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The purpose of this study was to replicate findings from an earlier pilot study in which we found a dose-related effect of the opioid antagonist naloxone on tic behavior in patients with Tourette's syndrome (TS). Fifteen subjects with TS were challenged with randomized doses (30 and 300 microg/kg) of naloxone at 3-day intervals. Videotaped recordings of tic behavior were counted in a "blind" fashion. We found that naloxone had opposite effects on tics at different dosages. The low dose caused a significant decrease in tics, whereas the high dose caused a significant increase in tics. Therefore, activity at opioid receptors appears to influence the expression of TS, and the difference in response to naloxone in TS subjects may be based on a dose-response effect.

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Currently available pharmacologic therapies for Tourette syndrome often are characterized by limited effectiveness and unacceptable side effect profiles. In recent years, however, a series of new approaches have emerged which may lead to novel, more effective, and better tolerated treatments of tics and associated behavioral problems. Especially promising is the wide range of new atypical antipsychotic medications with unique and diverse receptor affinity profiles that are entering clinical practice. Over the next few years, intensive research efforts will be required to characterize the effect of the new atypical antipsychotics in patients with Tourette syndrome and related disorders, and to determine which sets of symptoms and which subgroups of patients best respond to particular agents. In the near future, corticotropin-releasing factor antagonists and agents which act on excitatory amino acid neurotransmitter systems also will become available and may provide treatment interventions, which theoretically could alter the long term course and outcome of Tourette syndrome. In addition, nonpharmacologic interventions, such as immunologic and behavior therapies, are receiving increasing attention and may provide an alternative or supplement to medication for selected subgroups of Tourette syndrome patients.

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To examine the role of noradrenergic, dopaminergic, and serotonergic mechanisms in the pathobiology of obsessive compulsive disorder (OCD) and Tourette's syndrome (TS), concentrations of tyrosine (TYR), norepinephrine (NE), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), homovanillic acid (HVA), tryptophan (TRP), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the lumbar cerebrospinal fluid (CSF) of 39 medication-free OCD patients, 33 medication-free TS patients, and 44 healthy volunteers. CSF TYR concentrations were reduced (p < .05) in the OCD patients compared to the healthy subjects. CSF NE in TS patients was 55% higher than in healthy controls (p < .001) and 35% higher than in OCD patients (p < .001). After covarying for height, CSF HVA levels were reduced (p < .05) in the OCD group compared to TS patients but not compared to the normal volunteers. No mean differences in CSF MHPG, TRP, and 5-HIAA were observed in this study across the three groups. The CSF NE data support the hypothesis that noradrenergic mechanisms are involved in the pathobiology of TS. Alterations in the balance of noradrenergic, dopaminergic, and serotonergic systems are likely involved in the pathobiology of OCD.

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As in many other areas of science, improvements in research methodologies lead the way to powerful new understanding of disorders and their treatment. Great strides have been made in defining the phenomenology of TS and its relationship to other disorders. However, we have not yet reached a true consensus and developed treatment strategies based on that consensus. Clearly much research needs to be done. Identifying the putative gene for TS would greatly accelerate this process.

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Sensory phenomena in the form of premonitory urges and "just right" perceptions appear to be common features of tic disorders including TS. Shapiro et al. (5) proposed that these sensory phenomena are an idiosyncratic feature of TS that is present in a minority of TS patients. However, data from recent studies suggest that premonitory urges are common in TS and may even be a defining feature of the disorder. These findings further indicate that clinicians should inquire about the presence of premonitory urges during the assessment of individuals with movement disorders. Of particular interest for future research is the relationship of the anatomical location of the premonitory urge and the site of the tic. Further study of sensory phenomena in other movement disorders is also warranted.

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To evaluate the role of opioids in Tourette's syndrome (TS), we performed a dose-response study of the behavioral and neuroendocrine effects of the selective kappa agonist spiradoline mesylate (U-62066E) in five TS patients and five normal control subjects, aged 20 to 47. The intramuscularly administered doses of spiradoline were 0.0, 0.8, 1.6, and 3.2 micrograms/kg. Baseline and postdrug tic frequencies were determined from "blind" videotape tic counts and bedside clinician ratings. In comparison with placebo, the lowest dose of spiradoline was associated with significant decreases in cumulative postdrug counts of total tics and phonic tics, as well as in clinician ratings of postdrug motor tic frequencies. By contrast, there was a trend for tic frequencies to increase following the intermediate dose (1.6 micrograms/kg) of spiradoline. As a group, the TS subjects also secreted significantly more growth hormone following the 1.6 micrograms/kg dose of spiradoline than did the normal control subjects. These preliminary findings provide additional evidence for the involvement of opioids in TS and suggest (1) that opioids may exert dual modulatory effects on the expression of tic symptoms and (2) that some TS patients may be characterized by increased sensitivity of kappa receptors regulating growth hormone secretion.

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