Dopamine Dysregulation Syndrome

Parkinson’s disease is a progressive disorder characterised by bradykinesia, resting tremor, rigidity, and postural instability. Dopaminergic medications, such as levodopa and dopamine agonists, are standard treatments for the motor symptoms of Parkinson’s disease.

Parkinson’s disease is associated with many complications. Dopamine dysregulation syndrome (DDS) is one such condition that can arise during the long-term treatment of Parkinson’s disease. This condition is characterised by an addictive pattern toward the use of dopaminergic medicines. Patients may take doses far in excess of what has been prescribed and beyond what is required to manage their motor symptoms.

This excessive use of dopaminergic medicines can lead to dyskinesias and psychiatric adverse effects, such as mania and psychosis. Withdrawal symptoms can also occur which may present with dysphoria and anxiety. However, even when severe drug-induced adverse effects occur, patients with DDS are typically unwilling to reduce their use of these medicines.

The pathogenesis of DDS is poorly understood. One theory is that it may be related to stimulation of the mesolimbic pathway, a central part of the brain’s reward system. In susceptible individuals, stimulation of this pathway by dopaminergic medications may lead to addictive disorders such as DDS.

Behavioural disturbances associated with DDS

Studies suggest that two thirds of patients with DDS have impulse control disorder (ICD). Common ICDs in Parkinson’s disease include pathological gambling, hypersexuality, compulsive shopping, and compulsive eating.

Punding is another behavioural disturbance often associated with DDS. Punding is a complex stereotyped behaviour typified by repetitive, non-goal-oriented activities. Examples could include compulsively assembling and disassembling objects or sorting and re-sorting collections. While people may be aware of the disruptive and unproductive nature of their behaviour, they often exhibit intense fascination with their activity and become frustrated if interrupted.

The prevalence of punding in patients with Parkinson’s disease has been reported to be between 1.4% and 14%. This wide range reflects the different populations used in various studies. The lower prevalence rate was reported in a large study of unselected Parkinson’s patients, while the higher rate was found in a study specifically looking at patients taking high doses of dopaminergic medicines. However, this behaviour is likely to be underreported due to a lack of awareness and a reluctance of patients to discuss the issue.

Risk factors

The most important risk factor for DDS appears to be chronic high doses of dopaminergic medications. Other potential risk factors were highlighted in a retrospective longitudinal study of patients with Parkinson’s disease. This study suggest the following factors may be associated with a higher risk of DDS:

• Younger age of Parkinson’s disease onset;
• A personal history of depression;
• A personal or family history of substance abuse;
• A positive family history of Parkinson’s disease in a first-degree relative; and
• Greater change in motor performance between ‘Off’ and ‘On’ states.

Contrary to some earlier studies which found a higher prevalence in males, this study did not find any gender differences in the prevalence of DDS.

A greater understanding of risk factors is important as this could be used to identify patients predisposed to developing this disorder. Preventative strategies, such as supervision of medication use, have been suggested as a means of preventing DDS in high-risk patients.

Treatment

Dopamine dysregulation syndrome can cause significant functional impairment. Therefore, early identification and appropriate management are important. However, this condition is difficult to treat and likely to recur.

Optimisation of dopaminergic therapy is recommended as the first step in the management of DDS, although any changes to dopaminergic therapy should be managed by a specialist. Possible strategies that could be considered include reducing the dose of dopaminergic medicine and optimising adjunct therapies. Adjuncts include monoamine oxidase (MAO) B inhibitors (e.g. rasagiline) and catechol-O‑methyltransferase (COMT) inhibitors (e.g. entacapone). However, optimisation of oral dopaminergic medicines has only been shown to resolve DDS in less than 10% of cases, and may be associated with worsening motor symptoms and features of withdrawal.

When optimisation of oral therapy fails, more advanced treatment options could be considered. In one study, long-lasting resolution of DDS was achieved by 80% of patients switched to duodenal levodopa infusion and 57% of patients undergoing deep brain stimulation. However, sample sizes were small, and further research is required in this area. Case studies suggest that aripiprazole could have a potential place in the management of DDS. Aripiprazole is a partial agonist at dopamine D₂ receptors and also exhibits agonist activity at serotonin 5HT_1A receptors and antagonist activity at serotonin 5HT_2A receptors. This partial D₂ agonist activity has been trialled in other substance abuse disorders with some success, although further studies are required.

The support of family or carers has been found to be a significant factor in achieving optimal outcomes for these patients. Monitoring of compliance with dopaminergic therapy by caregivers is associated with long-lasting remission of DDS. This may include delivering medications directly to the patient and ensuring the patient does not have any hidden medications or additional healthcare providers.

Summary

Dopamine dysregulation syndrome is a complex condition that can significantly affect quality of life for people with Parkinson’s disease. Unfortunately, the condition remains poorly understood, and there is limited evidence to guide effective management. Existing studies have often yielded inconsistent results. This is likely due to variations in follow-up duration, assessment tools, and study populations. Effective supervision and support from caregivers should be encouraged in both the prevention and management of DDS.