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Concept: Pramipexole

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Beyond the cardinal motor symptoms, bradykinesia, rigidity, tremor and postural instability, defining the diagnosis of Parkinson’s disease, there is a big spectrum of non-motor features that patients may suffer from and that may reduce their quality of life. Non-motor symptoms are not only frequent but also often under-reported by patients and caregivers. As they are frequently under-recognized by clinicians, they remain consequently under-treated. This review wants to give a short overview of the importance of non-motor symptoms on patients' quality of life and helpful assessment tools that might facilitate recognition of non-motor features during clinical setting. Given the wide range of non-motor symptoms in Parkinson’s disease, we concentrate on common issues such as depression and sleep disorders like sleep-onset insomnia or sleep maintenance insomnia and restless legs syndrome. Thereby, we present some recent studies that have investigated the efficacy of dopaminergic drugs, especially dopamine agonists, revealing possible treatment strategies and thus improving disease management.

Concepts: Parkinson's disease, Substantia nigra, Dopamine, Haloperidol, Pramipexole, Ropinirole, Restless legs syndrome, Dopamine agonist

162

The cutaneous silent period (CSP) is a spinal inhibitory reflex primarily mediated by A-delta fibers. Prolonged CSPs have been reported in patients with restless legs syndrome (RLS) and idiopathic Parkinson’s disease (IPD). Dopaminergic medication normalizes the CSP, concurring with the effect of levodopa on CSPs. To date, CSPs have not been extensively studied in patients with multiple system atrophy (MSA). The purpose of this study was to confirm abnormal CSP findings in a group of MSA patients and to affirm the lack of influence of levodopa on CSPs during long-term treatment.

Concepts: Parkinson's disease, Parkinsonism, Neurotransmitter, Dopamine, Pramipexole, Ropinirole, Restless legs syndrome, Multiple system atrophy

28

Despite the prominent loss of motor skills, artistic capacities remain preserved in Parkinson’s disease (PD). Furthermore, artistic creativity may emerge in art-naïve PD patients treated with levodopa and dopamine agonists. The present review discusses reported PD patients who developed enhanced artistic skills under anti-Parkinsonian therapy and the course of this phenomenon in the clinical context. It is unclear whether creative drive is related to dopamine dysregulation, and the mechanisms remain speculative. The delineation of the particular constellation that enables this emergence in PD patients may shed light on the comprehension of the concept of creativity in general. (PsycINFO Database Record © 2013 APA, all rights reserved).

Concepts: Parkinson's disease, Neurotransmitter, Dopamine, All rights reserved, Creativity, Pramipexole, Ropinirole, Carbidopa

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Objective: This post-hoc analysis of a prospective open-label study investigated patients with restless legs syndrome (RLS) taking approved dosages (1, 2 or 3 mg/24 h) of rotigotine transdermal patch for up to 5 years. Research design and methods: Following 6 weeks' double-blind treatment, patients with moderate-to-severe RLS received open-label rotigotine titrated to optimal dosage. Main outcome measures: Safety was assessed by adverse events (AEs) and efficacy was assessed by the International Restless Legs Syndrome Study Group Rating Scale (IRLS). Results: Of 295 patients who entered the open-label study, 198 (67%) began the maintenance period taking rotigotine dosages of 1 - 3 mg/24 h, or increased their dosage from 0.5 mg in the first 3 months of the maintenance period. Of the 198 patients, 45 patients (23%) completed 5 years of follow-up within this dosage range, 79 patients (40%) had their dosage adjusted outside this range during follow-up and 74 patients (37%) withdrew (including 49 [25%] due to AEs and 6 [3%)] for lack of efficacy). Application site reactions were the most common AEs (102 of 198 patients [52%]), with an incidence of 35% (69 of 198) in year 1, 19% (19 of 102) in year 2, and 4 - 6% during each of years 3 - 5. Mean IRLS total score decreased from 27.1 ± 6.0 at double-blind baseline to 6.5 ± 6.5 at the beginning of maintenance, and to 7.4 ± 8.4 after 5 years' treatment on 1 - 3 mg/24 h (n = 45); 21 patients (47%) were classified as symptom-free (IRLS = 0). Conclusions: Consistent with the results for the overall population, rotigotine transdermal patch at approved dosages of 1 - 3 mg/24 h was generally well tolerated after the first year, with sustained efficacy in patients who completed 5 years of treatment at dosages of 1 - 3 mg/24 h.

Concepts: Medical statistics, Syndromes, Harshad number, Pramipexole, Restless legs syndrome, Dopamine agonist, Rotigotine

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OBJECTIVES: Sleep disorders, especially restless legs syndrome (RLS) and rapid eye movement sleep behavior disorder (RBD), are common in spinocerebellar ataxia type 3 or Machado-Joseph disease (MJD), and a possible underlying dopaminergic dysfunction is implicated. This study assessed the relationship between sleep disorders in MJD and dopamine transporter (DAT) densities. PATIENTS AND METHODS: Twenty-two patients with MJD and twenty healthy subjects were enrolled in this study. MJD patients underwent clinical sleep evaluation and polysomnography. SPECT with [(99m)Tc]-TRODAT-1, was performed in all subjects. RESULTS: DAT densities were significantly reduced in MJD group when compared to controls. No significant correlation was found between DAT densities and RLS or RBD in MJD. CONCLUSION: Our study failed to demonstrate a clear correlation between sleep disorders and DAT densities in MJD patients, hence suggesting that extrastriatal and non-presynaptic dopamine pathways could be implicated in MJD-related sleep disorders.

Concepts: Sleep, Dopamine, Rapid eye movement sleep, Spinocerebellar ataxia, Pramipexole, Restless legs syndrome, Machado-Joseph disease, Periodic limb movement disorder

28

Increased risk of heart valve disease during treatment with certain dopamine agonists, such as cabergoline, has been observed in patients with Parkinson’s disease. The same compound is used to treat hyperprolactinemia, but it is unknown whether this also associates with heart valve disease.

Concepts: Cohort study, Parkinson's disease, Prolactinoma, Pramipexole, Ropinirole, Cabergoline, Valvular heart disease, Bromocriptine

27

The use of dopamine agonists (DAs) has been associated with increased impulsivity and impulse control disorders in several diseases, including Parkinson’s disease. Such an effect of DAs on impulsivity has not been clearly characterized in hyperprolactinemic patients, where DAs are the mainstay of therapy. We studied the effects of DAs on impulsivity in hyperprolactinemic patients treated at a tertiary pituitary center, using validated psychometric tests. Cross-sectional study. Impulsivity was evaluated in 30 subjects, 10 hyperprolactinemic patients on DAs compared to two control groups; one comprising untreated hyperprolactinemic patients (n = 10) and a second group consisting of normoprolactinemic controls with pituitary lesions (n = 10). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (mean ± SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2 ± 2.7), as compared to the hyperprolactinemic control group (12.3 ± 2.5) and the normoprolactinemic group (14.7 ± 4.4) (p = 0.04). No statistically significant difference was found between groups with regards to the other impulsivity scales. In the DA-treated group, a correlation was observed between increased impulsivity (as assessed in the Experiential Discounting Task) and higher weekly cabergoline dose (r(2) = 0.49, p = 0.04). The use of DAs in hyperprolactinemic patients is associated with an increase in one aspect of impulsivity. This effect should be further characterized in larger, longitudinal studies.

Concepts: Scientific method, Statistical significance, Parkinson's disease, Attention-deficit hyperactivity disorder, Prolactinoma, Pramipexole, Ropinirole, Cabergoline

23

Restless legs syndrome (RLS) is commonly treated with the dopamine agonists pramipexole, and rotigotine, which target the inhibitory dopamine receptor subtype D3R. While initially highly effective, these compounds lose their efficacy in treating RLS over time, and long-term therapy regularly leads to a worsening of the symptoms (augmentation). This dopamine agonist-induced augmentation has become a prime concern in the treatment of RLS, and while alternate therapies are being proposed, the mechanisms leading to augmentation remain opaque. Evidence suggests that the prolonged D3R treatment may lead to a hyper-dopaminergic state and involve the excitatory dopamine D1 receptor (D1R) subtype. We here present an animal model in which we can test acute and long-term effects of dopamine D3R agonists in a behavior setting relevant to RLS and in which we can induce a switch of the drug effect similar to the one observed in RLS patients under chronic therapy. We also present evidence that we can reverse this long-term effect by blocking the D1R. Together, data from our new animal model indicate that the mechanisms leading to augmentation in RLS patients after long-term use of the currently used dopamine receptor agonists may be related to a D3R-induced upregulation of the D1R system. As such, our model can be used to assess the interactions between D3R and D1R and unravel the mechanisms that lead to augmentation, and it has the potential to serve as a Launchpad for the development of new pharmacological strategies for the treatment of both RLS and augmentation.

Concepts: Dopamine receptor, G protein coupled receptors, Dopamine receptor D3, Dopamine receptor D1, Pramipexole, Ropinirole, Restless legs syndrome, Dopamine agonist

14

Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia.

Concepts: Dopamine receptor, Agonist, Addiction, Antipsychotic, Dopamine, Pramipexole, Ropinirole, Restless legs syndrome

10

Effort-based decision-making is a cognitive process crucial to normal motivated behaviour. Apathy is a common and disabling complication of Parkinson’s disease, but its aetiology remains unclear. Intriguingly, the neural substrates associated with apathy also subserve effort-based decision-making in animal models and humans. Furthermore, the dopaminergic system plays a core role in motivating effortful behaviour for reward, and its dysfunction has been proposed to play a crucial role in the aetiology of apathy in Parkinson’s disease. We hypothesized that disrupted effort-based decision-making underlies the syndrome of apathy in Parkinson’s disease, and that this disruption may be modulated by the dopaminergic system. An effort-based decision-making task was administered to 39 patients with Parkinson’s disease, with and without clinical apathy, ON and OFF their normal dopaminergic medications across two separate sessions, as well as 32 healthy age- and gender-matched controls. On a trial-by-trial basis, participants decided whether to accept or reject offers of monetary reward in return for exerting different levels of physical effort via handheld, individually calibrated dynamometers. Effort and reward were manipulated independently, such that offers spanned the full range of effort/reward combinations. Apathy was assessed using the Lille apathy rating scale. Motor effects of the dopamine manipulation were assessed using the Unified Parkinson’s Disease Rating Scale part three motor score. The primary outcome variable was choice (accept/decline offer) analysed using a hierarchical generalized linear mixed effects model, and the vigour of squeeze (Newtons exerted above required force). Both apathy and dopamine depletion were associated with reduced acceptance of offers. However, these effects were driven by dissociable patterns of responding. While apathy was characterized by increased rejection of predominantly low reward offers, dopamine increased responding to high effort, high reward offers, irrespective of underlying motivational state. Dopamine also exerted a main effect on motor vigour, increasing force production independently of reward offered, while apathy did not affect this measure. The findings demonstrate that disrupted effort-based decision-making underlies Parkinson’s disease apathy, but in a manner distinct to that caused by dopamine depletion. Apathy is associated with reduced incentivization by the rewarding outcomes of actions. In contrast, dopamine has a general effect in motivating behaviour for high effort, high reward options without altering the response pattern that characterizes the apathetic state. Thus, the motivational deficit observed in Parkinson’s disease appears not to be simply secondary to dopaminergic depletion of mesocorticolimbic pathways, suggesting non-dopaminergic therapeutic strategies for apathy may be important future targets.

Concepts: Parkinson's disease, Basal ganglia, Substantia nigra, Neurotransmitter, Motivation, Unified Parkinson's Disease Rating Scale, Dopamine, Pramipexole