Dopamine dysregulation syndrome, also called hedonistic homeostatic dysregulation, is a disturbance that may complicate long-term DRT in PD patients (Evans and Lees, 2004; O’Sullivan et al., 2009). Prevalence of DDS in general population of PD patients is underestimated to be 3–4% (Evans and Lees, 2004; O’Sullivan et al., 2009) as patients are reluctant to discuss their embarrassing behaviors. The available data all come from specialist referral centers with inherent selection biases more or less. In a UK-based study, 15 of 364 PD patients (4.1%) were diagnosed with DDS. Similar results were reported by an Italian movement disorders clinic, with 7 of 202 PD patients (3.4%) exhibiting DDS.

Dopamine dysregulation syndrome is characterized by a bizarre phenomenon of an ineffectiveness of medications during “off” periods, and PD patients typically excuse this for maintaining not self-administering doses but an addiction of dopaminergic drugs in excess of those required to control their motor symptoms (Lawrence et al., 2003; Evans et al., 2005). After a period of treatment with high Levodopa equivalent daily dose (LEDD), drug-induced dyskinesias emerge together with socially harmful behaviors (Giovannoni et al., 2000; Merims et al., 2000). Avanzi et al. (2008) reported two male PD patients developing compulsive risk-seeking driving behavior as a result of self-administering high doses of levodopa. Occurrence of DDS was speculated to be due to short duration of levodopa action (Evans and Lees, 2004; Gallagher et al., 2007; O’Sullivan et al., 2009). Recently, DDS was also reported to be related to DA withdrawal syndrome (Limotai et al., 2012). Levodopa is still considered as the most potent trigger of DDS, but subcutaneous apomorphine and oral DAs may also be responsible (O’Sullivan et al., 2009). Additionally, the development of physiological tolerance to levodopa is mediated by central pharmacokinetic and pharmacodynamic changes related to progressive dopaminergic denervation. In PD patients with DDS, however, the psychological effects of “wearing-off” often precede any discernable physical changes. Evidence of maladaptations and sensitization occurring in DDS was noted as enhanced levodopa-induced ventral striatal dopamine release when compared with PD patients who do not compulsively taking dopaminergic drugs (Evans et al., 2006).

Personality traits related to impulsivity and sensation seeking (ISS) are associated with drug dependence, drug craving, and vulnerability to relapse. They also play a prominent role in the development of DDS (O’Sullivan et al., 2009). ISS traits, which include novelty-seeking and sensation seeking, are thought to be mediated through mesolimbic dopaminergic systems (Leyton et al., 2002). PD patients with DDS tend to have greater experimental drug use, higher score on ISS ratings, higher alcohol intake and younger PD onset than healthy controls or other PD patients without DDS (Evans et al., 2005; Gallagher et al., 2007; Voon et al., 2007). Besides, disruption of the reciprocal loops between the striatum and structures in the prefrontal cortex following dopamine depletion may predispose to DDS (O’Sullivan et al., 2009). Several studies seeking for candidate genes that may affect the dopamine “D2-like” receptor family and may be associated with impulsive personality traits got conflicting results (Strobel et al., 2003; Tsai et al., 2004). All in all, age at onset and novelty-seeking personality traits are considered to be the two strongest predictors of DDS in PD patients (Evans et al., 2005; Ondo and Lai, 2008).

Detailed, cautious, and specific enquiries to family members are essential. As outlined in most reports, once PD patients develop DDS, their long-term management becomes difficult (Evans et al., 2005; O’Sullivan et al., 2009; Katzenschlager, 2011). Discontinuation or reduction of dopaminergic drug does, levodopa particularly, should be the first adjustment, which may, however, induce severe motor disorder, depression, or anxiety. Once these conditions occurred, antidepressants should be considered regardless of data available are limited currently about the preferred subtypes of antidepressants in treating DDS. Reports based on cocaine-addicted individuals demonstrated that tricyclic antidepressants might be related with an increased risk of relapse. In addition to pharmaceutical therapies discussed above, deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy for advanced PD patients with the potential not only to allow significant reductions in drug dose but may improve “off”-medication motor symptoms (Weaver et al., 2009). However, the relationship between DDS and STN-DBS remains controversial (Schupbach et al., 2005; Witjas et al., 2005; Bandini et al., 2007; Lim et al., 2009; Eusebio et al., 2013). In 17 PD patients with DDS received bilateral STN-DBS, 12 were resolved or dramatically improved post-operatively (Krack et al., 2003; Funkiewiez et al., 2004; Witjas et al., 2005; Bandini et al., 2007; Knobel et al., 2008), but the remaining 5 patients failed to improve or even worsened (Houeto et al., 2002; Schupbach et al., 2005). Many postoperative PD patients overused dopaminergic drugs to avoid anxiety, dysphoria, and other non-motor symptoms (Evans et al., 2010). The combined effect of DRT and DBS on the limbic territory of the subthalamic nucleus could have precipitated DDS in these patients by inducing hyper-stimulation of the mesolimbic dopamine system (De la Casa-Fages and Grandas, 2012). Continuous jejunal levodopa infusion might have positive effects on DDS, ICDs, and punding as well as motor complications in PD patients (Nyholm et al., 2003, 2005; Odin et al., 2008; Devos, 2009; Catalan et al., 2013). However, the new therapy may not be useful in every instance because it also trigger behavioral abnormalities in sensitive PD patients (Cannas et al., 2013). Due to the putative efficacy of controlling ICBs with levodopa has only been described with small subjects groups (Gerschlager and Bloem, 2009; Valldeoriola and Camara, 2010; Catalan et al., 2013), further randomized controlled trials are urgently needed.

Prevalence of punding varies greatly in different studies because of disparities in study populations, assessment methods (questionnaire or direct interview) as well as diagnostic criteria. It is estimated to be between 0.34 and 14% in PD patients taking high doses of levodopa (> 800 mg/day). However, due to both the absence of related knowledge to punding among clinicians and reluctance of patients to debate their behaviors spontaneously, a widespread under-recognition of punding might have existed up to present (O’Sullivan et al., 2007; Fasano et al., 2008, 2010; Spencer et al., 2011).

Theories on the possible pathophysiology of punding in PD patients are still highly speculative. Previous studies found lesions to the basal ganglia might induce stereotyped behaviors, which resembled punding. Studies supported a causative role of abnormal dopaminergic transmission in the pathogenesis of punding (Spencer et al., 2011). The link between punding and high doses of DRT has already been established (Black and Friedman, 2006; Ferrara and Stacy, 2008; Wolters et al., 2008) including levodopa, DAs, and other alternative medicine (Fernandez and Friedman, 1999; Evans et al., 2004; Miwa et al., 2004; Fasano et al., 2006; Bonvin et al., 2007; Miyasaki et al., 2007). Additionally, the link between punding and dopamine D1, D2 agonists was proved to be closer than D3 and D4 agonists (Fasano and Petrovic, 2010). Moreover, punders were significantly more likely to use dopaminergic drugs acting on D1 receptor such as apomorphine and cabergoline than non-punders (Evans et al., 2004). Suárez et al. (2014) noted that chronic levodopa therapy alters the synaptic efficacy in D1 and D2 striatal medium spiny neurons. However, other researchers failed to find identifiable receptor stimulation profile (Silveira-Moriyama et al., 2006). Recent studies hypothesized that levodopa-induced dyskinesias and behavioral disorders observed in DDS and punding shared common mechanisms (Murer and Moratalla, 2011) involving alterations of glutamate homeostasis with combined activation of sensitized dopamine and NMDA receptors (Kalivas, 2009).

“Punding” is a set of aimless, stereotypical motor behaviors characterized by an intense fascination with repetitive manipulating and examining familiar objects (Black and Friedman, 2006). Many studies noted punding behaviors often arose from premorbid idiosyncratic habits, occupations, and pastimes (Evans et al., 2004; O’Sullivan et al., 2007). In contrast to other ICBs, punding is not driven by pleasure, anxiety, or obsessions. Patients demonstrate more behaviors that appear similar to traits seen in obsessive–compulsive disorders but more idiosyncratic and less distressing. However, any interruption or disruption of the activity often leads to irritation, anxiety, and frustration (Fullana et al., 2009). Punders are aware of the inapposite obtuse nature of the behaviors but even self-injury resulting from the stereotypes does not abort them (Evans et al., 2004). A positive correlation between the severities of punding and dyskinesia was found (Silveira-Moriyama et al., 2006). Moreover, a 52.8% higher prevalence of dyskinesia in punders over non-punders in Japan was reported (Miwa et al., 2004). Recently, repetitive behaviors are considered as an idiosyncratic side effect to dopaminergic therapy but not a dose- or duration-dependent phenomenon (Nguyen et al., 2010). Independently predictive factors of higher Punding Scale scores include higher impulsivity, poorer disease-related quality of life, younger age of PD onset, and higher daily medication dosage of DAs (Lawrence et al., 2007).

As pathophysiological mechanisms underlying punding have not been elucidated, it is difficult to develop therapeutic methods. The most efficacious strategy is proposed to prevent and diagnose the appearance of punding earlier. Physicians should be aware of normal to abnormal symptoms of punding as these behaviors are frequently undistinguishable and patients can not realize aberrant behaviors spontaneously with impaired insight. Specific treatment strategies should be adopted once punding is diagnosed: (1) the primary method is reduction of dopaminergic medications (Avila et al., 2011b). Symptoms of punding improved strikingly after reduction or cease of levodopa or DAs (Fernandez and Friedman, 1999; Kumar, 2005; Miwa and Kondo, 2008). However, caution is required to get a careful balance between the control of side effects and deterioration of motor symptoms (Aquino et al., 2013). Entacapone could be adopted in case of worsened motor condition (Evans et al., 2004). Selegiline, which was reported to enhance the levodopa function and generate amphetamine-like metabolites, should be avoided in PD patients with punding (Shin, 1997); (2) atypical antipsychotics, such as quetiapine and clozapine, are another therapy that may improve punding symptoms, but curative effect is inconsistent (Fasano et al., 2006, 2011; Bonvin et al., 2007; Miwa and Kondo, 2008; Hardwick et al., 2013). However, atypical antipsychotics are still recommended in controlling episodes of psychosis caused by compulsive DRT use and in raising overnight sleep time (Lawrence et al., 2003); (3) amantadine was recently reported to reduce punding by blocking N-methyl-d-aspartic acid receptors (Kashihara and Imamura, 2008; Fasano et al., 2011). However, further evidence to prove the effect is demanded and clinicians should regard the potential induction or worsening of psychosis due to the application of amantadine; (4) whether selective serotonin reuptake inhibitors (SSRIs) is efficacious in punding treatment has come to no conclusion (Kurlan, 2004; Miwa and Kondo, 2008) though SSRIs are shown to be effective in ICDs; (5) data regarding the effect of DBS surgery on punding symptoms in PD patients are limited. Symptoms may worsen, persist, or develop for the first time after DBS regardless of targeting the subthalamic nucleus or the globus pallidus internus (Lim et al., 2009); (6) though low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) has acquired beneficial effects in treating PD and levodopa-induced dyskinesia, effects on punding are uncertain. Recently, Nardone et al. (2013) reported that LF-rTMS produced therapeutic potential for punding, similar to that reported in PD patients with levodopa-induced dyskinesias. However, large-scale, definite studies should still be executed to test the validity of LF-rTMS.

The frequency of ICDs among PD patients ranges from 6 to 18.4% in Western studies (Fan et al., 2009; Lee et al., 2010; Weintraub et al., 2010; Auyeung et al., 2011; Callesen et al., 2013; Poletti et al., 2013). Weintraub et al. (2010) reported ICDs prevalence of 13.6% in a cross-sectional study by interviewing 3090 idiopathic PD patients in the United States and Canada. Valenca et al. (2013) found a higher ICDs prevalence (18.4%) in Brazil, which might be due to a higher proportion of DAs usage (89.3%). Recently, two studies suggested unexpectedly higher prevalence of 34.8 and 25% in Finnish and French, respectively (Joutsa et al., 2012b; Perez-Lloret et al., 2012). In contrast with Western countries, studies of prevalence and related predisposing factors of ICDs in Asian PD patients are relatively limited (Fan et al., 2009; Auyeung et al., 2011; Lim et al., 2011; Chiang et al., 2012; Tanaka et al., 2013) (Table S1 in Supplementary Material). Auyeung et al. (2011) reported that the prevalence of ICDs was 7% in Chinese PD subjects, which was higher than the previous reported prevalence of 3.53% (Fan et al., 2009). Multiple factors might explain the diverse prevalence of ICDs such as ethnic differences, environmental, cultural, and social factors as well as the dosage and type of dopaminergic medications (Chiang et al., 2012).

The exact mechanisms for ICDs development remain unknown. Reward-seeking behavior is mediated by the amygdala and nucleus accumbens, both of which receive dopaminergic projections from the ventral tegmental area (Ambroggi et al., 2008). This may be a pathological mechanism underlying DRT and ICDs that matters. Enhanced ventral striatal dopamine release due to hypersensitization of the ventral striatal circuitry may be another explanation (Evans et al., 2006). Complex interactions between DAs and dopamine receptor subtypes may lead to the development of ICDs in PD patients (Pontone et al., 2006). DAs, such as pramipexole and ropinirole, have remarkably specific binding affinities with D3 receptor (Gerlach et al., 2003), which are at least 100-fold greater than with D2 or D1 receptor. As a potential drug target, therefore, D3 receptor known to be localized to the mesolimbic system and involved with reward and motivated behaviors has aroused great concerns (Weintraub, 2008). This might be a momentous explanation why it was not levodopa or carbidopa but DAs that led to ICDs more frequently. Consequently, D3 antagonists might possess therapeutic utility in the resolution of pathological behaviors with elimination or reduction of the D3-preferring agonist (Dodd et al., 2005; Klos et al., 2005; Singh et al., 2007; Bostwick et al., 2009; Hassan et al., 2011). Experiments have been undertaken to test the efficacy of selective D3 receptor antagonists in rat models (Xi et al., 2004; Pak et al., 2006). Except for its larvaceous benefit in animal models (Peng et al., 2009; Khaled et al., 2010; Higley et al., 2011), D3 antagonists have also been administered to humans in single doses for imaging researches (Graff-Guerrero et al., 2010; Searle et al., 2010). CC genotype of the 2B subunit of the glutamate NMDA receptor might be more frequent in PD patients with ICDs than non-affected ones (Lee et al., 2009). Recently, a genetic variant affecting serotonin 2A receptor pathway was found to be associated with ICDs in PD patients receiving DRT, mainly under low-dopaminergic-dose conditions (Lee et al., 2012). Moreover, in comparison with PD patients without ICDs, those who have ICDs present severer cognitive impairments, particularly executive functions (Santangelo et al., 2009; Voon et al., 2010; Barone et al., 2011). Specific difficulties in inhibitory control during cognitive or motor performances have also been involved in the etiology of ICDs development (Seiss and Praamstra, 2004).

Impulse control disorders are a group of disorders characterized by failure to resist an impulse, drive, or temptation to perform harmful acts to the person or to others. The primary subtypes of ICDs include PG, hypersexuality, compulsive eating, and shopping, of which mere PG is included in the DSM-IV-TR. Except the categories mentioned above, many infrequent behaviors have been reported (Table S2 in Supplementary Material). In recent years, increasing evidence and awareness regarding the relationship between ICDs as motor complications and DRT in PD patients have arisen (Voon and Fox, 2007). The syndrome typically develops in male patients with early onset, orally or subcutaneously administered DRT (Lawrence et al., 2003; Giladi et al., 2007). Comparing 193 PD patients with 190 age/gender-matched healthy controls, Giladi et al. (2007) observed that male gender, younger age at PD motor symptom onset, and longer duration of treatment with DAs contributed independently and additively to the risk of developing ICDs. Except for features discussed, psychiatric co-morbidities are always companied as another important factor predisposing to ICDs.

Parkinson’s disease patients treated with DAs are more prone to develop ICDs than those do not use DAs (17.1 vs. 6.9%) (Weintraub et al., 2010). Dopaminergic augmentation of risk-taking behaviors may be a potential contributing mechanism for the emergence of ICDs in PD patients (Claassen et al., 2011). Weintraub et al. (2010) reported that ICD was present in 17.7% of PD patients taking both DAs and levodopa, 14.0% taking DAs, and 7.2% taking levodopa alone. Although the association between dopaminergic therapy and ICDs has been revealed, dose-dependent effect is not yet clear (Weintraub et al., 2010; Ambermoon et al., 2011; Voon et al., 2011a; Joutsa et al., 2012b). Cross-sectional studies are less effective in detecting possible dose-dependent effects because of variations in both the optimal agonist dose for controlling motor symptoms of PD and the severity of ICDs. Longitudinal studies, therefore, prone to be more essential. A few prospective studies investigated the relationship between ICDs and DAs reduction (Singh et al., 2007; Mamikonyan et al., 2008; Macphee et al., 2009; Bharmal et al., 2010; Joutsa et al., 2012a). After following up 290 Finnish PD patients for 15 months, Joutsa et al. (2012a) reported the effect of DAs on ICDs was dose-dependent. Acting on D1 receptor as well as aberrant and excessive expression of D3 receptor in the denervated dorsal striatum (Bordet et al., 1997; Bezard et al., 2003), levodopa tends to be related to ICDs with potential sensitizing or synergistic effects (Weintraub, 2008). Moreover, selegiline, rasagiline (two types of monoamine oxidase inhibitors type B), and lamotrigine (an anti-epileptic drug that decreases glutamate release in the synapse) were also reported to cause ICDs (Grabowska-Grzyb et al., 2006; Shapiro et al., 2006; Reyes et al., 2013).

Management of ICDs in PD patients presents challenges for clinicians because not only patients cannot wake up to aberrant behaviors but also no effective medicines are developed for ICDs. Most evidence reported on management of ICDs comes from empirical data with limited clinical trials to identify efficacious treatment. Once ICDs are diagnosed, patients should reduce or discontinue the dopaminergic drugs carefully to prevent the deterioration of motor symptoms or DA withdrawal symptoms, including anxiety, dysphoria, fatigue, dysautonomia, sleep disturbance, generalized pain, and medication cravings (Rabinak and Nirenberg, 2010). Discontinuing or significantly decreasing DAs exposure, even when offset by an augment of levodopa dosage, is momentous to balance the control of motor disorder and aberrant behaviors (Dodd et al., 2005; Mamikonyan et al., 2008). Besides, cognitive-behavioral therapies are receiving empirical support in non-PD populations and may be encouraged in PD patients (Carroll and Onken, 2005; Dowling et al., 2006). Moreover, antipsychotic drugs such as olanzapine or quetiapine coupled with either DAs or levodopa may be efficacious in ICDs treatment (Grant et al., 2008). The relationship between ICDs and DBS was reported with inconsistent results. PG improved or disappeared after bilateral STN-DBS in nine patients (Molina et al., 2000; Ardouin et al., 2006). However, in the remaining 18 patients (11 bilateral, 1 unilateral, and 6 not specified), ICDs or punding developed or turned decompensated post-operatively (8 PG, 7 hypersexuality, 2 punding, 1 intermittent explosive disorder, and kleptomania) (Romito et al., 2002; Kleiner-Fisman et al., 2003; Sensi et al., 2004; Machado et al., 2005; Ardouin et al., 2006; Lu et al., 2006; Morgan et al., 2006; Smeding et al., 2006, 2007). Selective stimulation of limbic region of STN and surrounding structures was also reported to trigger or worsen non-motor side effects (Voon et al., 2005, 2008; Frank et al., 2007; Mallet et al., 2007; Alberts et al., 2008; Moum et al., 2012). Therefore, many reports speculated the positive outcomes after STN-DBS might be related to discontinuation of dopaminergic treatment after surgery (Santangelo et al., 2013). Castrioto et al. concluded that STN-DBS could not only improve motor and non-motor behaviors, but induce excessive motor, cognitive, and emotional behavioral disinhibition. Fine-tuning of stimulation parameters with dopaminergic drugs was necessary to prevent or improve pathological behaviors (Castrioto et al., 2014).