Floyd R. Sallee

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 Tourettes 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 Tourettes 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.

Children Exposed to Disaster: II. Risk Factors for the Development of Post-Traumatic Symptomatology

OBJECTIVE To examine the influence of subject and exposure variables on the development of post-traumatic stress disorder (PTSD) symptoms and syndrome in children exposed to disaster. METHOD Three months after Hurricane Hugo, 5,687 school-aged children were surveyed about their experiences and reactions to the hurricane. Self-reports of PTSD symptoms were obtained by use of a PTSD Reaction Index. RESULTS The presence of PTSD symptoms was strongly related to childrens reported severity of the hurricane, degree of home damage sustained, and continued displacement; however, childrens level of trait anxiety and their reported emotional reactivity during the hurricane were more strongly related to the presence of PTSD symptoms than were the exposure factors. Different sets of risk factors appeared to differentially influence the development of the three DSM-III-R PTSD symptom clusters. Little evidence for a differential effect of the risk factors between females and males and younger and older children was found. CONCLUSIONS Level of trait anxiety appears to be the single strongest risk for the development of severe post-traumatic reactions. The higher rate of post-traumatic symptoms in females and younger children in combination with the absence of differential reaction to the risk factors suggests that females and younger children are more likely to develop posttraumatic reactions following a disaster.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders

Objective: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. Methods: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders–IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. Results: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (–5.5 ± 6.9 vs –3.0 ± 8.7, p = 0.063) and Tic Symptom Self-Report total score (–4.7 ± 6.5 vs –2.9 ± 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (–0.7 ± 1.2 vs –0.1 ± 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (–10.9 ± 10.9 vs –4.9 ± 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (–0.8 ± 1.1 vs –0.3 ± 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. Conclusions: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

Guanfacine Extended Release in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled Trial

OBJECTIVE This study compared the efficacy of guanfacine extended release (GXR), a selective alpha(2A)-adrenoceptor agonist, with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD This double-blind, 9-week, dose-ranging, parallel-design, multicenter trial randomized 6- to 17-year-olds with ADHD to once-daily oral GXR in 1-, 2-, 3-, and 4-mg doses or placebo. Primary outcome was change in total ADHD Rating Scale-IV score from baseline to endpoint. Secondary outcomes included changes in scores of hyperactive/impulsive and inattentive subscales; clinician and parent ratings; duration of clinical effect; and safety measures. RESULTS Statistically significant reductions in ADHD Rating Scale-IV scores were observed from baseline to endpoint at all doses of GXR, with effect sizes ranging from 0.43 to 0.62. In subjects receiving GXR, mean heart rate and systolic and diastolic blood pressure decreased as the dose of GXR increased and then returned toward baseline during the dose-maintenance and dose-tapering phases of the trial. Most frequent treatment-emergent adverse events (> or = 5%) were somnolence, headache, fatigue, sedation, dizziness, irritability, upper abdominal pain, and nausea. Somnolence, sedation, and fatigue adverse events emerged within the first 2 weeks of dosing and generally resolved by study end. CONCLUSIONS : Guanfacine extended-release was effective in reducing symptoms of ADHD. Adverse events were mild to moderate, did not interfere with improvements in attention, and rarely led to discontinuation.

Fluoxetine in children and adolescents with OCD: a placebo-controlled trial.

OBJECTIVE To examine the safety and efficacy of fluoxetine in child and adolescent obsessive-compulsive disorder (OCD). METHOD Between 1991 and 1998, 43 patients were randomly assigned to fluoxetine or placebo for 8 weeks. Dosing was fixed for the first 6 weeks (up to 60 mg/day) and then could be increased to 80 mg/day. Responders entered an 8-week maintenance phase. The primary outcome measures were the Childrens Yale-Brown Obsessive Compulsive Scale (CY-BOCS) and the Clinical Global Impression-Improvement (CGI-I) scale. Analyses were done on the intent-to-treat sample. RESULTS Fluoxetine patients (n = 21) had significantly lower CY-BOCS scores than placebo patients (n = 22) after 16 (but not 8) weeks. Fluoxetine responders (n = 11) had significantly lower CY-BOCS scores than placebo responders (n = 7) after an additional 8 weeks of treatment. After 16 weeks, 57% of fluoxetine (versus 27% of placebo) patients were much or very much improved on the CGI-I scale (p <.05). No patient terminated the study because of adverse medication effects. CONCLUSION Fluoxetine was well tolerated and effective for the treatment of child and adolescent OCD, but fluoxetines full effect took more than 8 weeks to develop.

Association of cortical disinhibition with tic, ADHD, and OCD severity in Tourette syndrome.

Hyperkinetic disorders may involve excess excitatory output from thalamus to cerebral cortex. Case–control, neurophysiological studies in persons with Tourette Syndrome (TS), Attention Deficit Hyperactivity Disorder (ADHD), and Obsessive‐Compulsive Disorder (OCD) support this model. To compare the strength of association between motor cortex inhibition and tic, ADHD, and OCD severity in TS, we used transcranial magnetic stimulation to measure motor cortex inhibition in 36 children and adults with TS. Current symptom severity was assessed with standard clinical rating scales and compared with neurophysiological measures using correlational and multivariate regression analyses. Severity of ADHD symptoms and motor tics were associated significantly and independently with short interval intracortical inhibition (SICI) (r2 = 0.50; F[2,27] = 13.7; P < 0.001), particularly in subjects not taking neuroleptics (r2 = 0.68; F[2,17] = 17.8; P < 0.0001). The correlation of cortical disinhibition was greater with ADHD symptoms severity (r = 0.53; P = 0.003) than with tic severity (r = 0.42; P = 0.02), suggesting that in TS, the association between SICI and ADHD symptoms may be more consistent or direct than the association between SICI and tics.

Treatment for Adolescents with Depression Study (TADS): Rationale, design, and methods

OBJECTIVES A rapidly growing empirical literature on the treatment of major depressive disorder (MDD) in youth supports the efficacy of short-term treatment with depression-specific cognitive-behavioral therapy or medication management with a selective serotonin reuptake inhibitor. These studies also identify a substantial probability of partial response and of relapse, which might be addressed by more intensive, longer-term treatments. METHOD Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is a multicenter, randomized, masked effectiveness trial designed to evaluate the short-term (12-week) and long-term (36-week) effectiveness of four treatments for adolescents with MDD: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. A volunteer sample of 432 subjects aged 12-17 years (inclusive) with a primary DSM-IV diagnosis of MDD who are broadly representative of patients seen in clinical practice will enter the study. The primary dependent measures rated blindly by an independent evaluator are the Childrens Depression Rating Scale and, for responder analysis, a dichotomized Clinical Global Impressions-Improvement score. Consistent with an intent-to-treat analysis, all patients, regardless of treatment status, return for all scheduled assessments. RESULTS This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial. CONCLUSION When completed, TADS will improve our understanding of how best to initiate treatment for adolescents with MDD.

Tic Reduction With Risperidone Versus Pimozide in a Randomized, Double-Blind, Crossover Trial

OBJECTIVE To compare the tic suppression, electrocardiogram (ECG) changes, weight gain, and side effect profiles of pimozide versus risperidone in children and adolescents with tic disorders. METHOD This was a randomized, double-blind, crossover (evaluable patient analysis) study. Nineteen children aged 7 to 17 years with Tourettes or chronic motor tic disorder were randomized to 4 weeks of treatment with pimozide or risperidone, followed by the alternate treatment after a 2-week placebo washout. The primary efficacy outcome measure was change in tic severity assessed by the Yale Global Tic Severity Scale (YGTSS). ECG results, weight gain, and side effects were also compared. RESULTS Compared to pimozide treatment, risperidone treatment was associated with significantly lower tic severity scores (YGTSS: baseline 43.3 +/- 17.5, pimozide 34.2 +/- 14.2, risperidone 25.2 +/- 13.6; p =.05). Weight gain during the 4-week treatment periods was greater for risperidone (mean 1.9 kg) than pimozide (1.0 kg). No patient suffered a serious adverse event, but 6 of 19 subjects failed to complete the protocol. Neither medication was associated with ECG changes. CONCLUSIONS In this study, risperidone appeared superior to pimozide for tic suppression but was associated with greater weight gain.

Long-Term Safety and Efficacy of Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

OBJECTIVE Short-term, controlled studies of extended-release guanfacine (GXR), a selective alpha(2A)-adrenoreceptor agonist, demonstrate efficacy in treating attention-deficit/hyperactivity disorder (ADHD) symptoms as monotherapy. This 2-year open-label study was conducted to further assess the long-term safety and efficacy of GXR. METHODS Study participants, aged 6-17 years with ADHD, had previously been exposed to GXR therapy alone or in combination with psychostimulants in one of two antecedent trials. In this study, doses were titrated to 1, 2, 3, or 4 mg/day of GXR alone or in combination with a psychostimulant. Safety and efficacy data collected at clinic visits over 24 months provided further evidence of the overall safety and efficacy of GXR for treating ADHD. RESULTS The majority of adverse events (AEs) were mild to moderate, and few patients discontinued the study because of an AE. Efficacy measures demonstrated significant improvement beginning in the first month and lasting through the end of the 24-month treatment period. Throughout the entire 2-year study, 202 subjects (77.1%) discontinued and 60 (22.9%) completed the study. CONCLUSIONS Overall, these data support that GXR monotherapy is generally safe and effective for treating ADHD.

Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes

OBJECTIVE To determine the efficacy and safety of clonidine, used alone or in combination with methylphenidate, in treating attention-deficit/hyperactivity disorder (ADHD). METHOD A 16-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 122 children, ages 7 to 12, with any subtype of ADHD, randomly assigned to clonidine, methylphenidate, clonidine in combination with methylphenidate, or placebo according to a 2 x 2 factorial design. In two successive 4-week titration periods, clonidine (or matching placebo) and added methylphenidate (or matching placebo) were adjusted to optimal doses and then continued for 8 weeks. The primary efficacy outcome was changed from baseline to week 16 on the Conners Teachers Abbreviated Symptom Questionnaire. Secondary outcomes included the Conners Abbreviated Symptom Questionnaire for Parents and the Childrens Global Assessment Scale. RESULTS On the Conners Teachers Abbreviated Symptom Questionnaire, clonidine was not found to improve ADHD symptoms, whereas subjects treated with methylphenidate showed significant improvement compared to those not treated with methylphenidate. Subjects treated with clonidine had greater improvements on the Conners Abbreviated Symptom Questionnaire for Parents and Childrens Global Assessment Scale, but also a higher rate of sedation compared with subjects not treated with clonidine. CONCLUSIONS Based on the Conners Teachers Abbreviated Symptom Questionnaire, methylphenidate offers the best combination of efficacy and tolerability for ADHD. Clonidine was well tolerated despite the frequency of sedation and did offer some benefit.