Larry Scahill

A placebo-controlled trial of risperidone in Tourette syndrome

Objective: To evaluate the efficacy and safety of risperidone in children and adults with Tourette syndrome. Methods: This was an 8-week, randomized, double-blind, placebo-controlled trial. The primary outcome measure was the Total Tic score of the Yale Global Tic Severity Scale (YGTSS). Results: Thirty-four medication-free subjects (26 children and 8 adults) ranging in age from 6 to 62 years (mean = 19.7 ± 17.0 years) participated. YGTSS Total Tic scores were similar at baseline (26.0 ± 5.1 for risperidone vs 27.4 ± 8.5 for placebo). After 8 weeks of treatment (mean daily dose of 2.5 ± 0.85), the 16 subjects on risperidone showed a 32% reduction in tic severity from baseline, compared to a 7% reduction for placebo patients (n = 18) (F[2,64] = 6.07; p = 0.004). The 12 children randomized to risperidone showed a 36% reduction in tic symptoms compared to an 11% decrease in the 14 children on placebo (F[2,48] = 6.38; p = 0.004). Two children on risperidone showed acute social phobia, which resolved with dose reduction in one subject but resulted in medication discontinuation in the other. A mean increase in body weight of 2.8 kg was observed in the risperidone group compared to no change in placebo (F[2,64] = 10.68; p = 0.0001). No extrapyramidal symptoms and no clinically significant alterations in cardiac conduction times or laboratory measures were observed. Conclusion: Risperidone appears to be safe and effective for short-term treatment of tics in children or adults with Tourette syndrome. Longer-term studies are needed to evaluate the durability of efficacy and safety over time.

Emergence of Self-Destructive Phenomena in Children and Adolescents during Fluoxetine Treatment

Self-injurious ideation or behavior appeared de novo or intensified during fluoxetine treatment of obsessive-compulsive disorder in six patients, age 10 to 17 years old, who were among 42 young patients receiving fluoxetine for obsessive-compulsive disorder at a university clinical research center. These symptoms required the hospitalization of four patients. Before receiving fluoxetine, four patients had major risk factors for self-destructive behavior including depression or prior suicidal ideation or self-injury. Three hypotheses concerning the apparent association between fluoxetine and these self-injurious phenomena are discussed: (1) coincidence; (2) disorganization of vulnerable individuals secondary to drug-induced activation; and (3) a specific serotonergic-mediated effect on the regulation of aggression.

Fluoxetine Treatment of Children and Adolescents with Tourette's and Obsessive Compulsive Disorders: Preliminary Clinical Experience

Fluoxetine hydrochloride is the first selective serotonin uptake inhibitor introduced commercially in the United States. This report describes preliminary clinical experience with fluoxetine in 10 children and adolescents, aged 8 to 15 years, with primary obsessive compulsive disorder (OCD) or Tourettes syndrome (TS) plus OCD. In general, fluoxetine, which was administered from 4 to 20 weeks at a dosage of 10 or 40 mg per day, was well tolerated. Adverse effects included behavioral agitation/activation in four patients and mild gastrointestinal symptoms in two patients. No abnormalities were noted in the seven children who had follow-up EKGs. Five of the 10 patients (50%) were considered responders; their obsessive-compulsive symptoms decreased substantially during treatment with fluoxetine. Responder rates were similar in the primary OCD (two of four, 50%) and TS + OCD (three of six, 50%) groups. In conclusion, short-term fluoxetine administration appears to be safe in children and adolescents. Placebo-controlled trials are needed to further assess the efficacy of fluoxetine.

Parent-defined target symptoms respond to risperidone in RUPP autism study: customer approach to clinical trials.

OBJECTIVEnA consumer-oriented efficacy assessment in clinical trials should measure changes in chief complaint and consumer request (symptoms of most concern to patient/caregiver), which may be diluted in change scores of multisymptom scales.nnnMETHODnIn the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network 8-week double-blind trial of risperidone versus placebo, the chief concerns of parents were collected at 0, 4, and 8 weeks (endpoint), in addition to standardized primary measures. Blinded clinical judges rated change from baseline to 4 and 8 weeks on a 9-point scale (1 = normalized, 5 = unchanged, 9 = disastrous); 94 participants had usable data.nnnRESULTSnThe most common symptoms identified by parents were tantrums, aggression, and hyperactivity. Interrater reliability was excellent. Mean ratings at endpoint were 2.8 +/- 1.2 on risperidone and 4.5 +/- 1.3 on placebo (p <.001). Ratings were collinear with Clinical Global Impression-Improvement and Aberrant Behavior Checklist Irritability subscale (primary dimensional measure). Effect size d was 1.4, compared to 1.2 on the Aberrant Behavior Checklist Irritability subscale. Effect sizes varied twofold by symptom category, largest for self-injury (2.11) and tantrums (1.95).nnnCONCLUSIONSnRisperidone was superior to placebo in reducing symptoms of most concern to parents of autistic children with irritable behavior. Rating individualized participant-chosen target symptoms seems a reliable, sensitive, efficient, and consumer-friendly way to assess treatment effect and might have clinical application.

Enhanced stress responsivity of tourette syndrome patients undergoing lumbar puncture

Tourettes syndrome (TS) is a complex inherited neuropsychiatric disorder that is characterized by multiple motor and phonic tics. Stress-related fluctuations in symptom severity and medication responsiveness are common, and patients often report that tics are worsened by fatigue, emotional trauma, and anxiety. We examined the effects of lumbar puncture (LP) stress on plasma adrenocorticotropin (ACTH) and cortisol, urinary catecholamines, and self- and clinician ratings of anxiety in 13 medication-free TS patients and 10 normal controls, ages 17 to 41 years. The TS patients secreted significantly more ACTH than the normal controls in response to the stress of the lumbar puncture. Compared to the controls the TS patients had significantly greater postLP mean and postLP peak ACTH levels. The TS patients also excreted significantly more norepinephrine in the 20 hr preceding the lumbar puncture and reported higher levels of anxiety before and during the procedure than the controls. In addition, urinary norepinephrine excretion of the TS patients was significantly correlated with clinician ratings of tic severity. The results were not related to current levels of depression and anxiety. Taken together, these findings suggest that a subset of TS patients may be characterized by heightened reactivity of the hypothalamic-pituitary-adrenal axis and related noradrenergic sympathetic systems.

Exacerbation of Gilles de la Tourette's syndrome associated with thermal stress A family study

Gilles de la Tourettes syndrome (TS) is a familial disorder that is often exacerbated by stress or fatigue. Here we present a family of a TS proband that has several members with obsessive-compulsive symptoms, a bleeding disorder, and an unusual sensitivity to heat. The proband, who is affected by all of these traits, was challenged with heat or exercise in climate-controlled conditions and showed a marked increase in the frequency of tics.

Influence of Age and Tic Disorders on Obsessive-Compulsive Disorder in a Pediatric Sample

BACKGROUNDnObsessive-compulsive disorder (OCD) is a heterogeneous disorder with emerging data suggesting that age of onset and/or the presence of tics may define clinically important subgroups.nnnOBJECTIVEnThis study set out to evaluate the impact of age and tic disorders on the symptom profile in a pediatric sample of patients with OCD ascertained from a specialty clinic.nnnMETHODSnEighty children with OCD (50 boys, 30 girls) were assessed for symptom type, severity, age of onset, presence of a tic disorder, and functional status. Each childs most impairing obsessions and compulsions were identified and compared by age category (above and below the age of 11 years) and according to the presence or absence of a tic disorder.nnnRESULTSnThe mean age of the sample was 11.1 +/- 3.19 years (range 4-18 years). The most common obsessions reported were contamination and worries about harm. Common compulsions included washing and rituals to prevent harm. The only significant differences across age groups were the percentage of religious worries and slightly higher severity of obsessions in the adolescent age group (p < 0.05). The presence of tics was associated with increased frequency of repetitive behavior unrelated to harm avoidance (p < 0.05). Children without a history of tics were more likely to describe incidents of contamination, washing, and repetitive request for reassurance (p < 0.05 for each).nnnCONCLUSIONnIn this convenient sample of clinically ascertained children, there were few phenotypic differences in children above or below the age of 11 years. Differences in the distribution of OCD symptoms according to the presence or absence of tics, which has been documented in adult samples, were evident in this sample.

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

To evaluate the role of opioids in Tourettes 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.

Methodological Issues in Designing a Multisite Trial of Risperidone in Children and Adolescents with Autism

OBJECTIVEnTo describe the methodological challenges and decisions made in developing a multisite, controlled study of risperidone in children and adolescents with autism.nnnMETHODSnReview the design considerations for clinical trials in children with autistic disorder accompanied by severe tantrums, aggressive and/or self-injurious behaviors. These design considerations include the definition of inclusion criteria that are relevant to clinical practice and matching study design to the goal of evaluating short- and long-term effects. Additional ethical and scientific issues concern the length of trial and sample size.nnnRESULTSnWe undertook a short-term, placebo-controlled study to evaluate the efficacy and safety of risperidone in children and adolescents with autistic disorder. This trial design was followed by an extended open-label maintenance on risperidone to confirm durability of treatment effects and to monitor safety. Finally, a placebo-controlled discontinuation study tested the need for continuous treatment.nnnCONCLUSIONSnIn the absence of standard pharmacological treatment for children with autistic disorder, a placebo-controlled study remains the most appropriate method of testing efficacy and safety. The clinical relevance of this study is enhanced by the addition of an extended maintenance phase followed by a placebo discontinuation.

The Home Situations Questionnaire-PDD version: factor structure and psychometric properties.

BACKGROUNDnThe Home Situations Questionnaire (HSQ) is a caregiver-rated scale designed to assess behavioural non-compliance in everyday settings that has been used in several studies in typically developing children. Currently there is no accepted measure of behavioural non-compliance in children with pervasive developmental disorders (PDDs).nnnMETHODSnInvestigators of the Research Units on Pediatric Psychopharmacology Autism Network modified the HSQ for children with PDDs by adding five items (making 25 total items), and used it as the primary outcome measure in a clinical trial. In the current investigation, we examined the factor structure and psychometric properties of the modified scale, the HSQ-PDD.nnnRESULTSnAn exploratory factor analysis with oblique rotations yielded two factors: Socially Inflexible (14 items) and Demand-Specific (six items). Item content of both factors appeared to fit well with the rubric of PDDs. Internal consistency, using Cronbachs alpha statistic, was 0.90 for Socially Inflexible, and 0.80 for Demand-Specific. The obtained sub-scales and HSQ-PDD Total score showed moderate correlations with selected sub-scales of the Aberrant Behavior Checklist, Child and Adolescent Symptom Inventory, and Childrens Yale-Brown Obsessive Compulsive Scale, and low correlations with the Vineland Adaptive Behavior sub-scales.nnnCONCLUSIONSnThe HSQ-PDD appears to be well suited for children with PDDs, although the Demand-Specific sub-scale may benefit from addition of more items. We provided sub-scale means and standard deviations for this relatively severe group of children with PDDs, and discussed the factor structure with respect to previous research.