Cathy L. Budman

Treatment of ADHD in children with tics: A randomized controlled trial

BACKGROUND The treatment of children with attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS) has been problematic because methylphenidate (MPH)--the most commonly used drug to treat ADHD--has been reported to worsen tics and because clonidine (CLON)--the most commonly prescribed alternative--has unproven efficacy. METHODS The authors conducted a multicenter, randomized, double-blind clinical trial in which 136 children with ADHD and a chronic tic disorder were randomly administered CLON alone, MPH alone, combined CLON + MPH, or placebo (2 x 2 factorial design). Each subject participated for 16 weeks (weeks 1-4 CLON/placebo dose titration, weeks 5-8 added MPH/placebo dose titration, weeks 9-16 maintenance therapy). RESULTS Thirty-seven children were administered MPH alone, 34 were administered CLON alone, 33 were administered CLON + MPH, and 32 were administered placebo. For our primary outcome measure of ADHD (Conners Abbreviated Symptom Questionnaire--Teacher), significant improvement occurred for subjects assigned to CLON (p < 0.002) and those assigned to MPH (p < 0.003). Compared with placebo, the greatest benefit occurred with combined CLON + MPH (p < 0.0001). CLON appeared to be most helpful for impulsivity and hyperactivity; MPH appeared to be most helpful for inattention. The proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH (20%) than those being administered CLON alone (26%) or placebo (22%). Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone. Sedation was common with CLON treatment (28% reported moderate or severe sedation), but otherwise the drugs were tolerated well, including absence of any evident cardiac toxicity. CONCLUSIONS Methylphenidate and clonidine (particularly in combination) are effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.

Contemporary Assessment and Pharmacotherapy of Tourette Syndrome

SummaryTo develop a guide to clinical assessment and pharmacotherapy for children and adults with Tourette syndrome (TS), we reviewed published literature over the past 25 years to identify original articles and reviews on the assessment and pharmacological treatment of Tourette syndrome, attention—deficit/hyperactivity disorder (ADHD) and obsessive—compulsive disorder (OCD). The literature search also included a survey of reviews published in book chapters. The assessment section was compiled from several reviews. Pharmacological treatments were classified into those with strong empirical support (as evidenced by two positive placebo-controlled studies for tics, OCD, or ADHD in TS samples); modest empirical support (one positive placebo-controlled study), or minimal support (open-label data only). We conclude that accurate diagnosis, including identification of comorbid conditions, is an essential step toward appropriate treatment for patients with TS. In many patients with TS, symptom management requires pharmacotherapy for tics or coexisting conditions. The evidence supporting efficacy and safety for medications used in patients with TS varies. But this evidence offers the best guide to clinical practice.

Explosive outbursts in children with Tourette's disorder

OBJECTIVE Sudden, explosive outbursts of behavior occur in some children with Tourettes disorder (TD). The etiology of these symptoms is unknown. This study investigated the relationship between explosive outbursts, TD, and its comorbid disorders. METHOD Tic type and severity and the presence of specific comorbid disorders were compared in 37 children with TD and explosive outbursts and 31 children with TD who did not have such symptoms. RESULTS Children with TD and explosive outbursts were more likely to demonstrate significant comorbid conditions, particularly attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and oppositional defiant disorder. Tic type and severity did not appear related to the presence of explosive outbursts. A highly significant relationship was demonstrated between the number of comorbid psychiatric diagnoses and explosive outbursts. CONCLUSIONS Explosive outbursts in children with TD resemble intermittent explosive disorder and may reflect dysregulation of diverse domains of brain function. The presence of such symptoms should alert the clinician to underlying comorbid conditions.

Genome-wide association study of Tourette's syndrome

Tourettes syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Clinical phenomenology of episodic rage in children with Tourette syndrome.

OBJECTIVE Episodic rage of unknown etiology causes significant morbidity in children with Tourettes syndrome (TS). Using modified Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for intermittent explosive disorder (IED), we developed a screen and symptom questionnaire to explore rage attack phenomenology and to preliminarily investigate whether symptom clusters can identify clinical subgroups of TS children with rage attacks. METHODS 48 children with TS between ages 7 and 17 years consecutively presenting with rage attacks completed the Rage Attacks Screen and Questionnaire. Data was subjected to factor analysis. Cluster analytic procedures were used to identify clinical subgroups. RESULTS Final cluster solution revealed four homogeneous subgroups of TS children with rage who were differentiated by predominant clinical characteristics: specific urge resolution, environmentally secure reactivity, nonspecific urge resolution or labile nonresolving. CONCLUSION Episodic rage in TS has stereotypic features, but diverse and complex etiologies. Identifying particular symptom clusters may facilitate improved treatment strategies.

Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control

Background: Self injurious behaviour (SIB), the deliberate, repetitive infliction of self harm, is present in a wide variety of neuropsychiatric disorders, including Tourette syndrome (TS). Although SIB occurs in up to 60% of individuals with TS, and can cause significant clinical impairment and distress, little is known about its aetiology. Objective: This study examined the relationship between SIB and other behavioural features that commonly co-occur with TS in nearly 300 subjects with TS participating in three genetic studies. SIB, obsessions, compulsions, tic severity, attention deficit hyperactivity disorder related impulsivity, risk taking behaviours, and rages were systematically assessed in all subjects. Methods: Using logistic regression, a best fit model was determined for both mild to moderate SIB and severe SIB. Results: Mild/moderate SIB in TS was correlated with the presence of obsessive and compulsive symptoms such as the presence of aggressive obsessions or violent or aggressive compulsions, and with the presence of obsessive−compulsive disorder and overall number of obsessions. Severe SIB in TS was correlated with variables related to affect or impulse dysregulation; in particular, with the presence of episodic rages and risk taking behaviours. Both mild/moderate and severe SIB were also correlated with tic severity. Conclusions: This study suggests that mild/moderate and severe SIB in TS may represent different phenomena, which has implications for clinical management of these symptoms.

Aripiprazole in children and adolescents with Tourette disorder with and without explosive outbursts.

OBJECTIVE We conducted a retrospective, observational study of aripiprazole for the treatment of tics and/or co-morbid explosive outbursts in 37 children and adolescents with Tourette disorder (TD). METHOD Thirty seven children and adolescents with TD, with and without explosive outbursts, and refractory to previous treatment were treated at one of two university affiliated specialty clinics. All diagnoses were made using Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria. Tic severity was rated using the Clinical Global Impressions Scale for tics (CGI-Tics) and frequency of explosive outbursts was assessed using the CGI-Rage; both measures were obtained at pretreatment baseline and at posttreatment follow up. RESULTS High rates of psychiatric co-morbidity were observed in these subjects: 31 of 37 (84%) subjects met criteria for obsessive-compulsive disorder (OCD), and 31 of 37 (84%) met criteria for attention-deficit/hyperactivity disorder (ADHD). Twenty nine of 37 (78%) subjects met criteria for intermittent explosive disorder (IED) minus criterion C; the remaining 8 subjects had TD only. Eight subjects (22%) discontinued treatment before 12 weeks due to inability to tolerate the drug. At follow up, tics reduced at a mean daily dose of 12.3 (7.50) mg in 29 of 29 (100%) subjects who completed the study, and explosive outbursts improved in 24/25 subjects (96%) who completed the study. Aripiprazole was tolerated reasonably well, although 8/37 (22%) subjects discontinued treatment; most common side effects included weight gain, akathisia, and sedation. CONCLUSION Aripiprazole should be investigated further as a treatment option for TD with and without co-morbid explosive outbursts.

Atomoxetine Treatment of ADHD in Children With Comorbid Tourette Syndrome

Objective: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). Method: Subjects (7-17 years old) with ADHD (Diagnostic and Statistical Manual of Mental Disorders, DSM-IV) and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine (0.5-1.5 mg/kg/day, n = 61) for approximately 18 weeks. Results: Atomoxetine subjects showed significantly greater improvement on ADHD symptom measures. Treatment was also associated with significantly greater reduction of tic severity on two of three measures. Significant increases were seen in mean pulse rate and rates of treatment-emergent nausea, decreased appetite, and decreased body weight. No other clinically relevant treatment differences were observed in any other vital sign, adverse event, laboratory parameter, or electrocardiographic measure. Conclusion: Atomoxetine is efficacious for treatment of ADHD and its use appears well tolerated in ADHD patients with comorbid TS. (J. of Att. Dis. 2008; 11(4) 470-481)

THE COURSE AND PROGNOSIS OF TOURETTE SYNDROME

The view of Tourette syndrome as a lifelong disorder, once held as a certainty, has changed considerably in the past two decades. It is now known that in the majority of cases, tics will ebb in severity and will no longer be problematic in the adult years. This discovery, however, has been accompanied by the realization that Tourette syndrome is a far more complex disorder than was originally discerned and that it has many unanswered questions.

Tic Symptom Profiles in Subjects with Tourette Syndrome from two Genetically Isolated Populations

BACKGROUND Tourette Syndrome (TS) has a complex etiology and wide variability in phenotypic expression. Identifying underlying symptom patterns may be useful for etiological and outcome studies of TS. METHODS Lifetime tic and related symptom data were collected between 1996 and 2001 in 121 TS subjects from the Central Valley of Costa Rica and 133 TS subjects from the Ashkenazi Jewish (AS) population in the US. Subjects were grouped by tic symptoms using an agglomerative hierarchical cluster analysis. Cluster membership was tested for association with available ancillary information (age of onset, tic severity, comorbid disorders, medication treatment and family history). RESULTS Cluster analysis identified two distinct groups in each sample, those with predominantly simple tics (cluster 1), and those with multiple complex tics (cluster 2). Membership in cluster 2 was correlated with increased tic severity, global impairment, medication treatment, and presence of comorbid obsessive-compulsive symptoms in both samples, and with family history of tics, lower verbal IQ, earlier age of onset, and comorbid obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in the AS sample. CONCLUSIONS This study provides evidence for consistent and reproducible symptom profiles in two independent TS study samples. These findings have implications for etiological studies of TS.