Although motor signs namely bradykinesia, rigidity and tremor are still considered as the core feature of diagnostic criteria for Parkinson disease (PD) [
71], increasing recognition has been given over time to non-motor manifestations of PD including cognitive, autonomic, and neuropsychiatric signs [
99]. Neuropsychiatric signs refer first of all to anxiety, apathy and depression that are frequently encountered in de novo drug-naïve PD patients [
54] and reverted when dopamine replacement therapy (DRT) is introduced [
66,
81]. Neuropsychiatric signs also encompass neuropsychiatric fluctuations (NPF), Impulse control disorders (ICDs) and related disorders, and psychosis that are frequently observed along the progression of PD pathology and the concurrent pulsatile administration of increasing doses of DRT [
25,
46,
52]. Therefore, behavioural disorders in PD have been conceptualized as a hypodopaminergic behavioural syndrome where apathy predominates, hyperdopaminergic behavioural syndrome which includes ICDs and other behavioural addictions, and non-motor fluctuations [
2,
75] that together, define two opposite sides of one behavioural spectrum [
81]. ICDs and related behaviors comprise a set of behaviors characterized by both impulsive and compulsive aspects. Impulsive aspects refer to an inability to resist an impulse or inappropriate drive despite harmful consequences for patients and their relatives, whereas compulsive aspects refer to the intrinsic repetitive nature of these behaviors that indicate a lack of self-control [
100]. As with drug addictions, ICDs and related disorders are underpinned by one common pathophysiological mechanism that consists in hypersensitization of reward circuits and heightened ventral striatal dopamine release in response to reward-related cues [
52]. Thus, from a clinical perspective, pathological gambling has been removed from ICDs in DSM-IV diagnostic criteria to be included into behavioural addictions in DSM-V. However, DSM-V nosology of ICDs and related disorders remains unclear and shared between ICDs and behavioural addictions. Based on the pathophysiology of those disorders, we prefer the label of behavioural addictions to describe the full spectrum of hyperdopaminergic behaviours [
6,
52]. Dopamine dysregulation syndrome (DDS) is a specific entity characterized by compulsive use of levodopa irrespective of motor-fluctuations and dyskinesias, along with behavioural changes from the spectrum of behavioural addictions [
30,
47]. Although DDS was initially thought to be driven by the severity of non-motor OFF symptoms such as pain or anxiety, a recent study argued that the non-motor “ON-drug” state was the driving force that enhance compulsive drug intake [
20]. Thus, patients who developed DDS might be seeking “ON-drug” euphoria rather than preventing “OFF-drug” dysphoria [
20]. Behavioural addictions result from complex interaction between individual risk factors, PD pathology and DRT. The purpose of the present review is to delineate the neurobiology and the clinical spectrum of behavioural addictions that are still under recognized despite their potential devastating consequences for patients and their relatives [
69].
Management of ICDs
Management of ICDs and related disorders remains challenging. Careful interview and education of patients and their relatives about risk factors: non-motor ON [
20], dyskinesia [
95,
97], DA intake (5 years cumulative risk of 50%) [
18] is a crucial step before starting DRT [
6]. Detection and evaluation of early changes in behaviors is mandatory when DRT is started. This consists of screening for benign changes along the behavioral spectrum from hypodopaminergia to hyperdopaminergia as well as neuropsychiatric fluctuations, using dedicated clinical scales [
6].
When ICDs occur, practical management will be adapted, taking into account severity of ICDs and impact on QOL, rather than the semiology itself. Basically, DA dose reduction, fractionation of L-Dopa must be first considered. Importantly, clinicians have to bear in mind that desensitization of the mesolimbic dopaminergic system is prolonged and may take weeks or months [
12,
13,
52,
86]. In such cases, adjunction of clozapine, amantadine or naltrexone may be helpful. Moreover, in cases of ICDs associated with DDS and severe motor fluctuations in younger PD patients, STN-DBS may represent an interesting therapeutic option.
DA should be carefully tapered below the individual threshold of inducing behavioral addictions, while avoiding the appearance of dopamine withdrawal syndrome [
72]. Continuous delivery of D2/D3 agonists using extended release formulations or transdermal administration should be preferred [
29], but overall all available dopamine agonists are very similar in effect. Apomorphine is the only available exception, as this agonist has a D1/D2 profile similar to endogenous dopamine with effects similar to L-dopa. Constant delivery of apomorphine with subcutaneous infusion using a mini-pump is a good alternative [
3,
89]. Although typically not mentioned in the literature as evidence based studies are lacking, L-Dopa fractionation that is indicated when motor complications and dyskinesia occur, should also be considered for the management of non-motor complications and behavioral addictions as the first approach in patients on L-dopa. Although studies are lacking, based on expertise this is the easiest and most effective approach. Efficacy of non-pulsatile administration of L-dopa has been shown in a prospective observational study of 66 consecutive PD patients treated with levodopa-carbidopa intestinal gel infusion. Catalan et al. [
14] found a significant 64,4% reduction of ICDs symptoms compared to baseline over the 6-month’s follow-up.
Clozapine, an atypical neuroleptic that improve levodopa induced psychosis and dyskinesia, has been reported to reduce ICDs symptoms in patients in which dopamine dose reduction did not improve those symptoms [
9,
76]. Conflicting results have been shown with amantadine, a glutamate receptor antagonist. Although one small double blind crossover study reported improvement in pathological gambling in PD patients [
87], the DOMINION study highlighted a positive correlation between amantadine and ICDs, even when taking into account levodopa and DA dosages [
102]. One small intervention study with the opioid antagonist naltrexone showed some evidence for an effect [
67]. This effect was corroborated by small clinical trials in other, non-PD-related behavioral addictions [
61]. Accordingly, additional data are needed to support the use of clozapine, amantadine or naltrexone for the treatment of ICDs and related disorders. STN-DBS is a well-established treatment for PD patients with motor complications. Moreover, drastic dopamine dose reduction following STN-DBS is responsible for substantial decrease of dyskinesia. Recently, a randomized controlled study comparing STN DBS plus medical therapy and best medical treatment over a period of 2 years, demonstrated a better behavioral outcome with STN DBS plus medical therapy compared to best medical treatment [
53]. Finally, the potential usefulness of cognitive behavioral therapy (CBT) for ICDs and related disorders has been highlighted in one randomized study [
65].