A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder.

OBJECTIVE: This study evaluated the efficacy and safety of guanfacine in treating children with tic disorders and attention deficit hyperactivity disorder (ADHD). METHOD: Subjects from a specialty tic disorders clinic were randomly assigned to receive 8 weeks of treatment with guanfacine or placebo under double-blind conditions. Follow-up visits occurred every 2 weeks for safety monitoring and dose adjustment. RESULTS: Thirty-four medication-free subjects (31 boys and three girls with a mean age of 10.4 years) with ADHD, combined type, and a tic disorder participated. After 8 weeks of treatment, guanfacine was associated with a mean improvement of 37% in the total score on the teacher-rated ADHD Rating Scale, compared to 8% improvement for placebo. Nine of 17 subjects who received guanfacine were blindly rated on the Clinical Global Improvement scale as either much improved or very much improved, compared with none of 17 subjects who received placebo. The mean score on the parent-rated hyperactivity index improved by 27% in the guanfacine group and 21% in the placebo group, not a significant difference. On the Continuous Performance Test, commission errors decreased by 22% and omission errors by 17% in the guanfacine group, compared with increases of 29% in commission errors and of 31% in omission errors in the placebo group. Tic severity decreased by 31% in the guanfacine group, compared to 0% in the placebo group. One guanfacine subject with sedation withdrew at week 4. Guanfacine was associated with insignificant decreases in blood pressure and pulse. CONCLUSIONS: Guanfacine appears to be a safe and effective treatment for children with tic disorders and ADHD.

Clinical and sensorimotor gating effects of ketamine in normals.

The clinical similarities between PCP psychosis and schizophrenia have contributed importantly to the development of the glutamate hypothesis of schizophrenia. Sensory gating, as measured by prepulse inhibition of the acoustic startle reflex (PPI), is impaired in patients with schizophrenia. In animals, the noncompetitive NMDA antagonists PCP and ketamine disrupt PPI in a way that resembles the defect seen in schizophrenia. The purpose of this work is to investigate the modulation of sensory gating in humans by subanaesthetic doses of ketamine. 16 healthy male subjects received a 60-min infusion of ketamine (0.5 mg/kg) or normal saline on two separate days in a randomized double-blind crossover design. Clinical ratings and PPI were done during the infusion on both days. Ketamine produced robust clinical effects. Dissociative symptoms as measured by the CADSS increased from 0 +/- 0.0 to 29.3 +/- 14.3; negative symptoms (Affect Rating Scale) increased from 17.2 +/- 0.8 to 24.8 +/- 3.1; and total BPRS scores increased from 18.3 +/- 0.8 to 26.4 +/- 5.1. ANOVAs for these ratings were all significant at the p <.000 level, although BPRS increases were not in the range seen in decompensated schizophrenic patients. The amplitudes of the startle responses to pulse-alone stimuli were not significantly different on ketamine and placebo days. Ketamine did not cause disruption in PPI as expected. On the contrary, in the first block of the PPI session ketamine significantly enhanced PPI (ANOVA; F=6.15, p =.026). These results indicate that the clinical effects of ketamine are not coupled with schizophrenic-like disruption of PPI in normal controls.

Patterns of response to acute naloxone infusion in Tourette's syndrome.

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.

Impaired prepulse inhibition of acoustic startle in schizophrenia.

BACKGROUND: Schizophrenics show deficits in sensorimotor gating, as measured by prepulse inhibition of acoustic startle (PPI). The goal of this investigation is to further characterize PPI and habituation deficits in schizophrenia, and to examine whether differing subgroups of schizophrenics would show comparable PPI deficits. METHODS: PPI was measured in 24 male schizophrenic subjects (9 acutely decompensated inpatients and 15 stable outpatients) and in 20 age-matched normal control subjects. Schizophrenic subjects were rated for positive and negative symptoms at the time of testing. RESULTS: Schizophrenic subjects showed deficits in prepulse inhibition and habituation as compared to normal subjects. Similar latency facilitation was produced by the prepulse in both groups. Acutely decompensated inpatients and stable outpatients did not differ in percent PPI. PPI did not correlate with severity of positive or negative symptoms. CONCLUSIONS: These results suggest that schizophrenic subjects have impaired central inhibitory mechanisms as measured by PPI, and support the hypothesis that periods of relative clinical remission are not accompanied by normalization of sensorimotor gating.

Ziprasidone treatment of children and adolescents with Tourette's syndrome: a pilot study.

OBJECTIVE: To evaluate the efficacy and tolerability of ziprasidone in children and adolescents with Tourette's syndrome and chronic tic disorders. METHOD: Twenty-eight patients aged 7 to 17 years were randomly assigned to ziprasidone or placebo for 56 days. Ziprasidone was initiated at a dose of 5 mg/day and flexibly titrated to a maximum of 40 mg/day. RESULTS: Ziprasidone was significantly more effective than placebo in reducing the Global Severity (p = .016) and Total Tic (p = .008) scores on the Yale Global Tic Severity Scale. Compared with placebo, ziprasidone significantly reduced tic frequencies as determined by blind videotape tic counts (p = .039). The mean (+/- SD) daily dose of ziprasidone during the last 4 weeks of the trial was 28.2 +/- 9.6 mg. Mild transient somnolence was the most common adverse event. No clinically significant effects were observed on specific ratings of extrapyramidal symptoms, akathisia, or tardive dyskinesia. CONCLUSIONS: In this limited sample, ziprasidone (5-40 mg/day) appears to be effective and well tolerated in the treatment of Tourette's syndrome. Ziprasidone may be associated with a lower risk of extrapyramidal side effects in children. However, additional studies are necessary to evaluate more fully its safety and efficacy in children with tic disorders.

Pharmacologic treatment of tic disorders.

The approach to treating children and adolescents with tic disorders has evolved in recent years such that complete elimination of tics is no longer the primary goal of treatment. Indeed, given the high frequency of psychiatric comorbidity in TS, treatment planning begins with identification of target symptoms. Although traditional neuroleptics still represent standard treatment for tics, many families and clinicians are reluctant to use these agents because of concern about the potential for short- and long-term side effects. Thus, there is great interest in the newer atypical neuroleptics. Interest in the atypical neuroleptics is understandable, but much more study is needed before these agents can become first-line treatments for tics. A small group of non-neuroleptic medications have been used in the treatment of tics. Of these, clonidine, guanfacine, tetrabenazine, pergolide, and botulinum toxin injections have shown some promise for suppressing tics. To date, however, only clonidine has been evaluated in randomized, controlled trials, and the results are not consistent across studies. Although comorbid ADHD is common in children with TS, treatment with stimulant medications was not recommended in children with tics. Recent data suggest that stimulants may be used in some children with TS without adverse effects. Until more is known about which children with ADHD and tic disorders can be safely treated with stimulants, however, the use of stimulants in this population should be undertaken with caution. A handful of nonstimulant medications have been used in the treatment of ADHD with some success, but more study is needed for most of these agents. Evaluation of the stimulants and nonstimulants for the treatment of ADHD in children and adolescents with tic disorders is an area worthy of large controlled trials.

Future therapies of Tourette syndrome.

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.

Assessment of diurnal variation of cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in healthy human females.

The role of serotonin (5-HT) in the pathogenesis and treatment of major neuropsychiatric disorders, including mood and anxiety disorders, continues to be the subject of extensive research. Previous studies examining central 5-HT functioning measured cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA) by using single or multiple lumbar punctures. A number of investigators have demonstrated the feasibility of continuous CSF sampling via an indwelling lumbar catheter to study CSF neurochemistry in healthy subjects and patients with neuropsychiatric illness. Four healthy female volunteers, aged 21-34 years, underwent continuous CSF sampling. CSF was collected at a constant rate of 1 ml every 10 minutes over a 30-hour period, with levels of tryptophan (TRP) and 5-HIAA measured every hour. Plasma was also obtained hourly for TRP determination. The results of this study indicate that CSF 5-HIAA, CSF TRP, and plasma TRP levels showed variation over time, but failed to show diurnal fluctuation. Intra-individual coefficients of variation determined for CSF 5-HIAA, CSF TRP, and plasma TRP ranged from 9.2 to 14.9%, 8.8 to 14.6%, and 14.7 to 19.0%, respectively. Continuous CSF sampling is safe and feasible in humans, and may prove useful for studies of central 5-HT neurotransmission in neuropsychiatric illness.

Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette's syndrome: preliminary clinical experience.

OBJECTIVE: Many children with Tourette's syndrome (TS) are handicapped more by difficulties with inattention, impulsivity, and hyperactivity than by their tics. However, stimulant medications used to treat attention-deficit hyperactivity disorder (ADHD) can exacerbate tics. Guanfacine is an alpha 2-adrenergic agonist that may have beneficial effects on attention, without the hypotensive or sedative effects of clonidine, which is often used as an alternative to stimulants. METHOD: An open-label study of guanfacine was performed in 10 children with TS+ADHD, aged 8 to 16 years. The duration of follow-up was 4 to 20 weeks, and the majority of subjects were treated with 1.5 mg/day. Ratings of tic severity and ADHD symptoms were obtained using the Yale Global Tic Severity Scale (YGTSS), the Tic Symptom Self Report (TSSR), and the Conners Parent Rating Scale. In addition, blind Continuous Performance Tests (CPTs) were performed at baseline and at two follow-up intervals in eight subjects. RESULTS: Guanfacine was associated with significant decreases in both commission errors (p < .02) and omission errors (p < .01) on the CPT. In addition, guanfacine caused a significant decrease in severity of motor (p < .02) and phonic (p < .02) tics as measured by the TSSR and the YGTSS, respectively. The most common side effects were transient sedation and headaches. CONCLUSION: Guanfacine may provide a safe alternative therapy for children with ADHD in the presence of tics. Future double-blind, controlled trials should be undertaken.

Risperidone treatment of children and adolescents with chronic tic disorders: a preliminary report.

OBJECTIVE: The purpose of this trial was to investigate the short-term safety and efficacy of risperidone in the treatment of chronic tic disorders in children and adolescents. METHOD: This was an 11-week open-label trial and included seven subjects (five boys and two girls) with a mean age of 12.9 +/- 1.9 years. The sample included five patients with Tourette's syndrome and two with chronic motor tic disorder. The children were seen at baseline and for two follow-up visits. Three children had a comorbid diagnosis of obsessive-compulsive disorder (OCD). RESULTS: Clinical response, as measured by the Yale Global Tic Severity Scale and the Children's version of the Yale-Brown Obsessive Compulsive Scale, revealed a statistically significant reduction in tic scores ranging from 26% [corrected] to 66%. One of three children with comorbid OCD showed substantial improvement; the other two subjects showed no change. The most frequent side effect was weight gain, which ranged from 8 to 14 lb. CONCLUSIONS: Risperidone, a neuroleptic with both serotonin- and dopamine-blocking properties, appears to be effective in reducing tic frequency and intensity in children and adolescents with chronic tic disorders.

Cerebrospinal fluid biogenic amines in obsessive compulsive disorder, Tourette's syndrome, and healthy controls.

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.

Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder. Comparison with Tourette's syndrome and healthy controls.

BACKGROUND: Limited neurobiological data have implicated central arginine vasopressin in the pathobiology of obsessive-compulsive disorder (OCD). Based on twin, family genetic, and pharmacological studies, some forms of OCD are etiologically related to Tourette's syndrome. The role of arginine vasopressin and related compounds such as oxytocin in Tourette's syndrome has not been previously explored. METHODS: To compare cerebrospinal fluid (CSF) levels of arginine vasopressin and oxytocin, we collected CSF at midday in a standardized fashion from a total of 83 individuals (29 patients with OCD, 23 patients with Tourette's syndrome, and 31 normal controls). We also collected family study data on each subject to determine which subjects had a family history positive for Tourette's syndrome, OCD, or related syndromes. RESULTS: In contrast to previous reports, we report similar concentrations of arginine vasopressin for all three groups but increased oxytocin levels in patients with OCD. Remarkably, this increase was observed only in a subset of patients with OCD (n = 22) independently identified as being without a personal or family history of tic disorders (P = .0003). In this subgroup of patients, the CSF oxytocin level was correlated with current severity of OCD (n = 19, r = .47, P < .05). CONCLUSIONS: A possible role for oxytocin in the neurobiology of a subtype of OCD is suggested by the elevated CSF levels of oxytocin and by the correlation between CSF oxytocin levels and OCD severity. These findings reinforce the value of family genetic data in identifying biologically homogeneous (and perhaps more etiologically homogeneous) groups of patients with OCD. Together with emerging pharmacological data showing differential responsiveness to treatment of tic-related OCD vs non-tic-related OCD, these data also argue strongly for the incorporation of tic-relatedness as a variable in biological and behavioral studies of patients with OCD.

Clozapine in the treatment of a young adolescent with schizophrenia.

Although recent reports have suggested that clozapine may be efficacious in the treatment of adolescents with schizophrenia, few studies have examined the use of clozapine in patients younger than 17 years of age. We describe highly successful trials of clozapine conducted in a 13-year-old girl and her cousin, both of whom developed severe symptoms of schizophrenia, which were refractory to neuroleptic medication, at the ages of 11 and 13 years, respectively. The pharmacology of and clinical experience with clozapine are reviewed.

Videotape tic counts in the assessment of Tourette's syndrome: stability, reliability, and validity.

OBJECTIVE: We examined the short- and long-term temporal stability of tic counts to estimate the minimum length of videotape needed for a reliable index of overall tic activity and determined the interrater reliability and validity of tic counts based on prolonged videotape segments (> 10 minutes). METHOD: Motor and phonic tic counts and clinician ratings were performed on 43 patients with Tourette's syndrome (TS), aged 7 to 50 years. Short-term stability was estimated by determining the mean interval-to-interval correlation of sequential equal-length segments from 30-minute videotape recordings of 20 subjects. Long-term stability was determined by correlating tic counts at 1-week (N = 14) and 2-week intervals (N = 11). In addition, tic counts were correlated with the most widely used clinical ratings of TS. RESULTS: The short-term stability data indicated that estimates of motor and phonic tic frequencies should be based on videotape counts of at least 5 minutes' duration. Tic counts also were highly reliable and were significantly correlated with clinical ratings with the Yale Global Tic Severity Scale and the Clinical Global Impression Scale for Tourette Syndrome. CONCLUSIONS: Standardized videotape tic counts can provide highly reliable, stable measures of tic frequencies that are moderately correlated with selected global ratings of tic severity.

The role of central oxytocin in obsessive compulsive disorder and related normal behavior.

Oxytocin (OT) is a neurosecretory nonapeptide synthesized in hypothalamic cells, which project to widely distributed sites in the CNS as well as the neurohypophysis. Central OT affects a variety of cognitive, grooming, affiliative, sexual, and reproductive behaviors in animals. Obsessive Compulsive Disorder (OCD) includes a range of cognitive and behavioral symptoms that bear some relationship to dimensions of behavior associated with OT. Anecdotal data and a recently completed cerebrospinal fluid (CSF) study provide evidence that some forms of OCD are related to OT dysfunction. Based on these findings, we hypothesize: 1) that some forms of OCD are at the extreme end of a range of normal behaviors that are mediated by OT and related systems; and that 2) some normal cognitive, affiliative, and sexual behaviors contain elements that are similar to features of OCD. Alternative hypotheses are considered, and a series of predictions are presented concerning the relationship between central OT and the onset, course, treatment response, and response to challenge procedures seen in this form of OCD.

Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette's syndrome: a pilot study.

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.