“Stress”

As a side effect of DRT, PD-ICD is undoubtedly a product of “stress” from DRT, particularly DAs.Reference Corvol, Artaud and Cormier-Dequaire^11, Reference Mortazavi, Hynes and Chernoff²² The “stress” function can be explained by a “overdose theory,” in which the comparatively intact ventral striatum (VS) and parts of the limbic system in dopaminergic projection degeneration can be overstimulated by the supplied DRT which efficiently counteracted dopamine shortage in the motion systems.Reference Barbosa, Hapuarachchi and Djamshidian^23–Reference Claassen, Stark and Spears²⁵ Furthermore, a larger lifelong mean daily dose and a longer cumulative duration of DAs were discovered to have significant dose-effect correlations with PD-ICDs.Reference Corvol, Artaud and Cormier-Dequaire^11, Reference Perez-Lloret, Rey and Fabre²⁶ The relationship between different DAs with variable receptor selectivity and ICDs is inconsistent, for instance, with a stronger dopamine receptor 3 (expressing preferentially in the limbic pathway) selectivity than bromocriptine, pramipexole is more likely to lead to PD-ICDs.Reference Seeman²⁷ Less selective, levodopa exhibits more physiological receptor activation pattern, nevertheless, it is also associated with more ICDs, particularly at high doses,Reference Weintraub, Koester and Potenza^2, Reference Simoni, Paoletti and Eusebi²⁸ and concurrent levodopa use in patients taking DAs can increase the risk of PD-ICDs.Reference Weintraub, Koester and Potenza² Moreover, delivery route and pharmaceutical formulation could also make a difference, as evidenced by the higher association of PD-ICDs with oral short-lasting DAs than with oral long-lasting or transdermal DAs.Reference Rizos, Sauerbier and Antonini^29, Reference Antonini, Chaudhuri and Boroojerdi³⁰ With stable plasma levels and elimination of pulsatile dopaminergic stimulation,Reference Nyholm³¹ levodopa-carbidopa intestinal gel therapy can lead to a lower risk of ICDs onset.Reference Todorova, Samuel, Brown and Chaudhuri³²

“Vulnerability”

As in the same condition, not all patients with PD on DRT would experience ICDs, indicating that potential genetic neurobiological substrates can contribute to them.Reference Tichelaar, Sayalı, Helmich and Cools³³ For instance, PD patients with ICDs were observed to have more preserved limbic-paralimbic connectivity than those without ICDs, and the stronger the preserved connectivity is, the heavier the ICD is.Reference Tessitore, De Micco and Giordano³⁴ Males with stronger connectivityReference Petersen, Van Wouwe and Stark^35–Reference Munro, McCaul and Wong³⁸ are more prone to PD-ICDs than females.Reference Cao, Xu, Zhao, Lv, Lu and Zhao³⁹

No association was found between the ICDs and polygenic risk score of PD, which indicated that ICDs and PD don’t share genetic susceptibility.Reference Ihle, Artaud and Bekadar⁴⁰ For ICDs’ susceptibility, we found its correlations with variants in genes encoding enzymes or receptors from the dopamine, opioid, serotonin,Reference Legarda, Vives and Beltran-Gomila⁴¹ norepinephrine, and glutamate pathways in PD and a previous review tabulated the findings of 7 candidate gene associations.Reference Kelly, Baig, Hu and Okai⁴² Based on that, predictive roles of the polymorphisms in opioid receptor gene (OPRM1)Reference Cormier-Dequaire, Bekadar and Anheim^43, Reference Kraemmer, Smith and Weintraub⁴⁴ and β-glucocerebrosidaseReference Amami, De Santis, Invernizzi, Garavaglia and Albanese⁴⁵ also got attention. Besides, the signal channel relevant genes of G protein-coupled receptors (dopamine receptors acted by DAs) can also play a role.Reference Prud’hon, Bekadar and Rastetter⁴⁶ Furthermore, decreased striatal dopamine transporter (DAT) concentrations in the VS were consistently found to predate and predict PD-ICDs with a positive connection with the severity.Reference Kara, Smith and Weintraub^47–Reference en Heuvel, Vriend and Nordbeck⁵¹ A positive relationship between reduced DAT availability in the VS and reduced metabolism in several cortical limbic and associative pathways or functionally related areas was found to facilitate the vulnerability.Reference Navalpotro-Gomez, Dacosta-Aguayo and Molinet-Dronda⁵² Furthermore, aid of a multi-polymorphism in genes implicated in glutamatergic, opioid, and monoaminergic signaling pathways was revealed to bring 11–16% increase in ICD predictability compared to assessing clinical factors alone.Reference Kraemmer, Smith and Weintraub^44, Reference Erga, Dalen and Ushakova⁵³

The variation of dopamine genes can affect impulse controlReference Nandam, Hester and Wagner⁵⁴ and further affect the response to DRT. Evidence revealed that ICD could be alleviated by DAs in the low dopamine genetic risk score (DGRS, including the dopamine receptor D1-3 (DRD1-3), Catechol-O-methyltransferase, and DAT) group and worsened in the high score group.Reference MacDonald, Stinear and Ren⁵⁵ Hall et al. further revealed the association that patients with a low DGRS were more prone to ICBs during DRT, but the number of ICBs may decrease over time.Reference Hall, Weaver, Compton, Byblow, Jenkinson and MacDonald^56, Reference Hall, Weightman, Jenkinson and MacDonald⁵⁷

“Catalysis”

Some certain demographic factors and PD-related factors could create an internal environment catalyzing the occurrence of PD-ICD.

For demographic factors, a younger age, pre-PD history of ICDs, history of substance abuse, and alcohol use have all been proposed to increase risk.^39,58–61 PD patients with ICDs have a more conserved brain metabolism environment than those without ICDs, thus, factors correlated with better metabolic environment, such as substance abuseReference Dragogna, Mauri, Marotta, Armao, Brambilla and Altamura⁶² and a younger age,Reference Weintraub, Koester and Potenza² could promote the occurrence of ICDs. Additionally, smoking,Reference Weintraub, Koester and Potenza^2, Reference Cao, Xu, Zhao, Lv, Lu and Zhao^39, Reference Liu, Luo, Mo, Wei, Tao and Han⁶³, caffeine usage,Reference Bastiaens, Dorfman, Christos and Nirenberg⁶⁴ poor education,Reference Antonini, Barone, Bonuccelli, Annoni, Asgharnejad and Stanzione⁶⁵ and unmarried statusReference Weintraub, Koester and Potenza^2, Reference Baig, Kelly and Lawton⁶⁶ have controversially been proposed.Reference Cao, Xu, Zhao, Lv, Lu and Zhao³⁹ Furthermore, some personality traits like irritability, impulsivity, and alexithymia were found to be predictive.^{29,30,67–73}

For PD-related factors, to begin, the significant difference in dopaminergic fiber degeneration between the striatum and extrastriatum is an inherent condition predisposing to ICD in PD.Reference Lee, Seo and Kim⁷⁴ Moreover, a younger age of PD onset, longer PD duration,Reference Antonini, Barone, Bonuccelli, Annoni, Asgharnejad and Stanzione⁶⁵ and severe motor symptom,Reference Callesen, Weintraub, Damholdt and Møller⁶⁰ may promote the occurrence of PD-ICD. Movement complications,Reference Bastiaens, Dorfman, Christos and Nirenberg⁶⁴ such as motor fluctuationsReference Jaakkola, Huovinen, Kaasinen and Joutsa⁷⁵ and dyskinesias,^76,77 as well as non-motor complications, such as depression,Reference Nikitina, Alifirova, Nurzhanova, Bragina, Zhukova and Brazovskaya⁷⁸ anxiety,Reference Waskowiak, Koppelmans and Ruitenberg⁷⁹ and apathyReference Scott, Eisinger and Burns⁸⁰ can also increase the risk.Reference Antonini, Barone, Bonuccelli, Annoni, Asgharnejad and Stanzione⁶⁵ PD-ICDs patients were found cognitive preservationReference Siri, Cilia and Reali⁸¹ perhaps due to better metabolic preservation.Reference Marín-Lahoz, Sampedro and Horta-Barba⁸² Sleep disorders, such as sleep disturbances and fragmentation, may increase the risk of PD-ICD which could promote or aggravate the sleep restriction and fragmentation, indicating a bidirectional link.Reference Figorilli, Congiu, Lecca, Gioi, Frau and Puligheddu⁸³ In addition, whether rapid eye movement sleep behavior disorder (RBD) can increase the risk of PD-ICDs remains debatable probably due to differences in evaluation methods or the unreliable results from a small number of patients.^39,84–86

The “vulnerability-catalysis-stress” model

The predictors above can predict the occurrence of PD-ICDs from 3 perspectives: the genetic factors may help predict the intrinsic basal predisposing vulnerability; the PD-related factors and demographic factors may act as a “catalyst” for some potential internal changes to ICD susceptibility; and the drug-related factors may act as external “stimuli” leading to a “stress response” and thus to PD-ICDs. In short, under “catalyst” conditions, the “stimulus” may produce “stress reaction” in genetic susceptible individuals, and chronic “stress reaction” promotes the eventual incidence of PD-ICD (Figure 1). Therefore, even though DRT is closely related to development of PD-ICD, the full and sustained remission rate of PD-ICD is relatively low after stopping DRT.Reference Siri, Cilia and Reali⁸¹ DRT only plays a “stress” role, and other factors may be dominant and difficult to reverse. This “vulnerability-catalysis-stress” model can be an improvement on the “vulnerability-stress” model.Reference Theis, Probst, Fernagut and van Eimeren¹³

Figure 1.

Factor profile for PD-ICDs. The profile summarizes the factors affecting occurrence and progression of PD-ICD. There are 70 factors affecting PD-ICD occurrence, including 25 genetic factors, 14 demographic factors, 16 PD-related factors, and 15 drug burden factors. These factors can be summarized to predict PD-ICDs from 3 aspects via a vulnerability-catalysis-stress model. Under “catalyst” conditions, the “stimulus” may produce “stress reaction” in individuals with genetic vulnerability, and chronic “stress reaction” leads eventual occurrence of PD-ICD. In addition, 9 factors are related to PD-ICD progression, including 4 internal mental factors, 2 external social factors, and 3 other factors.Reference Cao, Xu, Zhao, Lv, Lu and Zhao³⁹ Associated with PD-ICDs in the meta-analysis by Cao et al.Reference Cao, Xu, Zhao, Lv, Lu and Zhao³⁹ ICDs, impulse control disorders; PD, Parkinson’s disease; DAs, dopamine receptor agonists; DGRS, dopamine genetic risk score; EDS, excessive daytime sleepiness; RLS, restless legs syndrome; RBD, rapid eye movement sleep behavior disorder; LED, levodopa equivalent dose; LEDD, levodopa equivalent daily doses; DRD1, dopamine receptor D1; DRD2, dopamine receptor D2; DRD3, dopamine receptor D3; DAT, dopamine transporter; DDC, dopamine decarboxylase; GRIN2B, glutamate receptor ionotropic N-Methyl-d-aspartic acid 2B; HTR2A, serotonin receptor 2A; OPRK1, opioid receptor kappa; ANKK1, ankyrin repeat and kinase domain containing 1; OPRM1, mu opioid receptor; SLC22A1, organic cation transporter 1; COMT, catechol-O-methyltransferase; MAOB, monoamine oxidase type B; ADRA2C, adrenergic alpha2C receptor; SV2C, synaptic vesicle 2 C; SLC6A3, dopamine transporter gene; SLC6A4, serotonin transporter gene; SLC7A5, L-type amino acid transporter 1 gene; SLC18A2, monoamine transporter gene; SLC22A1, organic cation transporter gene; GBA, β-glucocerebrosidase.

From the 3 perspectives, Weintraub et al. developed a clinic-genetic tool, the ICD-risk score, with 7 easily obtained clinical variables (sex, age, ethnicity, disease duration, cohort, and DAs and levodopa therapies) and genotype for 2 single nucleotide polymorphisms (rs1800497 [in DRD2] and rs1799971 [in OPRM1]) to identify patients at high risk.Reference Weintraub, Posavi and Fontanillas⁸⁷ It can classify PD patients into groups with an ICD prevalence of 40% (highest risk quartile) and of 7% (lowest risk quartile),Reference Weintraub, Posavi and Fontanillas⁸⁷ so that clinicians could conduct a preliminary risk assessment for a better PD medication selection.

Considering the strong link between ICDs and DAs, it is critical for high-risk individuals to avoid or reduce the use of DAs. At the same time, the risk may be reduced by some interventions, such as promptly and effectively dealing with the PD-related complications (both motor and non-motor complications above), quitting smoking and drinking, avoiding substance abuse, improving the education level, improving marital status and receiving social satisfaction, which all deserve further investigations.

Predictors for progression

The qualitative research revealed that both internal factors (gene, mood, personal traits and coping methods) and external social factors (significant life events and social support networks) could influence the severity of PD-ICDs.^66,86,88,89. For instance, Parkin mutations,Reference Morgante, Fasano and Ginevrino⁹⁰ reduced DAT availability,^51,52 increased right-lateral fronto-striatal activation,Reference Paz-Alonso, Navalpotro-Gomez and Boddy⁹¹ and stronger preserved limbic-paralimbic connectivityReference Tessitore, De Micco and Giordano³⁴ have all been linked to increased severity of PD-ICD. Moreover, other factors like RBDReference Du, Huang and Ma⁸⁹ and high doses of DAs^77,92 were found to worsen the severity.

To summarize, we incorporated all these predictors and produced a profile for coding factors affecting occurrence and progression of PD-ICDs for future research reference (Figure 1).

DAs dose reducing or removal

Reducing or even withdrawing from DAs as the first-line therapy option can moderately relieve ICDs; a 40% remission rate was observed in 1 longitudinal studyReference Lee, J, Koh, Yoon, Lee, Kwon, Kim and Ki⁹⁴ and a 50% remission rate was reported in another with a longer follow-up period.Reference Corvol, Artaud and Cormier-Dequaire¹¹ Meanwhile, levodopa dosage can be raised to prevent worsening motor symptoms.Reference Mamikonyan, Siderowf and Duda⁹⁵ There are certain limitations to its usefulness. Switching from DAs to sustained-release formulations of levodopa/carbidopa, for example, can alleviate ICDs behaviors in PD patients, but ICD-related neuropsychiatric problems persisted after the 12-wk therapy.Reference Lee, J, Koh, Yoon, Lee, Kwon, Kim and Ki⁹⁴ Patients with pre-existing obsessive compulsive disorder were more likely to experience paradoxical aggravation of ICDs after DAs removal, which may assist in predicting refractoriness of this treatment on PD-ICD.Reference Choi, Lee and Jeon⁹⁶ Furthermore, patients who attempt to taper DAs may develop dopamine agonist withdrawal syndromes such as anxiety/panic, apathy, suicidality, diaphoresis, anorexia, and fatigue, complicating DA tapering.^97–99

DAs switch

DA switch is a method of altering the type of DAs and delivery routes. Following a thorough assessment of pharmacological contraindications, temporary replacement of pramipexole with bromocriptine with lower DRD3 selectivity may relieve or reverse the ICDs while maintaining the DRD2 stimulation for easing motor symptoms.Reference Seeman²⁷ Several studies have linked ICDs to pulsed dopaminergic treatment.Reference Evans, Pavese and Lawrence¹⁰⁰ Levodopa-carbidopa intestinal gel therapy can lower the risk of ICDs development by providing stable plasma levels and elimination of pulsatile dopaminergic stimulation,^31,32 and is appropriate for all patients with long disease duration.Reference Volkmann, Albanese and Antonini¹⁰¹ However, ICDs caused by this therapy may share a common mechanism with dopamine dysregulation syndrome.Reference Kashihara and Kitayama¹⁰² Furthermore, long-acting or transdermal DAs were found to lower ICD morbidity.Reference Rizos, Sauerbier and Antonini²⁹

Add-on therapy

Aside from adjustments in DRT, other pharmacological and non-pharmacological methods were investigated.

For pharmacological methods, as reward-based decision-making and impulsivity in ICDs are mediated by a complex neural network involving the dopaminergic, noradrenergic, and serotonergic pathways, as well as dopaminergic network,^103,104 many psychotropic agents targeting different pathways can be investigated as interventions.

Several drugs were tested and suggested effective based on limited evidence. Continuous apomorphine infusion may improve pre-existing ICDs, but as a potent dopamine agonist, it may also result in new or more ICDs.Reference Todorova, Samuel, Brown and Chaudhuri³² Amantadine, an anti-glutamatergic agent, may help with pathological gambling.Reference Thomas, Bonanni, Gambi, Di Iorio and Onofrj¹⁰⁵ by reducing hypersensitivity to rewards and maintaining activation toward uncertainty,Reference Cera, Bifolchetti and Martinotti¹⁰⁶ however, it has been linked to a higher risk of PD-ICDs.Reference Binck, Pauly and Kolber¹⁰⁷ Moreover, Safinamide is effective even at high doses. It can partially replace levodopa in treating motor symptoms while requiring less doses of other dopaminergic drugs and producing fewer side effects like ICDs.Reference Carrarini, Russo and Barbone¹⁰⁸ As an opioid antagonist, Naltrexone was demonstrated to be effective in treating pathological gambling in general populationReference Kim, Grant, Adson and Shin¹⁰⁹ while ineffective in the PD-ICD population from clinical general impression of change assessed by clinicians, although it did lower the severity.Reference Papay, Xie and Stern¹¹⁰ Other medications, such as citalopram, valproate, and clozapine, could be beneficial to ICDs as well.^111–114

To summarize, research into other drugs is ongoing, and none of them has sufficient evidence to date for treatment of ICDs. More clinical trials are required to determine the precise functions of them on PD-ICDs.

For non-pharmacological treatments, repetitive transcranial magnetic stimulation, a non-invasive therapy, could suppress or stimulate brain neurons using magnetic fields to improve impaired brain function and has been shown to have therapeutic promise for ICDs.^115,116 Second, since psychological traits have been linked to PD-ICDs,Reference Garlovsky, Simpson, Grünewald and Overton¹¹⁷ psychological therapies could be effective in treating PD-ICDs. Evidence suggested that integrating cognitive-behavioral therapy with routine medical care was more effective in reducing the severity of PD-ICDs than medical care alone.Reference Okai, Askey-Jones and Samuel¹¹⁸ Notably, patients with fewer ICDs and other psychiatric symptoms, better social functioning, and a lower dose of PD medication may benefit most from the cognitive-behavioral therapy.Reference Okai, Askey-Jones and Samuel¹¹⁸

Last but not least, deep brain stimulation (DBS) on either the subthalamic nucleus (STN) involved in cognitive control,Reference Eisinger, Cagle and Alcantara¹¹⁹ or the globus pallidus internusReference Kim, Baybayan, Moussawi and Mills¹²⁰ involved in reward expectation salienceReference Eisinger, Cagle and Alcantara¹¹⁹ can affect the reward processing and levels of impulsivity. Despite the fact that a prospective observational study found DBS could relieve PD-ICDs symptoms in the majority of patients,Reference Kim, Kim and Kim¹²¹ its use as a treatment for PD-ICD remains disputed. The palliative impact of DBS on the STN in ICDs could be attributable to a decrease in dopaminergic medications or the specific effect of stimulation^121–123 as others have found that DBS could reduce the severity of PD-ICDs regardless of medication modifications.Reference Rossi, De Jesus and Hess¹²⁴ Rarely, ICDs may deteriorate or appear as de novo ICDs after STN-DBS.^125,126 Moreover, significant changes in personality traits, such as increased apathy and harm avoidance, were observed, especially when DRT was drastically reduced.Reference Lhommée, Boyer and Wack¹²⁷

Given the disparity in DBS efficacy on PD-ICDs, factors influencing postoperative evolution of ICDs warranted investigation. First, studies have found that postoperative dopaminergic reduction in patients with mild PD (low dopaminergic drug doses, mild motor symptoms, and mild complications) was linked with ICDs remission^81,128; nevertheless, these patients had a higher tendency to become apathetic postoperatively.Reference Santin, Voulleminot and Vrillon¹²⁸ Moreover, younger age and personality traits such as irritability and compulsive behaviors have been linked to refractory ICDs.^96,129 Furthermore, the location of active contact within the STN may influence the result of postoperative ICDReference Mosley, Smith, Coyne, Silburn, Breakspear and Perry¹³⁰ with the ventral part of the STN favoring a rise in dysfunctional impulsivity.Reference Kardous, Joly and Giordana¹³¹ Additionally, oscillatory activity in the theta-alpha band was found to impact dopaminergic side effects.Reference Rodriguez-Oroz, López-Azcárate and Garcia-Garcia¹³² Thus, ICDs may be triggered, similar to dopaminergic treatment, when stimulation intensity is rapidly increased.Reference Castrioto, Lhommée, Moro and Krack¹³³ Consequently, more emphasis should be placed on electrode placement, parameter adjustment, and close monitoring during DBS surgery.

Current treatment status

One study preliminarily investigated the frequency and effects of these treatment options, and revealed that no-change was the most widely used treatment option (37.5%), followed by DAs removal (16.7%), DAs switch (12.5%) and DAs lowering (8.3%).Reference Rodríguez-Violante, Ríos-Solís and Esquivel-Zapata²¹ Fortunately, the majority achieved ICD remission regardless of treatment. Surprisingly, no change in the prevalence of PD-ICDs was observed throughout a 10-yr period before and after the screening and treatment methods were applied in clinical practice.Reference Jaakkola, Huovinen, Kaasinen and Joutsa⁷⁵ Some factors, such as the continued overdose of DAs despite decrease, as well as inadequate screening and treatment, may interpret this. This can serve as a reminder that much work remains to be done concerning clinical management.