Dose Of Pramipexole Research Articles

The adrenergic α2 antagonist atipamezole alters the behavioural effects of pramipexole and increases pramipexole concentration in blood plasma

Pramipexole is a dopaminergic agonist used in Parkinson's disease treatment. It is thought to exert its therapeutic and side effects through actions on dopamine D3 receptors. In a recent study, we found that at doses occupying D3 but not D2 receptors pramipexole reduced locomotion and operant responding for primary and conditioned reinforcement. These effects, however, were not blocked by a D3 receptor antagonist and were present in D3 knockout mice, suggesting non-D3 receptor mechanisms. Among the next highest affinity binding sites of pramipexole are adrenergic α2 receptors. Here we explored α2 receptor involvement in the behavioural effects of pramipexole. We found that the α2 antagonist atipamezole, which was itself behaviourally silent, counteracted pramipexole's reduction of locomotion, but not operant responding for water or a conditioned reinforcer. The resulting behavioural profile was similar to that of a higher dose of pramipexole, leading to the hypothesize that atipamezole mediates its behavioural effects by increasing pramipexole effective dose. In support of this hypothesis, we found that atipamezole increased pramipexole concentration in blood plasma. This is not likely due to an effect on drug metabolism since pramipexole is not known to undergo metabolic transformation. Future work should examine two alternative hypotheses; that pramipexole plasma concentration is elevated as the result of 1) competition with atipamezole for renal excretion, or 2) atipamezole blockade of peripheral α2 binding sites, thereby preventing pramipexole distribution to α2-rich tissues. The suggestion of adrenergic effects of pramipexole is important in light of recent interest in adrenergic pathophysiology in Parkinson's disease.

Hallucinations and dyskinesia with pramipexole in parkinson's disease-a case report

Pramipexole, a dopamine agonist has a tendency to induce psychotic symptoms, when used to treat Parkinson’s disease (PD). In most of the cases, patient’s psychosis developed after addition of Pramipexole and exacerbated after increasing the dosage. However there has been no case report in which Pramipexole has caused psychosis at lowest starting dose without any add on drug. Here we present a case of PD in which dyskinesia and psychosis appeared with first dose of Pramipexole, as low as 0.125mg. The patient was a 76 year old man with a one year history of PD. One year back patient observed tremors in his hand and slowing of movements. The neurologist prescribed Syndopa plus - 125, Benzhexol (schedule also same as Syndopa) and Pramipexole 0.125 mg at bedtime. The patient decided to start all medicines next day except Pramipexole (125mg) which he took at bed time. Within half an hour, patient started having visual and auditory hallucinations, along with abnormal movements and myoclonic jerks of hand, feet and mouth. He could be seen doing movements as if he is inserting needle in thread. According to him, he could visualize thieves trying to steal his car. Dechallenge with Pramipexole led to complete resolve of psychotic symptoms. After 4 weeks of therapy, there was a gradual but steady improvement in dyskinesia and tremors except slurring in speech.

Sternberg working memory performance following treatment with pramipexole in patients with moderate-to-severe restless legs syndrome

ObjectivesWe recently reported that the P300 amplitude related to the Sternberg working memory (WM) task was significantly lower in drug-naïve severe restless legs syndrome (RLS) patients than controls. Here, we evaluated the effects of pramipexole on the Sternberg WM task performance by event-related potential (ERP) study. MethodsThirteen drug-naïve RLS patients (52.0 ± 9.48 years) were enrolled in the study. Pramipexole was administered over a period of 12 weeks every night 1 h before bedtime. Two ERP studies were carried out: the first was performed just before giving the first dose of pramipexole and the second was conducted at 12–16 weeks after commencement of pramipexole administration. P300 amplitudes and reaction times were compared before and after treatment considering brain regions and memory load as within-subject factors. Clinical and sleep-related variables were correlated with P300 amplitude. ResultsAfter treatment with pramipexole, the International RLS Severity Scale (IRLS) score was significantly decreased. Sleep quality and depression were also significantly improved. Omission error was significantly reduced without significant change of commission error. Reaction time was significantly shortened, regardless of memory load size, following treatment with pramipexole. Parietal P300 amplitude was significantly increased after treatment with pramipexole for all memory load sizes. Increase of frontal P300 amplitude was significantly correlated with improvement of sleep duration, IRLS, Insomnia Severity Index, and Pittsburgh Sleep Quality Index score. ConclusionOur study suggested that pramipexole improves WM performance in patients with RLS in addition to improving RLS symptoms, sleep disturbance, and depression.

Chronic, but not acute, low doses of pramipexole increased risk-taking behavior in rats

Chronic, but not acute, low doses of pramipexole increased risk-taking behavior in rats

Pregabalin Calms Restless Legs by Unknown Mechanism

Oral pregabalin (Lyrica) significantly improved symptoms of moderate to severe restless leg syndrome (RLS), compared with both placebo and pramipexole, in an industry-sponsored, international randomized trial. Also, pregabalin was associated with significantly less worsening of symptoms than was pramipexole, Richard P. Allen, PhD, of the department of neurology at Johns Hopkins University, Baltimore, and his associates reported in the New England Journal of Medicine. Pregabalin also was associated with lower rates of nausea, vomiting, and headache than pramipexole, but patients taking pregabalin had higher rates of suicidal ideation, dizziness, somnolence, and weight gain – “factors that may limit its long-term use,” the investigators said. Dopaminergic drugs such as pramipexole are known to be associated with augmentation in which symptoms intensify and may involve more parts of the body and start earlier in the day than before treatment, so researchers have been searching for an alternative medication. Pregabalin is a nondopaminergic agent with analgesic and anticonvulsant activity. Dr. Allen and his colleagues assessed both agents in a study involving 719 adults with moderate to severe primary RLS who were treated and followed at 102 medical centers in the United States and Europe. In the double-blind trial sponsored by Pfizer, these patients were randomly assigned to receive 0.25 mg pramipexole, 0.5 mg pramipexole, 300 mg pregabalin, or matching placebo capsules every day for 12 weeks. At that time, all patients receiving placebo were randomly reassigned to one of the three active treatments for the remainder (40 weeks) of the 1-year study. At 12 weeks, patients who received pregabalin showed significantly greater improvement in International RLS (IRLS) Study Group Rating Scale scores than did those who received placebo. Patients who received pregabalin also reported greater improvement in waking after sleep onset, quality of sleep, number of nightly awakenings, and total sleep time. These measures also were significantly better for patients treated with 0.5 mg pramipexole when compared with placebo-treated patients, but not for those taking 0.25 mg pramipexole. In a noninferiority assessment, pregabalin outperformed both doses of pramipexole on reduction in IRLS score at both 12 weeks and 52 weeks. The finding that pregabalin is effective for RLS even though it has no direct effect on dopaminergic systems calls into question the rationale for dopaminergic therapies. Dopaminergic treatments have been predicated on the assumption that RLS results primarily from dopamine abnormalities, Dr. Allen and his associates noted (N. Engl. J. Med. 2014;370:621–631). A total of 50 serious adverse events occurred in 37 patients: 16 events in the pregabalin group, 22 events in the lower-dose pramipexole group, and 12 events in the higher-dose pramipexole group. This included 11 cases of suicidal ideation: 6 in the pregabalin group, 3 in the lower-dose pramipexole group, and 2 in the higher-dose pramipexole group. Editor's NoteLooks like Lyrica will be seeking Food and Drug Administration approval for restless leg syndrome, and it looks like it works reasonably well, with a different set of side effects from those seen with dopaminergic agents.It's a bit puzzling that a GABA-ergic drug would work for this condition. But benzodiazepines are often used with decent utility for restless legs. And if pregabalin works, maybe the much less expensive, noncontrolled, neurochemically similar drug gabapentin might be worth a try. That would be off label, of course, but for someone suffering with severe restless leg syndrome and limited response or intolerance of usual drugs, I'd consider it.— Karl Steinberg, MD, CMDEditor in Chief Looks like Lyrica will be seeking Food and Drug Administration approval for restless leg syndrome, and it looks like it works reasonably well, with a different set of side effects from those seen with dopaminergic agents. It's a bit puzzling that a GABA-ergic drug would work for this condition. But benzodiazepines are often used with decent utility for restless legs. And if pregabalin works, maybe the much less expensive, noncontrolled, neurochemically similar drug gabapentin might be worth a try. That would be off label, of course, but for someone suffering with severe restless leg syndrome and limited response or intolerance of usual drugs, I'd consider it. — Karl Steinberg, MD, CMD Editor in Chief

DI-102 Use of pramipexole in resistant depression: analysis of prescriptions over one year in a psychiatry unit

BackgroundSeveral studies suggest that pramipexole, a dopamine agonist approved for the treatment of Parkinson’s disease and restless legs syndrome, may possess antidepressant properties.PurposeThe objective was to assess the off-label prescriptions...

Rotigotine use in long-term treatment of restless legs syndrome: Experience in General University Hospital of Castellon

The restless legs syndrome (RLS) is neurologic disorder characterized by an urge to move the legs, accompany by dysesthesias that are exacerbated at rest or inactivity, yield with movement and worse in the evening and night. The quality of life can be severely compromised according to seriousness of the symptoms. Rotigotine in long-term treatments showed good result to control moderate and severe symptoms. This study described evolution of RLS evaluating efficacy of rotigotine trasndermal delivery system (patch per day) in long-term treatment. Patients came to our service, presenting exacerbated symptoms of RLS unimproved with previous treatments, we began treatment Rotigotine and followed in a period greater than six months. Database were obtained from clinical stories since 2010 until May 2013. Performing a literature search include, MedLINE, Cochrane Library, drug company Web sites, related with long- term pharmacological treatment and common complications that may arise. All our variables were analyzed and compared with results of the other studies. Obtained 57 patients with moderate and severe symptoms most affected age range is from 40 to 59 years (49%). 43.8% of patients received previously: Pramipexole dose 0.18 mg/day (36%) and 0.7 mg/day (8%), Ropinirole 0.25 mg (12%) and 0.5 mg daily (24%) and Clonazepam 0.5 mg/day (20%), no improvement. We began Rotigotine with onset dose of 2 mg/day in 65% of cases. Maintenance dose with a favor evolution was 2 and 4 mg/day in 42% and 22% of patients, respectively. Some adverse effects obtained: a single case of Augmentation with more than 1 year of treatment and in 4 patients had to suspend treatment because application skin reactions, between 6 months until 1 year of treatment. Dopaminergic adverse effects only be obtained in 3 patients within the first week. It exists a 67% patient with good evolution, including 6 patient with free symptoms, after 1 year of treatment. Some other carried out double-blind randomized compared with placebo, obtained good results improving the symptoms at dose 0.5 mg–4 mg/day of Rotigotine long-term treatment, and getting as more side effects skin reactions. As these studies, we get a significantly results an over half of the patients had an good evolución at dose of 2 mg/day. Less skin reactions, were obtained possible due to the cleaning measures we propose. It can be concluded that the results are consistent with the literature, getting less effect side comparing other studies. Sleep Medicine Unit, University General Hospital of Castellon Service of Neurology, University General Hospital of Castellon.

Dosing patterns of dopamine agonists for restless legs

In order to find out the total consumption of medicines by RLS patients, members of RLS patient organizations in Europe and North America were asked to supply this information. A detailed questionnaire was sent to 11,731 members of RLS Patient organizations in Austria, Belgium, Finland, France, Great Britain, Italy, Norway, Spain, Sweden, The Netherlands, Canada and the USA. 4278 questionnaires were returned, of which 4107 (35.0%) could be analyzed. Questions were asked on a variety of topics, including the total daily of the various medicines used. 73% of pramipexole doses and 80% of ropinirole doses reported were in line with internationally approved doses, (<=0.75 mg/day for pramipexole, and <=4.0 mg/day for ropinirole. Respondents in the USA tend to take significantly (p < 0.01) higher total daily doses of the dopamine agonists than do respondents in Europe; mean pramipexole, Europe 0.53 mg, USA 1.05 mg, Ropinirole, Europe 3.06 mg, USA 3.97 mg. There is no difference in respondent satisfaction with treatment in relation to dose. In view of the most recent scientific data on the intake of the dopamine agonists and the current opinion on optimal dosages of these medicines, the study indicates that both medicines are used in abundance, leading to significant over consumption, a much higher risk of augmentation and other side effects, lesser quality of life for these patients, as well as overspending of the healthcare costs worldwide. The authors wish to acknowledge the dedication of the thousands of RLS patients worldwide who helped complete this questionnaire and provided us with detailed and accurate information not hitherto known.

Prolactin and fMRI response to SKF38393 in the baboon.

Background. This study’s goal was to provide dose–response data for a dopamine agonist in the baboon using standard methods (replicate measurements at each dose, across a range of doses), as a standard against which to subsequently validate a novel pharmacological MRI (phMRI) method. Dependent variables were functional MRI (fMRI) data from brain regions selected a priori, and systemic prolactin release. Necessary first steps included estimating the magnitude and time course of prolactin response to anesthesia alone and to various doses of agonist. These first steps (“time course studies”) were performed with three agonists, and the results were used to select promising agonists and to guide design details for the single-dose studies needed to generate dose–response curves.Methods. We studied 6 male baboons (Papio anubis) under low-dose isoflurane anesthesia after i.m. ketamine. Time course studies charted the changes in plasma prolactin levels over time after anesthesia alone or after an intravenous (i.v.) dose of the dopamine D1-like agonists SKF82958 and SKF38393 or the D2-like agonist pramipexole. In the single-dose dopamine agonist studies, one dose of SKF38393 (ranging from 0.0928–9.28 mg/kg, N = 5 animals) or pramipexole (0.00928–0.2 mg/kg, N = 1) was given i.v. during a 40-min blood oxygen level dependent (BOLD) fMRI session, to determine BOLD and plasma prolactin responses to different drug concentrations. BOLD response was quantified as the area under the time-signal curve for the first 15 min after the start of the drug infusion, compared to the linearly predicted signal from the baseline data before drug. The ED50 (estimated dose that produces 50% of the maximal possible response to drug) for SKF38393 was calculated for the serum prolactin response and for phMRI responses in hypothalamus, pituitary, striatum and midbrain.Results. Prolactin rose 2.4- to 12-fold with anesthesia alone, peaking around 50–90 min after ketamine administration and gradually tapering off but still remaining higher than baseline on isoflurane 3–5 h after ketamine. Baseline prolactin level increased with age. SKF82958 0.1 mg/kg i.v. produced no noticeable change in plasma prolactin concentration. SKF38393 produced a substantial increase in prolactin release that peaked at around 20–30 min and declined to pre-drug levels in about an hour. Pramipexole quickly reduced prolactin levels below baseline, reaching a nadir 2–3 h after infusion. SKF38393 produced clear, dose-responsive BOLD signal changes, and across the four regions, ED50 was estimated at 2.6–8.1 mg/kg.Conclusions. In the baboon, the dopamine D1 receptor agonist SKF38393 produces clear plasma prolactin and phMRI dose–response curves. Variability in age and a modest sample size limit the precision of the conclusions.

Dopaminergic Influences on Emotional Decision Making in Euthymic Bipolar Patients

We recently reported that the D2/D3 agonist pramipexole may have pro-cognitive effects in euthymic patients with bipolar disorder (BPD); however, the emergence of impulse-control disorders has been documented in Parkinson's disease (PD) after pramipexole treatment. Performance on reward-based tasks is altered in healthy subjects after a single dose of pramipexole, but its potential to induce abnormalities in BPD patients is unknown. We assessed reward-dependent decision making in euthymic BPD patients pre- and post 8 weeks of treatment with pramipexole or placebo by using the Iowa Gambling Task (IGT). The IGT requires subjects to choose among four card decks (two risky and two conservative) and is designed to promote learning to make advantageous (conservative) choices over time. Thirty-four BPD patients completed both assessments (18 placebo and 16 pramipexole). Baseline performance did not differ by treatment group (F=0.63; p=0.64); however, at week 8, BPD patients on pramipexole demonstrated a significantly greater tendency to make increasingly high-risk, high-reward choices across the five blocks, whereas the placebo group's pattern was similar to that reported in healthy individuals (treatment × time × block interaction, p<0.05). Analyses of choice strategy using the expectancy valence model revealed that after 8 weeks on pramipexole, BPD patients attended more readily to feedback related to gains than to losses, which could explain the impaired learning. There were no significant changes in mood symptoms over the 8 weeks, and no increased propensity toward manic-like behaviors were reported. Our results suggest that the enhancement of dopaminergic activity influences risk-associated decision-making performance in euthymic BPD. The clinical implications remain unknown.

Effects of pramipexole on the processing of rewarding and aversive taste stimuli

Pramipexole, a D2/D3 dopamine receptor agonist, has been implicated in the development of impulse control disorders in patients with Parkinson's disease. Investigation of single doses of pramipexole in healthy participants in reward-based learning tasks has shown inhibition of the neural processing of reward, presumptively through stimulation of dopamine autoreceptors. This study aims to examine the effects of pramipexole on the neural response to the passive receipt of rewarding and aversive sight and taste stimuli. We used functional magnetic resonance imaging to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 16 healthy volunteers who received a single dose of pramipexole (0.25 mg) and placebo in a double-blind, within-subject, design. Relative to placebo, pramipexole treatment reduced blood oxygen level-dependent activation to the chocolate stimuli in the areas known to play a key role in reward, including the ventromedial prefrontal cortex, the orbitofrontal cortex, striatum, thalamus and dorsal anterior cingulate cortex. Pramipexole also reduced activation to the aversive condition in the dorsal anterior cingulate cortex. There were no effects of pramipexole on the subjective ratings of the stimuli. Our results are consistent with an ability of acute, low-dose pramipexole to diminish dopamine-mediated responses to both rewarding and aversive taste stimuli, perhaps through an inhibitory action of D2/3 autoreceptors on phasic burst activity of midbrain dopamine neurones. The ability of pramipexole to inhibit aversive processing might potentiate its adverse behavioural effects and could also play a role in its proposed efficacy in treatment-resistant depression.

Dopaminergic involvement in effort-based but not impulsive reward processing in smokers

BackgroundA reduction in reward responsivity and an increase in temporal discounting of rewards are both evident in smokers during acute abstinence compared to satiation. However, it is not yet known whether these processes can be modulated pharmacologically in smokers, other than with nicotine or tobacco. MethodsA double-blind placebo controlled crossover design assessed the effects of 0.5mg pramipexole, a dopamine D2/D3 agonist, in smokers following 2h of abstinence. Reward responsivity was measured using an effort-based card sorting task. Temporal discounting of monetary reward was assessed using Area Under the Curve (AUC) analysis, and affective and subjective effects were indexed. ResultsOn placebo, smokers showed an equivalent speed of card sorting when a financial incentive was provided compared to when it was not. Conversely, more cards were sorted under rewarded compared to non-rewarded trials after pramipexole, indicating an improvement in reward responsivity. Temporal discounting of monetary reward was not affected by pramipexole. Drug treatment also decreased positive affect and increased drowsiness. ConclusionsA single dose of pramipexole can enhance effort-based reward responsivity, but does not alter temporal discounting in smokers. These findings highlight pharmacological correlates of reward processing deficits in nicotine dependence and offer potential targets for their treatment.

Physostigmine and Restless Legs Syndrome

Restless legs syndrome (RLS) is a common neurologic disorder that uncommonly manifests in the perioperative period. Its anesthetic implications were recently discussed,1,2but the reviewers did not reference a 2005 case report that described rapid relief of symptoms with physostigmine.3Their perioperative recommendations for prevention and treatment were based on the current theory of causation involving dysfunctional central iron and dopamine metabolism and six case reports in which no patient experienced prompt resolution of symptoms. Oral administration of the dopamine D2/D3 receptor agonist, 0.125 mg pramipexole, produced relief after 30 min.4We report the second case of prompt relief of RLS symptoms with intravenous physostigmine.A 65-yr-old man presented for endoscopic ultrasound and fine needle aspiration of a submucosal gastric lesion. The patient met the international standard essential criteria for RLS: irresistible urge to move his legs, accompanied by unpleasant sensory complaints in his legs; increased agitation when the nursing staff insisted that he remain still; symptoms at home relieved by walking; and symptoms that are worse in the evening but reasonably controlled with dopamine D2/D3 receptor agonist therapy.1,5His daily dose of pramipexole, extended-release 1.5 mg after dinner, was twice the maximum daily dose usually recommended for RLS6and may reflect the severity of the syndrome. However, it is less than the average dose used to treat early Parkinson disease.7His other comorbidities (medications) included obesity, obstructive sleep apnea, diabetes mellitus type 2 (insulin, metformin, glipizide), hypertension (lisinopril), coronary artery disease (aspirin, lovastatin), gastroesophageal reflux (omeprazole), and osteoarthritis (oxaprozin).Anesthesia was provided with 2 mg midazolam, 440 mg propofol, and 10 mg ketamine intravenously (IV). He also received 4 mg ondansetron, 0.2 mg glycopyrrolate, and 20 mg IV esmolol and oxymetazoline intranasally before insertion of a nasopharyngeal airway. He was conversant on arrival in the recovery room. Within minutes he became agitated and tried to get off his stretcher to walk. He exhibited severe restlessness in both legs and complained of lower extremity tingling and tugging. The differential diagnoses in this setting included hypoxia (SpO298%), hypoglycemia (blood glucose 168 mg/dL), emergence delirium (conversant, oriented), neuroleptic-induced akathisia (no droperidol given), peripheral neuropathy, and a RLS flare (patient stated, “It’s my restless legs”). Administration of 1 mg IV physostigmine attenuated these symptoms within 3 min. Symptoms completely resolved with a second dose of 1 mg physostigmine. Five hours later, he was free of symptoms, despite not yet taking his usual evening dose of pramipexole.It is difficult to reconcile this apparent effectiveness of physostigmine with the current view of the pathophysiology of RLS – central iron insufficiency altering the dopaminergic system with a decrease in the number of D2 receptors in the putamen, increased activity of tyrosine hydroxylase, and increased dopamine transporter density in the caudate, putamen, and striatum.1,8,9But the cholinergic and dopaminergic systems do interact in certain brain regions, e.g. , striatal cholinergic output is dopamine D2 receptor-mediated.10In summary, two patients with acute manifestations of RLS syndrome obtained prompt sustained relief after administration of physostigmine. A clinical trial in the nonperioperative setting is needed to confirm this beneficial effect. A positive outcome could spur a different line of research into the mechanisms involved.Jeff Peacock, M.D., Girish Mishra, M.D., Raymond C. Roy, M.D., Ph.D.**Wake Forest School of Medicine, Winston-Salem, North Carolina. rroy@wakehealth.edu

A Case of Ropinirole-Induced Compulsive Behavior

To the Editor: Parkinson’s disease is a neuropsychiatric condition. Dopamine agonists are used extensively in the treatment of Parkinson’s. A retrospective review in 2009 of patients with Parkinson’s disease reported a frequency of 13.2% for compulsive behavior including new-onset pathological gambling and hypersexuality after being started on therapeutic doses of pramipexole or ropinirole.1 Several reports and reviews have been published on this topic. Here we present a case of new-onset compulsive behavior with the dopamine agonist ropinirole in a patient who presented in a mental health clinic setting. Case report. Mr A, a 41-year-old white, married male veteran with a history of Parkinson’s disease with cognitive impairment as well as DSM-IV-TR posttraumatic stress disorder and major depressive disorder, single episode, moderate, was referred to the mental health clinic by his primary care physician for management of his psychiatric symptoms. The patient reported that his depressive symptoms had been stable since he started treatment with venlafaxine 2 months earlier, but for the past few months he was having compulsive behavior, including intense sexual desires toward other women, and had started to gamble on scratchcards, on which he had lost $1,000 to $1,500 in a month. This was unusual for him, as he had a supportive and loving wife and had never gambled before. He had noted an increase in appetite (weight gain of 20 lb [9.1 kg]), endorsed that he had compulsive eating behaviors, and drank about a 20-pack of beer per day. He also described having nightmares and vivid dreams and endorsed having visual hallucinations in the form of shadows in the room on multiple occasions. This behavior had been causing stress in his marriage. He had no previous history of strokes, seizures, bipolar disorder, psychosis, impulse-control disorder, or drug dependence. His psychiatric medications included venlafaxine 150 mg twice daily, zolpidem 10 mg at bedtime, and clonazepam 1 mg twice daily, and his Parkinson’s disease medications included tablet carbidopa/levodopa 25 mg/250 mg every 3 hours, ropinirole 3 mg 3 times daily, entacapone 200 mg every 5 hours, and donepezil 10 mg at bedtime. Other medications were tramadol, losartan, flunisolide nasal inhaler, albuterol metered-dose inhaler, cetirizine, formoterol inhaler, and mometasone metered-dose inhaler. Mr A informed us that, at his last visit, his neurologist had increased his ropinirole dosage from 1 mg orally twice daily to 3 mg orally twice daily, as he was experiencing dyskinesia, swallowing difficulty, gradual decline in memory, and worsening of his Parkinson’s symptoms. Review of medical records confirmed that he indeed started having this weight gain and impulsive behavior within the first few weeks after the ropinirole dose was increased. After conducting a literature search on ropinirole, we decided to discontinue the medication. Following discontinuation, the symptoms resolved completely, and Mr A started to have weight loss and did not have the urge to gamble; however, his Parkinson’s motor symptoms reemerged. Thus, he was restarted on ropinirole at 0.5 mg orally twice daily for 1 wk and then increased to 1 mg orally twice daily, which he tolerated well without reemergence of his symptoms. The appearance of symptoms on increasing the dose and then improvement with reducing the dose suggests a strong correlation between ropinirole and impulsive behavior. This case highlights the importance of awareness regarding drug-related psychiatric symptoms that may originate in the course of management of Parkinson’s disease. Physicians who care for patients taking dopamine agonists should watch for and differentiate between conditions including drug-induced adverse effects from primary psychiatric disorders and work in collaboration with neurologists to manage these treatment-emergent adverse effects.

Caffeine drinking, cigarette smoking, and dopaminergic replacement therapy dose in Parkinson’s disease

The objective of this study is to assess the effect of smoking and caffeine intake in the dosage of dopaminergic replacement therapy. Patients were recruited from the movement disorders clinic of the National Institute of Neurology and Neurosurgery in Mexico City. An interviewer-administered structured questionnaire was given to all subjects regarding their smoking and caffeine drinking habits. Dopaminergic replacement therapy information was collected and levodopa, dopamine agonists, and levodopa equivalent daily doses were calculated. 146 Parkinson's disease patients (50 % female) were included. All patients were on antiparkinsonian treatment, with a mean levodopa equivalent daily dose (LEDD) of 550.2 ± 408. Patients were stratified according to smoking and caffeine drinking status. 104 (71.2 %) of the patients were "never smokers", 33 (22.6 %) were "former smokers" and 9 (6.2 %) were "current smokers". 40 (27.4 %) patients reported no history of caffeine intake, 36 (24.7 %) were former consumers and 70 (47.9 %) were current caffeine drinkers. No association between LEDD and smoking or caffeine intake was found. A weak positive correlation (r = 0.22, p < 0.04) was found between the daily dose of pramipexole and the daily intake of caffeine. LEDD, levodopa daily dose and dopamine agonist daily dose were not related to smoking or caffeine intake status. We found a weak correlation between caffeine daily intake and pramipexole dose. Further prospective exploration is needed to address the interaction of concomitant A2A antagonism induced by caffeine intake and dopaminergic replacement therapy.

P11. Management of augmentation in a severe case of restless legs syndrome secondary to alport syndrome

Introduction Renal failure is often associated with severe RLS. First line treatment for RLS are non-ergot derivate dopamine-agonists but augmentation is one of the most frequent cause of discontinuation of long-term treatment in RLS. Herein we describe the management of a very severe case of augmentation in a case of RLS secondary to renal failure due to collagen IV-related nephropathy, the alport syndrome (ATS) characterized by sensorineural hearing loss, ocular disorders and in all males with this X-linked disease renal failure. Methods A 56-year-old man with chronic renal failure due to familial ATS and treated by peritoneal dialysis for 1 year came to our attention because of worsening of insomnia due to severe pre-existing RLS. He suffered for RLS since the age of 10 years and started to be treated with pramipexole for the last 2 years. At the moment of our evaluation he was taking a single 0.75 mg night time dose of pramipexole. He reported a severe worsening of the symptoms in the last 3 months with an significant intensification of RLS symptoms during daytime, an extension of symptoms from lower to upper limbs and trunk, and a faster onset of symptoms when at rest, thus presenting with a clear augmentation phenomenon. He reported a mean total sleep time per night of Fig. 1 ). Treatment was substituted with 0.375 mg of pramipexole extended release at 4 pm and than increased to 0.75 mg. A global clinical improvement was documented by a further actigraphy recording (mean TST 7.10 h), hallucinations and aggressive behavior dissolved, and diurnal motor activity reduced ( Fig. 1 ). Conclusions This is the first description of RLS in a patient with ATS. The particular severe case of augmentation was documented by actigraphy and full recovery was achieved by simply changing from the regular to the extended release form of pramipexole. The management of augmentation is one of the most difficult challenge in the chronic treatment of RLS with dopamine-agonists.

Suicide Without Depression After Withdrawal of a Dopamine Agonist in a Patient With Parkinson's Disease

Back to table of contents Previous article Next article LettersFull AccessSuicide Without Depression After Withdrawal of a Dopamine Agonist in a Patient With Parkinson's DiseaseMélanie Flament, M.D., Gwenolé Loas, M.D., Ph.D., Olivier Godefroy, M.D., Ph.D., and Pierre Krystkowiak, M.D., Ph.D.Mélanie FlamentSearch for more papers by this author, M.D., Gwenolé LoasSearch for more papers by this author, M.D., Ph.D., Olivier GodefroySearch for more papers by this author, M.D., Ph.D., and Pierre KrystkowiakSearch for more papers by this author, M.D., Ph.D.Published Online:1 Oct 2011https://doi.org/10.1176/jnp.23.4.jnpe32AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: A recent multicenter study1 reported that the prevalence of impulse-control disorders (ICD) was 2.72-fold higher in Parkinson's disease (PD) patients treated by dopamine agonists than in PD patients not treated by these medications. Several case reports of attempted suicide or suicide in patients treated by dopamine agonists with pathological gambling have been published.2 A recent cross-sectional study3 on 128 PD patients examined associations between current suicidal and/or death ideation and neurological, neuropsychological, and psychiatric variables. Interestingly, a history of ICD disorders was not a statistically significant factor, but was associated with a trend (p<0.07). On multivariate logistic regression, major depression, psychosis, and elevated score on the Beck Hopelessness Scale were independent predictors of current suicidal and/or death ideation.Case ReportWe report the case of a 44-year-old man treated for juvenile idiopathic Parkinson's disease (PD) with pramipexole (0.7 mg three times daily) and l-dopa-benzeraside (62.5 mg three times daily) for 2 years. The dose of pramipexole was then increased to 0.7-mg tablets 4.5 per day. Several days later, he developed severe ICD with hypersexuality: increased libido, visiting of pornographic websites, and adultery. Six months later, pramipexole was decreased, then stopped, and l-dopa was continued alone. Hypersexuality rapidly resolved, but the patient experienced mixed anxiety/depressive disorder, and he was then admitted to the psychiatric department of a general hospital for 3 weeks and was treated with fluoxetine (20 mg/day). At the last psychiatric visit, 4 weeks after discharge from hospital, the patient's main complaint was related to his sexual activity; he said that he had sexual intercourse much less frequently than while he was taking pramipexole. Despite his marked anxiety, he did not present any symptoms of depression. The following day, he experienced a benign fall while jogging and then committed suicide by hanging from a tree, 2 months after withdrawal of pramipexole.DiscussionThis case report illustrates, for the first time, a potential link between suicide and ICD. Suicide due to depression was excluded by the psychiatric assessment on the day before the patient's death. When pramipexole was stopped, compulsive hypersexuality diminished dramatically and then resolved. The patient was then unable to accept his “normal” sexual activity and experienced a kind of pathological bereavement leading to hopelessness. Another hypothesis could be that the suicide was the result of impulsive behavior secondary to dopamine-agonist treatment, but the fall appeared to be the triggering event in a “hopelessness” patient. This potential cause can be excluded because L-dopa treatment was stable at low dose (187.5 mg/day). However, duration of the illness usually facilitates psychological acceptance and elaboration of the illness by the patient, as proposed by several authors using the term “work of disease” or “disease experience.” The patient's paradoxically increased physical or sexual capacities could considerably interfere with this “work of disease” and increase the risk of suicide. This case report suggests the need to identify patients at risk of suicidal behavior before administering dopamine agonists. The presence of impulse-control disorder and not only depression must therefore be investigated in PD patients who attempt suicide.University Department of NeurologyUniversity Department of PsychiatryUniversité de Picardie Amiens, FranceCorrespondence: Prof. Gwenolé Loas e-mail: Loas.[email protected]fr1. Weintraub D , Koester J , Potenza MN , et al.: Impulse-control disorders in Parkinson disease: a cross-sectional study of 3,090 patients. Arch Neurol 2010; 67:589–595Crossref, Medline, Google Scholar2. Kolla BN , Mansukhani MP , Barraza R , et al.: Impact of dopamine agonists on compulsive behaviors: a case series of pramipexole-induced pathological gambling. Psychosomatics 2010; 51:271–273Crossref, Medline, Google Scholar3. Kostic V , Pekmezovic T , Tomic A , et al.: Suicide and suicidal ideation in Parkinson's disease. J Neurol Sci 2010; 289:40–43Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByHospital care for mental health and substance abuse conditions in Parkinson's disease9 December 2016 | Movement Disorders, Vol. 31, No. 12Subthalamic Nucleus Versus Globus Pallidus Internus Deep Brain Stimulation: Translating the Rematch Into Clinical Practice10 April 2014 | Movement Disorders Clinical Practice, Vol. 1, No. 1 Volume 23Issue 4 Fall 2011Pages E32-E32 Metrics PDF download History Published online 1 October 2011 Published in print 1 October 2011

Dopamine D1/5 and D2/3 agonists differentially attenuate somatic signs of nicotine withdrawal in rats

Abrupt tobacco/nicotine cessation after chronic use causes various withdrawal symptoms/signs. There is evidence that dysfunction of brain dopaminergic system might be responsible for some nicotine withdrawal symptoms. The hypothesis for the present study was that different dopaminergic agonists would relieve different nicotine withdrawal signs. Adult male Sprague–Dawley rats were used. (−)-Nicotine bitartrate (9mg/kg/day, salt content) or equimolar sodium tartrate was infused into each rat via a subcutaneous (s.c.) osmotic minipump for 7days. To assess nicotine withdrawal signs, several somatic abstinence signs including teeth-chattering/chews, stretches/gasps, ptosis, shakes, and yawns were counted one day after removal of pumps. These signs were attenuated by the s.c. injection of 0.4mg/kg nicotine bitartrate. Both a dopamine D1/5 agonist (SKF81297) and a D2/3 agonist (pramipexole) relieved abstinence signs dose-dependently but differentially. SKF81297 (0.32mg/kg, s.c.) reduced teeth-chattering/chews but not shakes. Pramipexole (1mg/kg, s.c.) decreased both teeth-chattering/chews and shakes. A low dose of pramipexole (0.1mg/kg, s.c.) significantly increased yawns, consistent with previous studies that the stimulation of D3 receptors induces yawning. These results indicate that a D2-selective agonist should be considered a candidate to relieve nicotine withdrawal symptoms.

Pathological gambling plus hypersexuality in restless legs syndrome: a new case

Emerging clinical data indicate that dopaminergic agonists used to treat restless legs syndrome may be associated with dopamine dysregulation syndrome, particularly pathological gambling. We report a new case with pathological gambling plus hypersexuality and impotence in an old patient treated with a small dose (0.18 mg daily at bedtime) of pramipexole for restless legs syndrome for 5 months. The time relationship and the resolution upon discontinuation of dopaminergic agonists suggest a causative association. Our new case confirms that restless legs syndrome patients should be cautioned about potential dopamine dysregulation syndrome coinciding with dopaminergic agonists, as it can be reversed by drug withdrawal.

Reward processing abnormalities in Parkinson's disease

The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward. Pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid-A-mediated inhibition in the motor cortex, measured by paired transcranial magnetic stimulation, changes with expectation and uncertainty of money rewards generated by a slot machine simulation. We examined the role of dopamine in this phenomenon by testing 13 mildly affected patients with Parkinson's disease, off and on dopaminergic medications, and 13 healthy, age-matched controls. Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired transcranial magnetic stimulation in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired transcranial magnetic stimulation response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk-taking behavior on the Iowa Gambling Task. However, pramipexole increased risk-taking behavior more in patients showing lower paired transcranial magnetic stimulation response amplitude during low expectation. These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that the physiological state of the motor cortex changes with risk-taking tendency in patients on pramipexole. The cortical response to reward expectation may represent an endophenotype for risk-taking behavior in patients on agonist treatment.