Yves Dion

Risperidone in the treatment of tourette syndrome: a double-blind, placebo-controlled trial.

A double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 weeks of treatment with risperidone in the management of 48 adolescent and adult patients with Tourette syndrome. Twenty-four patients were randomly assigned to treatment with risperidone in doses of 0.5 to 6.0 mg/day, and 24 were assigned to placebo. The dosage of medication was increased in fixed increments during the first week of double-blind treatment and thereafter in a flexible dose regimen according to clinical response. Risperidone, at a median dose of 2.5 mg/day (range, 1 to 6 mg/day), was found to be significantly (p < 0.05) superior to placebo on the Global Severity Rating of the Tourette Syndrome Severity Scale. The proportion of patients who improved by at least one point on this seven-point scale was 60.8% in the risperidone group and 26.1% in the placebo group. Treatment with risperidone was accompanied by an improvement in global functioning in patients with average to above-average impairment at baseline as measured by the Global Assessment of Functioning scale. With respect to extrapyramidal symptom scores measured on the Extrapyramidal Symptom Rating Scale, hypokinesia and tremor increased in the risperidone group, but the effect on tremor was largely confined to subjects with higher baseline tremor scores. There were no significant differences in dystonic reactions, dyskinetic movements, subjective parkinsonism, or akathisia. Risperidone did not increase obsessive-compulsive symptoms. Fatigue and somnolence were the most common adverse events associated with risperidone.

Lifetime Prevalence, Age of Risk, and Genetic Relationships of Comorbid Psychiatric Disorders in Tourette Syndrome

IMPORTANCE Tourette syndrome (TS) is characterized by high rates of psychiatric comorbidity; however, few studies have fully characterized these comorbidities. Furthermore, most studies have included relatively few participants (<200), and none has examined the ages of highest risk for each TS-associated comorbidity or their etiologic relationship to TS. OBJECTIVE To characterize the lifetime prevalence, clinical associations, ages of highest risk, and etiology of psychiatric comorbidity among individuals with TS. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional structured diagnostic interviews conducted between April 1, 1992, and December 31, 2008, of participants with TS (n = 1374) and TS-unaffected family members (n = 1142). MAIN OUTCOMES AND MEASURES Lifetime prevalence of comorbid DSM-IV-TR disorders, their heritabilities, ages of maximal risk, and associations with symptom severity, age at onset, and parental psychiatric history. RESULTS The lifetime prevalence of any psychiatric comorbidity among individuals with TS was 85.7%; 57.7% of the population had 2 or more psychiatric disorders. The mean (SD) number of lifetime comorbid diagnoses was 2.1 (1.6); the mean number was 0.9 (1.3) when obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) were excluded, and 72.1% of the individuals met the criteria for OCD or ADHD. Other disorders, including mood, anxiety, and disruptive behavior, each occurred in approximately 30% of the participants. The age of greatest risk for the onset of most comorbid psychiatric disorders was between 4 and 10 years, with the exception of eating and substance use disorders, which began in adolescence (interquartile range, 15-19 years for both). Tourette syndrome was associated with increased risk of anxiety (odds ratio [OR], 1.4; 95% CI, 1.0-1.9; P = .04) and decreased risk of substance use disorders (OR, 0.6; 95% CI, 0.3-0.9; P = .02) independent from comorbid OCD and ADHD; however, high rates of mood disorders among participants with TS (29.8%) may be accounted for by comorbid OCD (OR, 3.7; 95% CI, 2.9-4.8; P < .001). Parental history of ADHD was associated with a higher burden of non-OCD, non-ADHD comorbid psychiatric disorders (OR, 1.86; 95% CI, 1.32-2.61; P < .001). Genetic correlations between TS and mood (RhoG, 0.47), anxiety (RhoG, 0.35), and disruptive behavior disorders (RhoG, 0.48), may be accounted for by ADHD and, for mood disorders, by OCD. CONCLUSIONS AND RELEVANCE This study is, to our knowledge, the most comprehensive of its kind. It confirms the belief that psychiatric comorbidities are common among individuals with TS, demonstrates that most comorbidities begin early in life, and indicates that certain comorbidities may be mediated by the presence of comorbid OCD or ADHD. In addition, genetic analyses suggest that some comorbidities may be more biologically related to OCD and/or ADHD rather than to TS.

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.

Canadian Guidelines for the Evidence-Based Treatment of Tic Disorders: Pharmacotherapy:

This article seeks to provide the practising clinician with guidance on the pharmacological management of tic disorders in children and adults. We performed a systematic review of the literature on the treatment of tic disorders. A multi-institutional group of 14 experts in psychiatry, child psychiatry, neurology, pediatrics, and psychology engaged in a consensus meeting. The evidence was presented and discussed, and nominal group techniques were employed to arrive at consensus on recommendations. A strong recommendation is made when the benefits of treatment clearly outweigh the risks and burdens, and can apply to most patients in most circumstances without reservation. With a weak recommendation, the benefits, risks, and burdens are more closely balanced, and the best action may differ depending on the circumstances. Based on these principles, weak recommendations were made for the use of pimozide, haloperidol, fluphenazine, metoclopramide (children only), risperidone, aripiprazole, olanzapine, quetiapine, ziprasidone, topiramate, baclofen (children only), botulinum toxin injections, tetrabenazine, and cannabinoids (adults only). Strong recommendations were made for the use of clonidine and guanfacine (children only). While the evidence supports the efficacy of many of the antipsychotics for the treatment of tics, the high rates of side effects associated with these medications resulted in only weak recommendations for these drugs. In situations where tics are not severe or disabling, the use of a medication with only a weak recommendation is not warranted. However, when tics are more distressing and interfering, the need for tic suppression to improve quality of life is stronger, and patients and clinicians may be more willing to accept the risks of pharmacotherapy.

Canadian Guidelines for the Evidence-Based Treatment of Tic Disorders: Behavioural Therapy, Deep Brain Stimulation, and Transcranial Magnetic Stimulation:

This clinical guideline provides recommendations for nonpharmacological treatments for tic disorders. We conducted a systematic literature search for clinical trials on the treatment of tics. One evidence-based review (including 30 studies) and 3 studies on behavioural interventions, 3 studies on deep brain stimulation (DBS), and 3 studies on transcranial magnetic stimulation (TMS) met our inclusion criteria. Based on this evidence, we have made strong recommendations for the use of habit reversal therapy and exposure and response prevention, preferably embedded within a supportive, psychoeducational program, and with the option to combine either of these approaches with pharmacotherapy. Although evidence exists for the effcacy of DBS, the quality of this evidence is poor and the risks and burdens of the procedure are fnely balanced with the perceived benefts. Our recommendation is that this intervention continues to be considered an experimental treatment for severe, medically refractory tics that have imposed severe limitations on quality of life. We recommend that the procedure should only be performed within the context of research studies and by physicians expert in DBS programming and in the management of tics. There is no evidence to support the use of TMS in the treatment of tics. However, the procedure is associated with a low rate of known complications and could continue to be evaluated within research protocols. The recommendations we provide are based on current knowledge, and further studies may result in their revision in future.

Social disinhibition is a heritable subphenotype of tics in Tourette syndrome

Objective: To identify heritable symptom-based subtypes of Tourette syndrome (TS). Methods: Forty-nine motor and phonic tics were examined in 3,494 individuals (1,191 TS probands and 2,303 first-degree relatives). Item-level exploratory factor and latent class analyses (LCA) were used to identify tic-based subtypes. Heritabilities of the subtypes were estimated, and associations with clinical characteristics were examined. Results: A 6-factor exploratory factor analysis model provided the best fit, which paralleled the somatotopic representation of the basal ganglia, distinguished simple from complex tics, and separated out socially disinhibited and compulsive tics. The 5-class LCA model best distinguished among the following groups: unaffected, simple tics, intermediate tics without social disinhibition, intermediate with social disinhibition, and high rates of all tic types. Across models, a phenotype characterized by high rates of social disinhibition emerged. This phenotype was associated with increased odds of comorbid psychiatric disorders, in particular, obsessive-compulsive disorder and attention-deficit/hyperactivity disorder, earlier age at TS onset, and increased tic severity. The heritability estimate for this phenotype based on the LCA was 0.53 (SE 0.08, p 1.7 × 10−18). Conclusions: Expanding on previous modeling approaches, a series of TS-related phenotypes, including one characterized by high rates of social disinhibition, were identified. These phenotypes were highly heritable and may reflect underlying biological networks more accurately than traditional diagnoses, thus potentially aiding future genetic, imaging, and treatment studies.

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome

OBJECTIVE Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts. METHOD Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated. RESULTS The authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not. CONCLUSIONS The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.

Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis

Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis.

Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome

BACKGROUND The unique phenotypic and genetic aspects of obsessive-compulsive (OCD) and attention-deficit/hyperactivity disorder (ADHD) among individuals with Tourette syndrome (TS) are not well characterized. Here, we examine symptom patterns and heritability of OCD and ADHD in TS families. METHOD OCD and ADHD symptom patterns were examined in TS patients and their family members (N = 3494) using exploratory factor analyses (EFA) for OCD and ADHD symptoms separately, followed by latent class analyses (LCA) of the resulting OCD and ADHD factor sum scores jointly; heritability and clinical relevance of the resulting factors and classes were assessed. RESULTS EFA yielded a 2-factor model for ADHD and an 8-factor model for OCD. Both ADHD factors (inattentive and hyperactive/impulsive symptoms) were genetically related to TS, ADHD, and OCD. The doubts, contamination, need for sameness, and superstitions factors were genetically related to OCD, but not ADHD or TS; symmetry/exactness and fear-of-harm were associated with TS and OCD while hoarding was associated with ADHD and OCD. In contrast, aggressive urges were genetically associated with TS, OCD, and ADHD. LCA revealed a three-class solution: few OCD/ADHD symptoms (LC1), OCD & ADHD symptoms (LC2), and symmetry/exactness, hoarding, and ADHD symptoms (LC3). LC2 had the highest psychiatric comorbidity rates (⩾50% for all disorders). CONCLUSIONS Symmetry/exactness, aggressive urges, fear-of-harm, and hoarding show complex genetic relationships with TS, OCD, and ADHD, and, rather than being specific subtypes of OCD, transcend traditional diagnostic boundaries, perhaps representing an underlying vulnerability (e.g. failure of top-down cognitive control) common to all three disorders.

Prevalence and predictors of hair pulling disorder and excoriation disorder in Tourette syndrome

Trichotillomania/hair pulling disorder (HPD) and excoriation/skin picking disorder (SPD) are childhood-onset, body-focused repetitive behaviors that are thought to share genetic susceptibility and underlying pathophysiology with obsessive–compulsive disorder (OCD) and Tourette syndrome (TS). We sought to determine the prevalence of DSM-5 HPD and SPD in TS patients, and to identify clinical factors most associated with their co-morbidity with TS. Participants included 811 TS patients recruited from TS specialty clinics for a multi-center genetic study. Patients were assessed using standardized, validated semi-structured interviews. HPD and SPD diagnoses were determined using a validated self-report questionnaire. HPD/SPD prevalence rates were calculated, and clinical predictors were evaluated using regression modeling. 3.8 and 13.0% of TS patients met DSM-5 criteria for HPD and SPD, respectively. In univariable analyses, female sex, OCD, and both tic and obsessive–compulsive symptom severity were among those associated with HPD and/or SPD. In multivariable analyses, only lifetime worst-ever motor tic severity remained significantly associated with HPD. Female sex, co-occurring OCD, ADHD, and motor tic severity remained independently associated with SPD. This is the first study to examine HPD and SPD prevalence in a TS sample using semi-structured diagnostic instruments. The prevalence of HPD and SPD in TS patients, and their association with increased tic severity and co-occurring OCD, suggests that clinicians should screen children with TS and related disorders for HPD/SPD, particularly in females and in those with co-occurring OCD. This study also helps set a foundation for subsequent research regarding HPD/SPD risk factors, pathophysiology, and treatment models.