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Background: It remains controversial whether late levodopa administration is a reasonable approach to reducing the risk of levodopa-induced dyskinesia in Parkinson's disease., Objective: This study aimed to investigate the effects of levodopa sparing on the development of levodopa-induced dyskinesia., Methods: We retrospectively reviewed medical records for patients with de novo Parkinson's disease who visited the Yonsei Parkinson Center between April 2009 and June 2015 and received at least 2 years of treatment. Among 657 patients with drug-naïve Parkinson's disease who met the study criteria, 90 were initially treated with dopamine agonists (levodopa-sparing group; levodopa supplementation after 2.15 years). Another 90 patients who were initially treated with levodopa (levodopa group) were matched to the 90 patients for age, sex, follow-up duration, Parkinson's disease duration, Unified Parkinson's Disease Rating Scale Part III scores, and baseline dopamine transporter availability in the posterior putamen. The effects of levodopa sparing on dyskinesia development were assessed with Kaplan-Meier estimates and a stratified Cox regression model adjusted for age of onset, sex, dopamine transporter availability, and daily levodopa dose per weight., Results: The levodopa-sparing group had a comparable age of onset (54.80 ± 7.36 years) to the levodopa group (56.53 ± 6.16 years). The Kaplan-Meier analysis revealed that the risk of levodopa-induced dyskinesia after treatment initiation was similar between the groups. Once the levodopa-sparing group started levodopa supplementation, they had a higher risk of developing levodopa-induced dyskinesia. However, a stratified Cox regression model indicated that hazard ratios for levodopa sparing to levodopa-induced dyskinesia development were 0.138 (95% confidence interval 0.024-0.785) after treatment initiation and 0.438 (95% confidence interval 0.105-1.832) after levodopa initiation., Conclusion: Late levodopa administration was associated with a low risk of dyskinesia after adjusting for confounding effects and may be a reasonable strategy for prolonging the levodopa-induced dyskinesia-free period in Parkinson's disease.

Augmentation syndrome is one of the most severe complications of RLS. It is characterised by a worsening of treated symptoms; principally an increase in the severity of symptoms and an earlier onset time. Augmentation syndrome occurs primarily with dopaminergic treatments. It is crucial for the patient to be sufficiently well informed to prevent its occurrence and the prescription of too high doses of dopaminergic agonists avoided. In the presence of augmentation syndrome confirmed using the diagnostic criteria, the specialist treating the restless legs syndrome should quickly modify the patient's treatment. In this article, our expert group proposes a practical strategy for the diagnosis, prevention and treatment of augmentation syndrome., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: Parkinson's disease (PD) is characterized by motor symptoms such as bradykinesia, rigidity, alteration of postural reflexes and tremor at rest and other non-motor symptoms such as changes in sleep patterns and sexual behavior. However, little is known about paraphilic sexual behaviors., Aim: To summarize the number of cases of zoophilic behaviors in patients with PD between January 2000 and December 2017., Development: A review was carried out in PubMed, Scopus and Virtual Health Library. Eleven articles were identified by title; six were excluded because they did not present cases related to zoophilic behavior. We found five cases of men, usually with PD of several years of course, taking dopamine agonists and who presented the zoophilic behaviors followed increasing of the dose. The zoophilic behaviors decreased with reducing doses of dopamine agonists and taking atypical antipsychotic such as clozapine or quetiapine., Conclusions: It is limited the case reports of zoophilic behaviors in patients with PD. The patients reported are men in whom the dose of dopamine agonists was increased. It is important that the clinical follow-up of patients with PD disease includes a careful review of sexual behaviors including those of the paraphilic spectrum.

Background: In order to increase treatment choices for patients with Parkinson disease (PD), we performed a retrospective assessment of adverse events associated with a novel once-daily extended-release (ER) formulation versus the standard immediate-release (IR) of the nonergolinic dopamine agonist, pramipexole., Methods: The PubMed and Embase databases, as well as the foreign language medical information resource retrieval platform were searched from 2007 to 2017. The relative risks (RR) of various adverse events with 95% confidence intervals (95% CIs) were generated. The Modified Jadad score (MJs) was used to assess the quality of individual studies. Funnel plots were used to evaluate publication bias., Results: Three randomized controlled trials involving 1021 patients were included in this meta-analysis. We evaluated common adverse events associated with pramipexole in the gastrointestinal and nervous systems. These included the typical gastrointestinal symptom of nausea (RR = 0.96, 95% CI: 0.72-1.28; P = .80 > .05) and nervous system symptoms of somnolence (RR = 1.16, 95% CI: 0.95-1.43; P = .14 > .05), dizziness (RR = 1.11, 95% CI: 0.80-1.54; P = .54 > .05), and dyskinesia (RR = 0.87, 95% CI: 0.47-1.60; P = .66 > .05)., Conclusion: Patients with PD treated with 2 different pramipexole formulations (ER and IR) had similar incidences of common adverse events.

Impulse control disorders (ICD) are frequent side effects of dopamine replacement therapy (DRT) used in Parkinson's disease (PD) with devastating consequences on the patients and caregivers. ICD are behavioural addictions including compulsive gambling, shopping, sexual behaviour, and binge eating that are mainly associated with dopamine D2/D3 agonists. Their management is a real clinical challenge due to the lack of therapeutic alternative. Clinical studies have identified demographic and clinical risk factors for ICD such as younger age at disease onset, male gender, prior history of depression or substance abuse, REM sleep behaviour disorders and higher rate of dyskinesia. PD patients with ICD may also have a specific pattern of dopaminergic denervation in the ventral striatum. Specific evaluation tools have now been designed to better evaluate the severity and impact of ICD in PD. Patients with ICD display altered processing of reward and loss, and decisional bias associated with altered activity in cortical and subcortical areas such as the orbitofrontal cortex, amygdala, insula, anterior cingular cortex, and ventral striatum. Preclinical studies have demonstrated that D2/D3 agonists induce impairments in behavioural processes likely relevant to ICD such as risk-taking behaviour, preference for uncertainty, perseverative responding and sustained drive to engage in gambling-like behaviour. Whether interactions between dopamine denervation and DRT significantly contribute to the pathogenesis of ICD remains poorly understood so far, although features unique to PD have been identified in patients with ICD. Large-scale longitudinal studies are needed to better identify subjects with increased risk to develop ICD and develop therapeutic options.

Evidence suggests that impulse control deficits contribute to excessive food intake in some individuals with obesity. In addition to its known role in regulating appetite and glucose metabolism, the hormone leptin also directly modulates the activity of central dopamine systems. Although dopamine is involved in regulating impulsivity, the influence of leptin per se on this cognitive domain remains unclear. This study explored the performance of male leptin knockout (KO) and wild type (WT) rats in the 5-Choice Serial Reaction Time task (5CSRTT) of motor impulsivity and visuospatial attention. Behavioural performance was assessed under baseline conditions, following 4 weeks high-fat diet (HFD; 60 kcal%) consumption, and after acute pharmacological challenge with the indirect dopamine agonist, amphetamine. Subjects were also tested for glucose tolerance and insulin sensitivity, and dorsal and ventral striatal tissue was assayed ex vivo for markers of dopaminergic transmission. Obese KO rats learned the 5CSRTT at a slower rate compared to WT rats, in a manner suggestive of mild attentional impairment. However, task performance at baseline and after HFD intake was similar to that of WT controls. HFD intake reduced omissions across all subjects, whereas amphetamine challenge revealed a prominent genotype effect on 5CSRTT performance, with potentiated levels of impulsive responding and faster response times in KO rats compared to WT animals. Effects of amphetamine on other variables were similar between genotypes. Notably, the expression of striatal dopaminergic markers was unchanged in KO rats, and neither chronic food restriction nor HFD intake altered the impairments in glucose or insulin metabolism previously reported in these animals. These data suggest that leptin deficiency enhances impulsive action under conditions of dopaminergic challenge, yet this seems independent of overt changes in the expression of post-synaptic markers of dopamine signalling in striatal regions., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD)., Methods: We used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined., Results: Among 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4-55.7, DA ever users 51.5% [95% CI 41.8-62.1], DA never users 12.4% [95% CI 4.8-30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78-10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation., Conclusion: In this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation., Clinicaltrialsgov Identifier: NCT01564992., (© 2018 American Academy of Neurology.)

Background and Objectives: There is an unmet medical need for additional treatment options for Parkinson's disease. This was a Phase I, double-blind clinical trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of the novel dopamine D1 receptor partial agonist, PF-06669571, in subjects with idiopathic Parkinson's disease on a stable dose of L-DOPA., Methods: Subjects received PF-06669571 (or matching placebo) titrated from 1 mg to 3 mg over 7 days. The primary pharmacodynamic endpoint was the change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III total motor score at the pharmacodynamic time of maximum change from baseline on day 7., Results: Twenty subjects were randomized and 19 completed the study. Maximum plasma concentrations (C max ) of PF-06669571 were reached 3.35 and 3.19 h post-dose on day 1 and day 7. Geometric mean C max and area under the plasma concentration-time profile from time 0 to 24 h post-dose on day 7 were 92.51 ng/mL and 1626 ng·h/mL, respectively. The primary pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement; however, the criteria were met in a sensitivity analysis excluding data from a L-DOPA outlier (L-DOPA dose of 2550 mg/d). The most common adverse events (AEs) were nausea (experienced by 2 subjects each in the PF-06669571 and placebo groups). There were no permanent discontinuations or dose reductions due to AEs., Discussion: Multiple daily doses of PF-06669571 were safe and well tolerated with no notable safety concerns. The pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement. CLINICALTRIALS., Gov Identifier: NCT02565628.

Dopamine agonists such as pramipexole are commonly used in the treatment of restless legs syndrome (RLS) as well as Parkinson's disease. Pramipexole's common side effects are well documented; however, adverse skin reactions are less well known. In this case, a 45-year-old male farmer presented with excessive daytime tiredness and reported a history suggestive of RLS. He was initiated on pramipexole but developed a maculopapular erythematous rash in sun-exposed areas 8 days after its commencement. The skin rash resolved following pramipexole's cessation and it is thought the patient experienced a drug-induced photosensitivity reaction to pramipexole. This case highlights the potential for photosensitivity reactions to pramipexole, which is especially significant in countries like Australia where UV solar radiation is especially high., (© Royal College of Physicians 2018. All rights reserved.)

Real-world data from large cohorts of patients with Parkinson's disease on the long-term effectiveness of different dopamine-substituting drug therapies are rare. The objective of this study was to obtain information on real-world management of PD with dopamine-substituting drugs. SP0854 (NCT00599339) was a prospective, multicenter, non-interventional, multiple-cohort, post-authorization safety study of rotigotine versus other dopaminergic therapies. The study was also part of a European Medicines Agency risk-management plan for the non-ergoline dopamine agonist rotigotine, focussing on cardiovalvular fibrosis. Eligible patients requiring monotherapy with a dopamine agonist, or levodopa in combination with a dopamine agonist were followed for ≤ 33 months; 1531 of 2195 patients completed the study. Mean motor scores improved for all dopamine-substituting treatments. Patients with more severe motor-symptoms/increased disability were more likely to receive levodopa alone or in combination with a DA at study onset. More patients who started on combination therapy with levodopa remained on this treatment versus those starting on dopaminergic monotherapy. This real-world study showed that the dopamine-substituting therapies were efficacious, with a safety profile consistent with that expected of dopaminergic treatments. Cardiovalvular pathology was rare and not found to be causally-related to rotigotine.

Background: PD0013 was a 6-month noninterventional study in clinical practice comparing effectiveness/tolerability of rotigotine+levodopa in younger (<70 years) vs. older (≥70 years) Parkinson's disease (PD) patients., Methods: Patients previously received levodopa for ≥6 months as monotherapy/in combination with another dopamine-agonist (DA). Primary variable: Unified PD Rating Scale (UPDRS) Part-II change from baseline to end-of-observation-period (EOP)., Results: 91 younger/99 older patients started rotigotine; 68 younger/62 older patients completed the study. Most switched from levodopa+another DA. Addition of rotigotine as first DA was more common in older patients (20.2% vs.15.4%). Mean ± SD rotigotine-exposure: 6.1 ± 3.4 mg/24h younger vs. 4.9 ± 2.4 mg/24h older. Eleven patients changed levodopa dose. At EOP, improvement in mean UPDRS-II was greater in younger patients (p = 0.0289). UPDRS-II responder-rate (≥20% decrease in UPDRS-II score) was higher in younger patients (42.3% vs. 25.9%). Improvement across age groups was similar on PD Sleep Scale-2 and Clinical Global Impressions-Improvement Scale. Adverse drug reactions (ADRs), and discontinuations because of ADRs, were more common among older patients. There were no new safety signals., Conclusions: Despite low rotigotine doses, when added to levodopa/switched from levodopa+another DA, rotigotine led to greater improvement in UPDRS-II in younger patients (<70 years). Individual patient data revealed clinically meaningful improvements in UPDRS-II in both groups.

Background: Subcutaneous apomorphine is used for the treatment of Parkinson's disease (PD); however, infusion site reactions are a common adverse event (AE), which can lead to treatment discontinuation. Apomorphine formulations that are more tolerable and convenient for use are needed., Objective: Our aim was to compare the toxicity and bioavailability of ND0701, a new concentrated formulation of apomorphine free base, with one of the commercially available apomorphine HCl formulations (APO-go ® , Britannia Pharmaceuticals Ltd)., Methods: (1) Preclinical study: 16 minipigs were randomly assigned to placebo, APO-go ® , and ND0701 groups, and treated for 28 days. Pharmacokinetic, clinical, and pathological assessments were performed. (2) Phase I study: 18 healthy volunteers participated in an open-label, two-sequence, randomized, three single-dose, partial crossover study to compare the pharmacokinetics, safety, and tolerability of ND0701 with APO-go ® (1%)., Results: (1) Preclinical study: No systemic toxicity was observed in apomorphine-treated minipigs, but local skin reactions were observed at the infusion sites. These effects were less frequent and less severe and recovery was more rapid for ND0701 compared with APO-go ® . (2) Phase I study: Both formulations were safe and well tolerated under the conditions of the study and no severe or serious treatment-emergent AEs were reported. Infusion site nodules were reported more frequently, with higher severity, and recovered slower at APO-go ® -treated sites compared with ND0701-treated sites. Bioavailability of apomorphine was comparable between the two formulations., Conclusion: Based on these pilot studies, ND0701 appears to be superior to APO-go ® in terms of tolerability and safety, while maintaining comparable bioavailability with APO-go ® , and shows promise as a future treatment for PD.

Background: Impulse control disorders (ICDs) comprise abnormal behaviors frequently found in patients with Parkinson's disease (PD) receiving antiparkinsonian medication. ICDs in PD would develop when dopaminergic treatment overstimulates the dopamine receptor D3 (DR3). Here we studied whether DR3 gene (DRD3) is associated to ICD in PD patients with early-onset (EOPD)., Methods: We performed association analysis of the rs6280 DRD3 single nucleotide variation (SNV) (Ser9Gly) in a clinical sample of 126 non early-onset PD (NEOPD) and 73 EOPD (age at onset < 45). ICD was evaluated using the Questionnaire for Impulsive-Compulsive Disorders (QUIP) in PD., Results: In the total sample, we found that a younger onset of PD is linked to ICD traits with a potentially addictive reinforcement (ICDARs, behavioral addictions) (p = .017) and a trend for total ICDs (p = .078) while punding was not associated (p = .75). EOPD sample showed an increase of DRD3 C+ genotype for ICD (p = .022) and ICDARs (p = .043) but not for punding (p = .170). The post-hoc analyses including the time of evolution and Pramipexol or Ropinirole treatments, confirmed the independent effect of the DRD3 upon ICDs (p = .028) and ICDARs (p = .041) as well as the interaction between DRD3 and Pramipexol treatment upon ICDARs (OR = 4.60, 95% CI 1.20-17.632, p = .026). The NEOPD group showed no association between DRD3 and ICDs., Conclusions: We found that behavioral addictions in PD are associated with an early onset of the disease, the rs6280 DRD3 SNV and the type of dopamine agonist. Further investigation in independent samples is warranted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: In the last few decades, therapeutic uses of medicinal compounds present in food as a normal constituent has risen substantially, largely because of their fewer side effects and adequate efficacy. This study is designed to investigate a role of brain serotonin (5-HT) and dopamine (DA) in the potential nootropic, anxiolytic, and other beneficial effects of Nigella sativa (NS) and Olea europaea (OE) oil in rat models., Methods: Animals were treated with NS and OE oil orally at doses of 0.1 ml/kg and 0.25 ml/kg for 5 weeks. Food intake and body weight change, anxiety-like effects in elevated plus maze and activity in a novel and familiar environment were monitored weekly. Effects on learning and memory after 5 weeks treatment were monitored using Morris water maze test. Neurochemical analysis was carried using HPLC-ECD method., Results: NS and OE oil administration enhanced learning and memory in Morris water maze test and the effects were greater in NS than OE oil-treated animals. Low dose of OE oil increased exploration in an open field, higher dose of OE oil and both doses of NS oil produced no consistent effect on open field exploration. Effects of both oils on anxiety-like behavior, food and water intake, and activity in activity box were either not consistent or did not occur. The treatment increased homovanillic acid (HVA). 5-HT levels increased in high dose of NS oil and low dose of OE oil-treated groups. Low dose NS oil decreased 5-HT., Discussion: The present study suggests that active components in NS and OE oil may prove useful in treating impaired cognition. OE oil may produce psychostimulant-like effect. Modulation of DA and serotonin neurotransmission seems important in the pharmacological effect of these oils.

Background: Prolactinomas are typically treated nonsurgically with a dopamine agonist. Once the tumor shrinks, adjacent eloquent structures, such as the optic apparatus, can become skeletonized and herniate into the dilated parasellar space., Case Description: A 48-year-old man with a prolactin-secreting macroadenoma treated with cabergoline presented with progressive bitemporal hemianopsia. Magnetic resonance imaging showed no recurrence of disease and a stretched optic chiasm herniating into an empty sella. Elevation of the optic chiasm via a transnasal transsphenoidal approach with ALLODERM graft and septal cartilage strut was performed. The patient was discharged home the next day with significant improvement in vision; magnetic resonance imaging showed interval elevation of the optic chiasm., Conclusions: We review secondary empty sella syndrome and discuss surgical strategies for optic chiasmapexy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Nausea and vomiting are commonly associated with medication use. Dopaminergic agonists have been associated with these symptoms, but their impact in patients without Parkinson's disease, such as those with restless legs syndrome (RLS), is not well characterized., Aims: We sought to determine whether the non-ergoline dopamine agonist ropinirole is associated with nausea and vomiting in adults with RLS., Methods: We conducted a systematic review using PUBMED, EMBASE, and clinical trial databases to identify placebo-controlled clinical trials of ropinirole for RLS treatment. We extracted data including dosing schedule and the proportion of patients reporting nausea and/or vomiting. We also determined hazard ratios (HR) using a random effects proportional hazard model., Results: We extracted data from a pool of 13 studies. The prevalence of nausea in the ropinirole-treated RLS group (RLS-R; N = 1528) was 37.2% compared to 9.4% in the placebo-treated RLS group (RLS-P; N = 1395) (p < 0.0001). The prevalence of vomiting in the RLS-R group was 10.9% compared to 2.6% in the RLS-P group (p < 0.0001). Ropinirole use was associated with a higher risk of reporting nausea (HR 5.924 [4.410-7.959], p < 0.001) and experiencing vomiting (HR 4.628 [3.035-7.057], p < 0.0001). Nausea and vomiting represented nearly 50% of all adverse events reported., Conclusions: Nausea and vomiting are quite common side effects in those using ropinirole for RLS. As RLS is more widely recognized and treated; the prevalence of ropinirole-induced nausea and vomiting could grow substantially. Ropinirole use should be considered as a cause of chronic nausea and vomiting.

Camptocormia, a condition that involves the abnormal flexion of the trunk and results in a forward-bending posture, is relatively common during the course of Parkinson disease (PD). Despite this, there is ongoing controversy concerning its mechanisms and no consensus regarding the underlying etiology. This report demonstrates a case in which a dopaminergic agonist (DA) was implicated in the onset of camptocormia episodes in a non-PD patient who developed camptocormia after the start of DA treatment. Over a course of 8 years, the patient experienced intermittent camptocormia, which resulted in multiple falls. After cessation of the DA, the patient showed decreased camptocormia symptoms. This case report suggests that clinicians should consider the possibility of DA-induced camptocormia in patients with PD and non-PD patients receiving DA treatments, and serves to caution clinicians regarding the administration of DAs.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopamine neurons of the central nervous system. The disease determines a significant disability due to a combination of motor symptoms such as bradykinesia, rigidity and rest tremor and non-motor symptoms such as sleep disorders, hallucinations, psychosis and compulsive behaviors. The current therapies consist in combination of drugs acting to control only the symptoms of the illness by the replacement of the dopamine lost. Although patients generally receive benefits from this symptomatic pharmacological management, they also show great variability in drug response in terms of both efficacy and adverse effects. Pharmacogenetic studies highlighted that genetic factors play a relevant influence in this drug response variability. In this review, we tried to give an overview of the recent progresses in the pharmacogenetics of PD, reporting the major genetic factors identified as involved in the response to drugs and highlighting the potential use of some of these genomic variants in the clinical practice. Many genes have been investigated and several associations have been reported especially with adverse drug reactions. However, only polymorphisms in few genes, including DRD2, COMT and SLC6A3, have been confirmed as associated in different populations and in large cohorts. The identification of genomic biomarkers involved in drug response variability represents an important step in PD treatment, opening the prospective of more personalized therapies in order to identify, for each person, the better therapy in terms of efficacy and toxicity and to improve the PD patients' quality of life.

Introduction: The use of psychostimulants has been present in common medical practice since the 20th century and has undergone an exponential growth in terms of the number of prescriptions., Aim: To review the current state of knowledge about the side effects of psychostimulants in the child and teen populations., Development: A review was performed by searching in different databases and included clinical analyses, observational prospective studies and systematic reviews. A minimum increase in blood pressure and heart rate are observed, but some studies highlight an underestimation of the long-term risk. As regards appetite and growth, almost all the current literature points to a slowing of the rate of growth, which is regained on interrupting treatment. One important factor, as is the parallel evolution of bone age, has not been evaluated in most of the studies carried out to date. No significant worsening of sleep was noted in patients treated with psychostimulants with respect to those who are not being treated. With regard to the central nervous system, there does not seem to be any evidence of an increased risk of the appearance or exacerbation of tics following introduction of the treatment. Affect and emotion are areas that have been barely explored., Conclusions: It is important to have more evidence on the safety of these drugs. It is therefore essential to have access to studies that cover a period of time consistent with the duration of these treatments.

Background: Neuroleptic malignant syndrome (NMS) is a rare but severe undesired complication of psychopharmacological treatment. The mortality has shown a significant decrease since its first description. Knowledge of NMS is important for every clinician because of the need for rapid diagnosis and treatment., Objective: This article presents a review and critical appraisal of the current study situation for NMS. Recommendations for diagnostics, differential diagnostics and treatment are presented particularly from a clinical perspective., Material and Methods: A literature review with the keywords "neuroleptic malignant syndrome", "Malignes neuroleptisches Syndrom" and various psychotropic drugs was performed in PubMed. The database of the Working Group for Pharmaceutical Treatment of Psychiatric Diseases (Arbeitsgemeinschaft für Arzneimitteltherapie bei psychiatrischen Erkrankungen, AGATE) was analyzed with respect to registered cases of the undesired side effect NMS., Results: In contrast to the first description, which also led to the name, there are now case reports of clinical conditions similar to NMS, which were obviously triggered by several groups of psychotropic drugs not just antipsychotic agents (German: Neuroleptika). Treatment recommendations exist whereby the effectiveness cannot always be scientifically substantiated; however, it is still undisputed that a rapid initiation of treatment is of great importance., Discussion: The psychiatrist must be familiar with the symptoms of NMS, its differential diagnosis and the therapeutic options for a rapid and effective treatment. Further studies are urgently needed for scientific substantiation of the pathophysiology of NMS and to develop evidence-based guidelines for treatment.

Objectives: Few studies have investigated the risk factors for motor vehicle accidents (MVA) in individuals with Parkinson's disease (PD) in Japan., Materials and Methods: We sent an anonymous questionnaire to 1417 patients with PD who had received medical care certificates for Intractable Diseases during the 2014 fiscal year from the Aomori Prefectural Government in Japan. Data from patients with PD who previously or currently held a driving license at the time of the survey were analyzed., Results: Complete datasets were obtained from 384 patients with PD who were either past or present driving license holders. Fifty-seven patients had caused at least one MVA in the last 5 years before the survey. Logistic regression analyses revealed that ergot-dopamine agonist (DA) use and excessive daytime sleepiness (Epworth Sleepiness Scale score ≥ 10) were the best predictors of MVAs. Patients having caused non-sleep-related MVAs had significantly longer disease durations, more frequent ergot-DA use, and higher cognition and communication subscores on the Parkinson's Disease Questionnaire-39 than those without non-sleep-related MVAs (P < .05). The Epworth Sleepiness Scale scores of PD patients with sleep-related MVAs were significantly higher than those of patients without sleep-related MVAs (P < .01)., Conclusions: Excessive daytime sleepiness and ergot-DA use may be important predictive risk factors for MVAs in PD. Daytime sleepiness appears to be related to sleep-related MVAs in PD, whereas disease progression and ergot-DA use may contribute to non-sleep-related MVAs., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Brexpiprazole is a new dopamine partial agonist antipsychotic in the same class as aripiprazole. This paper will briefly review brexpiprazole and compare it with aripiprazole., Conclusions: Brexpiprazole and aripiprazole are both partial agonists at dopamine D 2 , and serotonin 5-HT 1A and antagonists at serotonin 5-HT 2A and noradrenergic α 1B receptors. However, the two drugs are significantly different in potencies at various receptors; neurochemical profiles predict that brexpiprazole may be comparable with aripiprazole in its antipsychotic efficacy but may cause less akathisia, extrapyramidal side effects (EPS) and activation. In pivotal trials brexpiprazole demonstrated antipsychotic efficacy in short and long-term studies; it was also found to be an effective adjunct in patients with major depression resistant to antidepressants. Akathisia can occur early in treatment with brexpiprazole, as can minor weight gain and prolactin elevation. Indirect data extrapolations from pivotal studies suggest that brexpiprazole and aripiprazole have comparable efficacy but brexpiprazole may cause less akathisia. Like aripiprazole, brexpiprazole has been approved in the USA for use in schizophrenia and antidepressant-resistant depression. Although much more clinical experience is needed, brexpiprazole appears to be distinct from aripiprazole and a promising new 'metabolically-friendly' antipsychotic option for treatment of psychoses and mood disorders.

Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc). Despite many researches, there is still no cure for this disease. Levodopa is the first line treatment of PD, but the long term use of it leads to motor impairments and dyskinesias. The dopamine agonists are the preferred choice for the treatment of PD. They are neuroprotective in nature but have side effects., Objective: Our aim was to review the work that has been carried out on dopamine agonists and the future possibilities to reduce their side effects., Conclusion: In this review, we highlighted the metabolism of dopamine, different types of dopamine agonists with their properties and possible side effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: Dopamine agonists (DAs) are recommended as first-line treatment for patients with hyperprolactinemia. Generally, it is accepted that patients with hyperprolactinemia do not need lifelong medication, but the optimal timing for DA withdrawal has not been determined. The aim of this systematic review and meta-analysis is to assess the impact of DA withdrawal on the clinical outcomes of patients with hyperprolactinemia, and to explore possible factors affecting successful DA withdrawal., Methods: The databases of PubMed, Cochrane and EMBASE were searched up to May 2016., Results: The proportion of patients with persisting normoprolactinemia after DA withdrawal reached 36.6% in a random effects model (95% CI, 29.4-44.2%; I-squared: 82.5%). Data of stratified analysis showed that the success rate of drug withdrawal was high in patients using cabergoline (CAB) as the only treatment (41.2%; 95% CI 32.3-50.4%) and those using CAB over 24 months (48.7%; 95% CI 38.9-58.5%), especially in patients with idiopathic hyperprolactinemia (73.2%; 95% CI 55.6-87.7%). In addition, patients who received a low maintenance dose of CAB, and had a significant reduction in tumor size (over 50%) before withdrawal, were more likely to achieve success (51.5 and 49.4%, respectively)., Conclusion: The success rate of DA withdrawal has increased in recent years. Further, the success rate of CAB withdrawal was higher than that of bromocriptine, especially in patients with a duration of treatment longer than 24 months. Conclusively, the probability of success was higher in patients who received low-dose CAB maintenance treatment and those who achieved a significant reduction in tumor size before withdrawal.

Rationale: 2-Bromoterguride, a dopamine D 2 receptor partial agonist with antagonist properties at serotonin 5-HT 2A receptors and α 2C -adrenoceptors, meets the prerequisites of a putative atypical antipsychotic drug (APD). We recently showed that 2-bromoterguride is effective in tests of positive symptoms of schizophrenia in rats without inducing extrapyramidal side effects or metabolic changes., Objective: In continuation of our recent work, we now investigated the effect of 2-bromoterguride on apomorphine and phencyclidine (PCP)-induced disruptions of prepulse inhibition (PPI) of the acoustic startle response, a measure of sensory gating. In addition, we used subchronic PCP treatment to produce cognitive deficits and social aversion, and assessed the effect of 2-bromoterguride on the performance in the novel object recognition (NOR) task (model for studying cognitive deficit symptoms of schizophrenia) and the social interaction test (model for studying negative symptoms of schizophrenia). Finally, we extended the side effect profile of 2-bromoterguride by measuring the prolactin response to systemic administration of the drug in rats., Results: Treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) reversed PPI deficits induced by apomorphine and PCP, respectively. Subchronic PCP induced impairments in object memory and social interaction behavior which were ameliorated by 2-bromoterguride but not by clozapine and aripiprazole, respectively. Prolactin concentration in blood serum was not elevated at 1, 2, or 4 h post-2-bromoterguride treatment, which further supports the safe and effective use of this drug., Conclusions: Our data support 2-bromoterguride as a promising APD candidate due to its beneficial effect on cognitive impairments and negative symptoms of schizophrenia.

Impulse control disorders (ICDs) are a well-known adverse effect of dopamine agonists (DAAs). This critical review aims to summarize data on the prevalence and factors associated with the development of an ICD simultaneous to DAA use. A search of two electronic databases was completed from inception to July 2017. The search terms were medical subject headings (MeSH) terms including "dopamine agonists" AND "disruptive disorders", "impulse control disorders", or "conduct disorders". Articles had to fulfill the following criteria to be included: (i) the target problem was an ICD; (ii) the medication was a dopaminergic drug; and (iii) the article was an original article. Of the potential 584 articles, 90 met the criteria for inclusion. DAAs were used in Parkinson's disease (PD), restless legs syndrome (RLS) or prolactinoma. The prevalence of ICDs ranged from 2.6 to 34.8% in PD patients, reaching higher rates in specific PD populations; a lower prevalence was found in RLS patients. We found only two studies about prolactinoma. The most robust findings relative to the factors associated with the development of an ICD included the type of DAA, the dosage, male gender, a younger age, a history of psychiatric symptoms, an earlier onset of disease, a longer disease duration, and motor complications in PD. This review suggests that DAA use is associated with an increased risk in the occurrence of an ICD, under the combined influence of various factors. Guidelines to help prevent and to treat ICDs when required do exist, although further studies are required to better identify patients with a predisposition.

Introduction: Continuous apomorphine infusion (CAI) is an advanced therapy in fluctuating Parkinson's disease (PD). The use of CAI is controversial in PD patients with cognitive dysfunction including visual hallucinations (VHs), and orthostatic hypotension (OH). This study was set-up to analyze the effectiveness and safety of CAI in elderly PD patients with cognitive dysfunction., Methods: This new-user cohort study identified fluctuating PD patients who started CAI treatment at the rehabilitation unit of Parkinson Expertise Center (RU-PEC) Groningen, from November 2004 until 2016. Efficacy and safety data included motor function, cognitive status, OH and VHs, and was analyzed retrospectively. Pre-existent non-motor symptoms were treated optimally before starting CAI., Results: Forty-five fluctuating PD patients (age: 70.9 ± 8.1 yrs, disease duration: 10.8 ± 4.8 yrs) were identified, with pre-existing cognitive dysfunction, VHs (71%), and OH (26%). During the stay at RU-PEC (median 52 days) apomorphine was successfully titrated without worsening of pre-existing VHs and OH. The mean daily apomorphine dose was 66 ± 28 mg, accompanied by a reduction of levodopa-equivalent daily dose (LEDD) with 17%. The duration of ON-time and OFF-time significantly improved with +2.36 h (25%) and -1.66 h (-45%), respectively, while dyskinesia duration did not change. During long-term follow-up (median of 26 months) VHs and OH worsened in 9 and 4 patients, which necessitated discontinuation in 4 cases., Conclusion: This study demonstrates that CAI is also an effective treatment in advanced PD patients with concomitant cognitive dysfunction including VHs and OH, provided that these comorbidities are treated adequately as well., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The main adverse effects of dopaminergic drugs used in Parkinson's disease are hypotension, somnolence, hallucinations and impulse control disorder. Less common is leg edema. We report on a 68-year-old male receiving levodopa and pramipexole consulting for severe leg edema lasting two years, whose etiology was not ascertained with multiple lab tests. This edema subsided substantially when pramipexole was discontinued and the dose of levodopa was increased to treat motor symptoms.

Objective: To describe a case of aripiprazole-induced problem gambling and impulse-control deficit in a gambling-naïve patient following commencement of low-dose aripiprazole., Method: Case report., Results: This case adds to the literature on the dopamine partial agonist aripiprazole causing or exacerbating problem gambling, and extends that literature to low-dose use of aripiprazole in the gambling naïve., Conclusions: When commencing a patient on aripiprazole the possibility of emergence of problem gambling and other impulse-control deficits should be monitored, even in those with no history of similar behaviours and even on a low dose.

Context Management of prolactinomas during pregnancy has always been a challenge. There is a concern about the risk of tumor growth, as well as the effects of the treatment on the developing fetus. Another issue that has been less studied is the outcome of women with prolactinoma after pregnancy and lactation. Objectives To evaluate remission of hyperprolactinaemia after pregnancy and lactation in women with prolactinoma. To describe the safety of dopamine agonists for the fetus and pregnancy outcomes. Methods A retrospective study of 32 pregnancies in women with prolactinoma was conducted in a single-centre. Other causes of hyperprolactinemia were excluded. Prolactin level was recorded at the time of diagnosis, during treatment, and during follow-up. Results The pregnancies resulted in one spontaneous abortion (3.1%) and 31 live births (96.9%). No stillbirths, multiple or ectopic pregnancies or trophoblastic disease were recorded. There was only one malformation (club foot) recorded (3.1%) and normalisation of prolactin after pregnancy without medical treatment occurred in 12% of patients. Conclusions Fetal exposure to bromocriptine or cabergoline during pregnancy is not associated with an increased risk of adverse neonatal or pregnancy disclosures. There is considerable diversity among endocrinologists in the management of prolactinomas during pregnancy and after birth, which indicates that there is a need for better consensus and for carefully drawn-up guidelines to follow., Competing Interests: Conflicts of Interest: The authors have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Rationale: Hyperprolactinemia is a highly prevalent adverse effect of many antipsychotic agents, with potentially serious health consequences. Several guidelines have been developed for the management of this condition; yet, their concordance has not been evaluated., Objectives: The objectives of this paper were (1) to review current clinical guidelines; (2) to review key systematic evidence for management; and (3) based on our findings, to develop an integrated management recommendation specific to male and female patients who are otherwise clinically stabilised on antipsychotics., Methods: We performed searches of Medline and EMBASE, supplemented with guideline-specific database and general web searches, to identify clinical guidelines containing specific recommendations for antipsychotic-induced hyperprolactinemia, produced/updated 01/01/2010-15/09/2016. A separate systematic search was performed to identify emerging management approaches described in reviews and meta-analyses published ≥ 2010., Results: There is some consensus among guidelines relating to baseline PRL screening (8/12 guidelines), screening for differential diagnosis (7/12) and discontinuing/switching PRL-raising agent (7/12). Guidelines otherwise diverge substantially regarding most aspects of screening, monitoring and management (e.g. treatment with dopamine agonists). There is an omission of clear sex-specific recommendations. Systematic literature on management approaches is promising; more research is needed. An integrated management recommendation is presented to guide sex-specific clinical response to antipsychotic-induced hyperprolactinemia. Key aspects include asymptomatic hyperprolactinemia monitoring and fertility considerations with PRL normalisation., Conclusion: Further empirical work is key to shaping robust guidelines for antipsychotic-induced hyperprolactinemia. The integrated management recommendation can assist clinician and patient decision-making, with the goal of balancing effective psychiatric treatment while minimising PRL-related adverse health effects in male and female patients.

Background: PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation., Objectives: We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors., Methods: Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity., Results: Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions., Conclusions: These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Introduction: Rotigotine was demonstrated to be efficacious and well-tolerated in three placebo-controlled studies (CLEOPATRA-PD/PREFER/SP921) of patients with advanced-stage Parkinson's disease (PD), most of whom were Caucasian. This multicenter phase 3 study (SP1037; NCT01646255) was the first to investigate the efficacy and safety of rotigotine in Chinese patients with advanced-stage PD., Methods: Chinese patients with PD, inadequately controlled on levodopa (stable dose ≥200 mg/day), with ≥2.5 h/day "off" time, and Hoehn & Yahr stage 2-4, were randomized 1:1 to receive transdermal rotigotine or placebo, titrated over ≤7 weeks, maintained at optimal/maximum dose (4-16 mg/24 h) for 12 weeks. Primary efficacy variable: mean change in absolute "off" time (according to patient diaries) from baseline to end of maintenance. Safety variables included adverse events (AEs) and discontinuations due to AEs., Results: 346 patients were randomized and 89.9% completed the study (87.8% placebo; 92.0% rotigotine). All were Chinese (58.7% male; mean ± SD age: 62.2 ± 8.9 years; mean ± SD time since PD diagnosis: 6.62 ± 3.70 years). Rotigotine significantly reduced "off" time vs placebo (LS mean [95% CI] treatment difference: -1.20 h/day [-1.83, -0.57]; p = 0.0002), and resulted in more responders (≥30% decrease in "off" time: 36.9% placebo; 48.8% rotigotine; p = 0.0269). AEs were reported for 86 (50.0%) placebo- and 103 (59.2%) rotigotine-treated patients; 15 discontinued due to AEs (placebo 7; rotigotine 8). The most common AEs (≥5%) were dizziness, nausea, pruritus, and dyskinesia., Conclusions: Rotigotine was efficacious in Chinese patients with advanced-stage PD as add-on therapy to levodopa, significantly reducing "off" time vs placebo; the treatment difference was similar to that observed in previous studies of mainly Caucasian patients. Rotigotine was generally well-tolerated and had a similar AE profile to those observed in previous studies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Nocturnal hypokinesia is a common symptom in Parkinson's disease (PD), negatively affecting quality of life of both patients and caregivers. However, evidence-based treatment strategies are limited., Objective: To evaluate the efficacy of rotigotine transdermal patch, using a wearable sensor, in the management of nocturnal immobility., Methods: 34 PD subjects with nocturnal immobility were randomized to receive rotigotine transdermal patch (mean ± SD of 10.46 ± 4.63 mg/24 h, n = 17) or placebo patch (n = 17). Treatment was titrated to an optimal dose over 1-8 weeks, then maintained for 4 weeks. Primary endpoints were objective parameters assessing axial rotation measured using an axial inertial sensor (the NIGHT-Recorder) over two nights at the patients' home. Scale-based assessments were also performed., Results: There was a significant difference, in favor of rotigotine, in change from baseline score in the number of turns in bed (ANCOVA, p = 0.001), and degree of axial turn (p = 0.042). These objective improvements were mirrored by significantly greater improvements in clinical scale-based assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS) total scores (p = 0.009), UPDRS-motor scores (p < 0.001), UPDRS-axial scores (p = 0.01), the Modified Parkinson's Disease Sleep Scale (p < 0.001), the Nocturnal Akinesia Dystonia and Cramp Scale (p = 0.003) and the eight-item PD Questionnaire (PDQ-8) scores (p = 0.01) from baseline to end of treatment in patients given rotigotine compared to placebo., Conclusion: We show that the rotigotine patch provides a significant improvement in nocturnal symptoms as assessed using both objective measures and clinical rating scales. The study demonstrates the feasibility of using wearable sensors to record objective outcomes in PD-related clinical trials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Behaviour may be influenced by pituitary hormones or treatments. Dopamine agonist (DA) indicated in prolactinomas treatment can cause side effects, and especially impulse control disorders. In the context of prolactinomas treatment, impulse control disorders (ICD) have been reported like gambling, compulsive shopping, but mostly hypersexuality. These ICD can occur with low AD doses, and seem to be independent of type of molecule and psychiatric medical history. The main pathophysiologic hypothesis is a dysregulation of dopaminergic pathway involved in reward system. Given the possible devastating social impact of these ICD, they have to be screened in patients treated with DA. Our social behaviour can also be impacted by oxytocin. This hormone secreted on physiologic state at posterior pituitary, but also by others areas of brain and brainstem, has an impact on attachment in pair partners and in parent-child relationship, but also in empathy behaviour. Oxytocin affects as well eating behaviour with an anorexigenic impact. Studies on small populations assessed the relevance of an oxytocin treatment in several endocrine and nutritional pathologies like post-surgery craniopharyngioma, panhypopituitarism and obesity. Despite promising results, several pitfalls prevent yet the oxytocin use in clinical practice., (© 2017 Elsevier Masson SAS. Tous droits réservés.)

Background: Some reports have suggested an association between dopamine agonists and hiccups, involuntary contractions that merit full clinical attention because they can be very debilitating. Many drugs frequently used to treat hiccups are formally contraindicated in Parkinson's disease due to their liability to worsen motor symptoms, making the treatment of hiccups problematic in this disease. The objective of the present study was to analyze all spontaneous reports of hiccups from the European Pharmacovigilance Database in patients with Parkinson's disease and/or on dopaminergic drugs. Finally, we sought to identify evidence-based recommendations on the management of hiccups in Parkinson's disease., Methods: We searched for all reports of hiccups in the European Pharmacovigilance Database (EudraVigilance) and calculated proportional reporting ratios for dopamine agonists and hiccups. We reviewed the literature on Parkinson's disease, dopamine agonists, and hiccups, searching for specific treatment recommendations for hiccups in this disease., Results: Both rotigotine and pramipexole fulfilled the criteria to generate a safety signal. We found 32 and 13 cases of hiccups associated with dopamine agonists in EudraVigilance and the literature, respectively. There were no specific recommendations for the management of hiccups in Parkinson's disease in the clinical guidelines consulted., Conclusions: We have found evidence that rotigotine and pramipexole are associated with the appearance of hiccups and that this adverse reaction occurs predominantly in males. Given the scarce information available, specific recommendations are needed in clinical guidelines for the adequate management of hiccups in Parkinson's disease.

Restless legs syndrome (RLS) is a chronic disorder causing clinically significant discomfort to approximately 3% of adults. Although RLS was first identified centuries ago, our understanding of this disorder, its causes, and its treatments is still evolving. In particular, our knowledge of the potential negative effects of RLS treatments, including dopaminergic augmentation, continues to expand. Augmentation, which refers to a paradoxical treatment-related increase in RLS symptoms, has been associated with all three dopamine agonists approved for the treatment of RLS - rotigotine, pramipexole, and ropinirole. This review presents key information on prevention and treatment of dopaminergic augmentation from the recently published consensus-based guidelines issued by the International RLS Study Group task force in conjunction with the European RLS Study Group and the RLS Foundation for first-line treatment of RLS/Willis-Ekbom disease. If dopamine agonists are used to treat RLS, it is recommended that the dosage should be kept as low as possible without exceeding the maximum dose recommended for RLS treatment. As the frequency of augmentation with the rotigotine patch may only be slightly lower than that associated with pramipexole or ropinirole, medications that are effective and have little risk of augmentation, such as alpha-2-delta ligands, may be considered for initial RLS treatment. In addition, we present our clinical experience with treating patients with dopaminergic augmentation by highlighting 2 case studies and practical considerations when treating different patient populations. Applying current RLS augmentation diagnosis and treatment guidelines, as well as collecting detailed histories of worsening RLS symptoms, is critical for patient safety and effective management of RLS augmentation.

Since the effect of a percutaneous absorption-type dopamine agonist (DA) preparation, rotigotine patch, stably persists by once-a-day application, this dosage form is appropriate for Parkinson's disease patients showing levodopa induced wearing off phenomenon. On the other hand, skin disorders, mainly application site reaction, are characteristic problems associated with use of the patch. In this study, to clarify the influence of a topical agent used to prevent or treat rotigotine patch-induced skin disorder on continuation of the patch application, patients who started rotigotine patch application at our hospital were retrospectively surveyed. The one-year continuation rate of rotigotine patch application was 37.3% (53 of 142 cases). It was insufficient to prevent skin disorders, only by the pre-treatment of a moisturizing agent alone. Regarding the effective rate of topical agents used to treat skin disorders, that of very strong-class steroids was 89.5%, being significantly higher than those of weak steroids, moisturizing agents, and antihistamines. It was suggested that for countermeasures against rotigotine patch-induced skin disorders, treatment with very strong-class steroids for external use early after development of skin disorders is more effective than preventive treatment with topical agents regardless of the type. (Received March 30, 2017; Accepted May 16, 2017; Published September 1, 2017).

Dropped head (DH) syndrome is a phenomenon of disproportionate neck anteflexion that has been reported in patients with Parkinson disease (PD). Antiparkinsonian medications such as dopaminergic agonists (DAs) have been implicated in the onset of DH episodes. Deep brain stimulation (DBS) is an important therapeutic option after the failure of conventional treatments such as DA therapy in patients with PD. Here, we report the case of a patient with rigid-akinetic parkinsonism who developed DH syndrome after the initiation of DA treatment. Dopaminergic agonist treatment was required to stabilize motor dysfunction during a period of 5 years; yet, the patient experienced no improvements in DH during this time. Thus, we initiated DBS as an alternative therapy and gradually withdrew DA therapy. The patient recovered from long-term DH after the discontinuation of rotigotine treatment. Accordingly, this case highlights DA treatment as a possible cause of DH and the use of DBS to allow the discontinuation of DA treatment while preserving motor function in patients with PD.

We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D 2 R) availability in Parkinson's disease (PD) patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [ 11 C]raclopride PET scan in an OFF medication condition for quantification of striatal D 2 R availability in vivo . Parametric images of [ 11 C]raclopride non-displaceable binding potential were generated from the dynamic [ 11 C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D 2 R and a mean 3.5% increase in putaminal D 2 R availability compared to healthy controls. Lower caudate [ 11 C]raclopride BP ND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D 2 R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D 2 Rs availability in both caudate and putamen. No associations between striatal D 2 R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D 2 R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D 2 R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

Introduction: Dopamine agonists are a mainstay of treatment for patients with Parkinson disease (PD). However, side effects limit their use, often necessitating dose change. Upon withdrawal, patients may experience dopamine agonist withdrawal syndrome (DAWS). To date, there is no established protocol for the prevention or treatment of DAWS., Methods: We performed a retrospective chart review of PD patients who were taking a dopamine agonist., Results: In our large cohort of 313 PD patients who were on a dopamine agonist, we found that 39.5% (n=124) had a change in their dose of medication for various reasons, including 102 patients who experienced a side effect on a dopamine agonist. Twenty out of 102 patients (19.6%) developed symptoms consistent with DAWS, whereas 1 out of 22 patients (4.5%) who had medication dose changed due to any other reason (e.g. dyskinesias, DBS surgery, decreased by another provider, etc.) developed symptoms consistent with DAWS. Our DAWS population had a shorter duration of PD, less exposure to a dopamine agonist, and was on a lower dose compared to those patients who did not develop DAWS. Agitation was the most common DAWS symptom reported in our cohort. Interestingly, in terms of developing DAWS, the prevalence of DAWS (19.0% vs 16.5%; p=0.76) between partial versus total discontinuation was not significantly different whether the dopamine agonist dose was decreased (21 patients) or completely stopped (103 patients)., Conclusion: Contrary to previous reports, we have found that other side effects besides impulse control behavioral disorders also increase risk for developing DAWS. Furthermore, the prevalence of DAWS did not differ between partial versus total discontinuation of the dopamine agonist., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Restless legs syndrome (RLS) is a sensorimotor neurologic disorder characterized by an unpleasant urge to move the legs, often accompanied by leg dysesthesias. Symptoms predominate in the evening or at night and often cause significant distress and disruption of sleep. Several non-opioid classes of drugs provide initial relief from the symptoms of RLS. Among these, however, the efficacy of dopamine agonists can wane over time or even paradoxically 'augment' the severity of symptoms during the course of long-term treatment. Opioids can alleviate RLS symptoms, even in patients who have become refractory to, or do not tolerate, other drugs. In a carefully selected group of patients with severe RLS that has not been effectively managed with other therapies, opioids may be an appropriate treatment.

Purpose: To review the data regarding a new antipsychotic, cariprazine., Conclusions: Cariprazine is a dopamine D3, D2 partial agonist, with greater affinity to D3. It has been examined for schizophrenia, bipolar mania, bipolar depression, and unipolar depression. It has demonstrated efficacy in schizophrenia and mania, and has recently been approved by the U.S. Food and Drug Administration. However, it has a more inconsistent effect in depression, both unipolar and bipolar. Adverse effects include extrapyramidal symptoms, akathisia, and gastrointestinal distress., Practice Implications: Cariprazine will be a promising addition in the treatment of patients with acute mania and schizophrenia., (© 2016 Wiley Periodicals, Inc.)