Use Of Dopamine Replacement Therapy Research Articles

Anxiety predicts impulsive-compulsive behaviours in Parkinson's disease: Clinical relevance and theoretical implications

Patients with Parkinson's disease (PD) often present symptoms of anxiety, depression and apathy. These negative affect manifestations have been recently associated with the presence of impulsive compulsive behaviours (ICBs). However, their relation with the use of dopamine replacement therapy (DRT), a renewed risk factor for ICBs, is still not fully understood. Elucidating the role of these different ICBs predictors in PD could inform both prevention/intervention recommendations as well as theoretical models. In the present study, we have analysed data collected in 417 PD patients, 50 patients with Parkinsonian symptoms but with scan without evidence of dopaminergic deficit (SWEDD), and 185 healthy controls (HC). We examined each patient's clinical profile over a two-year time window, investigating the role of both negative affect and DRT on ICBs. Results confirmed the presence of higher levels of anxiety in both the clinical groups, and of higher level of ICBs in SWEDD patients, respect to both PD and HC. Mixed model analyses revealed a statistically significant association between anxiety and ICBs in the SWEDD patients who did not take any DRT. Findings suggest the independence between anxiety and DRT in ICBs development, and provide new evidence for the motivational opponency theoretical framework.

Implications of dopaminergic medication withdrawal in Parkinson's disease.

The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson’s disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus.

Impulse Control and Related Disorders in Parkinson's Disease: Special Issues and Implications

Impulse control disorders (ICDs) are a group of disorders characterized by a failure to resist an impulse or temptation that results in a pattern of behavior that is harmful or interferes with daily functioning. ICDs in Parkinson's disease are associated with the use of dopamine replacement therapy, particularly a class of drugs known as dopamine agonists. In people with Parkinson's disease on dopamine agonists, the prevalence of ICDs is around 14%. ICDs are challenging to diagnose and treat, and often cause significant harm to patients and their families once they occur. To help prepare clinicians to meet this challenge, the following review discusses the epidemiology and best-evidence strategies to identify and manage ICDs in Parkinson's disease. [ Psychiatr Ann . 2020;50(3):107–112.]

Striatal changes underlie MPEP-mediated suppression of the acquisition and expression of pramipexole-induced place preference in an alpha-synuclein rat model of Parkinson's disease.

Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson's disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co-administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson's disease/dopamine replacement therapy related reward bias.

Impact of Impulse Control Disorders on Sleep-Wake Regulation in Parkinson's Disease.

Sleep disturbances are common in patients with Parkinson's disease (PD) and are even more prevalent in patients with behavioural addictions, such as pathological gambling, compulsive sexual behaviour, compulsive buying, binge eating, punding, and the compulsive use of dopamine replacement therapy. An overview of the relationship between these impulse control disorders and sleep disturbances is given and potential underlying mechanisms and treatment strategies are covered.

COMPULSIVE USE OF DOPAMINE REPLACEMENT THERAPY AMONG PARKINSON'S DISEASE PATIENTS: IF IT LOOKS LIKE A DUCK, SWIMS LIKE A DUCK AND QUACKS LIKE A DUCK . . .

COMPULSIVE USE OF DOPAMINE REPLACEMENT THERAPY AMONG PARKINSON'S DISEASE PATIENTS: IF IT LOOKS LIKE A DUCK, SWIMS LIKE A DUCK AND QUACKS LIKE A DUCK . . .

COMPULSIVE USE OF DOPAMINE REPLACEMENT THERAPY IN PARKINSON'S DISEASE: INSIGHTS INTO THE NEUROBIOLOGY OF ADDICTION

COMPULSIVE USE OF DOPAMINE REPLACEMENT THERAPY IN PARKINSON'S DISEASE: INSIGHTS INTO THE NEUROBIOLOGY OF ADDICTION

Continuous drug delivery in early- and late-stage Parkinson’s disease as a strategy for avoiding dyskinesia induction and expression

The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of L: -dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by L: -dopa than by dopamine agonist drugs. This has been associated with the short duration of L: -dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of L: -dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD.

Clinical aspects of impulsive compulsive behaviours in Parkinson's disease

Impulsive–compulsive behaviours (ICBs) are an increasingly well-recognised adverse-effect of dopaminergic medications used to treat Parkinson's disease. ICBs include pathological gambling, compulsive sexual behaviour, compulsive buying, and binge eating, together with punding and the addiction-like compulsive use of dopamine replacement therapy, or dopamine dysregulation syndrome. The prevalence of ICBs was approximately 14% in a large study undertaken in specialist movement disorder clinics.Dopamine dysregulation syndrome is more associated with compulsive l-dopa use, whereas other ICBs are more linked with oral dopamine agonist use. Other mechanisms implicated in the development and perpetuation of ICBs in PD include aberrant learning from reward-related situations, including decreased learning from negative feedback, increased measures of impulsivity or sensation seeking, and strong preference for immediate over future rewards.Treatment options for impulsive–compulsive behaviours include pharmacological, surgical and psychological interventions. The early recognition and prevention of ICBs, coupled with awareness of clinical risk factors for the development of these behaviours is of paramount importance, given the lack of specific treatments for these sometimes debilitating behaviours.

Compulsive use of dopamine replacement therapy: a model for stimulant drug addiction?

The compulsive use of dopamine replacement therapy (DRT) or dopamine dysregulation syndrome (DDS) is one of the behavioural disturbances reported in some patients with Parkinson's disease (PD) and other disorders who are receiving DRT. We draw this phenomenon to the attention of the addiction field as a topic deserving of more systematic study. We outline: the clinical features, epidemiology and clinical correlates of the disorder; the unresolved issues in its definition and diagnosis; and its potential relevance to neurobiological models of psychostimulant addiction. We argue that compulsive DRT use may provide a useful model for drug addiction, while advancing our understanding of the neurobiology of addiction and improving the management of PD patients with the disorder.

AG.03 Impulsive and compulsive behaviours in Parkinson's disease

Impulsive-compulsive behaviours (ICBs) are an increasingly well-recognised side-effect of dopaminergic medications used to treat Parkinson's disease (PD). These include pathological gambling, hypersexuality, compulsive shopping, binge eating, punding and compulsive use...

Impulse control disorders in Parkinson’s disease: clinical characteristics and implications

Impulse control disorders (ICDs), specifically those related to excessive gambling, eating, sex and shopping, have been observed in a subset of people with Parkinson's disease (PD). Although some initial case reports claimed that dopamine replacement therapies, particularly dopamine agonists, cause ICDs, more recent, larger and better controlled studies indicate a more complicated picture. While dopamine replacement therapy use is related to ICDs, other vulnerabilities, some related to PD and/or its treatment directly and others seemingly unrelated to PD, have also been associated with ICDs in PD. This suggests a complex etiology with multiple contributing factors. As ICDs occur in a sizable minority of PD patients and can be associated with significant distress and impairment, further investigation is needed to identify factors that can predict who may be more likely to develop ICDs. Clinical implications are discussed and topics for future research are offered.

Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours

Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinson's disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinson's disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinson's disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinson's disease groups following L-dopa challenge with neutral cues. The group with Parkinson's disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinson's disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive-compulsive behaviours and addictions and may have important implications with regards to advertisement legislation in an effort to prevent the onset of behavioural addictions.

Impulsive‐compulsive spectrum behaviors in pathologically confirmed progressive supranuclear palsy

There is growing awareness of impulsive-compulsive spectrum behaviors (ICBs) in patients with Parkinson's disease (PD) treated with dopamine replacement therapy (DRT). These include pathological gambling, hypersexuality, compulsive shopping, binge eating, punding and compulsive use of DRT, or dopamine dysregulation syndrome. In PD, difficulties exist in separating the effects of DRT from the underlying disease process and aberrant dopaminergic systems in determining the aetiology of ICBs. Recent reports of ICBs associated with dopamine agonist use for conditions other than PD may suggest a significant etiological role for these medications, but currently published cases thus far lack pathological confirmation of diagnoses. We present three cases of pathologically confirmed progressive supranuclear palsy who developed ICBs in association with dopamine agonist use. Pathological comparisons between these three cases and other case series of progressive supranuclear palsy are made.

Treating Parkinson's disease: Dopamine dysregulation syndrome and impulse control

Dopamine dysregulation syndrome (DDS) has emerged as a recognized complication of dopamine replacement therapy (DRT) in the treatment of Parkinson's disease. This syndrome is characterized by increased addictive patterns of behaviour in relation to DRT use, and results in impulse control disorders (ICDs), including compulsive gambling, compulsive shopping, compulsive eating, hypersexuality and punding (repetitive and excessive, aimless behaviour). Such symptoms can have devastating social, occupational and financial effects on the patient and the carer. The clinical manifestation of DDS is often not straightforward: the patient may not have the insight to recognize symptoms, and the symptoms of the syndrome do not always occur in a recognized pattern of disease progression and may be expressed individually. Clinical staff may find the assessment of DDS in clinical practice very difficult. It is important to gain evidence from carers, but this may not always be easy due to a sense of loyalty or feelings of guilt and shame. This article aims to describe the syndrome and highlight the psychosocial issues related to DDS, and the medical and surgical management options available, as well as developments in psychological therapies.

Long‐term follow‐up of impulse control disorders in Parkinson's disease

Recent studies have linked dopamine agonist (DA) usage with the development of impulse control disorders (ICDs) in Parkinson's disease (PD). Little is known about optimal management strategies or the long-term outcomes of affected patients. To report on the clinical interventions and long-term outcomes of PD patients who developed an ICD after DA initiation. Subjects contacted by telephone for a follow-up interview after a mean time period of 29.2 months. They were administered a modified Minnesota Impulse Disorder Interview for compulsive buying, gambling, and sexuality, and also self-rated changes in their ICD symptomatology. Baseline and follow-up dopamine replacement therapy use was recorded and verified by chart review. Of 18 subjects, 15 (83.3%) participated in the follow-up interview. At follow-up, patients were receiving a significantly lower DA levodopa equivalent daily dosage (LEDD) (Z = -3.1, P = 0.002) and a higher daily levodopa dosage (Z = -1.9, P = 0.05), but a similar total LEDD dosage (Z = -0.47, P = 0.64) with no changes in Unified Parkinson's Disease Rating Scale motor score (Z = -1.3, P = 0.19). As part of ICD management, 12 (80.0%) patients discontinued or significantly decreased DA treatment, all of whom experienced full or partial remission of ICD symptoms by self-report, and 10 (83.3%) of whom no longer met diagnostic criteria for an ICD. For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms.

Recognition of a dopamine replacement therapy dependence syndrome in Parkinson's disease: a pilot study ☆

Patients with Parkinson's disease may use Dopamine Replacement Therapy (DRT) in excess of therapeutic need. We investigate whether a group of 10 patients with Parkinson's disease, provisionally diagnosed with “Hedonistic Homeostatic Dysregulation” because of their excessive use of DRT, met established operational psychiatric criteria for substance dependence, compared with 10 patients with Parkinson's disease compliant with prescribed DRT. Using a semi-structured questionnaire designed to distinguish between adaptive therapeutic dependence on DRT and a maladaptive pathological pattern of DRT use, in conjunction with the SCID-1, we found that seven of the patients deemed by their treating physicians to be misusing DRT fulfilled operational criteria for maladaptive dependence in contrast to none of the compliant group. The majority experienced dysphoric “withdrawal” symptoms in the “off” state and increased their dose of DRT in an effort to control their mood. They also continued to use high doses of DRT despite disabling dyskinesias and social difficulties. This study provides preliminary evidence that some patients with Parkinson's disease may become maladaptively dependent on DRT. This finding has both clinical relevance for the treatment of PD and further implicates dopaminergic pathways in the genesis of substance dependence.

The effect of a D2-specific dopamine agonist (Pramipexole) on response time in early Parkinson’s disease patients

The long-term use of dopamine replacement therapy leads to dyskinesias in some Parkinson’s disease (PD) patients, which may be specific to the D1 subtype of dopamine (DA) receptor. The purpose of this study was to test the effectiveness of a D2-specific DA agonist, Pramipexole, in PD patients. In a double-blind design, 6 patients took increasing doses of Pramipexole over the course of 24 weeks, and were tested in a total of 15 sessions on four measures of movement efficacy: tapping speed, simple response time, choice response time, and sequencing. Compared with 3 placebo control patients, those on active medication showed faster tapping speeds and simple response times. Choice response time and sequencing were not affected by medication status. The D2 subtype of DA receptor may be especially important in movement speed, and may contribute less to more cognitive aspects of movement.