Tic reduction with pergolide in a randomized controlled trial in children.
ABSTRACT To determine whether pergolide, a mixed D1/D2/D3 dopamine agonist, is efficacious and safe in the treatment of children with chronic tic disorders and Tourette syndrome.
Neuroleptics, which block dopamine transmission, are currently used to treat children with severe tics, but major side effects and limited efficacy reduce clinical utility. Prior open-label and crossover studies of pergolide suggest potential benefit.
The authors enrolled 57 children and adolescents, ages 7 to 17 years, randomizing them in a 2:1 ratio to either pergolide (0.15 to 0.45 mg per day) or placebo. Tic symptoms had to be >30 on the Yale Global Tic Severity Scale (YGTSS). The primary outcome measure was change in tic severity assessed by YGTSS.
Compared to placebo treatment, pergolide treatment was associated with lower tic severity scores (treatment effect 8.8, pergolide vs placebo; 95% CI 0.1 to 17.6; p = 0.05) and attention-deficit hyperactivity disorder symptoms scores (treatment effect 3.8; 95% CI 0.7 to 6.8; p = 0.02). No patient had a serious adverse event and pergolide was well tolerated.
In this randomized, placebo-controlled trial, pergolide appeared to be an efficacious and safe medication for tic reduction in children, and may also improve attention-deficit hyperactivity disorder symptoms.
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ABSTRACT: Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success. © 2014 International Parkinson and Movement Disorder SocietyMovement Disorders 12/2014; 30(1). DOI:10.1002/mds.26120 · 5.63 Impact Factor
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ABSTRACT: Tourette syndrome is a complex neurobehavioral disorder defined by multiple motor and at least 1 vocal tic, persisting over 1 year, waxing and waning in severity, and not explained by another condition. The condition may range from mild nuisance to debilitating and disabling in severity. Management includes counseling and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions. Traditionally, alpha-2 agonists and dopamine receptor antagonists have been utilized. In addition, a number of different pharmacotherapies have been implemented in the search for improved management of tics with better tolerability. In rare, severely disabling cases, neuromodulation with deep brain stimulation may be indicated. Optimal brain targets and candidate selection are still in evolution. This article will review the evidence for current medical and surgical therapies with a focus on recent updates.Current Neurology and Neuroscience Reports 07/2014; 14(7):458. DOI:10.1007/s11910-014-0458-4 · 3.67 Impact Factor
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ABSTRACT: Dopamine has been hypothesized to modulate response inhibition. To test this hypothesis, we used functional magnetic resonance imaging (fMRI) to measure the effects of the dopamine prodrug levodopa on the brain responses to a well-validated response inhibition task (go/no-go, or GNG). Since abnormalities of response inhibition and dopamine have been thought to underlie tics and other symptoms of Tourette syndrome, we studied 8 neuroleptic-naive adults with tic disorders as well as 10 well-matched healthy controls. Subjects were pretreated with the peripheral decarboxylase inhibitor carbidopa, then scanned during GNG and control blocks, both before and during i.v. levodopa infusion. Both groups had similar task performance and task-related regional brain activity before and during levodopa infusion. Levodopa did not affect reaction times or accuracy, so fMRI findings can be interpreted without concern that they simply reflect a performance difference between conditions. Levodopa did affect the magnitude of GNG-related fMRI responses in the right cerebellum and right parietal cortex, significantly reducing both. Pre-levodopa activity in the right cerebellum correlated with reaction times (higher magnitudes associated with faster reaction times), and pre-levodopa activity in the right parietal cortex correlated with false alarm rate (higher magnitudes associated with higher error). In summary, right parietal and cerebellar regions important in mediating specific aspects of the GNG task were modulated by levodopa, suggesting a region-specific role for dopamine in response inhibition.Cognitive Brain Research 05/2004; DOI:10.1016/S0926-6410(04)00101-6 · 3.77 Impact Factor