Elsevier

The Lancet Neurology

Volume 16, Issue 3, March 2017, Pages 238-250
The Lancet Neurology

Review
Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update

https://doi.org/10.1016/S1474-4422(17)30004-2Get rights and content

Summary

Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.

Introduction

Chronic treatment with dopaminergic medications, such as those used to manage Parkinson's disease, is commonly associated with motor and behavioural side-effects that include dyskinesias1 and impulse control disorders.2 Involuntary movements (ie, chorea and dystonia) associated with chronic levodopa treatment, termed levodopa-induced dyskinesias, occur in up to 80% of treated patients. A multicentre study2 has shown that impulse control disorders, which include gambling disorder, compulsive shopping, compulsive sexual behaviours, and binge eating, occur in about 17% of individuals on dopaminergic medications.

Other addictive behaviours, such as compulsive medication use (dopamine dysregulation syndrome) and punding (repetitive non-goal-directed simple or complex behaviours, including hobbyism), are associated with impulse control disorders. Compulsive medication use, particularly of levodopa and fast-acting dopamine agonists, is also associated with dyskinesias.

In this Review, we present updated evidence regarding the epidemiology and the cognitive dysfunction associated with these prevalent and disabling side-effects of dopamine replacement therapy. We will also describe and compare the mechanisms underlying motor (levodopa-induced dyskinesias) and non-motor (impulse control disorders) side-effects associated with dopamine agonists, and discuss potential treatments for patients with impulse control disorders.

Section snippets

Epidemiology and risk factors

In the largest multicentre study (n=3090) of impulse control disorders in patients with Parkinson's disease (DOMINION),2 these disorders were identified in 14% of patients on any dopaminergic medication and 17% of patients treated with a dopamine agonist (compulsive gambling in 5%, compulsive sexual behaviour in 3·5%, compulsive shopping in 6%, and binge-eating disorder in 4%), and were more common in patients treated with dopamine agonists than in patients who were treated with other

The role of Parkinson's disease

The susceptibility of patients with Parkinson's disease to impulse control disorders might be due to a pre-existing biological predisposition towards addictions or might occur as a result of dopaminergic medications modulating the neurobiology of Parkinson's disease. Notably, impulse control disorders also occur with chronic dopaminergic medications in patients with restless leg syndrome (however, their prevalence might be lower than in patients with Parkinson's disease, possibly related to

Effects of chronic dopaminergic medications

Dopaminergic medications can influence endogenous dopamine function in the brain at a presynaptic (figure 3) or synaptic level (figure 1). Chronic dopamine agonist or levodopa treatment can interfere with the phasic and tonic activity of dopaminergic neurons, and might be associated with long-term neuroadaptation, which can include regulation of receptor and transporter density.

In rodents, acute pramipexole treatment decreases the mean firing rate and burst firing activity (possibly reflecting

Learning from reward and loss

Dopaminergic medications can influence cognitive processes such as learning from feedback, risk-taking, and impulsivity. Dopaminergic medications are hypothesised to enhance learning from positive feedback (ie, rewards) and impair learning from negative feedback (ie, losses); this relative imbalance presents as impulsivity.13 Novel rewards are associated with enhanced striatal phasic dopamine release, also known as positive prediction error (or the difference between what one receives and what

Impulsivity in Parkinson's disease

Emerging evidence suggests that patients with Parkinson's disease and impulse control disorders have impairments in decisional but not motor impulsivity. Impulsivity is a heterogeneous construct manifested by a tendency towards rapid, ill considered, disinhibited choices. Impulsivity can be broadly divided into decisional forms, including delay discounting (preference of a small immediate over a larger delayed reward), reduced sensitivity to adverse outcomes (negative prediction errors) during

Treatment of impulse control disorders

The symptoms of impulse control disorders improve after decreasing or discontinuing dopamine agonist treatment in patients with Parkinson's disease. However, the replacement of dopamine agonists with levodopa for the treatment of motor symptoms is not tolerable for many patients. Patients with Parkinson's disease and impulse control disorders are at an increased risk for developing dopamine agonist withdrawal syndrome—a syndrome characterised by craving, autonomic, and psychiatric

Conclusions and future directions

Emerging evidence highlights the overlapping mechanisms underlying impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease (appendix). This evidence emphasises the interactions between chronic dopaminergic medications, the neurobiology of Parkinson's disease, and underlying individual susceptibility.

Chronic dopamine agonist medication is associated with a mild decrease in phasic dopaminergic activity (figure 3), which might lead towards a decrease in goal-directed or

Search strategy and selection criteria

We searched MEDLINE using the following terms: (“Parkinson” OR “dopamine agonist” OR “levodopa”) AND (“impulse control disorder” OR “impulsivity” OR “addiction” OR “dyskinesia”) limited to articles published in English between Sept 3, 2011, and Sept 3, 2016. The abstracts were reviewed for relevant manuscripts.

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