Genome-wide association study of Tourette's syndrome.

Tourette's 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.

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.

An open-label study of the treatment efficacy of olanzapine for Tourette's disorder.

BACKGROUND: An open-label trial was performed to explore efficacy and safety of olanzapine, an atypical neuroleptic with diverse receptor activity including both dopamine-2 and serotonin-2A and -2C antagonism, for treatment of Tourette's disorder. METHOD: Ten adult patients aged 20 to 44 years with Tourette's disorder were treated using an open-label, flexible dosing schedule for 8 weeks. Three patients who continued olanzapine were reevaluated after 6 months. Three subjects were psychotropic medication naive, 5 patients experienced intolerable side effects with conventional neuroleptics, and 2 patients had remote (> or = 10 years) successful response to conventional neuroleptics. Tic severity was rated by the Yale Global Tic Severity Scale; weight, vital signs, and adverse effects were assessed weekly. Electrocardiogram, laboratory studies, and comorbid symptoms, assessed by the Yale-Brown Obsessive Compulsive Scale and ADHD Behavior Checklist for Adults, were measured at baseline and at week 8. RESULTS: Two of 10 patients prematurely discontinued olanzapine owing to excessive sedation. Of 8 patients who completed the 8-week trial, 4 (50%) demonstrated reduction of global tic severity scores by > or = 20 points, and 6 (75%) demonstrated reductions by > or = 10 points. No significant changes in comorbid symptoms were demonstrated. Sedation, weight gain, increased appetite, dry mouth, and transient asymptomatic hypoglycemia were the most common side effects. Tic improvements were maintained in 3 patients reassessed 6 months later. Final olanzapine dosages ranged from 2.5 mg to 20 mg daily (mean = 10.9 mg/day). CONCLUSION: This open-label study suggests that olanzapine should be explored as a potential alternative to conventional neuroleptic medications for treatment of motor tics and Tourette's disorder.

Explosive outbursts in children with Tourette's disorder.

OBJECTIVE: Sudden, explosive outbursts of behavior occur in some children with Tourette's 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.

Rage attacks in children and adolescents with Tourette's disorder: a pilot study.

BACKGROUND: Sudden, explosive episodes of rage occur in a significant number of clinically referred children with Tourette's disorder and cause considerable psychosocial morbidity. The etiology of these symptoms is unknown. We conducted a pilot study of 12 consecutive children with Tourette's disorder and rage attacks to determine whether comorbidity of Tourette's-associated disorders is related to these symptoms. METHOD: Twelve consecutive children with Tourette's disorder who presented with rage attacks were evaluated, including 2 females and 10 males. Tourette's disorder diagnosis, presence of comorbid disorders, and tic severity were assessed using DSM-IV diagnostic criteria and standardized rating scales. RESULTS: All 12 children met diagnostic criteria for Tourette's disorder, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). Two children were also diagnosed with comorbid oppositional defiant disorder, and 4 children were diagnosed with comorbid conduct disorder. None of the subjects met diagnostic criteria for a mood disorder. All subjects had only mild tic severity. CONCLUSION: The clinical phenomenon of rage attacks in children with Tourette's disorder resembles intermittent explosive disorder and may reflect specific underlying neurologic disturbances. This pilot study suggests that rage attacks in Tourette's disorder may be related to the presence of comorbid disorders.

Paroxetine treatment of episodic rages associated with Tourette's disorder.

BACKGROUND: Episodic rages have been estimated to occur in as many as 30% of patients with Tourette's syndrome (Tourette's disorder), but their treatment has never been systematically investigated. We report on the results of an open-label pilot study using paroxetine for the treatment of Tourette's disorder-associated rage episodes. METHOD: Forty-five Tourette's/rage patients (DSM-IV) were treated with paroxetine, specifically to control their rages. Other symptoms such as tics, attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) were not targeted by this study. Treatment was deemed to be therapeutic when rage symptoms were diminished by 75% or more by patient report and were diminished in frequency by at least 1 point on a 4-point scale devised by the authors. RESULTS: After 8 weeks on paroxetine treatment, 29 patients (76% of those who completed the study) reported that rages were significantly diminished or completely absent. Nine patients reported no significant change in rages. Seven patients did not complete the study (3 because of side effects and 4 whose rage frequency increased). The mean dose of paroxetine was 33 mg/day; minimum effective dose was 15 mg/day. CONCLUSION: We were unable to determine any factors that significantly altered the efficacy of paroxetine for treatment of Tourette's disorder-associated rage episodes. The great majority (87%) of the patients had both ADHD and OCD in addition to Tourette's disorder. The age, sex, and concomitant use of other medications revealed no significant differences in treatment outcome. The results suggest that paroxetine may have an important role in the clinical treatment of episodic rages in Tourette's disorder patients.

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.

Risperidone as a treatment for Tourette's syndrome.

BACKGROUND: An open-label trial was performed to assess the efficacy and safety of risperidone, a benzisoxazole derivative with potent D2 and 5-HT2 antagonism, for treatment of Tourette's syndrome. METHOD: Thirty-eight patients with Tourette's syndrome volunteered to take risperidone for treatment of their tics. All patients had failed to respond adequately to conventional treatments (with neuroleptics such as haloperidol and/or with the alpha 2-adrenergic agonist clonidine) or had suffered from intolerable side effects from such treatments. Patients were rated for tic severity by the Yale Global Tic Severity Scale (YGTSS) before treatment and after 1 month of treatment with risperidone. Patients were monitored carefully for side effects and clinical response. RESULTS: Of the 38 patients, 8 discontinued risperidone treatment before the end of the trial because of intolerable side effects. At the end of the 4-week trial, 22 patients (58%) were improved, 7 patients (18%) had no appreciable change in their symptoms, and 1 patient (3%) had a documented worsening of tics. Doses of risperidone at the end of the trial ranged from 0.5 mg to 9 mg/day (mean = 2.7 mg/day). CONCLUSION: This open clinical trial suggests that risperidone may be a promising alternative to conventional medications used for treating the symptoms of Tourette's syndrome.

Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette's disorder.

A variety of side effects developed in children treated with neuroleptics for Tourette's disorder. Of 208 children, 34 manifested dose-related symptoms of dysphoria, nine experienced a worsening of symptoms of Tourette's disorder that was attributed to akathisia, five became hostile and aggressive, three developed "fog states" that disappeared with discontinuation of neuroleptics or treatment with primidone, and three experienced symptoms of tardive dyskinesia that resolved with time. This data base of neuroleptic-treated children with Tourette's disorder demonstrates a variety of subtle and underrecognized side effects that may not be as readily discernible in children receiving neuroleptics for a primary psychiatric disorder.

A follow-up of 78 patients with Gilles de la Tourette's syndrome.

The authors conducted a follow-up study of 78 patients with Gilles de la Tourette's syndrome. Four of the patients were in spontaneous remission; 59 patients taking haloperidol showed an average improvement of 79.3% and the remaining patients, 3 of whom were taking medication other than haloperidol and 12 of whom were not taking any medication, showed an average improvement of 24.7%. Side effects were the main cause of discontinuing haloperidol. The authors found that response to haloperidol was unrelated to family history of tics, age at onset, type or severity of symptoms, or signs of organicity.