Yale Global Tic Severity Scale Total Tic Score Research Articles

Randomized, double-blind, placebo-controlled trial of aripiprazole oral solution in children and adolescents with Tourette’s disorder

BackgroundAripiprazole is the most frequently recommended antipsychotic for the treatment of tics in children and adolescents with Tourette’s disorder (TD). However, to date, a randomized controlled trial for aripiprazole oral solution has not been conducted despite being widely preferred by children. Therefore, we examined whether aripiprazole oral solution is effective for treating tics.MethodsAll patients received a flexible dose of aripiprazole oral solution (1 mg/mL, range: 2–20 mg) with a starting dose of 2 mg. The target dose for patients weighing < 50 kg was 2, 5, and 10 mg/day, and that for patients weighing ≥ 50 kg was 5, 10, 15, and 20 mg/day. The primary efficacy endpoint was the mean change in the Yale Global Tic Severity Scale-total tic score (YGTSS-TTS) from baseline to week 8.ResultsOf the 121 patients enrolled, 59 patients (96.7%) in the aripiprazole group and 53 patients (88.3%) in the placebo group completed the study. The aripiprazole group showed significantly greater improvement in the YGTSS-TTS from baseline to week 8 than the placebo group (least squares mean difference [95% confidence interval (CI)] −5.5 [95% CI − 8.4 to − 2.6]). At week 8, the response rate (i.e., percentage of patients with a Tourette’s Syndrome Clinical Global Impression-Improvement score of 1 or 2) of the aripiprazole group (86.4%) was significantly higher than that of the placebo group (56.6%; odds ratio: 3.6, p < 0.001). The incidence of treatment-emergent adverse events (TEAEs) reported in at least one patient was 86.9% in the aripiprazole group and 65.5% in the placebo group. All TEAEs were mild or moderate in severity. No serious adverse events or deaths occurred during the study.ConclusionsOur findings suggest that aripiprazole oral solution is an effective, well-tolerated, and safe treatment for children and adolescents with TD.Trial registrationClinicalTrials.gov Identifier: NCT03487783. Registered 4 April 2018.

Correlations of altered functional connectivity in resting-state fMRI and symptom severity in tic disorders

IntroductionVocal and motor tics are characteristic for Tic disorders (TD) and Tourette’s syndrome (APA 2022) . Because of the pathophysiology of the disorders not being fully understood and the presence of the externally measurable symptoms; great attention has been paid to the cortico-striatal regions of patients with TD . In addition to the alterations in motor symptoms patients can experience a premonitory urge (PU) which can be felt before a tic (Reese et al. Behav. Ther. 2014; 45 177–186) . Previous studies found an impact of these urges on sensory perception, attention and social cognition as well as an involvement of the brain regions insula, anterior cingulate cortex (ACC) and the temporoparietal junction (TPJ) (Seeley J. Neurosci. 2019; 39 9878–9882, Kucyi et al. J. Neurophysiol. 2012; 108 3382–3392, Uddin et al. Brain Topogr. 2019; 32 926–942) . These findings lead to the idea of altered functional connectivity of the salience network (SN) in patients with TD.ObjectivesThis study aims to investigate the connectivity changes of the SN in patients with TD. We examined functional resting-state scans of patients with TD and searched for possible correlations between the tic and PU severity and the connectivity of the SN.Methods 21 Patients (mean age: 30.9 years ± 10.0 [range = 19–57], 6 females) diagnosed with TD, and 20 healthy controls (mean age: 29.7 years ± 8.9 [range = 18–50], 5 females) underwent a resting-state fMRI scan. Functional and anatomical images were conducted on a 3T Siemens Prisma fit MRI scanner. PU and tic severity were measured by the Premonitory Urges for Tics Scale (PUTS) and the Yale Global Tic Severity Scale (YGTSS). The connectivity analysis of the resting-state scans was done using the CONN toolbox v21.a. After pre-processing and de-noising steps, a whole-brain seed-based connectivity analysis was carried out with the seeds being the major cortical nods of the SN. For the correlation analysis a linear regression of the YGTSS score/PUTS score and the brain connectivity of the seed regions was conducted.ResultsThe PUTS score was 25.3±5.4 (range 10-33) and the YGTSS total tic score was 23.1±7.9 (range 10-38) for the patients. The connectivity analysis revealed a significant difference in connectivity between the groups for the ACC, the right insula and the TPJ. A negative correlation between the YGTSS scores and the connectivity of the left insula and the right superior frontal gyrus (SFG) was shown in the correlation analysis. No significant correlation was found for the PUTS scores in the investigated seed regions.ConclusionsThe right SFG mediates motor urgency and inhibitory control. Since we found a negative correlation between the insula and the right SFG regarding to higher YGTSS scores of the patients, our results might shed some light on the pathophysiology regarding lower inhibitory control in patients which experience higher tic severity.Disclosure of InterestNone Declared

Prospective follow-up study of youth and adults with onset of functional tic-like behaviours during the COVID-19 pandemic.

Very little is known about the long-term prognosis of patients with functional tic-like behaviours (FTLBs). We sought to characterize the trajectory of symptom severity over a 12-month period. Patients with FTLBs were included in our prospective longitudinal child and adult clinical tic disorder registries at the University of Calgary. Patients were prospectively evaluated 6 and 12 months after their first clinical visit. Tic inventories and severity were measured with the Yale Global Tic Severity Scale (YGTSS). Eighty-three youths and adults with FTLBs were evaluated prospectively until April 2023. Mean YGTSS total tic severity scores were high at baseline, with a mean score of 29.8 points (95% confidence interval [CI] = 27.6-32.1). Fifty-eight participants were reevaluated at 6 months, and 32 participants were reevaluated at 12 months. The YGTSS total tic severity score decreased significantly from the first clinical visit to 6 months (raw mean difference = 8.9 points, 95% CI = 5.1-12.7, p < 0.0001), and from 6 to 12 months (raw mean difference = 6.4 points, 95% CI = 0.8-12.0, p = 0.01). Multivariable linear regression demonstrated that tic severity at initial presentation and the presence of other functional neurological symptoms were associated with higher YGTSS total tic scores at 6 months, whereas younger age at baseline, receiving cognitive behavioural therapy for anxiety and/or depression, and prescription of selective serotonin reuptake inhibitors were associated with lower YGTSS total tic scores at 6 months. We observed a meaningful improvement in tic severity scores in youth and adults with FTLBs over a period of 6-12 months.

Safety and Efficacy of Long-Term Deutetrabenazine Use in Children and Adolescents with Tics Associated with Tourette Syndrome: An Open-Label Extension Study.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics. To assess the safety and efficacy of deutetrabenazine (Teva Neuroscience, Inc, Parsippany, NJ), a vesicular monoamine transporter 2 inhibitor, in children and adolescents with TS. Alternatives for Reducing Tics in TS (ARTISTS) open-label extension (OLE) (NCT03567291) was a 54-week, global, phase 3, open-label extension study of deutetrabenazine (6-48 mg daily) conducted May 28, 2018 to April 3, 2020 with a 2-week randomized withdrawal period. Participants (6-16 years of age) had TS and active tics causing distress or impairment. Safety (primary outcome) was assessed by treatment-emergent adverse events (TEAEs) and clinical laboratory testing. Efficacy was measured by the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS). The intent-to-treat population (228 participants; mean age, 12.0 years; 79.8% male; 86.4% white) had a median (range) duration of exposure of 28.4 (0.3-52.9) weeks. Of 227 participants in the safety analysis, 161 (70.9%) reported ≥1 TEAE (exposure-adjusted incidence rate, 2.77/patient-year), of which 95 (41.9%) were treatment related. The most frequently reported TEAEs were headaches, somnolence, nasopharyngitis, weight increases, and anxiety. No additional safety signals were observed. Worsening of YGTSS-TTS after the 2-week randomized withdrawal was not statistically significant (least squares mean difference, -0.4; P = 0.78). Several exploratory measures showed sustained improvement throughout the treatment periods. In this long-term, open-label trial, deutetrabenazine was well tolerated with low frequency of TEAEs. There was no significant difference in tics between treatment arms during the 2-week randomized withdrawal period, however, descriptive statistics and comparison with baseline showed a numeric improvement in tics, quality of life, and other measures.

Increasing Ecopipam Exposure Improves Yale Global Tic Severity Scale-Total Tic Scores (YGTSS-TTS) in Children and Adolescents with Tourette Syndrome (TS): Results from a Population Pharmacokinetic (popPK) Model-Based Simulation Using D1AMOND Trial Data (P5-9.007)

<h3>Objective:</h3> To develop popPK and exposure-response (E-R) models to characterize the relationship between ecopipam concentrations and efficacy as well as safety in children and adolescents (ages 6 to &lt;18 years) with TS. <h3>Background:</h3> Ecopipam is a first-in-class selective dopamine-1 receptor antagonist in development for TS. Results from the 12-week randomized, double-blind placebo-controlled phase 2b D1AMOND trial demonstrated 2 mg/kg/day ecopipam significantly reduced motor and phonic tics (YGTSS-TTS) and was well-tolerated. Understanding the PK of ecopipam and its active metabolite, the intrinsic/extrinsic factors affecting variability, and the relationships between exposure and efficacy/safety in TS are key to perform model-based simulations to ensure the optimal dose in TS. <h3>Design/Methods:</h3> In D1AMOND, a responder was defined as a ≥25% improvement in YGTSS-TTS. Logistic regression modeling was used to determine the relationship between responder status and exposure (area-under-the-curve, AUC) of ecopipam and its active metabolite (E+M) in children and adolescents with TS. <h3>Results:</h3> The steady-state (E+M) AUC exposure predicted clinical YGTSS-TTS responders at week 12. A 2-compartment model with first-order absorption and elimination described plasma concentration-time data for ecopipam and a 1-compartment model with first order elimination described the active metabolite concentration-time data. The final logistic regression model was based on the combined steady-state AUC for E+M as a univariate predictor for a clinical responder. The odds of ≥25% improvement in YGTSS-TTS increased near linearly by 6.8% for each 100 unit increase in E+M steady-state AUC. E-R modeling of safety parameters was not performed as there were not enough adverse events in the study to model. <h3>Conclusions:</h3> These data demonstrate a positive relationship between ecopipam exposure and efficacy in pediatric patients with TS. This study validates the D1AMOND trial ecopipam dosing and informed the posology for a confirmatory Phase 3 trial, currently recruiting patients. <b>Disclosure:</b> Dr. Freidy has received personal compensation for serving as an employee of Allucent. Dr. Pene Dumitrescu has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Allucent. Dr. Pene Dumitrescu has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for TEVA Pharmaceutics. Dr. Pene Dumitrescu has stock in GlaxoSmithkline. Dr. Schmith has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Emalex Biosciences. Dr. Schmith has received research support from Emalex BIosciences. The institution of Dr. Gilbert has received research support from NIMH. The institution of Dr. Gilbert has received research support from Emalex. The institution of Dr. Gilbert has received research support from Erydel. The institution of Dr. Gilbert has received research support from PTC Therapeutics. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Medical Second Opinion Expert with Teldoc/Advanced Medical. Dr. Gilbert has received personal compensation in the range of $5,000-$9,999 for serving as a Medical Expert with Department of Health and Human Services/Vaccine Injury Compensation Program. Atul Mahableshwarkar has received personal compensation for serving as an employee of Emalex Biosciences. Atul Mahableshwarkar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ecor1 Capital. Atul Mahableshwarkar has stock in Johnson &amp; Johnson. Dr. Dubow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Paragon Biosciences. Dr. Dubow has stock in Avadel Pharmaceuticals. Dr. Cunniff has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Cunniff has stock in Harmony Biosciences. Dr. Cunniff has stock in Emalex Biosciences. Mr. Kim has received personal compensation for serving as an employee of Emalex Biosciences. Mrs. Miller has received personal compensation for serving as an employee of Emalex Biosciences. Mrs. Miller has stock in Emalex Biosciences. Dr. Wanaski has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Wanaski has stock in Paragon Biosciences.

Design of a Phase 3 Maintenance-of-Effect Trial of Ecopipam in Tourette Syndrome (P12-11.011)

<h3>Objective:</h3> To design an efficient, maintenance-of-effect trial for ecopipam in Tourette Syndrome (TS) while further informing the risk profile. <h3>Background:</h3> Ecopipam is a selective dopamine 1 receptor antagonist in development for TS. A 12-week, parallel group, Phase 2b trial of ecopipam in TS demonstrated a clinically meaningful, statistically significant reduction in tics without inducing weight gain, metabolic syndrome, EKG changes, or drug-induced movement disorders associated with dopamine 2 receptor antagonists. Ideally, a Phase 3 trial should both confirm efficacy and observe safety over a longer duration of exposure. <h3>Design/Methods:</h3> We designed an enriched-enrollment, randomized withdrawal (EERW) clinical trial to best meet maintenance-of-efficacy and safety objectives. All enrolled subjects receive ecopipam for 12 weeks. Those with a ≥25% improvement in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) at both weeks 8 and 12 are randomized, double-blinded, 1:1 to continue ecopipam or down-titrate to placebo, for an additional 12 weeks. The primary maintenance-of-effect endpoint is time-to-relapse where relapse is defined as 1. a ≥50% loss of the YGTSS-TTS improvement, 2. required use of tic rescue medication, or 3. hospitalization for TS. The trial completes when the number of relapses has reached the pre-specified target sufficient to differentiate ecopipam from placebo with 85% power. Trial simulations and sensitivity analysis were performed across key variables. <h3>Results:</h3> The number of relapses required is a function of the two relapse rates individually. Previous results suggest, conservatively, that 34% of participants randomized to ecopipam and 65% randomized to placebo will relapse, yielding a target of 49 relapse events for completion. Simulations informed both enrollment and duration requirements. <h3>Conclusions:</h3> This EERW design meets feasibility requirements, provides up to 24 weeks of safety data, and is powered to determine maintenance of efficacy of ecopipam for TS while reducing placebo exposure for this serious disorder. <b>Disclosure:</b> Dr. Cunniff has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Cunniff has stock in Harmony Biosciences. Dr. Cunniff has stock in Emalex Biosciences. The institution of Dr. Gilbert has received research support from NIMH. The institution of Dr. Gilbert has received research support from Emalex. The institution of Dr. Gilbert has received research support from Erydel. The institution of Dr. Gilbert has received research support from PTC Therapeutics. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Medical Second Opinion Expert with Teldoc/Advanced Medical. Dr. Gilbert has received personal compensation in the range of $5,000-$9,999 for serving as a Medical Expert with Department of Health and Human Services/Vaccine Injury Compensation Program. Dr. Wanaski has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Wanaski has stock in Paragon Biosciences. Dr. Bittman has stock in IQVIA. Dr. Bittman has received personal compensation in the range of $100,000-$499,999 for serving as a President with Bittman Biostat, Inc.. Dr. Dubow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Paragon Biosciences. Dr. Dubow has stock in Avadel Pharmaceuticals. Atul Mahableshwarkar has received personal compensation for serving as an employee of Emalex Biosciences. Atul Mahableshwarkar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ecor1 Capital. Atul Mahableshwarkar has stock in Johnson &amp; Johnson.

The Rush Video-Based Tic Rating Scale-Revised: A Practice-Oriented Revision.

The Modified Rush Video-Based Tic Rating Scale (MRVS) is the most widely used video-based scale for assessing tic severity in patients with Tourette syndrome (TS). However, shortcomings of the MRVS, including a lack of clear instructions, a time-consuming recording procedure, and weak correlations with the gold standard for tic assessment, the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS), limits its use in research settings, although video assessments are generally considered objective, reliable, and time-saving measurements. We aimed to revise the MRVS (MRVS-R) to simplify and standardize the assessment procedure and improve the correlation with the YGTSS-TTS. We used 102 videos of patients with TS or persistent motor tic disorder filmed according to the MRVS. We compared the tic frequency assessed by MRVS with frequencies according to MRVS-R based on a 5-min (instead of a 10-min) video to investigate whether reducing the recording time leads to significant changes. In addition, we adapted the MRVS to the YGTSS and defined new anchor values for motor and phonic tic frequency based on frequency distributions as assessed in our sample. Finally, we compared the MRVS-R and MRVS regarding psychometric properties and correlation with the YGTSS-TTS. Cutting video recording time in half did not significantly affect assessments of motor and phonic tic frequencies. Psychometric properties were acceptable. Most important, proposed revisions of the MRVS improved correlation with the YGTSS-TTS. The MRVS-R is a simplified version of the MRVS with comparable psychometric qualities, but higher correlations with the YGTSS-TTS.

Efficacy and safety of Jiu-Wei-Xi-Feng granules for treating tic disorders in children: study protocol for a randomized controlled equivalence trial

BackgroundTic disorders (TD) is a neuropsychiatric disease with twitch as the main manifestation in childhood. Jiu-Wei-Xi-Feng granules has been marketed in China for treating children with TD. As Long Gu (Os Draconis) in the composition of this Chinese patent medicine is a rare and expensive medicinal material protected by the Chinese government, therefore, we consider replacing it with Mu Li (Concha Ostreae) that has the same effect and is cheaper. This study is designed to evaluate the clinical equivalence between Jiu-Wei-Xi-Feng granules (Os Draconis replaced by Concha Ostreae) (JWXFD) and Jiu-Wei-Xi-Feng granules (original formula) (JWXFO) in children with TD (consumption of renal yin and liver wind stirring up internally syndrome).Methods/designThis is a multicenter, randomized, double-blind, equivalence trial comparing the efficacy and safety of JWXFD and JWXFO in treating Children with tic disorders (consumption of renal yin and liver wind stirring up internally syndrome). A total of 288 patients will be recruited and randomly assigned to two groups in a 1:1 ratio. The treatment course is 6 weeks, with a 2 weeks follow-up. The primary outcome is the mean change value from baseline to 6th week by the Yale Global Tic Severity Scale total tic score (YGTSS-TTS). Secondary outcomes include total effective rate of tic, Yale Global Tic Severity Scale (YGTSS) scores and its factor scores (the degree of motor tics, phonic tics and social function damage), Clinical Global Impression-Severity scale, and TCM syndrome efficacy.DiscussionThe design of this study refers to a large number of similar research design points, and asked for opinions of peer experts, and finally reached a consensus. This trial will provide high-quality evidence on the clinical equivalence between JWXFD and JWXFO and provide a basis for the marketing of JWXFD.Trial registrationChiCTR2000032312Registered on 25 April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52630

ONLINE-TICS: Internet-Delivered Behavioral Treatment for Patients with Chronic Tic Disorders.

Comprehensive Behavioral Intervention for Tics (CBIT) is considered a first-line therapy for tics. However, availability of CBIT is extremely limited due to a lack of qualified therapists. This study is a multicenter (n = 5), randomized, controlled, observer-blind trial including 161 adult patients with chronic tic disorders (CTD) to provide data on efficacy and safety of an internet-delivered, completely therapist-independent CBIT intervention (iCBIT Minddistrict®) in the treatment of tics compared to placebo and face-to-face (f2f) CBIT. Using a linear mixed model with the change to baseline of Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) as a dependent variable, we found a clear trend towards significance for superiority of iCBIT (n = 67) over placebo (n = 70) (−1.28 (−2.58; 0.01); p = 0.053). In addition, the difference in tic reduction between iCBIT and placebo increased, resulting in a significant difference 3 (−2.25 (−3.75; −0.75), p = 0.003) and 6 months (−2.71 (−4.27; −1.16), p < 0.001) after the end of treatment. Key secondary analysis indicated non-inferiority of iCBIT in comparison to f2f CBIT (n = 24). No safety signals were detected. Although the primary endpoint was narrowly missed, it is strongly suggested that iCBIT is superior compared to placebo. Remarkably, treatment effects of iCBIT even increased over time.

Cross-disorder comparison of sensory over-responsivity in chronic tic disorders and obsessive-compulsive disorder

BackgroundSensory over-responsivity (SOR) refers to excessively intense and/or prolonged behavioral responses to environmental stimuli typically perceived as non-aversive. SOR is prevalent in several neurodevelopmental disorders, including chronic tic disorders (CTDs) and obsessive-compulsive disorder (OCD). Few studies have examined the extent and clinical correlates of SOR across disorders, limiting insights into the phenomenon's transdiagnostic clinical and biological relevance. Such cross-disorder comparisons are of particular interest for CTDs and OCD given their frequent co-occurrence. ObjectiveWe sought to compare the magnitude of SOR between adults with CTD and adults with OCD and to identify the clinical factors most strongly associated with SOR across these disorders. MethodsWe enrolled 207 age- and sex-matched participants across four diagnostic categories: CTD without OCD (designated “CTD/OCD-”; n = 37), CTD with OCD (“CTD/OCD+”; n = 32), OCD without tic disorder (“OCD”; n = 69), and healthy controls (n = 69). Participants completed a self-report battery of rating scales assessing SOR (Sensory Gating Inventory, SGI), obsessive-compulsive symptoms (Dimensional Obsessive-Compulsive Scale, DOCS), inattention and hyperactivity (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-5), anxiety (Generalized Anxiety Disorder-7), and depression (Patient Health Questionnaire-9). CTD participants were also administered the Yale Global Tic Severity Scale (YGTSS). To examine between-group differences in SOR, we compared SGI score across all groups and between pairs of groups. To examine the relationship of SOR with other clinical factors, we performed multivariable linear regression. ResultsCTD/OCD-, CTD/OCD+, and OCD participants were 86.7%, 87.6%, and 89.5%, respectively, more likely to have higher SGI total scores than healthy controls. SGI total score did not differ between CTD/OCD-, CTD/OCD+, and OCD groups. In the regression model of log-transformed SGI total score, OCD diagnosis, DOCS score, and ASRS-5 score each contributed significantly to model goodness-of-fit, whereas CTD diagnosis and YGTSS total tic score did not. ConclusionSOR is prevalent in adults with CTD and in adults with OCD but does not significantly differ in magnitude between these disorders. Across CTD, OCD, and healthy control adult populations, SOR is independently associated with both obsessive-compulsive and ADHD symptoms, suggesting a transdiagnostic relationship between these sensory and psychiatric manifestations. Future cross-disorder, longitudinal, and translational research is needed to clarify the role and prognostic import of SOR in CTDs, OCD, and other neurodevelopmental disorders.

Efficacy and Safety of Fixed-Dose Deutetrabenazine in Children and Adolescents for Tics Associated With Tourette Syndrome

Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires. The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate. In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. ClinicalTrials.gov Identifier: NCT03571256.

Clinical Correlates of Health-Related Quality of Life in Adults With Chronic Tic Disorder.

Tics are the hallmark feature of Tourette syndrome (TS), but psychiatric and sensory symptoms are widely prevalent and increasingly recognized as core manifestations of the disorder. Accumulating evidence suggests that these psychiatric and sensory symptoms exert greater influence on quality of life (QOL) than tics themselves. However, much remains uncertain about determinants of QOL in TS due to the complexity of the clinical presentation. Here, we sought to clarify the association between health-related QOL (HRQOL) and common psychiatric and sensory symptoms in adults with TS and other chronic tic disorders. To do so, we prospectively recruited 52 patients from a tertiary care clinic to complete self-report measures assessing HRQOL (Gilles de la Tourette-Quality of Life Scale, GTS-QOL), depression (Patient Health Questionnaire-9, PHQ-9), anxiety (Generalized Anxiety Disorder Scale-7, GAD-7), obsessive-compulsive symptoms (Dimensional Obsessive-Compulsive Scale, DOCS), attention deficit hyperactivity disorder symptoms (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-V), and premonitory urge (Premonitory Urge to Tic Scale, PUTS). All participants were also administered the Yale Global Tic Severity Scale (YGTSS) to quantify tic severity. Using correlational analysis and multivariable linear regression modeling, we found that GTS-QOL score was significantly associated with scores from all other rating scales, with the exception of the PUTS. GTS-QOL was most strongly associated with PHQ-9, followed by ASRS-V, GAD-7, DOCS, and YGTSS total tic score. The regression model including these five independent variables, as well as sex, explained 79% of GTS-QOL score variance [F(6,40) = 29.6, p < 0.001]. Specific psychiatric symptoms differentially impacted physical, psychological, and cognitive HRQOL. Systematic assessment of psychiatric comorbidities is imperative for clinical care and clinical research efforts directed at improving QOL in adults with chronic tic disorders.

Yale Global Tic Severity Scale (YGTSS): Psychometric Quality of the Gold Standard for Tic Assessment Based on the Large-Scale EMTICS Study.

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale “European Multicentre Tics in Children Study” (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (rs = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (rs = 0.24), obsessive–compulsive symptoms (rs = 27) as well as internalizing symptoms (rs = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors “motor tics” and “phonic tics,” but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

Defining tic severity and tic impairment in Tourette Disorder

ObjectiveTreatment guidelines for Tourette's Disorder (TD) are based on patients' degree of tic severity and impairment. However, clear benchmarks for determining tic severity and impairment have not been established. This study examined benchmarks of tic severity and tic impairment using the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impression of Severity (CGI-S). MethodIndividuals with TD or another Tic Disorder (N = 519) recruited across nine sites were administered a diagnostic interview, the YGTSS, and the CGI-S. Correlations and trend analyses contrasted YGTSS scores across CGI-S ratings. A logistic regression model examined predictive benchmarks for tic severity, tic impairment, and global severity. Model classifications were compared against CGI-S ratings, and agreement was examined using kappa. ResultsSpearman correlations between the CGI-S and YGTSS scores ranged from 0.54 to 0.63 (p < 0.001). Greater CGI-S ratings were associated with a linear stepwise increase in YGTSS Total Tic scores, Impairment scores, and Global Severity scores. Despite moderate-to-strong associations (ρ = 0.45–0.56, p < 0.001) between the CGI-S and predictive logistical regression models, only fair agreement was achieved when applying classification benchmarks (κ = 0.21–0.32, p < 0.001). ConclusionsCGI-S ratings are useful to characterize benchmarks for tic severity, tic impairment, and global severity on the YGTSS. Logistic regression model benchmarks had only fair agreement with the CGI-S and underscore the heterogeneity of TD symptoms. Collectively, findings offer guidance on the delineation of tic severity categorizations to apply evidence-based treatment recommendations.

Sensory Hypersensitivity Severity and Association with Obsessive-Compulsive Symptoms in Adults with Tic Disorder.

BackgroundSensory hypersensitivity, defined as heightened awareness of and reactivity to external stimuli, is a bothersome symptom that affects up to 80% of adults with Tourette syndrome (TS). Such widespread prevalence suggests sensory hypersensitivity is a core feature of the disorder, but its severity and association with other clinical features of TS remain largely unexplored. Complicating matters, sensory hypersensitivity has been observed in two neurodevelopmental disorders commonly comorbid with TS: obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD).ObjectiveWe sought to measure sensory hypersensitivity in TS patients relative to healthy controls and to investigate the relationship of sensory hypersensitivity with OCD and ADHD symptoms in the context of TS.MethodsWe recruited 34 adults with TS or chronic tic disorder to undergo evaluation with the Yale Global Tic Severity Scale (YGTSS) and a battery of validated self-report instruments assessing sensory hypersensitivity (Sensory Gating Inventory, SGI; Sensory Perception Quotient, SPQ), premonitory urge (Premonitory Urge to Tic Scale, PUTS), OCD (Dimensional Obsessive-Compulsive Scale, DOCS), and ADHD (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-V). Age- and sex-matched healthy controls were recruited to complete SGI and psychiatric measures.ResultsSGI and SPQ scores strongly correlated (rs = −0.73, p < 0.0001) within patients. SGI total score was significantly higher in patients versus controls (119.0 vs 67.6, U =−5.3, p < 0.0001), indicating greater sensory hypersensitivity in the tic disorder group. SGI score correlated modestly with PUTS, DOCS, and ASRS-V scores but not with YGTSS total tic score. Hierarchical linear regression analysis revealed that, of the tested variables, only DOCS score contributed significantly to mean SGI score, with β ranging from 1.03 (p = 0.044) to 1.41 (p = 0.001). A simple linear regression model with DOCS as the independent variable accounted for 31.9% of SGI score variance.ConclusionSensory hypersensitivity is prominent in adults with tic disorder and is independently associated with obsessive-compulsive symptom severity.

A multicenter examination and strategic revisions of the Yale Global Tic Severity Scale.

To examine the internal consistency and distribution of the Yale Global Tic Severity Scale (YGTSS) scores to inform modification of the measure. This cross-sectional study included 617 participants with a tic disorder (516 children and 101 adults), who completed an age-appropriate diagnostic interview and the YGTSS to evaluate tic symptom severity. The distributions of scores on YGTSS dimensions were evaluated for normality and skewness. For dimensions that were skewed across motor and phonic tics, a modified Delphi consensus process was used to revise selected anchor points. Children and adults had similar clinical characteristics, including tic symptom severity. All participants were examined together. Strong internal consistency was identified for the YGTSS Motor Tic score (α = 0.80), YGTSS Phonic Tic score (α = 0.87), and YGTSS Total Tic score (α = 0.82). The YGTSS Total Tic and Impairment scores exhibited relatively normal distributions. Several subscales and individual item scales departed from a normal distribution. Higher scores were more often used on the Motor Tic Number, Frequency, and Intensity dimensions and the Phonic Tic Frequency dimension. By contrast, lower scores were more often used on Motor Tic Complexity and Interference, and Phonic Tic Number, Intensity, Complexity, and Interference. The YGTSS exhibits good internal consistency across children and adults. The parallel findings across Motor and Phonic Frequency, Complexity, and Interference dimensions prompted minor revisions to the anchor point description to promote use of the full range of scores in each dimension. Specific minor revisions to the YGTSS Phonic Tic Symptom Checklist were also proposed.

A D1 Receptor Antagonist, Ecopipam, for Treatment of Tics in Tourette Syndrome

Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and tic-reducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS. This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1-2) and then 100 mg daily (weeks 3-8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored. Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18-63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was -0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted.

Aripiprazole in Children and Adolescents with Tourette's Disorder: An Open-Label Safety and Tolerability Study

The aim of this study was to conduct a prospective safety and tolerability study of aripiprazole for the treatment of tics in children and adolescents with Tourette's disorder (TD). Eleven subjects (10 males) with TD (age 9-19 years, mean 13.36, standard deviation [SD] 3.33) who did not respond or were unable to tolerate previous tic medication were treated with aripiprazole in an open-label, flexible-dosing study over 10 weeks. Tic severity was rated using the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impressions Scale for tics (CGI-Tics) at baseline and at follow-up. The mean (+/-SD) daily dose for aripiprazole was 4.5 +/- 3.0 mg. Mean (+/-SD) YGTSS Global Severity scores reduced from 61.82 +/- 13.49 at baseline to 33.73 +/- 15.18 at end point; mean YGTSS total tic scores reduced from 28.18 +/- 7.74 at baseline to 16.73 +/- 7.54 at end point. Mean (+/-SD) CGI-Tic severity scores reduced from 4.45 +/- 0.52 (moderate-marked) at baseline to 3.18 +/- 0.60 (mild) at end point. On the CGI-Tic improvement scale, 10 (91%) subjects achieved 1 ("very much improved") or 2 ("much improved") at end point. Most common adverse effects included appetite increase and weight gain in 5 subjects, mild extrapyramidal effects in 7 subjects, and headaches and tiredness/fatigue in 7 subjects; 1 subject experienced akathisia and muscle cramps. Aripiprazole appears to be a safe and tolerable treatment in children and adolescents with TD that appears to reduce tics; it should be further investigated as a treatment option in controlled trials.

An Open-Label Study of the Efficacy and Tolerability of Aripiprazole for Children and Adolescents With Tic Disorders

This study aimed to investigate the efficacy and tolerability of aripiprazole, an atypical antipsychotic with dual agonist and antagonist actions toward dopaminergic imbalance and partial serotonin-2A receptor antagonism, for treating children and adolescents with tic disorders. Twenty-four outpatients aged 7 to 18 years with DSM-IV-diagnosed tic disorders were treated with aripiprazole using an open-label, flexible dosing schedule for 8 weeks from January 2005 to August 2006. The Korean versions of the Yale Global Tic Severity Scale (YGTSS), the Clinical Global Impressions-Improvement scale (CGI-I), and the CGI-Severity of Illness scale (CGI-S) scores were used to measure the drug efficacy. Side effects were assessed using an adverse effect checklist, the Extrapyramidal Symptom Rating Scale, height and weight measurements, laboratory tests, and electrocardiograms. Aripiprazole was prematurely discontinued in 6 (25%) of the 24 subjects due to intolerable adverse effects. After a mean of 9.8 +/- 4.8 mg/day of aripiprazole for 8 weeks, there was a 52.8% reduction in the mean YGTSS Total Tic scores (from 26.7 +/- 5.5 to 12.6 +/- 7.6, p < .001). Nineteen patients (79.2%) showed either much improved or very much improved status according to the CGI-I. The CGI-S score was also reduced (from 5.5 +/- 0.5 to 3.0 +/- 1.4, p < .001). The initial dose of 5 mg/day aripiprazole for 2 weeks was also found to reduce tic symptoms significantly (Total Tic scores decreased from 26.7 +/- 5.5 to 17.9 +/- 8.7, p < .001). Fourteen subjects (58.3%) experienced unwanted side effects, the most common being hypersomnia (37.5%), nausea (20.8%), and headache (16.6%). This open-label study suggests that aripiprazole is an efficacious and safe treatment for children and adolescents with tic disorders.