Higher Doses Of Dopamine Agonists Research Articles

Impulse Control Disorders in Parkinson's Disease and Atypical Parkinsonian Syndromes-Is There a Difference?

Impulse control disorders (ICDs) are characterized by potentially harmful actions resulting from disturbances in the self-control of emotions and behavior. ICDs include disorders such as gambling, hypersexuality, binge eating, and compulsive buying. ICDs are known non-motor symptoms in Parkinson's disease (PD) and are associated primarily with the use of dopaminergic treatment (DRT) and especially dopamine agonists (DA). However, in atypical parkinsonism (APS), such as progressive supranuclear palsy (PSP) or multiple system atrophy (MSA), there are only single case reports of ICDs without attempts to determine the risk factors for their occurrence. Moreover, numerous reports in the literature indicate increased impulsivity in PSP. Our study aimed to determine the frequency of individual ICDs in APS compared to PD and identify potential factors for developing ICDs in APS. Our prospective study included 185 patients with PD and 35 with APS (27 patients with PSP and 9 with MSA) hospitalized between 2020 and 2023 at the Neurological Department of University Central Hospital in Katowice. Each patient was examined using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) to assess ICDs. Additionally, other scales were used to assess the advancement of the disease, the severity of depression, and cognitive impairment. Information on age, gender, age of onset, disease duration, and treatment used were collected from medical records and patient interviews. ICDs were detected in 23.39% of patients with PD (including binge eating in 11.54%, compulsive buying in 10.44%, hypersexuality in 8.79%, and pathological gambling in 4.40%), in one patient with MSA (hypersexuality and pathological gambling), and in 18.52% of patients with PSP (binge eating in 3.70%, compulsive buying in 7.41%, and hypersexuality in 11.11%). We found no differences in the frequency of ICDs between individual diseases (p = 0.4696). We confirmed that the use of higher doses of DA and L-dopa in patients with PD, as well as a longer disease duration and the presence of motor complications, were associated with a higher incidence of ICDs. However, we did not find any treatment effect on the incidence of ICDs in APS. ICDs are common and occur with a similar frequency in PD and APS. Well-described risk factors for ICDs in PD, such as the use of DRT or longer disease duration, are not fully reflected in the risk factors for ICDs in APS. This applies especially to PSP, which, unlike PD and MSA, is a tauopathy in which, in addition to the use of DRT, other mechanisms related to the disease, such as disorders in neuronal loops and neurotransmitter deficits, may influence the development of ICDs. Further prospective multicenter studies recruiting larger groups of patients are needed to fully determine the risk factors and mechanisms of ICD development in APS.

Decision-Making and Impulse-Control Disorders in Parkinson's Disease

Objective: Dopaminergic treatment is proved to ameliorate motor deficits in Parkinson's disease (PD); however, it could have negative effects on behavior and cognition, including impulse controlling and decision-making. We aimed (1) to investigate the decision-making and impulse-control disorders (ICDs) of PD patients and their correlations with sociodemographical and clinical variables, dopaminergic treatment in particular, and (2) to determine the relation of decision-making with ICDs. Methods: The sample of 39 patients with PD and 37 healthy controls underwent cognitive tests and the task which analyzed decision-making (Iowa Gambling Task [IGT]). Besides assessing motor and nonmotor symptoms of patients with PD, ICDs were also scanned using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease. Results: Although patients with PD performed similarly to healthy controls on IGT, decision-making profile in PD related to clinical variables: dopaminergic treatment and duration of illness. In addition to this younger age of onset, higher dose of dopamine agonists, longer duration of illness, and impaired decision-making were together accounted for a substantial amount of variance in impulsive behaviors. Conclusions: Dopaminergic medication likely contributes to the impairment in decision-making, which may be the underlying mechanism of ICDs. Further studies will be necessary to understand the potential implications of this finding.

Editors' note: Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease

In the article “Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease,” Dr. Klepitskaya et al. reported sustained improvement in symptoms of restless legs syndrome (RLS) over 2 years in 22 patients with Parkinson disease (PD) who underwent subthalamic nucleus (STN) deep brain stimulation (DBS), despite a decrease in dopaminergic treatment. Drs. Marques et al. point out that the article misinterpreted the results of their previous study, which showed an emergence of RLS in patients with PD with a higher dose of dopamine agonists and a lower decrease in dopaminergic treatment after STN DBS. They discuss the paradoxical findings of STN DBS apparently improving preexisting RLS but causing emergence of RLS in some patients with PD and the need for further research. In response, Dr. Klepitskaya acknowledges these comments including the misinterpretation. A correction appears on page 871. In the article “Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease,” Dr. Klepitskaya et al. reported sustained improvement in symptoms of restless legs syndrome (RLS) over 2 years in 22 patients with Parkinson disease (PD) who underwent subthalamic nucleus (STN) deep brain stimulation (DBS), despite a decrease in dopaminergic treatment. Drs. Marques et al. point out that the article misinterpreted the results of their previous study, which showed an emergence of RLS in patients with PD with a higher dose of dopamine agonists and a lower decrease in dopaminergic treatment after STN DBS.

Reader response: Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease.

Several studies assessed the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on restless legs syndrome (RLS) symptoms in patients with Parkinson disease (PD) with conflicting results.1–5 As underlined by Klepitskaya et al.,1 one crucial variable is dopaminergic therapy, as emergence of RLS after STN DBS in patients with PD has been reported after abrupt decrease of dopaminergic treatment.3 Klepitskaya et al. argued that, in a previous study we conducted,5 patients with emergence of RLS after STN DBS took a higher dose and had a more significant reduction of dopamine agonists compared to those without emergence with RLS. Yet, we actually reported the opposite, showing an emergence of RLS in patients with PD with a higher dose of dopamine agonists postoperatively and with a lesser decrease of dopamine agonists after STN DBS.5

Editors' note: Mystery Case: Bilateral temporal crescent sparing after cardiac arrest

In their Mystery Case, Lindegger et al. presented the unique visual fields of a middle-aged man who complained of tunnel vision 6 months following a cardiac arrest. One challenge to the case was the appearance of the Goldmann perimetry findings, which are nearly the opposite of what would be seen in a lesion affecting the optic chiasm. Instead of having bitemporal loss of vision, the patient had sparing of the most peripheral temporal visual fields with additional sparing of the binocular central fields. Among the 394 survey responses to the case, only 22% of readers correctly localized the lesion to the bilateral calcarine cortex (38% localized the lesion incorrectly to the chiasm). Dr. Rosenberg, a neuro-ophthalmologist, appropriately considers these Goldmann visual field findings controversial, and even contrary to our current understanding of visual pathways. Sparing of the far peripheral nasal fields and crossing of the vertical meridian peripherally would be untenable for bilateral occipital lobe lesions and probably explains why the survey participants had great difficulty localizing the lesion. Lindegger et al. respond that the manual perimetry was performed by an experienced technician, but that some of these atypical visual field findings may have resulted from the fixation losses and cognitive impairment that follows cardiac arrest. In the article “Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease,” Dr. Klepitskaya et al. reported sustained improvement in symptoms of restless legs syndrome (RLS) over 2 years in 22 patients with Parkinson disease (PD) who underwent subthalamic nucleus (STN) deep brain stimulation (DBS), despite a decrease in dopaminergic treatment. Drs. Marques et al. point out that the article misinterpreted the results of their previous study, which showed an emergence of RLS in patients with PD with a higher dose of dopamine agonists and a lower decrease in dopaminergic treatment after STN DBS.

Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist.

The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated – apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension – with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies.

The course of insomnia in Parkinson's disease

IntroductionInsomnia is a debilitating symptom in Parkinson's disease (PD) that has been scarcely investigated in a longitudinal design. Knowledge of factors associated with occurrence of insomnia may provide clues for an increased understanding of underlying pathophysiology and facilitate early detection.The objective of this study is to examine the course and factors associated with longitudinal changes in insomnia severity in patients with PD. MethodsAnalyses were performed in data of the SCOPA-PROPARK cohort, a 5-year longitudinal cohort study (2003–2011) of 421 PD patients who have been examined annually. Linear mixed models were used to identify factors associated with longitudinal changes in scores of the SCOPA-SLEEP-Nighttime sleep (NS) problems section. A generalized estimating equations (GEE) analysis was performed to determine which baseline variables were associated with the different aspects of insomnia (sleep initiation or maintenance difficulty). ResultsBaseline SCOPA-SLEEP-NS scores were available for 412 patients, of whom 110 (27%) had insomnia (i.e. score ≥ 7). Of the remaining 302 patients, 99 (33%) developed insomnia at some point during follow-up. More severe depressive symptoms, motor fluctuations, higher dopamine agonist doses and sleep medication use were independently associated with higher SCOPA-SLEEP-NS scores over time. GEE analysis did not identify an unique set of determinants that affected specific aspects of insomnia. ConclusionThe presence of depressive symptoms, motor fluctuations and the use of higher doses of dopamine agonists are associated with more severe insomnia. Attention to these aspects could potentially contribute to a better management of insomnia symptoms in PD.

Association of the DRD2 CAn-STR and DRD3 Ser9Gly polymorphisms with Parkinson's disease and response to dopamine agonists

Dopamine agonists (DAs) play important roles in the treatment of Parkinson's disease (PD). Currently, it is thought that genetic variations in the genes encoding dopamine receptors (DR) are important factors in determining inter-individual variability in drug responses. To investigate the association between Dopamine receptor D type 2 (DRD2) dinucleotide short tandem repeat (CAn-STR) and Dopamine receptor D type 3 (DRD3) Ser9Gly polymorphisms and the risk of PD, as well as the possible reasons for PD patients using different doses of DAs, we recruited 168 idiopathic PD patients and 182 controls. There were no significant differences in DRD2 CAn-STR and DRD3 Ser9Gly genotypes (p=0.184, p=0.196) or in allele frequencies (p=0.239, p=0.290) between PD patients and controls. There was no association between DRD2 CAn-STR polymorphism and doses of DAs. Among three different DRD3 Ser9Gly genotypes (Ser/Ser, Ser/Gly, Gly/Gly), patients carrying Gly/Gly genotype used higher doses of DAs than patients with Ser/Gly and Ser/Ser genotypes (p=0.001). In pramipexole subgroup, the Gly/Gly group took more pramipexole than the other genotype groups (p<0.001), whereas the doses of piribedil were not significantly different among three genotypes (p=0.735). Our results suggest that genotype in DRD3 Ser9Gly was the main factor determining different doses of DAs and PD patients carrying Gly/Gly genotype require higher doses of pramipexole for effective treatment. This study may provide insights into understanding possible reasons for different responses to DAs in Chinese PD patients.

Emergence of restless legs syndrome after subthalamic stimulation in Parkinson's disease: a dopaminergic overstimulation?

ObjectiveStudies investigating the effects of subthalamic deep-brain stimulation (DBS-STN) on restless legs syndrome (RLS) in Parkinson's disease (PD) are limited and report conflicting results, with some describing the emergence of RLS after DBS-STN, while others report postoperative improvement of this disorder. Severe decrease in postoperative dopaminergic medications dose, which may unmask RLS symptoms, has been proposed to explain the emergence of RLS after surgery. We aimed to specifically identify factors associated with the risk of developing RLS after DBS-STN in order to enhance our comprehension of the underlying mechanisms contributing to the development of RLS in PD. PatientsIn this observational prospective study, we evaluated the occurrence of RLS in 31 patients with PD originally free from RLS symptoms, six months after bilateral chronic DBS-STN, and compared clinical and treatment parameters of patients who developed postoperative RLS with those of patients without postoperative RLS. ResultsSix patients out of 31 reported post-operative emergence of RLS. There was no between-group difference in demographic data, pre-operative treatment parameters or clinical improvement measures after DBS-STN. However, PD patients with emergence of RLS after DBS-STN had a higher dose of dopamine agonists at postoperative evaluation compared to PD patients without emergence of RLS (p = 0.040) and a lower percentage of decrease in dopamine agonists (p = 0.043). ConclusionOverstimulation resulting from cumulative effects of dopamine agonists and STN-DBS may induce changes in excitability of the dopaminergic system, leading to an emergence of RLS. Clinicians should take into account this phenomenon while adjusting pharmacological treatment after surgery.

Impulse control behaviours in patients with Parkinson's disease after subthalamic deep brain stimulation: de novo cases and 3-year follow-up

ObjectiveTo document the occurrence of impulse control behaviours (ICBs) in patients with Parkinson's disease after 3 years of continuous deep brain stimulation (DBS) of the subthalamic nucleus (STN).MethodsDetailed neurological and...

Impulsiv-zwanghafte Verhaltensstörungen in einer deutschen Stichprobe ambulant versorgter Parkinson-Patienten

Impulsive-compulsive behaviours (ICBs) are frequent complications of Parkinson's disease (PD), associated with treatment by dopamine agonists (DAs). These include impulse control disorders (ICDs), repetitive behaviour (RB) and the dopamine-dysregulation syndrome (DDS). A subsample of 72 patients of a large longitudinal study (n = 739) was screened with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP). Results were associated with socio-demographic, clinical and neuropsychological parameters. A large proportion of the sample reported ICBs (60%), RBs were most frequent (47 %). Patients with ICBs consumed higher doses of DAs (343 ± 177 mg vs. 390 ± 153 mg; p < 0.01). Pramipexole was associated with RB but not ICDs (273 ± 225 mg and 53 ± 106 mg vs. 151 ± 209 mg in patients without ICB). Patients with ICDs reported more dyskinesias (UPDRS IV: 1.78 ± 1.6 vs. 0.55 ± 1.1 points; p = 0.012) and patients with multiple ICBs a longer duration of PD (9.3 ± 5.0 vs. 6.2 ± 4.0 years; p = 0.026) and worse quality of life (PDQ39: 29.9 ± 13.8 vs. 20.3 ± 13.4 points; p = 0.036) compared to patients without any ICB. ICBs are frequent even in outpatients with moderate duration and severity of PD and associated with DA dose. Because of possible serious psychosocial consequences, detecting and managing them is of high importance.

Parkinson’s disease: a multi-faceted disease

The content of this supplement of the Journal of Neurology is the essence of lectures and workshops which were presented during the 11th German Parkinson Expert Meeting in Dresden in October 2010. Cutting-edge information on many major developments in the field of Parkinson’s disease (PD) is provided. The etiopathogenesis of PD is still unknown, although we have unraveled interplay between oxidative stress, genetic abnormalities, mitochondrial dysfunction, inflammation and apoptosis. In spite of these findings, the initial step in the development of PD is unknown. More and more important information is being gained from the study of patients with familiar PD as their genetic abnormalities are elucidated, and, to a lesser degree, from non-familiar PD patients. A major focus of modern PD research is on the premotor phase of the disease. Many patients present first with hyposmia, REM sleep disorder, depression, constipation or other autonomic disturbances, before they develop motor signs. Thus, a better understanding of the pre-motor phase could lead to early treatment with potential neuroprotective agents. In the paper by Winkler et al., a Parkinson’s disease risk score is presented which aims for the early diagnosis of PD. The most recent findings in PD suggest that patients have a relatively bad drug adherence, maybe due to the complexity of the drug regimen or due to progressive cognitive impairment. For this reason, once daily formulations are preferable. In addition, long-lasting continuous dopamine replacement therapy prohibits the occurrence of dyskinesia. There is good evidence that extended release preparations such as ropinirole PR lead to equal efficacy with better tolerability when compared with immediate release preparations. Both de novo patients and those in advanced stages of the disease derive benefit from these preparations. It is of particular note that even advanced patients tolerate ropinirole PR and improve significantly with respect to motor function, especially with being ‘‘on’’. In a head to head comparison, the extended release preparation was even superior to the immediate release form. Non-motor symptoms are becoming of particular interest, since they lead to a major impairment of the quality of life of our patients. A whole variety of non-motor symptoms is discussed in detail in this supplement, and special focus is placed on sleep impairment in PD. REM sleep disbehavior is one of the early signs of PD and should give rise to careful clinical examination. The use of modern extended release preparations of dopamine agonists, has led to an improvement in sleep, especially sleep quality and early morning akinesia. Nonetheless, there are still many patients who wake up too early or wake up due to nocturia. A detailed description is given for different specific sleep disturbances such as restless legs syndrome, rapid eye movement sleep behaviour disorder, periodic limb movements in sleep and obstructive sleep apnea. Impulse control disorders have not previously played a major role in PD treatment. However, we now know that levodopa, and in particular, high doses of dopamine agonists, may cause hypersexuality, binge eating, gambling, This article is part of a supplement sponsored by GlaxoSmithKline.

Cabergoline therapy for prolactinomas: is valvular heart disease a real safety concern?

Dopamine agonists (DAs) are the first-line therapy for the treatment of hyperprolactinemia, with cabergoline, an ergot-derived selective D2-receptor agonist, being the preferred and most widely used drug. Recent studies reported cardiac valve regurgitations in patients with Parkinson’s disease treated with high doses of DA, raising concerns about the safety of cabergoline in patients with hyperprolactinemia. To date, seven case–control studies have examined the potential association between cardiac valvular abnormalities and cabergoline therapy in patients with hyperprolactinemia. Overall, a total of 463 patients exposed to low doses of cabergoline (mean cumulative doses: 204–443 mg) for a mean duration of 45–79 months have been included in these studies. Patients in all the studies were asymptomatic without clinical signs of cardiac disease. Six studies did not show any association between cabergoline therapy and clinically relevant valvular regurgitation, whereas one study found an increased rate of moderate tricuspid regurgitation. In this report, we review and discuss the results of these studies and emphasize the limitations of the methodology used in the published literature. The clinical significance of the present findings has yet to be confirmed by future larger prospective studies with rigorous echocardiographic protocols and prolonged duration of follow-up.

Mechanisms Underlying Dopamine-Mediated Reward Bias in Compulsive Behaviors

Pathological behaviors such as problem gambling or shopping are characterized by compulsive choice despite alternative options and negative costs. Reinforcement learning algorithms allow a computation of prediction error, a comparison of actual and expected outcomes, which updates our predictions and influences our subsequent choices. Using a reinforcement learning model, we show data consistent with the idea that dopamine agonists in susceptible individuals with Parkinson's disease increase the rate of learning from gain outcomes. Dopamine agonists also increase striatal prediction error activity, thus signifying a "better than expected" outcome. Thus, our findings are consistent with a model whereby a distorted estimation of the gain cue underpins a choice bias toward gains.

The Cabergoline-Resistant Prolactinoma Patient: New Challenges

What do we do with the patient with a prolactinoma who is resistant or only partially responsive to a dopamine agonist? Fortunately, this is an infrequent problem. Only about one quarter of patients are unable to normalize their prolactin (PRL) levels with bromocriptine, and more than three quarters of these can be treated successfully with cabergoline (1). Because of overall greater efficacy and tolerability, cabergoline has generally become the treatment of choice for most patients with prolactinomas. In this issue of the Journal, Ono et al. (2) found that 11 of 60 previously untreated patients (18.3%) required more than 2 mg/wk cabergoline to normalize PRL levels. Of these, four required 3 mg/wk, two required 6 mg/wk, four required 9 mg/wk, and one required 11 mg/wk to normalize PRL levels. They also reported 26 resistant patients who required similar doses. Of 150 patients, normalization of PRL was eventually achieved in all but one, but doses had to be raised to high levels in many (2). In another study, Di Sarno et al. (3) found that 10 of 56 patients (17.9%) with macroadenomas, and six of 60 patients (10%) with microadenomas required larger than usual doses of cabergoline, but they used only a maximum of 7 mg/wk and did not achieve PRL normalization in any of these resistant patients. We’ve also encountered a number of resistant patients and reported one who had small, continued, stepwise reductions in PRL as the dose of cabergoline was increased to 3 mg/d (4). This discussion regarding dopamine agonist resistance has dealt only with PRL levels and not tumor size reduction. Although most patients have some tumor size reduction if they have substantial PRL reductions, this is not invariable, and a discordance can occur between these two outcomes (1). However, a patient who has minimal or no PRL reduction will also have no tumor size reduction. The major problem clinically is the patient with primary dopamine resistance. Patients who initially respond to a dopamine agonist and later become resistant are far less common; reasons include noncompliance, institution of gonadal steroid replacement which causes dopamine resistance in the lactotrophs, and the fortunately rare development of a carcinoma (1). In other cases, the cause of this secondary lack of response is not known. Resistance to dopamine agonists does not involve impairment of drug absorption or drug affinity to the dopamine D2 receptor (1). Rather, resistance is associated with a decrease in D2 receptor gene transcription, resulting in a 4-fold decrease in the number of D2 receptors on the cell membrane (1). In addition, there is a decrease in the G protein that couples the D2 receptor to adenylyl cyclase, further decreasing the ability of dopamine to inhibit PRL secretion (1). There are several possible approaches for treatment of patients who are resistant to dopamine agonists. Patients taking bromocriptine should simply be converted to cabergoline, because most will then respond (1). For the patient resistant to cabergoline, the most common approach is to increase the dose of cabergoline, as long as a reduction in PRL levels can be demonstrated with each stepwise increase. Patients generally tolerate such dose increases quite well. In the report of Ono et al. (2), 14 of 150 patients had transient adverse effects, including headache, stomach discomfort, dizziness, constipation, sleepiness, anorexia, nasal congestion, and leg edema. We can also draw upon the experience obtained in patients with Parkinson’s disease who are treated with doses of cabergoline up to 3–6 mg/d. In these patients, gastrointestinal side effects have been reported in 33%, dizziness in 26%, sleep disturbance in 21%, constipation in 19%, edema in 13%, and dyskinesias in 2% (5). The use of high doses of dopamine agonists in Parkinson’s disease, however, has recently drawn attention to a new and potentially more serious issue, that of cardiac valvular abnormalities. This phenomenon was first reported in 2002 for pergolide (6) and in 2004 for cabergoline (7). Subsequently, other reports have shown a 3to 6-fold increased risk of valvular abnormalities in Parkinson’s disease patients treated with high doses (3–6 mg/d) of pergolide and cabergoline (8–12). In a metaanalysis done by Simonis et al. (11), 34% of patients treated with

High dose dopamine agonist treatment and combination of dopamine agonists

Moving towards a more dopamine agonist based therapy is often an effective way to counteract motor fluctuations in patients with advanced Parkinson's disease. It is thereby an impression that higher doses of dopamine agonists than those normally recommended can lead to further improvements compared to treatment with dopamine agonists in the normal dose range. There are now a number of open-label clinical studies with different dopamine agonists confirming that this might be an effective strategy. There are also single studies indicating that combining different dopamine agonists might be a further treatment alternative with similar effects compared to high dose dopamine agonist treatment. In line with this we performed a study comparing the use of high doses of the dopamine agonist cabergoline with normal-dose treatment. Thirty-four patient with idiopathic Parkinson's disease were included in the study and 32 of these performed the whole study. Cabergoline was raised from a mean daily dosis of 6.4mg to a daily dosis of 13.7mg over a period of up to 20 weeks. The doses were then held constant for at least 6 weeks. Clinical evaluations were performed after 0, 1, 8, 16, 26 and 27 weeks. The time per day with dyskinesia and dystonia was shortened and the maximum dyskinesia/dystonia intensity was reduced with high dose cabergoline. Also part of the day with severe „off“ symptomatology and the symptomatology in „worst off“ improved. The mean L-dopa dose was reduced from 606 mh/day to 370mg/day. Evaluation with clinical global impression scales confirmed a clear improvement in a majority of the patients. Also the health related quality of life scale PDQ-39 showed an improvement regarding total score and all subscales appart from congnition. The most common side effect was hallucinations. There is now an urgent need for controlled studies and long-term studies, to investigate to what degree this treatment strategy shall be an option for Parkinson patients. Especially it will be important to further explore the risk for side effects. This concerns especially hallucinations and other psychotic symptoms. It also concerns cardiac valvular fibrosis, where it is still unclear which dopamine agonists that are at risk and if this side effect is dose-dependent. Until further information is available high dose dopamine agonist treatment and combination of dopamine agonists shall be handled by physicians with profound experience in Parkinson treatment and the patients shall regularly be monitored for the mentioned side effects. It seems clear that both these treatment options can be highly effective regarding improvement of motor symptomatology and can be considered especially in patients with motor fluctuations in spite of otherwise optimized p.o. therapy and low tendency to psychotic side effects.

A case of a prolactinoma resistant to dopamine agonists

Dopamine agonists are the drugs of choice in the treatment of prolactinomas, the most common type of pituitary adenomas. However, up to 25% of prolactinomas do not respond to these drugs and alternative treatments have to be considered. We describe a 37-year old female with a microprolactinoma who, although having received all available formulations of dopamine agonists over a period of 11 years, did not respond either clinically--diminution of galactorrhea and restoration of her menstrual cycle--or hormonally through normalisation of the elevated prolactin levels. Throughout the same period, the size of the adenoma remained unchanged. While on high doses of dopamine agonists, the patient presented with side effects such as nausea, vomiting, orthostatic hypotension and tachycardia without any symptoms of psychosis. Therefore, either the dose of the dopamine agonists was not toxic enough for the mesolimbic dopaminergic pathway to be activated or the patient was dopamine-resistant in this pathway as well.

Pergolide-associated ‘sleep attacks’ in a patient with restless legs syndrome

The occurrence of irresistible sleep episodes (‘sleep attacks’) has been noted in patients with Parkinson's syndrome treated with dopa-agonists. This is the first report of ‘sleep attacks’ in a patient with restless legs syndrome in whom treatment with pergolide was reduced from 2 to less than 1 mg/day. ‘Sleep attacks’ were accompanied by a reduced mean sleep latency of 5 min and 20 s (without sleep onset REM periods) on a multiple sleep latency test. ‘Sleep attacks’ disappeared when pergolide was tapered off and substituted with pramipexol. The appearance of ‘sleep attacks’ as a ‘withdrawal’ effect of pergolide is consistent with a wakefulness-promoting action of postsynaptic dopaminergic receptors at higher doses of dopamine agonists.

Impulsive aggression is associated with lifetime history of suicide attempt. Towards a description of patients with serotonergic dysfunction

Dopamine agonists (DAs) play important roles in the treatment of Parkinson's disease (PD). Currently, it is thought that genetic variations in the genes encoding dopamine receptors (DR) are important factors in determining inter-individual variability in drug responses. To investigate the association between Dopamine receptor D type 2 (DRD2) dinucleotide short tandem repeat (CAn-STR) and Dopamine receptor D type 3 (DRD3) Ser9Gly polymorphisms and the risk of PD, as well as the possible reasons for PD patients using different doses of DAs, we recruited 168 idiopathic PD patients and 182 controls. There were no significant differences in DRD2 CAn-STR and DRD3 Ser9Gly genotypes (p = 0.184, p = 0.196) or in allele frequencies (p = 0.239, p = 0.290) between PD patients and controls. There was no association between DRD2 CAn-STR polymorphism and doses of DAs. Among three different DRD3 Ser9Gly genotypes (Ser/Ser, Ser/Gly, Gly/Gly), patients carrying Gly/Gly genotype used higher doses of DAs than patients with Ser/Gly and Ser/Ser genotypes (p = 0.001). In pramipexole subgroup, the Gly/Gly group took more pramipexole than the other genotype groups (p < 0.001), whereas the doses of piribedil were not significantly different among three genotypes (p = 0.735). Our results suggest that genotype in DRD3 Ser9Gly was the main factor determining different doses of DAs and PD patients carrying Gly/Gly genotype require higher doses of pramipexole for effective treatment. This study may provide insights into understanding possible reasons for different responses to DAs in Chinese PD patients.

P.1.075 Citalopram in depressed cardiac patients

Dopamine agonists (DAs) play important roles in the treatment of Parkinson's disease (PD). Currently, it is thought that genetic variations in the genes encoding dopamine receptors (DR) are important factors in determining inter-individual variability in drug responses. To investigate the association between Dopamine receptor D type 2 (DRD2) dinucleotide short tandem repeat (CAn-STR) and Dopamine receptor D type 3 (DRD3) Ser9Gly polymorphisms and the risk of PD, as well as the possible reasons for PD patients using different doses of DAs, we recruited 168 idiopathic PD patients and 182 controls. There were no significant differences in DRD2 CAn-STR and DRD3 Ser9Gly genotypes (p = 0.184, p = 0.196) or in allele frequencies (p = 0.239, p = 0.290) between PD patients and controls. There was no association between DRD2 CAn-STR polymorphism and doses of DAs. Among three different DRD3 Ser9Gly genotypes (Ser/Ser, Ser/Gly, Gly/Gly), patients carrying Gly/Gly genotype used higher doses of DAs than patients with Ser/Gly and Ser/Ser genotypes (p = 0.001). In pramipexole subgroup, the Gly/Gly group took more pramipexole than the other genotype groups (p < 0.001), whereas the doses of piribedil were not significantly different among three genotypes (p = 0.735). Our results suggest that genotype in DRD3 Ser9Gly was the main factor determining different doses of DAs and PD patients carrying Gly/Gly genotype require higher doses of pramipexole for effective treatment. This study may provide insights into understanding possible reasons for different responses to DAs in Chinese PD patients.