Impulse control disorders in Parkinson's disease: Review of pathophysiology, epidemiology, clinical features, management, and future challenges
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.237019
Source of Support: None, Conflict of Interest: None
Keywords: Behavior, compulsive, dopamine, impulsive, Parkinson's disease
Impulse control disorders (ICDs) or impulsive–compulsive behaviors (ICBs) suggest an inability to curb the urge or temptation to perform an act which is detrimental to oneself or others., Recent study shows that the prevalence of ICB can be more than 25% among the idiopathic Parkinson's disease (PD) population. ICDs in PD generally suggest one of the four major disorders: pathological gambling (PG), hypersexuality, compulsive eating, and excessive buying/shopping, whereas some closely related phenomena such as punding, dopamine dysregulation syndrome (DDS), hoarding, and hobbyism are generally included under the broader heading of ICBs., PG and hypersexuality are more common in male PD patients while excessive shopping is commoner in female PD patients.
Pathophysiology of ICDs
The nigrostriatal, mesocortical, and mesolimbic dopaminergic pathways play a crucial role in the pathogenesis of ICB in PD patients. Long-term use of dopamine agonists (DAs) results in downregulation of the dopamine 2 (D2) receptors expression. Consequently, the PD patients seek higher than normal stimuli to obtain sufficient rewards. Moreover, the limbic area, including the nucleus accumbens area which controls the reward and emotions, contains greater numbers of D3 receptors. DA drugs preferentially act on these D3 receptors while levodopa targets D1/D2 receptors. The D1/D2 receptors are abundant in the caudate nucleus and putamen. The caudate nucleus and putamen have no major role in impulse control and reward-seeking behaviors, so levodopa poses a lesser risk of ICD. The second possible reason is the greater tonic dopamine release and reduced phasic release. Any action of greater uncertainty such as a buying spree triggers the tonic dopamine release but the phasic release of dopamine occurs when a reward is anticipated. This phasic dopamine release is suppressed when the reward is not granted. The greater tonic release of dopamine will lead to a relative dopamine deficit and reduced reward sensation.
The role of genetic polymorphism in the genesis of ICB
Single nucleotide polymorphism (SNP) in dopaminergic receptors D1, D2, and D3 and glutamate receptor N-methyl-D-aspartate (NMDA) are the two most widely studied pathways for PD-ICD. The GRIN 2B (Glutamate [NMDA] receptor subunit epsilon-2) variant is the most important of the NR2 [NMDA receptor 2] subtypes of NMDA receptor where SNP was found to have an association with the risk of ICD. GRIN 2B is more commonly expressed in striatum. Hydroxytryptamine receptor (HTR2A), dopa decarboxylase (DDC), and dopamine transporter 1 (DAT1) gene polymorphism were also found to have an association with PD-related ICD. Krishnamoorthy et al., recently observed a novel association between the dopamine receptor type 3 (DRD3) p.S9G(rs6280) CT genotype and the ICD trait in a cohort of Indian PD patients. A large prospective study concluded that the role of DRD3 polymorphism on the risk of ICD in the Caucasian PD population was insignificant. Kraemmer et al., suggested that the opioid receptor kappa 1 (OPRK1) rs702764: TC genotype increases the risk of ICD in the whole PD population. However, the OPRK1 genotypes rs702764: TC and rs702764: CC, HTR2A genotype rs6313: GA and rs6313: AA, DDC genotype rs383709: -/AGAG, rs3837091: -/- and rs1451375: AA, all increased the risk of ICD in PD patients using DA. One review found no association of the DAT gene SLC6A4 gene or the catechol O-methyl transferase (COMT) gene Val158 Met with PD-related ICD.
The DRD1 rs4867798, DRD1 rs4532, DRD2/ANKK1 rs1800497, and GRIN2B rs7301 but not D4/D5 receptor polymorphism were associated with increased risk of developing ICD among 91 Malaysian PD patients. A South Korean study found that the variants of DRD2 and 5-HTTLPR were not associated with the risk of developing ICD. The impact of the c. 102T>C variant was significantly enhanced in the lower levodopa equivalent dose (LED) group, increasing the risk of ICDs by 2.8 and 6.9 times in CT and TT carriers, respectively. However, the c. 102T>C variant had no statistically significant effect on the development of ICDs in the higher LED group. An Italian study found no association between the COMT Met/met genotype, DRD2 Taq1A, and DAT1 polymorphism and the risk of developing ICDs in PD patients. Hoenicka et al., analyzed the role of addiction-related gene ankyrin repeat and kinase domain containing 1 and found no association between the Taq1A SNP and ICD. The PD patients with GRIN 2B c.2664C>T genotype “AG” preferred the high-frequency of gain disadvantageous deck of the Iowa Gambling Task (test for ICD). [Table 1] summarizes the research studies on genetic polymorphism related to ICDs in PD.
The genetic studies on ICD need to adopt a multiethnic and integrated approach to include dopaminergic, serotonergic, glutamatergic, and opioid pathways as the emerging evidences suggest the influence of multiple factors in the development of ICD. The effect of genetic polymorphism can only be accurately assessed when the PD patients (the controls) are also treated with similar doses of DAs as the cases with ICD in order to have comparable dopaminergic state in both the groups. Genetic polymorphism plays an important role in the generation of ICD in the lower LED PD group but not in the higher dose group.
Epidemiology and risk factors
The common ICDs reported are compulsive eating, buying, gambling, sexual behaviors, and lately, the cyber addictions ,,,,,,, [Table 2]. The major risk factors for ICB in PD patients are use of DAs, male gender, young patient, depression, smoking, drug abuse, genetic factors, and family history of ICDs [Table 2]. PD patients with Parkin mutations showed a higher frequency of ICBs with DAs, pramipexole and ropinirole, though longer-acting formulations of the DAs and rotigotine were less likely to result in ICB., Male patients are more prone to hypersexuality and eating disorders while compulsive shopping is commoner among female patients across Europe, North America, and Asia., The prevalence of ICD was found to be 6–43% patients in many studies from North and Latin America, Asia, and Europe [Table 3].,,,,,,,, The largest ICD study on PD patient conducted so far (DOMINION study in US and Canada) involving 3090 patients reported a 6-monthly ICD prevalence of 13.6%. The nature of ICD varied widely across countries. Pathological gambling was the commonest ICD in North American PD patients (5%), compulsive medication use in China (11.3%), punding (12.4%) and hypersexuality (11.04%) in India, hypersexuality in Finland, hobbyism and punding in Denmark, etc. [Table 3]. The prevalence of the type of ICD or ICB can be influenced by the cultural, religious, and socioeconomic factors, e.g., pathological gambling is likely to be less prevalent or underreported in India and China as public gambling or casino visiting is not a socially accepted custom in these countries.,,,,
Recent studies show that ICB has a higher prevalence in young unmarried male subjects and in patients with a longer duration of the disease.,,,, The motor performance, Hoehn and Yahr (H&Y) stages, as well as cognitive faculties were similar in the ICD and the non-ICD PD patients but the ICD group had a higher prevalence of nonmotor symptoms, including depression, sleep disorders, and higher scores in the non-motor symptoms assessment scale Non Motor Symptoms Scale (NMSS) across many domains. The ICD patients showed higher scores in sleep disorders, fatigue, and sexual dysfunction. However, a higher prevalence of depression in PD-ICD patients might explain symptoms such as tiredness, apathy, or sleep disorders. ICD patients had a higher educational qualification and a greater tendency to indulge in substance abuse in the Italian population. However, a recent study from China showed no statistically significant difference in educational achievements between ICB positive and negative PD patients. The prevalence of ICD was higher in patients on combined levodopa and DAs than in patients on levodopa or DA alone. The development of ICD in PD is far more complex than its development when DA is used alone.
Pathological gambling was one of the earliest ICDs to be described. Pathological gambling is inappropriate, recurrent, and persistent maladaptive gambling activity that adversely affects family, personal, and professional life. The prevalence of pathological gambling is between 4 and 8% and is higher among the US PD patients with ICD.,,, The prevalence is higher in DA users. The preferred gambling methods described include slot machines, internet gambling, and gambling techniques, which are repetitive, require less cortical processing, and high reward uncertainty. High reward uncertainty is a characteristic of tonic ventral tegmental area neural activity. Often gamblers develop ritualistic behaviors such as lucky charms, lucky clothes, etc., to improve their chances of winning.
Compulsive sexual behavior is excessive and distressing sexual thoughts persisting for more than 1 month that interfere with social and occupational activity.,, Compulsive sexual behaviors involve excessive preoccupation with sexual thoughts, internet pornography, desire for frequent genital stimulation, promiscuity and telephone sex, etc., and are often underreported. Their prevalence is stated to be more than 4% in DA users and almost 2% in PD patient not taking DAs. Related behaviors such as zoophilia, change in sexual preference, and paraphilia were also reported in the literature.,
Compulsive eating is consumption of large amounts of food more than once than is usually needed to alleviate hunger without any associated purging behavior.,, According to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), this disorder involves eating until one is feeling uncomfortably full, or solitary eating because of shame or disgusted self-image about the eaten quantity. PD patients usually lose weight during the early stages. However, compulsive eating can trigger significant weight gain and thus further reduce mobility.
Compulsive buying or shopping
Compulsive buying is seen in more than 3% of PD population and is more common in women. It is seen in more than 7% of the DA users. Compulsive shopping can cause significant financial and social distress., These habits are irresistible, intrusive, time-consuming, and distressing.
The major ICBs found in PD are punding, hoarding, DDS, and hobbyism.
Punding generally refers to intense fascination to repeatedly manipulate, examine, or handle technical equipment or common objects along with an extended involvement in monologues devoid of contents.,,,, Patients with punding have a higher rate of obsessive compulsive traits than is present in control subjects. Punding is classified as a compulsive behavior as this does not lead to satisfaction or joy, and performance of the act leads to relief., The higher prevalence of dyskinesia among PD patients with punding suggests a similar mechanism. One study in the UK found that the prevalence of punding was more than 14% in people with an intake of >800 mg/day LED.
Dopamine Dysregulation syndrome
DDS is a form of addiction where people with PD need abnormally higher dose of dopamine replacement therapy (DRT) for their parkinsonism., The need for dopamine replacement gets progressively worse. During the on-phase, patients can go for “walkabouts.”, Often the dysphoria and anxiety during the withdrawal phase is coupled with an aggressive demand for DRT. Patients with previous mood disorders are more prone to have the DDS. Though DDS can be seen with both DRT and DA, the risk is much higher with levodopa and apomorphine.
Hoarding suggests acquiring or failure to discard a large number of substances of no or little value., Often, this habit results in an inhabitable condition for family members. Hoarding like other ICBs can lead to significant distress to other family members. Hoarding of levodopa or DAs can be found in people with DDS.
Miscellaneous compulsive behaviors
Hobbyism suggests repetitive and excessive complex motor activities such as writing, gardening, collecting, use of internet, etc. Walkabout is a form of restlessness leading to aimless and excessive wandering (walking or driving). Miscellaneous impulsive behaviors reported include locking and unlocking doors, excessive generosity, reckless driving, excessive smoking and drug addiction, and recurrent pet killing (in a juvenile PD patient)., One patient developed compulsive drumming and beating of percussion instruments following pramipexole therapy, and one developed a habit of compulsive singing after DRT.,
Screening tools for Impulse Control Behaviors
Various rating scales and questionnaires are available to assess the ICB in PD [Table 4]. The widely used scales are Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP), QUIP Rating Scale Version (QUIP-RS), Modified Minnesota Impulsive Disorders Interview, Dopamine Dysregulation Syndrome-Patient and Caregiver Inventory, Parkinson's Impulse Control Scale.,,,, The Scale for Outcome in Parkinson Disease Psychiatric Complications is also a validated screening tool for psychiatric complications in PD. A separate questionnaire for punding and gambling (South Oak Gambling Screen) is also available.,
QUIP, the most widely studied questionnaire for ICB in PD, has 30 questions. QUIP was found to be 100% sensitive and specific when filled by both patients and informants. QUIP-RS is also a validated compact version of the QUIP and can be used to monitor changes over time.
The medical management is summarized in [Table 4]. The main medical management of ICB remains either discontinuation of DAs or switching to a DA with lesser risk of ICBs. The DOMINIAN study found both levodopa and dopamine to be independent risk factors for ICD. Driver-Dunckley et al., noticed that pathological gambling improved when pramipexole was changed to ropinirole, though recently, the DOMINION study found a similar prevalence of ICD between pramipexole and ropinirole users. Burkhard et al., revealed that ICD symptoms disappeared or decreased when DA was replaced by either subthalamic stimulation or catechol-O-methyltransferase (COMT) inhibitor. Bastiaens et al., reported that ICB symptoms resolved in all 10 patients who discontinued DA therapy. Mamikonyan et al., claimed that 83% PD-related ICD patients did not satisfy the diagnostic criteria for ICD after the cessation of DA therapy and their Unified Parkinson's Disease Rating Scale (UPDRS) Motor Score did not change significantly. However, Sohtaoǧlu et al., contradicted the claim by reporting an increment in the UPDRS score in 74% of PD patients who fully recovered from the ICD. When DAs cannot be withdrawn or reduced, it is preferable to use a longer-acting formulation as the risk of ICD is lower with prolonged release formulation.
The role of amantadine in ICD is controversial. One small study revealed that amantadine abolished or reduced expenditures, due to gambling, by 75–90% in 2–3 days. A few other studies have also reported a higher frequency of ICDs such as hypersexuality and pathological gambling.,, On the one hand, amantadine had a dopamine-enhancing effect, leading to increased risk of ICD, and on the other hand, it also has an anti-glutaminergic effect protecting the patient from the risk of ICD.
There are anecdotal reports of valproate improving the ICD in 3 PD patients. A small open-level study revealed that topiramate could reduce the severity of impulsive behavior and global impulsiveness. Bermejo et al., reported that zonisamide reduced the severity of ICD. One case series suggested that clozapine could improve ICD symptoms that persisted even after the cessation of DA therapy. Gerschlager and Bloem  demonstrated an interesting example where switching from oral to enteral higher dose of continuous levodopa infusion completely cured gambling and punding after 1 year. The authors suggested the role of pulsatile dopamine release in the generation of ICB.
A 3-year clinical observational study reported a relatively low rate (9.7%) of new cases on apomorphine infusion with clinically relevant ICD. García Ruiz et al., reported that only one out of the 82 patients treated with long-term apomorphine therapy developed hypersexuality disorders. In a multicenter open-label prospective study, Martinez-Martin et al., reported that only 4 patients developed ICD after apomorphine infusion and none needed discontinuation of therapy. A recent 10-year review by Moore et al., found apomorphine to be least often associated with ICD among all DAs. Though apomorphine infusion looks promising, it needs further study to determine its role in the generation or treatment of ICD.
Deep Brain Stimulation
The role of deep brain stimulation in ICB is not quite clear as studies revealed conflicting results. As a successful DBS can result in levodopa dose reduction, prospective studies claimed that hyperdopaminergic manifestations such as ICDs would reduce post DBS. Ardouin et al., and Bandini et al., reported improvement in ICDs after subthalamic nucleus (STN) DBS [Table 5] Shotbolt et al., reported that ICD in 3 patients completely resolved after the DBS surgery. Lhommée et al., even claimed that disabling dopaminergic drug overuse and drug-induced behavioral addictions should be included as a new indication for DBS surgery. However, Akakin et al., described a patient who developed hypersexuality despite motor improvement post DBS. Kim et al., reported 40% new incidences of ICD after the DBS. In a recent survey, 67% of the Parkinson study group centers observed at least one case of de novo ICD after DBS surgery. Rogers et al., reported that PD patients with DBS showed a tendency to increase the value of losses that they were willing to play with while gambling, when shifting from the DBS-off to DBS-on conditions. A retrospective analysis conducted by Moum et al., discovered 17 new cases of ICD after the DBS implantation. The incidences were seen regardless of unilateral or bilateral, or SNT or global pallidus interna (Gpi) stimulation. The DBS improves some ICDs related to the hyperdopaminergic state by reducing dopaminergic drug requirement but can also deactivate the limbic system–basal ganglia loop and hyperactivate ventral striatum to precipitate new ICDs.
ICD needs a strong defining criteria as it is not always easy to draw a clear line of demarcation between the socially acceptable accentuation of impulsivity and the development of ICD. Most of the ICD studies failed to address the issue of cyber addictions such as video games, online pornography, or gambling etc., as an emerging ICD in PD. The mobile games can provide near constant reinforcement in a PD patient and can lead to more impulsive playing habits. Moreover, the mobile and the internet are easily accessible and socially acceptable so that their use often goes unnoticed till their addiction becomes a major problem in PD. Previously, Wu et al., revealed that PD patients with ICD have a higher tendency to use the internet in comparison to healthy controls or patients with PD without ICD. A recent study found that self-reporting of ICD symptoms by the PD patients was only 2% though the prevalence of ICD was 27% in PD patients. All ICD screening instruments need prospective, multicenter, cross-validation studies as literature has revealed a wide discrepancy in the ICD prevalence with various ICD questionnaires. The future studies also need to clarify the exact influence of DBS and apomorphine on the ICD incidence and prevalence. Further studies are needed to explore the relationship among the dose of levodopa, ethnicity, and genetic polymorphism in the generation of ICD. Moreover, genetic polymorphism study must be conducted in association with functional neuroimaging and clinical assessment tools to improve the accuracy of ICD risk prediction.
ICB in PD remains a major global problem. The major risk factors for ICB include a young male patient, previous psychiatric comorbidities, substance abuse, and DAs.
Financial support and sponsorship
Sponsorship: The author received travel grant from Merck Serono Limited, UK to attend dystonia update meeting in London in 2018.
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]