Holman AJ. Impulse control disorder behaviors associated with pramipexole used to treat fibromyalgia. J Gambl Stud. 2009;25(3):425–31.
Heim B, Djamshidian A, Heidbreder A, Stefani A, Zamarian L, Pertl MT, et al. Augmentation and impulsive behaviors in restless legs syndrome: coexistence or association? Neurology. 2016;87(1):36–40.
Beccuti G, Guaraldi F, Natta G, Cambria V, Prencipe N, Cicolin A, et al. Increased prevalence of impulse control disorder symptoms in endocrine diseases treated with dopamine agonists: a cross-sectional study. J Endocrinol Invest. 2021;44(8):1699–706.
Wright A, Rickards H, Cavanna AE. Impulse-control disorders in gilles de la tourette syndrome. J Neuropsychiatry Clin Neurosci. 2012;24(1):16–27.
Porteret R, Bouchez J, Bayle FJ, Varescon I. ADH/D and impulsiveness: prevalence of impulse control disorders and other comorbidities, in 81 adults with attention deficit/hyperactivity disorder (ADH/D). Encephale. 2016;42(2):130–7.
Garcia FD, Thibaut F. Sexual addictions. Am J Drug Alcohol Abuse. 2010;36(5):254–60.
Djamshidian A, Averbeck BB, Lees AJ, O’Sullivan SS. Clinical aspects of impulsive compulsive behaviours in Parkinson’s disease. J Neurol Sci. 2011;310(1–2):183–8.
Friedman JH. Punding on levodopa. Biol Psychiatry. 1994;36(5):350–1.
Barbosa P, O’Sullivan SS, Joyce E, Lees AJ, Warner TT, Djamshidian A. Neuropsychiatric features of punding and hobbyism in Parkinson’s disease. Mov Disord Clin Pract. 2022;9(1):82–6.
O’Sullivan SS, Evans AH, Quinn NP, Lawrence AD, Lees AJ. Reckless generosity in Parkinson’s disease. Mov Disord. 2010;25(2):221–3.
O’Sullivan SS, Djamshidian A, Evans AH, Loane CM, Lees AJ, Lawrence AD. Excessive hoarding in Parkinson’s disease. Mov Disord. 2010;25(8):1026–33.
Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry. 2000;68(4):423–8.
Friedman JH, Chang V. Crack cocaine use due to dopamine agonist therapy in Parkinson disease. Neurology. 2013;80(24):2269–70.
Averbeck BB, O’Sullivan SS, Djamshidian A. Impulsive and compulsive behaviors in Parkinson’s disease. Annu Rev Clin Psychol. 2014;10:553–80.
Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for impulsive-compulsive disorders in Parkinson’s Disease-Rating Scale. Mov Disord. 2012;27(2):242–7.
Evans AH, Strafella AP, Weintraub D, Stacy M. Impulsive and compulsive behaviors in Parkinson’s disease. Mov Disord. 2009;24(11):1561–70.
Robbins TW, Gillan CM, Smith DG, de Wit S, Ersche KD. Neurocognitive endophenotypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends Cogn Sci. 2012;16(1):81–91.
Evans AH, Katzenschlager R, Paviour D, O’Sullivan JD, Appel S, Lawrence AD, et al. Punding in Parkinson’s disease: its relation to the dopamine dysregulation syndrome. Mov Disord. 2004;19(4):397–405.
Antonini A, Barone P, Bonuccelli U, Annoni K, Asgharnejad M, Stanzione P. ICARUS study: prevalence and clinical features of impulse control disorders in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2017;88(4):317–24.
Barbosa PM, Grippe T, Lees AJ, O’Sullivan S, Djamshidian A, Warner TT. Compulsive sexual behaviour in Parkinson’s disease is associated with higher doses of levodopa. J Neurol Neurosurg Psychiatry. 2018;89(10):1121–3.
Barbeau A. L-dopa therapy in Parkinson’s disease: a critical review of nine years’ experience. Can Med Assoc J. 1969;101(13):59–68.
Bowers MB Jr, Van Woert M, Davis L. Sexual behavior during L-dopa treatment for Parkinsonism. Am J Psychiatry. 1971;127(12):1691–3.
Shapiro SK. Hypersexual behavior complicating levodopa (I-dopa) therapy. Minn Med. 1973;56(1):58–9.
Vela L, Martinez Castrillo JC, Garcia Ruiz P, Gasca-Salas C, Macias Macias Y, Perez Fernandez E, et al. The high prevalence of impulse control behaviors in patients with early-onset Parkinson’s disease: a cross-sectional multicenter study. J Neurol Sci. 2016;368:150–4.
Corvol JC, Artaud F, Cormier-Dequaire F, Rascol O, Durif F, Derkinderen P, et al. Longitudinal analysis of impulse control disorders in Parkinson disease. Neurology. 2018;91(3):e189-201.
Rabano-Suarez P, Martinez-Fernandez R, Natera-Villalba E, Parees I, Martinez-Castrillo JC, Alonso-Canovas A. Impulse control disorders in Parkinson’s disease: has COVID-19 related lockdown been a trigger? Mov Disord Clin Pract. 2021;8(6):940–3.
Voon V, Hassan K, Zurowski M, de Souza M, Thomsen T, Fox S, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology. 2006;67(7):1254–7.
McElroy SL, Keck PE Jr, Pope HG Jr, Smith JM, Strakowski SM. Compulsive buying: a report of 20 cases. J Clin Psychiatry. 1994;55(6):242–8.
Voon V, Sohr M, Lang AE, Potenza MN, Siderowf AD, Whetteckey J, et al. Impulse control disorders in Parkinson disease: a multicenter case-control study. Ann Neurol. 2011;69(6):986–96.
Callesen MB, Weintraub D, Damholdt MF, Moller A. Impulsive and compulsive behaviors among Danish patients with Parkinson’s disease: prevalence, depression, and personality. Parkinsonism Relat Disord. 2014;20(1):22–6.
Djamshidian A, Jha A, O’Sullivan SS, Silveira-Moriyama L, Jacobson C, Brown P, et al. Risk and learning in impulsive and nonimpulsive patients with Parkinson’s disease. Mov Disord. 2010;25(13):2203–10.
Housden CR, O’Sullivan SS, Joyce EM, Lees AJ, Roiser JP. Intact reward learning but elevated delay discounting in Parkinson’s disease patients with impulsive-compulsive spectrum behaviors. Neuropsychopharmacology. 2010;35(11):2155–64.
Frank MJ, Seeberger LC, O’reilly RC. By carrot or by stick: cognitive reinforcement learning in parkinsonism. Science. 2004;306(5703):1940–3.
Voon V, Reynolds B, Brezing C, Gallea C, Skaljic M, Ekanayake V, et al. Impulsive choice and response in dopamine agonist-related impulse control behaviors. Psychopharmacology. 2010;207(4):645–59.
Cools R, Rogers R, Barker RA, Robbins TW. Top-down attentional control in Parkinson’s disease: salient considerations. J Cogn Neurosci. 2010;22(5):848–59.
Bodi N, Keri S, Nagy H, Moustafa A, Myers CE, Daw N, et al. Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson’s patients. Brain. 2009;132(Pt 9):2385–95.
Djamshidian A, O’Sullivan SS, Lees A, Averbeck BB. Effects of dopamine on sensitivity to social bias in Parkinson’s disease. PLoS ONE. 2012;7(3): e32889.
Voon V, Pessiglione M, Brezing C, Gallea C, Fernandez HH, Dolan RJ, et al. Mechanisms underlying dopamine-mediated reward bias in compulsive behaviors. Neuron. 2010;65(1):135–42.
Piray P, Zeighami Y, Bahrami F, Eissa AM, Hewedi DH, Moustafa AA. Impulse control disorders in Parkinson’s disease are associated with dysfunction in stimulus valuation but not action valuation. J Neurosci. 2014;34(23):7814–24.
Drew DS, Muhammed K, Baig F, Kelly M, Saleh Y, Sarangmat N, et al. Dopamine and reward hypersensitivity in Parkinson’s disease with impulse control disorder. Brain. 2020;143(8):2502–18.
Claassen DO, van den Wildenberg WP, Ridderinkhof KR, Jessup CK, Harrison MB, Wooten GF, et al. The risky business of dopamine agonists in Parkinson disease and impulse control disorders. Behav Neurosci. 2011;125(4):492–500.
Djamshidian A, O’Sullivan SS, Lees A, Averbeck BB. Stroop test performance in impulsive and non impulsive patients with Parkinson’s disease. Parkinsonism Relat Disord. 2011;17(3):212–4.
Wylie SA, Claassen DO, Huizenga HM, Schewel KD, Ridderinkhof KR, Bashore TR, et al. Dopamine agonists and the suppression of impulsive motor actions in Parkinson disease. J Cogn Neurosci. 2012;24(8):1709–24.
Barbosa P, Kaski D, Castro P, Lees AJ, Warner TT, Djamshidian A. Saccadic direction errors are associated with impulsive compulsive behaviours in Parkinson’s disease patients. J Parkinsons Dis. 2019;9(3):625–30.
Coe BC, Munoz DP. Mechanisms of saccade suppression revealed in the anti-saccade task. Philos Trans R Soc Lond B Biol Sci. 2017;372(1718):20160192.
Ye Z, Hammer A, Camara E, Munte TF. Pramipexole modulates the neural network of reward anticipation. Hum Brain Mapp. 2011;32(5):800–11.
Leroi I, Barraclough M, McKie S, Hinvest N, Evans J, Elliott R, et al. Dopaminergic influences on executive function and impulsive behaviour in impulse control disorders in Parkinson’s disease. J Neuropsychol. 2013;7(2):306–25.
Joutsa J, Voon V, Johansson J, Niemela S, Bergman J, Kaasinen V. Dopaminergic function and intertemporal choice. Transl Psychiatry. 2015;5: e491.
Sellitto M, Ciaramelli E, di Pellegrino G. Myopic discounting of future rewards after medial orbitofrontal damage in humans. J Neurosci. 2010;30(49):16429–36.
Djamshidian A, O’Sullivan SS, Sanotsky Y, Sharman S, Matviyenko Y, Foltynie T, et al. Decision making, impulsivity, and addictions: do Parkinson’s disease patients jump to conclusions? Mov Disord. 2012;27(9):1137–45.
Djamshidian A, O’Sullivan SS, Foltynie T, Aviles-Olmos I, Limousin P, Noyce A, et al. Dopamine agonists rather than deep brain stimulation cause reflection impulsivity in Parkinson’s disease. J Parkinsons Dis. 2013;3(2):139–44.
Djamshidian A, O’Sullivan SS, Wittmann BC, Lees AJ, Averbeck BB. Novelty seeking behaviour in Parkinson’s disease. Neuropsychologia. 2011;49(9):2483–8.
Kataoka H, Sugie K. Delusional jealousy (Othello syndrome) in 67 patients with Parkinson’s disease. Front Neurol. 2018;9:129.
Sachdeva J, Harbishettar V, Barraclough M, McDonald K, Leroi I. Clinical profile of compulsive sexual behaviour and paraphilia in Parkinson’s disease. J Parkinsons Dis. 2014;4(4):665–70.
Hinkle JT, Perepezko K, Mills KA, Pontone GM. Attentional dysfunction and the punding spectrum in Parkinson’s disease. Parkinsonism Relat Disord. 2021;84:23–8.
Phu AL, Xu Z, Brakoulias V, Mahant N, Fung VS, Moore GD, et al. Effect of impulse control disorders on disability and quality of life in Parkinson’s disease patients. J Clin Neurosci. 2014;21(1):63–6.
Scott BM, Eisinger RS, Burns MR, Lopes J, Okun MS, Gunduz A, et al. Co-occurrence of apathy and impulse control disorders in Parkinson disease. Neurology. 2020;95(20):e2769–80.
O’Sullivan SS, Loane CM, Lawrence AD, Evans AH, Piccini P, Lees AJ. Sleep disturbance and impulsive-compulsive behaviours in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2011;82(6):620–2.
Hinkle JT, Perepezko K, Rosenthal LS, Mills KA, Pantelyat A, Mari Z, et al. Markers of impaired motor and cognitive volition in Parkinson’s disease: correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias. Parkinsonism Relat Disord. 2018;47:50–6.
Fantini ML, Macedo L, Zibetti M, Sarchioto M, Vidal T, Pereira B, et al. Increased risk of impulse control symptoms in Parkinson’s disease with REM sleep behaviour disorder. J Neurol Neurosurg Psychiatry. 2015;86(2):174–9.
Latella D, Maggio MG, Maresca G, Saporoso AF, Le Cause M, Manuli A, et al. Impulse control disorders in Parkinson’s disease: a systematic review on risk factors and pathophysiology. J Neurol Sci. 2019;398:101–6.
Jesus S, Labrador-Espinosa MA, Adarmes AD, Mendel-Del Barrio C, Martinez-Castrillo JC, Alonso-Canovas A, et al. Non-motor symptom burden in patients with Parkinson’s disease with impulse control disorders and compulsive behaviours: results from the COPPADIS cohort. Sci Rep. 2020;10(1):16893.
Voon V, Napier TC, Frank MJ, Sgambato-Faure V, Grace AA, Rodriguez-Oroz M, et al. Impulse control disorders and levodopa-induced dyskinesias in Parkinson’s disease: an update. Lancet Neurol. 2017;16(3):238–50.
Marin-Lahoz J, Sampedro F, Martinez-Horta S, Pagonabarraga J, Kulisevsky J. Depression as a risk factor for impulse control disorders in Parkinson disease. Ann Neurol. 2019;86(5):762–9.
Zarit SH, Todd PA, Zarit JM. Subjective burden of husbands and wives as caregivers: a longitudinal study. Gerontologist. 1986;26(3):260–6.
Roland KP, Jenkins ME, Johnson AM. An exploration of the burden experienced by spousal caregivers of individuals with Parkinson’s disease. Mov Disord. 2010;25(2):189–93.
Leroi I, Harbishettar V, Andrews M, McDonald K, Byrne EJ, Burns A. Carer burden in apathy and impulse control disorders in Parkinson’s disease. Int J Geriatr Psychiatry. 2012;27(2):160–6.
Johnson D, Townsend L, David A, Askey-Jones S, Brown R, Samuel M, et al. Predictors of burden in carers of patients with impulse control behaviors in Parkinson’s disease. Mov Disord Clin Pract. 2023;10(9):1360–7.
Voon V, Potenza MN, Thomsen T. Medication-related impulse control and repetitive behaviors in Parkinson’s disease. Curr Opin Neurol. 2007;20(4):484–92.
Augustine A, Winstanley CA, Krishnan V. Impulse control disorders in Parkinson’s disease: from bench to bedside. Front Neurosci. 2021;15: 654238.
Weintraub D, Posavi M, Fontanillas P, Tropea TF, Mamikonyan E, Suh E, et al. Genetic prediction of impulse control disorders in Parkinson’s disease. Ann Clin Transl Neurol. 2022;9(7):936–49.
Ricciardi L, Lambert C, De Micco R, Morgante F, Edwards M. Can we predict development of impulsive-compulsive behaviours in Parkinson’s disease? J Neurol Neurosurg Psychiatry. 2018;89(5):476–81.
Fasano A, Petrovic I. Insights into pathophysiology of punding reveal possible treatment strategies. Mol Psychiatry. 2010;15(6):560–73.
Aoki R, Shiraishi M, Mikami K, Kamo T. Deterioration of postural deformity in Parkinson’s disease patients with punding and hobbyism. J Clin Neurosci. 2019;69:179–83.
Bastiaens J, Dorfman BJ, Christos PJ, Nirenberg MJ. Prospective cohort study of impulse control disorders in Parkinson’s disease. Mov Disord. 2013;28(3):327–33.
Morrow CB, Hinkle JT, Seemiller J, Mills KA, Pontone GM. Examining the link between impulse control disorder and antidepressant use in Parkinson’s disease. Parkinsonism Relat Disord. 2023;117: 105918.
Poletti M, Frosini D, Pagni C, Claudio L, del Paolo D, Roberto C, et al. Alexithymia is associated with impulsivity in newly-diagnosed, drug-naive patients with Parkinson’s disease: an affective risk factor for the development of impulse-control disorders? J Neuropsychiatry Clin Neurosci. 2012;24(4):E36–7.
Goerlich-Dobre KS, Probst C, Winter L, Witt K, Deuschl G, Moller B, et al. Alexithymia: an independent risk factor for impulsive-compulsive disorders in Parkinson’s disease. Mov Disord. 2014;29(2):214–20.
Baig F, Kelly MJ, Lawton MA, Ruffmann C, Rolinski M, Klein JC, et al. Impulse control disorders in Parkinson disease and RBD: a longitudinal study of severity. Neurology. 2019;93(7):e675–87.
Sierra M, Carnicella S, Strafella AP, Bichon A, Lhommee E, Castrioto A, et al. Apathy and impulse control disorders: yin & yang of dopamine dependent behaviors. J Parkinsons Dis. 2015;5(3):625–36.
Leroi I, Andrews M, McDonald K, Harbishettar V, Elliott R, Byrne EJ, et al. Apathy and impulse control disorders in Parkinson’s disease: a direct comparison. Parkinsonism Relat Disord. 2012;18(2):198–203.
Theis H, Probst C, Fernagut PO, van Eimeren T. Unlucky punches: the vulnerability-stress model for the development of impulse control disorders in Parkinson’s disease. NPJ Parkinsons Dis. 2021;7(1):112.
Weintraub D, Papay K, Siderowf A, Parkinson’s Progression Markers Initiative. Screening for impulse control symptoms in patients with de novo Parkinson disease: a case-control study. Neurology. 2013;80(2):176–80.
Djamshidian A, Cardoso F, Grosset D, Bowden-Jones H, Lees AJ. Pathological gambling in Parkinson’s disease: a review of the literature. Mov Disord. 2011;26(11):1976–84.
de Chazeron I, Durif F, Chereau-Boudet I, Fantini ML, Marques A, Derost P, et al. Compulsive eating behaviors in Parkinson’s disease. Eat Weight Disord. 2019;24(3):421–9.
de Chazeron I, Durif F, Lambert C, Chereau-Boudet I, Fantini ML, Marques A, et al. A case-control study investigating food addiction in Parkinson patients. Sci Rep. 2021;11(1):10934.
Zahodne LB, Susatia F, Bowers D, Ong TL, Jacobson CEt, Okun MS, et al. Binge eating in Parkinson’s disease: prevalence, correlates and the contribution of deep brain stimulation. J Neuropsychiatry Clin Neurosci. 2011;23(1):56–62.
Contin M, Lopane G, Marini L, Mohamed S, Sambati L, De Massis P, et al. Screening for impulse control disorders in Parkinson’s disease and dopamine agonist use: a study of pharmacokinetic and psychological risk factors. Neurol Sci. 2023;44(2):565–72.
Bharmal A, Lu C, Quickfall J, Crockford D, Suchowersky O. Outcomes of patients with Parkinson disease and pathological gambling. Can J Neurol Sci. 2010;37(4):473–7.
Gallagher DA, O’Sullivan SS, Evans AH, Lees AJ, Schrag A. Pathological gambling in Parkinson’s disease: risk factors and differences from dopamine dysregulation. An analysis of published case series. Mov Disord. 2007;22(12):1757–63.
Hassan A, Bower JH, Kumar N, Matsumoto JY, Fealey RD, Josephs KA, et al. Dopamine agonist-triggered pathological behaviors: surveillance in the PD clinic reveals high frequencies. Parkinsonism Relat Disord. 2011;17(4):260–4.
Biundo R, Weis L, Abbruzzese G, Calandra-Buonaura G, Cortelli P, Jori MC, et al. Impulse control disorders in advanced Parkinson’s disease with dyskinesia: the ALTHEA study. Mov Disord. 2017;32(11):1557–65.
Garcia-Ruiz PJ, Martinez Castrillo JC, Alonso-Canovas A, Herranz Barcenas A, Vela L, Sanchez Alonso P, et al. Impulse control disorder in patients with Parkinson’s disease under dopamine agonist therapy: a multicentre study. J Neurol Neurosurg Psychiatry. 2014;85(8):840–4.
Soileau LG, Talbot NC, Storey NR, Spillers NJ, D’Antoni JV, Carr PC, et al. Impulse control disorders in Parkinson’s disease patients treated with pramipexole and ropinirole: a systematic review and meta-analysis. Neurol Sci. 2024;45(4):1399–408.
Fusaroli M, Giunchi V, Battini V, Gringeri M, Rimondini R, Menchetti M, et al. Exploring the underlying mechanisms of drug-induced impulse control disorders: a pharmacovigilance-pharmacodynamic study. Psychiatry Clin Neurosci. 2023;77(3):160–7.
Fabbri M, Ferreira JJ, Rascol O. COMT inhibitors in the management of Parkinson’s disease. CNS Drugs. 2022;36(3):261–82.
Azevedo Kauppila L, Pimenta Silva D, Ferreira JJ. Clinical utility of opicapone in the management of Parkinson’s disease: a short review on emerging data and place in therapy. Degener Neurol Neuromuscul Dis. 2021;11:29–40.
Etminan M, Sodhi M, Samii A, Procyshyn RM, Guo M, Carleton BC. Risk of gambling disorder and impulse control disorder with aripiprazole, pramipexole, and ropinirole: a pharmacoepidemiologic study. J Clin Psychopharmacol. 2017;37(1):102–4.
Lertxundi U, Hernandez R, Medrano J, Domingo-Echaburu S, Garcia M, Aguirre C. Aripiprazole and impulse control disorders: higher risk with the intramuscular depot formulation? Int Clin Psychopharmacol. 2018;33(1):56–8.
De Wit LE, Wilting I, Souverein PC, van der Pol P, Egberts TCG. Impulse control disorders associated with dopaminergic drugs: a disproportionality analysis using vigibase. Eur Neuropsychopharmacol. 2022;58:30–8.
O’Sullivan SS, Evans AH, Lees AJ. Dopamine dysregulation syndrome: an overview of its epidemiology, mechanisms and management. CNS Drugs. 2009;23(2):157–70.
Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease: pathophysiologic and clinical implications. N Engl J Med. 1988;318(14):876–80.
Cools R, Barker RA, Sahakian BJ, Robbins TW. Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb Cortex. 2001;11(12):1136–43.
Park YS, Sammartino F, Young NA, Corrigan J, Krishna V, Rezai AR. Anatomic review of the ventral capsule/ventral striatum and the nucleus accumbens to guide target selection for deep brain stimulation for obsessive-compulsive disorder. World Neurosurg. 2019;126:1–10.
Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology. 2004;47(Suppl. 1):227–41.
Barbosa P, Hapuarachchi B, Djamshidian A, Strand K, Lees AJ, de Silva R, et al. Lower nucleus accumbens alpha-synuclein load and D3 receptor levels in Parkinson’s disease with impulsive compulsive behaviours. Brain. 2019;142(11):3580–91.
Vriend C, Pattij T, van der Werf YD, Voorn P, Booij J, Rutten S, et al. Depression and impulse control disorders in Parkinson’s disease: two sides of the same coin? Neurosci Biobehav Rev. 2014;38:60–71.
Biundo R, Weis L, Facchini S, Formento-Dojot P, Vallelunga A, Pilleri M, et al. Patterns of cortical thickness associated with impulse control disorders in Parkinson’s disease. Mov Disord. 2015;30(5):688–95.
Tessitore A, Santangelo G, De Micco R, Vitale C, Giordano A, Raimo S, et al. Cortical thickness changes in patients with Parkinson’s disease and impulse control disorders. Parkinsonism Relat Disord. 2016;24:119–25.
Pellicano C, Niccolini F, Wu K, O’Sullivan SS, Lawrence AD, Lees AJ, et al. Morphometric changes in the reward system of Parkinson’s disease patients with impulse control disorders. J Neurol. 2015;262(12):2653–61.
Carriere N, Lopes R, Defebvre L, Delmaire C, Dujardin K. Impaired corticostriatal connectivity in impulse control disorders in Parkinson disease. Neurology. 2015;84(21):2116–23.
Tessitore A, Santangelo G, De Micco R, Giordano A, Raimo S, Amboni M, et al. Resting-state brain networks in patients with Parkinson’s disease and impulse control disorders. Cortex. 2017;94:63–72.
Evans AH, Pavese N, Lawrence AD, Tai YF, Appel S, Doder M, et al. Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Ann Neurol. 2006;59(5):852–8.
Berke JD, Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 2000;25(3):515–32.
Steeves TD, Miyasaki J, Zurowski M, Lang AE, Pellecchia G, Van Eimeren T, et al. Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study. Brain. 2009;132(Pt 5):1376–85.
O’Sullivan SS, Wu K, Politis M, Lawrence AD, Evans AH, Bose SK, et al. Cue-induced striatal dopamine release in Parkinson’s disease-associated impulsive-compulsive behaviours. Brain. 2011;134(Pt 4):969–78.
van Eimeren T, Pellecchia G, Cilia R, Ballanger B, Steeves TD, Houle S, et al. Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD. Neurology. 2010;75(19):1711–6.
Ray NJ, Miyasaki JM, Zurowski M, Ko JH, Cho SS, Pellecchia G, et al. Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson’s patients with medication-induced pathological gambling: a [11C] FLB-457 and PET study. Neurobiol Dis. 2012;48(3):519–25.
Verger A, Klesse E, Chawki MB, Witjas T, Azulay JP, Eusebio A, et al. Brain PET substrate of impulse control disorders in Parkinson’s disease: a metabolic connectivity study. Hum Brain Mapp. 2018;39(8):3178–86.
Cilia R, Ko JH, Cho SS, van Eimeren T, Marotta G, Pellecchia G, et al. Reduced dopamine transporter density in the ventral striatum of patients with Parkinson’s disease and pathological gambling. Neurobiol Dis. 2010;39(1):98–104.
Voon V, Rizos A, Chakravartty R, Mulholland N, Robinson S, Howell NA, et al. Impulse control disorders in Parkinson’s disease: decreased striatal dopamine transporter levels. J Neurol Neurosurg Psychiatry. 2014;85(2):148–52.
Vriend C, Nordbeck AH, Booij J, van der Werf YD, Pattij T, Voorn P, et al. Reduced dopamine transporter binding predates impulse control disorders in Parkinson’s disease. Mov Disord. 2014;29(7):904–11.
Smith KM, Xie SX, Weintraub D. Incident impulse control disorder symptoms and dopamine transporter imaging in Parkinson disease. J Neurol Neurosurg Psychiatry. 2016;87(8):864–70.
Papay K, Xie SX, Stern M, Hurtig H, Siderowf A, Duda JE, et al. Naltrexone for impulse control disorders in Parkinson disease: a placebo-controlled study. Neurology. 2014;83(9):826–33.
Liang JW, Shanker VL, Groves M. Naltrexone for impulse control disorders in Parkinson disease: a placebo-controlled study. Neurology. 2015;84(13):1386–7.
Zhang XL, Wang GB, Zhao LY, Sun LL, Wang J, Wu P, et al. Clonidine improved laboratory-measured decision-making performance in abstinent heroin addicts. PLoS ONE. 2012;7(1): e29084.
Laurencin C, Timestit N, Marques A, Duchez DD, Giordana C, Meoni S, et al. Efficacy and safety of clonidine for the treatment of impulse control disorder in Parkinson’s disease: a multicenter, parallel, randomised, double-blind, phase 2b clinical trial. J Neurol. 2023;270(10):4851–9.
Kehagia AA, Housden CR, Regenthal R, Barker RA, Muller U, Rowe J, et al. Targeting impulsivity in Parkinson’s disease using atomoxetine. Brain. 2014;137:1986–97.
Borchert RJ, Rittman T, Passamonti L, Ye Z, Sami S, Jones SP, et al. Atomoxetine enhances connectivity of prefrontal networks in Parkinson’s disease. Neuropsychopharmacology. 2016;41(8):2171–7.
Weintraub D, Hoops S, Shea JA, Lyons KE, Pahwa R, Driver-Dunckley ED, et al. Validation of the questionnaire for impulsive-compulsive disorders in Parkinson’s disease. Mov Disord. 2009;24(10):1461–7.
Abrantes AM, Friedman JH, Brown RA, Strong DR, Desaulniers J, Ing E, et al. Physical activity and neuropsychiatric symptoms of Parkinson disease. J Geriatr Psychiatry Neurol. 2012;25(3):138–45.
Lee JY, Jeon B, Koh SB, Yoon WT, Lee HW, Kwon OD, et al. Behavioural and trait changes in parkinsonian patients with impulse control disorder after switching from dopamine agonist to levodopa therapy: results of REIN-PD trial. J Neurol Neurosurg Psychiatry. 2019;90(1):30–7.
Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol. 2010;67(1):58–63.
Weintraub D. Management of psychiatric disorders in Parkinson’s disease : neurotherapeutics - movement disorders therapeutics. Neurotherapeutics. 2020;17(4):1511–24.
Djamshidian A, Poewe W, Hogl B. Impact of impulse control disorders on sleep-wake regulation in Parkinson’s disease. Parkinsons Dis. 2015;2015: 970862.
Richard IH, McDermott MP, Kurlan R, Lyness JM, Como PG, Pearson N, et al. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology. 2012;78(16):1229–36.
Seppi K, Ray Chaudhuri K, Coelho M, Fox SH, Katzenschlager R, Perez Lloret S, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease: an evidence-based medicine review. Mov Disord. 2019;34(2):180–98.
Lhommee E, Klinger H, Thobois S, Schmitt E, Ardouin C, Bichon A, et al. Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviours. Brain. 2012;135(Pt 5):1463–77.
Barbosa P, Lees AJ, Magee C, Djamshidian A, Warner TT. A retrospective evaluation of the frequency of impulsive compulsive behaviors in Parkinson’s disease patients treated with continuous waking day apomorphine pumps. Mov Disord Clin Pract. 2017;4(3):323–8.
Todorova A, Samuel M, Brown RG, Chaudhuri KR. Infusion therapies and development of impulse control disorders in advanced Parkinson disease: clinical experience after 3 years’ follow-up. Clin Neuropharmacol. 2015;38(4):132–4.
Barbosa PM, Djamshidian A, O'Sullivan SS, de Pablo-Fernandez E, Korlipara P, Morris HR, et al. The long-term outcome of impulsive compulsive behaviours in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2019;90(11):1288–9.
Sohtaoglu M, Demiray DY, Kenangil G, Ozekmekci S, Erginoz E. Long term follow-up of Parkinson’s disease patients with impulse control disorders. Parkinsonism Relat Disord. 2010;16(5):334–7.
Mamikonyan E, Siderowf AD, Duda JE, Potenza MN, Horn S, Stern MB, et al. Long-term follow-up of impulse control disorders in Parkinson’s disease. Mov Disord. 2008;23(1):75–80.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
Open access funding provided by University of Innsbruck and Medical University of Innsbruck.
Conflicts of Interest/Competing Interests
Federico Carbone and Atbin Djamshidian have no conflicts of interest that are directly relevant to the content of this article.
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Availability of Data and Material
Not applicable.
Code Availability
Not applicable.
Authors’ Contributions
AD: concept and design of the work, project organisation, writing of the first draft, review and critique. FC: concept and design of the work, project organisation, writing of the first draft, review and critique. All authors have read and approved the final version and agree to be accountable for the work.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Carbone, F., Djamshidian, A. Impulse Control Disorders in Parkinson’s Disease: An Overview of Risk Factors, Pathogenesis and Pharmacological Management. CNS Drugs 38, 443–457 (2024). https://doi.org/10.1007/s40263-024-01087-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40263-024-01087-y