A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders.

BACKGROUND: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. METHODS: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. RESULTS: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05-0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A's inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. CONCLUSIONS: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.

The effects of Shaoma Zhijing granules and its main components on Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) represents a neurodevelopmental disorder characterized by an uncertain etiology and influencing factors. Frequently, it co-occurs with conditions such as attention deficit hyperactivity disorder, obsessive-compulsive disorder, and sleep disturbances, which have garnered substantial attention from the research community in recent years. Clinical trials have demonstrated that Shaoma Zhijing Granules (SMZJG, 5-ling granule, also known as TSupport or T92 under U.S. development), a traditional Chinese medicine compound, is an effective treatment for TS. PURPOSE: To conduct scientometric analysis on developing trends, research countries and institutions, current status, hot spots of TS and discuss the underlying mechanisms of SMZJG and its main components on TS. The aim is to provide valuable reference for ongoing clinical and basic research on TS and SMZJG. STUDY DESIGN & METHODS: Using Tourette syndrome, SMZJG and its main components along with their synonyms as keywords, we conducted a comprehensive search across major scientific databases including the Web of Science Core Collection, PubMed and China National Knowledge Infrastructure (CNKI) databases. A total of 5952 references and 99 patents were obtained. Among these, 5039 articles and reviews, as well as 54 patents were analyzed by Citespace and VOSviewer software. RESULTS: The available evidence indicates that the SMZJG's components likely exert their mechanisms in treating TS by regulating the dopaminergic pathway system, neurotransmitter imbalances, reducing neuroinflammation, promoting the repair of nerve damage and improving sleep disorders. CONCLUSION: This comprehensive analysis lays the foundation for an extensive exploration of the feasibility and clinical applications of SMZJG in TS treatment.

Activation of M4 muscarinic receptors in the striatum reduces tic-like behaviours in two distinct murine models of Tourette syndrome.

BACKGROUND AND PURPOSE: Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors-the two most abundant muscarinic receptors in the striatum-reduced tic-related behaviours in mouse models of TS. EXPERIMENTAL APPROACH: Studies were conducted using CIN-d and D1CT-7 mice, two TS models characterized by early-life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos. KEY RESULTS: Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models. M4, but not M1, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals. CONCLUSION AND IMPLICATIONS: Activation of striatal M4, but not M1, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.

Efficacy of cannabinoids in neurodevelopmental and neuropsychiatric disorders among children and adolescents: a systematic review.

A better understanding of the endocannabinoid system and a relaxation in regulatory control of cannabis globally has increased interest in the medicinal use of cannabinoid-based products (CBP). We provide a systematic review of the rationale and current clinical trial evidence for CBP in the treatment of neuropsychiatric and neurodevelopmental disorders in children and adolescents. A systematic search of MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Trials was performed to identify articles published after 1980 about CBP for medical purposes in individuals aged 18 years or younger with selected neuropsychiatric or neurodevelopmental conditions. Risk of bias and quality of evidence was assessed for each article. Of 4466 articles screened, 18 were eligible for inclusion, addressing eight conditions (anxiety disorders (n = 1); autism spectrum disorder (n = 5); foetal alcohol spectrum disorder (n = 1); fragile X syndrome (n = 2); intellectual disability (n = 1); mood disorders (n = 2); post-traumatic stress disorder (n = 3); and Tourette syndrome (n = 3)). Only one randomised controlled trial (RCT) was identified. The remaining seventeen articles included one open-label trial, three uncontrolled before-and-after trials, two case series and 11 case reports, thus the risk of bias was high. Despite growing community and scientific interest, our systematic review identified limited and generally poor-quality evidence for the efficacy of CBP in neuropsychiatric and neurodevelopmental disorders in children and adolescents. Large rigorous RCTs are required to inform clinical care. In the meantime, clinicians must balance patient expectations with the limited evidence available.

Efficacy and Safety of Acupuncture Combined with Herbal Medicine for Children and Adolescents with Tourette Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: With the increasing prevalence of Tourette syndrome (TS), the search for alternative therapy for TS is a growing public concern. In recent years, a growing number of randomized controlled trials (RCTs) have revealed the value of acupuncture combined with herbal medicine for the treatment of TS; however, its holistic efficacy and safety remains unclear. This study aimed to evaluate the efficacy and safety of acupuncture combined with herbal medicine and to provide preliminary evidence for clinical practice. METHODS: Eight databases were searched from their establishment to November 27, 2022, to collect RCTs of acupuncture combined with herbal medicine for TS treatment. Two researchers independently completed the study screening, data extraction, and risk of bias assessment by using NoteExpress, Excel, and Cochrane Risk of Bias Tool 2.0 (RoB 2.0). Stata 15.0 software was applied to conduct meta-analysis. RESULTS: A total of 1,400 participants in 18 RCTs were included. Compared with the Western medicine, acupuncture combined with herbal medicine had better curative effect in the field of effective rate (risk ratio [RR] = 1.18, 95% CI: [1.12, 1.23], p < 0.05, I2 = 0%), Yale Global Tic Severity Scale (YGTSS) total score (mean difference [MD] = -3.91, 95% CI: [-5.49, -2.33], p < 0.05, I2 = 96.4%), TCM syndrome total score (MD = -2.42, 95% CI: [-3.71, -1.13], p < 0.05, I2 = 87.1%), and serum IgE negative rate (RR = 3.41, 95% CI: [1.69, 6.87], p < 0.05, I2 = 0%). Furthermore, acupuncture combined with herbal medicine reduced the adverse reaction rate (RR = 0.20, 95% CI: [0.14, 0.30], p < 0.05, I2 = 0%) and the recurrence rate (RR = 0.27, 95% CI: [0.13, 0.52], p < 0.05, I2 = 0%). CONCLUSION: This study demonstrated the efficacy and safety of acupuncture combined with herbal medicine, which is probably a better alternative therapy for TS. However, the small number, low quality, and potential bias of the included studies caused the limitations of our results. More high-quality RCTs are required to provide supplementary evidence in the future.Mit der steigenden Prävalenz des Tourette-Syndroms (TS) ist die Suche nach alternativen Therapien für TS zunehmend zu einer Angelegenheit von öffentlichem Interesse geworden. In den vergangenen Jahren zeigte eine immer größer werdende Zahl randomisierter, kontrollierter Studien den Nutzen der Akupunktur in Kombination mit Heilkräutern; ihre ganzheitliche Wirksamkeit und Sicherheit ist jedoch weiterhin nicht klar. Mit dieser Studie sollten die Wirksamkeit und Sicherheit von Akupunktur in Kombination mit Heilkräutern beurteilt und erste Belege für die klinische Praxis gewonnen werden.Acht (8) Datenbanken wurden ab ihrer Einrichtung bis zum 27. November 2022 nach randomisierten kontrollierten Studien (RCTs) über Akupunktur in Kombination mit Heilkräutern zur Behandlung von TS durchsucht. Das Screening der Studien, die Datenextraktion und die Bewertung des Verzerrungsrisikos wurden von zwei unabhängigen Forschern mit Hilfe von NoteExpress, Excel und dem Cochrane Risk of Bias Tool 2.0 (RoB 2.0) durchgeführt. Die Metaanalyse erfolgte mit der Software Stata 15.0.Insgesamt wurden 1400 Teilnehmer in 18 RCTs eingeschlossen. Im Vergleich zur westlichen Medizin (WM) hatte Akupunktur in Kombination mit Heilkräutern eine bessere kurative Wirkung in Bezug auf die Wirksamkeitsrate (RR = 1,18, 95%-KI [1,12, 1,23], p < 0,05, I2 = 0%), den Gesamtscore der Yale Global Tic Severity Scale (YGTSS) (MD = -3,91, 95%-KI [-5,49, -2,33], p < 0,05, I2 = 96,4%), den TCM-Syndrom-Gesamtscore (MD = -2,42, 95%-KI [-3,71, -1,13], p < 0,05, I2 = 87,1%) und die Serum-IgE-Negativrate (RR = 3,41, 95%-KI [1,69, 6,87], p <0,05, I2 = 0 %). Darüber hinaus verringerte Akupunktur in Kombination mit Heilkräutern die Nebenwirkungsrate (RR = 0,20, 95%-KI [0,14, 0,30], p < 0,05, I2 = 0%) sowie die Rezidivrate (RR = 0,27, 95%-KI [0,13, 0,52], p < 0,05, I2 = 0%).Diese Studie belegt die Wirksamkeit und Sicherheit der Akupunktur in Kombination mit Heilkräutern, die wahrscheinlich eine bessere alternative Therapie für TS darstellt. Unsere Ergebnisse werden allerdings durch die geringe Zahl, die niedrige Qualität und die potenzielle Verzerrung der eingeschlossenen Studien eingeschränkt. Zukünftig sind weitere hochwertige RCTs erforderlich, die zusätzliche Belege liefern.

Pharmacological treatment of Tourette's syndrome: from the past to the future.

Tourette's syndrome (TS) is a neuropsychiatric disease featuring tics and vocal tics, with a prevalence of approximately 1%, including 75% of the total number of male patients. TS seriously disturbs the patients' career, education, and life and brings a serious and unbearable psychological burden to the patients themselves and their families. At present, there are no specific clinical medications recommended for treating TS. Therefore, it is necessary to select the appropriate medication for symptomatic treatment based on the doctor's personal experience and the patient's symptoms, with the main goal of relieving symptoms, thus improving the patient's social skills and psychological problems. Here we conducted a comprehensive search on PubMed to review and organize the history and current status of the development of drug therapy for TS through a timeline format. We also systematically evaluated the effects of each drug for TS treatment to summarize the current problems and new research directions and to provide some ideas for clinical treatment.

Real-world experience with VMAT2 inhibitors in Tourette syndrome.

OBJECTIVES: We aimed to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine for treatment of Tourette syndrome, focusing on therapeutic benefits, side effect profile, and accessibility for the off-label use of these drugs. METHODS: We performed a retrospective chart review, supplemented with a telephone survey, of all our patients treated for their tics with VMAT2 inhibitors over a period of 4 years from January 2017 until January 2021. RESULTS: We identified 164 patients treated with the various VMAT2 inhibitors (tetrabenazine, n = 135; deutetrabenazine, n = 71; valbenazine, n = 20). Data on the mean treatment duration and daily dosages were collected. The response to VMAT2 inhibitors was assessed by a Likert scale by comparing the symptom severity before initiation and while on treatment. Side effects were mild and mostly consisted of depression as the major side effect but there was no suicidality reported. CONCLUSION: VMAT2 inhibitors are effective and safe in the treatment of tics associated with Tourette syndrome but are not readily accessible by patients in the United States, partly because of lack of approval by the Food and Drug Administration.

CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders - Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study.

Preliminary data suggest that cannabis-based medicines might be a promising new treatment for patients with Tourette syndrome (TS)/chronic tic disorders (CTD) resulting in an improvement of tics, comorbidities, and quality of life. This randomized, multicenter, placebo-controlled, phase IIIb study aimed to examine efficacy and safety of the cannabis extract nabiximols in adults with TS/CTD (n = 97, randomized 2:1 to nabiximols:placebo). The primary efficacy endpoint was defined as a tic reduction of ≥ 25% according to the Total Tic Score of the Yale Global Tic Severity Scale after 13 weeks of treatment. Although a much larger number of patients in the nabiximols compared to the placebo group (14/64 (21·9%) vs. 3/33 (9·1%)) met the responder criterion, superiority of nabiximols could formally not be demonstrated. In secondary analyses, substantial trends for improvements of tics, depression, and quality of life were observed. Additionally exploratory subgroup analyses revealed an improvement of tics in particular in males, patients with more severe tics, and patients with comorbid attention deficit/hyperactivity disorder suggesting that these subgroups may benefit better from treatment with cannabis-based medication. There were no relevant safety issues. Our data further support the role of cannabinoids in the treatment of patients with chronic tic disorders.

Ecopipam for Tourette Syndrome: A Randomized Trial.

BACKGROUND AND OBJECTIVES: All US Food and Drug Administration-approved medications for Tourette syndrome are antipsychotics, and their use is limited by the risk of weight gain, metabolic changes, and drug-induced movement disorders. Several small trials suggest that ecopipam, a first-in-class, selective dopamine 1 receptor antagonist, reduces tics with a low risk for these adverse events. This trial sought to further evaluate the efficacy, safety, and tolerability of ecopipam in children and adolescents with moderate to severe Tourette syndrome. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, phase 2b trial. Subjects aged ≥6 to <18 years with a baseline Yale Global Tic Severity Score Total Tic Score of ≥20 were randomly assigned 1:1 to ecopipam (n = 76) or placebo (n = 77). The primary endpoint was mean change over 12 weeks in the Yale Global Tic Severity Score Total Tic Score. The Clinical Global Impression of Tourette Syndrome Severity was the secondary endpoint. Safety and tolerability were evaluated at each study visit. RESULTS: Total tic scores were significantly reduced from baseline to 12 weeks in the ecopipam group compared with placebo (least squares mean differences -3.44, 95% confidence interval -6.09 to -0.79, P = .01). Improvement in Clinical Global Impression of Tourette Syndrome Severity was also greater in the ecopipam group (P = .03). More weight gain was seen in subjects assigned to placebo. No metabolic or electrocardiogram changes were identified. Headache (15.8%), insomnia (14.5%), fatigue (7.9%), and somnolence (7.9%) were the most common adverse events. CONCLUSIONS: Among children and adolescents with TS, ecopipam reduces tics to a greater extent than placebo, without observable evidence of common antipsychotic-associated side effects.

European Society for the Study of Tourette Syndrome 2022 criteria for clinical diagnosis of functional tic-like behaviours: International consensus from experts in tic disorders.

BACKGROUND AND PURPOSE: In 2020, health professionals witnessed a dramatic increase in referrals of young people with rapid onset of severe tic-like behaviours. We assembled a working group to develop criteria for the clinical diagnosis of functional tic-like behaviours (FTLBs) to help neurologists, pediatricians, psychiatrists, and psychologists recognize and diagnose this condition. METHODS: We used a formal consensus development process, using a multiround, web-based Delphi survey. The survey was based on an in-person discussion at the European Society for the Study of Tourette Syndrome (ESSTS) meeting in Lausanne in June 2022. Members of an invited group with extensive clinical experience working with patients with Tourette syndrome and FTLBs discussed potential clinical criteria for diagnosis of FTLBs. An initial set of criteria were developed based on common clinical experiences and review of the literature on FTLBs and revised through iterative discussions, resulting in the survey items for voting. RESULTS: In total, 24 members of the working group were invited to participate in the Delphi process. We propose that there are three major criteria and two minor criteria to support the clinical diagnosis of FTLBs. A clinically definite diagnosis of FTLBs can be confirmed by the presence of all three major criteria. A clinically probable diagnosis of FTLBs can be confirmed by the presence of two major criteria and one minor criterion. CONCLUSIONS: Distinguishing FTLBs from primary tics is important due to the distinct treatment paths required for these two conditions. A limitation of the ESSTS 2022 criteria is that they lack prospective testing of their sensitivity and specificity.

Comparative efficacy, tolerability, and acceptability of pharmacological interventions for the treatment of children, adolescents, and young adults with Tourette's syndrome: a systematic review and network meta-analysis.

BACKGROUND: In clinical practice guidelines there is no consensus about the medications that should be initially offered to children and young people with Tourette's syndrome. To provide a rigorous evidence base that could help guide decision making and guideline development, we aimed to compare the efficacy, tolerability, and acceptability of pharmacological interventions for Tourette's syndrome. METHODS: For this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, Embase, PsycINFO, PubMed, Web of Science, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov, for published and unpublished studies from database inception to Nov 19, 2021. We included double-blind randomised controlled trials of any medication administered as a monotherapy for at least 1 week against another medication or placebo in children and adolescents (aged ≥4 years and ≤18 years), adults (>18 years), or both, diagnosed with Tourette's syndrome according to standardised criteria. We excluded studies that exclusively recruited participants with comorbid attention-deficit hyperactivity disorder or obsessive-compulsive disorder. The primary outcome was change in severity of tic symptoms (efficacy). Secondary outcomes were treatment discontinuations due to adverse events (tolerability) and for any reason (acceptability). Pharmacological interventions were examined considering medication categories and medications individually in separate analyses. Summary data were extracted and pooled with a random-effects network meta-analysis to calculate standardised mean differences for efficacy and odds ratios for tolerability and acceptability, with 95% CIs. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was pre-registered in PROSPERO (CRD42022296975). FINDINGS: Of the 12 088 records identified through the database search, 88 records representing 39 randomised controlled trials were included in the network meta-analysis; these 39 randomised controlled trials comprised 4578 participants (mean age 11·8 [SD 4·5] years; 3676 [80·8%] male participants) and evaluated 23 individual medications distributed across six medication categories. When considering medication categories, first-generation (standardised mean difference [SMD] -0·65 [95% CI -0·79 to -0·51]; low certainty of evidence) and second-generation (-0·71 [-0·88 to -0·54]; moderate certainty of evidence) antipsychotic drugs, as well as α-2 agonists (-0·21 [-0·39 to -0·03]; moderate certainty of evidence), were more efficacious than placebo. First-generation and second-generation antipsychotic drugs did not differ from each other (SMD 0·06 [95% CI -0·14 to 0·25]; low certainty of evidence). However, both first-generation (SMD 0·44 [95% CI 0·21 to 0·66]) and second-generation (0·49 [0·25 to 0·74]) antipsychotic drugs outperformed α-2 agonists, with moderate certainty of evidence. Similar findings were observed when individual medications were considered: aripiprazole (SMD -0·60 [95% CI -0·83 to -0·38]), haloperidol (-0·51 [-0·88 to -0·14]), olanzapine (-0·83 [-1·49 to -0·18]), pimozide (-0·48 [-0·84 to -0·12]), risperidone (-0·66 [-0·98 to -0·34]), and clonidine (-0·20 [-0·37 to -0·02]) all outperformed placebo, with moderate certainty of evidence. Antipsychotic medications did not differ from each other, but there was low to very low certainty of evidence for these comparisons. However, aripiprazole (SMD -0·40 [95% CI -0·69 to -0·12]) and risperidone (-0·46 [-0·82 to -0·11]) outperformed clonidine, with moderate certainty of evidence. Heterogeneity or inconsistency only emerged for a few comparisons. In terms of tolerability and acceptability, there were no relevant findings for any of the efficacious medication categories or individual medications against each other or placebo, but there was low to very low certainty of evidence associated with these comparisons. INTERPRETATION: Our analyses show that antipsychotic drugs are the most efficacious intervention for Tourette's syndrome, while α-2 agonists are also more efficacious than placebo and could be chosen by those who elect not to take antipsychotic drugs. Shared decision making about the degree of tic-related severity and distress or impairment, the trade-offs of efficacy and safety between antipsychotic drugs and α-2 agonists, and other highly relevant individual factors that could not be addressed in the present analysis, should guide the choice of medication for children and young people with Tourette's syndrome. FUNDING: None.

Is Traditional Chinese Medicine Effective in Treating Tic Disorders (Tourette Syndrome)? A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Traditional Chinese medicine (TCM) is a type of alternative medicine that has been widely utilized in the prevention and treatment of neuropsychiatric diseases such as schizophrenia, ADHD, Alzheimer disease, and Tourette syndrome (TS) in many countries. However, the results regarding TCM's effectiveness and safety in treating TS are conflicting. Therefore, the goal of the present study is to analyze and summarize the available literature related to the efficacy of TCM in the treatment of tic disorders, especially TS. METHODS: Relevant articles for the meta-analysis were searched using appropriate keywords from PubMed, MEDLINE, and CENTRAL databases. Event data for TCM for the treatment of TS in the control and intervention arms were determined from the randomized controlled trials, and diagnostic odds ratio (DOR) and risk of bias analysis were performed. Meta-analysis was performed using MedCalc software, and suitable parameters to assess heterogeneity were computed. RESULTS: Twelve randomized clinical trials with a total of 1,681 TS patients were included as per the inclusion criteria. The patients' clinical symptoms were improved to a greater extent, and the pooled DOR of 1.311 with a 95% confidence interval (CI) value ranging from 0.804 to 2.139 and I2 value of 72.04% were obtained. The pooled relative risk was 1.09, with a 95% CI value ranging from 0.97 to 1.268. The data heterogeneity was assessed, and we achieved a Q value of 33.54, a p value of 0.0004, and I2 value of 67.21% with a 95% CI value of 32.91-82.10. All these values are statistically significant, with p < 0.005, and confirmed the effectiveness of TCM for TS patients. CONCLUSION: The present meta-analysis on account of these statistically significant results highly recommends using TCM to treat TS.

A Double-Blind, Randomized, Controlled Crossover Trial of Cannabis in Adults with Tourette Syndrome.

Background: The number of effective evidence-based treatment options for patients with Tourette syndrome (TS) is limited. Emerging evidence shows cannabinoids as promising for the treatment of tics. Objectives: To compare the efficacy and tolerability of single doses of three vaporized medical cannabis products and placebo in reducing tics in adults with TS. Methods: In a randomized, double-blind, crossover design, each participant received a vaporized single 0.25 g dose of Δ9-tetrahydrocannabinol (THC) 10%, THC/cannabidiol (CBD) 9%/9%, CBD 13%, and placebo at 2-week intervals. Our primary outcome was the Modified Rush Video-Based Tic Rating Scale (MRVTRS), taken at baseline and at 0.5, 1, 2, 3, and 5 h after dose administration. Secondary measures included the Premonitory Urge for Tics Scale (PUTS), Subjective Units of Distress Scale (SUDS), and Clinical Global Impression-Improvement (CGI-I). Correlations between outcomes and cannabinoid plasma levels were calculated. Tolerability measures included open-ended and specific questions about adverse events (AEs). Results: Twelve adult patients with TS were randomized, with nine completing the study. There was no statistically significant effect of product on the MRVTRS. However, there was a significant effect of THC 10%, and to a lesser extent THC/CBD 9%9%, versus placebo on the PUTS, SUDS, and CGI-I. As well, there were significant correlations between plasma levels of THC and its metabolites, but not CBD, with MRVTRS, PUTS, and SUDS measures. There were more AEs from all cannabis products relative to placebo, and more AEs from THC 10% versus other cannabis products, particularly cognitive and psychomotor effects. Most participants correctly identified whether they had received cannabis or placebo. Conclusions: In this pilot randomized controlled trial of cannabis for tics in TS, there was no statistically significant difference on the MRVTRS for any of the cannabis products, although the THC 10% product was significantly better than placebo on the secondary outcome measures. Also, THC and metabolite plasma levels correlated with improvement on all measures. The THC 10% product resulted in the most AEs. ClinicalTrials.gov ID: NCT03247244.

Multivariate classification provides a neural signature of Tourette disorder.

BACKGROUND: Tourette disorder (TD), hallmarks of which are motor and vocal tics, has been related to functional abnormalities in large-scale brain networks. Using a fully data driven approach in a prospective, case-control study, we tested the hypothesis that functional connectivity of these networks carries a neural signature of TD. Our aim was to investigate (i) the brain networks that distinguish adult patients with TD from controls, and (ii) the effects of antipsychotic medication on these networks. METHODS: Using a multivariate analysis based on support vector machine (SVM), we developed a predictive model of resting state functional connectivity in 48 patients and 51 controls, and identified brain networks that were most affected by disease and pharmacological treatments. We also performed standard univariate analyses to identify differences in specific connections across groups. RESULTS: SVM was able to identify TD with 67% accuracy (p = 0.004), based on the connectivity in widespread networks involving the striatum, fronto-parietal cortical areas and the cerebellum. Medicated and unmedicated patients were discriminated with 69% accuracy (p = 0.019), based on the connectivity among striatum, insular and cerebellar networks. Univariate approaches revealed differences in functional connectivity within the striatum in patients v. controls, and between the caudate and insular cortex in medicated v. unmedicated TD. CONCLUSIONS: SVM was able to identify a neuronal network that distinguishes patients with TD from control, as well as medicated and unmedicated patients with TD, holding a promise to identify imaging-based biomarkers of TD for clinical use and evaluation of the effects of treatment.

Jing-an oral liquid alleviates Tourette syndrome via the NMDAR/MAPK/CREB pathway in vivo and in vitro.

CONTEXT: Jing-an oral liquid (JA) is a Chinese herbal formula used in the treatment of Tourette syndrome (TS); however, its mechanism is unclear. OBJECTIVE: To investigate the effects of JA on amino acid neurotransmitters and microglia activation in vivo and in vitro. MATERIALS AND METHODS: Sixty male Sprague-Dawley rats were divided into a control group and 5 TS groups. TS was induced in rats with intraperitoneal injection of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1 mg/kg) and in BV2 cells with lipopolysaccharide. Control and model rats were administered saline, whereas treatment groups were administered JA (5.18, 10.36, or 20.72 g/kg) or tiapride (a benzamide, 23.5 mg/kg) by gavage once daily for 21 days. Stereotypic behaviour was tested. The levels of N-methyl-d-aspartate receptor (NMDAR)/mitogen-activated protein kinase/cAMP response element-binding protein (CREB)-related proteins in striatum and BV2 cells were measured via western blots. CD11b and IBa1 levels were also measured. Ultra-high-performance liquid-chromatography was used to determine γ-aminobutyric acid (GABA), glutamic acid (Glu), and aspartic acid (ASP) levels. RESULTS: JA markedly alleviated the stereotype behaviour (25.92 ± 0.35 to 13.78 ± 0.47) in rats. It also increased NMDAR1 (0.48 ± 0.09 to 0.67 ± 0.08; 0.54 ± 0.07 to 1.19 ± 0.18) expression and down-regulated the expression of p-ERK, p-JNK, p-P38, and p-CREB in BV2 cells and rat striatum. Additionally, Glu, ASP, GABA, CD11b, and IBa1 levels were significantly decreased by JA. DISCUSSION AND CONCLUSIONS: JA suppressed microglia activation and regulated the levels of amino acid neurotransmitters, indicating that it could be a promising therapeutic agent for TS.

Current and emerging pharmacotherapeutic strategies for Tourette syndrome.

INTRODUCTION: Tourette syndrome (TS) is a chronic tic disorder characterized by both motor and vocal tics. The vast majority of patients present with co-morbid behavioral problems, especially tic-related obsessive-compulsive behaviors and attention-deficit and hyperactivity disorder. Evidence-based guidelines on the pharmacotherapy of TS have become available in recent years. AREAS COVERED: The main purpose of this paper is to provide an overview of the current and emerging pharmacotherapeutic strategies for TS. A comprehensive search for the literature on the pharmacotherapy of tics was conducted using multiple databases (MEDLINE, Scopus, Web of Science, and Google Scholar), without date limits. EXPERT OPINION: In consideration of the heterogeneity of the TS phenotypes, pharmacotherapy should be tailored to the individual patient. The choice of the pharmacological agent should take into account both the efficacy-to-tolerability ratio and the presence of co-morbid conditions. Evidence-based pharmacotherapy should aim at improving health-related quality life within a dynamic framework that typically requires active monitoring of the clinical presentation and reevaluation of the treatment intervention over time.

Randomized controlled trials on the use of cannabis-based medicines in movement disorders: a systematic review.

Anecdotal references, preclinical, and non-randomized studies support the therapeutic potential of cannabinoids for movement disorders (MD). To create an evidenced-based point of view for patients and physicians, we performed a systematic review of randomized controlled trials (RCT) on the use of cannabinoids in MD. The seven RCTs found on PD used different cannabis formulations. No improvement of motor symptoms was shown in any of the two RCTs with this as primary outcome (PO), but in the nabilone group, an improvement in quality of life was documented. Of the three RCTs having levodopa-induced dyskinesia as PO, only one using nabilone showed a reduction. Anxiety and anxiety-induced tremor could be reduced in the cannabidiol group as well as anxiety and sleeping problems in the nabilone group in another RCT. In two RCTs with Tourette syndrome, an improvement in tics was revealed. From three RCTs on Huntington's disease only one found symptoms relief using nabilone. No reduction of dystonia could be shown in the two included RCTs. The limited number of available but small and inhomogeneous RCTs precludes reliable conclusions. Therefore, more and smartly designed RCTs are urgently needed.

Treatments for Tourette syndrome in children and young adults: a systematic review / Tratamento da síndrome de Tourette em crianças e jovens adultos: uma revisão sistemática

INTRODUCTION: Tourette's Syndrome (TS) is a neurodevelopmental disorder characterized by motor and / or vocal tics for more than 12 months. TS affects about 0.8% of pediatric patients and is associated with great functional impairment and psychological distress. The present study aims to list and compare the effectiveness of therapies used in children and young people with TS. METHODS: PubMed / MEDLINE, Cochrane Library, ScienceDirect, SciELO and Lilacs were used from September 2020 to April 2021 to search for randomized clinical trials with pharmacological, behavioral, physical or alternative interventions for tics in children and young people with ST. RESULTS: 13 clinical trials were included, of which six pharmacological, six behavioral and one of other conformation. The global score on the Yale Global Tic Severity Scale showed evidence in favor of Habit Reversal Training (HRT) and Comprehensive Behavioral Intervention for Tics (CBIT). Evidence from two studies suggests that antipsychotic medications improve tic scores. Evidence from other interventions has shown no conclusive benefit. CONCLUSIONS: The present study identified benefits with the use of antipsychotics. The study also found that HRT and CBIT showed improvement in reducing the severity of tics, in addition to not having any adverse effects. These therapies showed significant clinical improvement, but there is no comparison between the use of these isolated approaches in relation to their use associated with medications. In view of the different forms of therapy, further studies are needed to identify the effectiveness and the profile of adverse effects of these interventions.

INTRODUÇÃO: A Síndrome de Tourette (ST) é um distúrbio do neurodesenvolvimento caracterizado por tiques motores e/ou vocais por mais de 12 meses. A ST afeta cerca de 0,8% dos pacientes pediátricos e associa-se a grande comprometimento funcional e sofrimento psíquico. O presente estudo tem como objetivo listar e comparar a eficácia das terapias utilizadas em crianças e jovens com ST. MÉTODOS: PubMed/MEDLINE, Cochrane Library, ScienceDirect, SciELO e Lilacs foram usados desde setembro de 2020 até abril de 2021 para a busca de ensaios clínicos randomizados com intervenções farmacológicas, comportamentais, físicas ou alternativas para tiques em crianças e jovens com ST. RESULTADOS: 13 ensaios clínicos foram incluídos, dos quais seis farmacológicos, seis comportamentais e um de outra conformação. A pontuação global na Yale Global Tic Severity Scale, apresentou evidências a favor do Treinamento de Reversão de Hábito (TRH) e Intervenção Comportamental Abrangente para Tiques (ICAT). As evidências de dois estudos sugerem que medicamentos antipsicóticos melhoram os escores de tiques. Evidências de outras intervenções não mostraram nenhum benefício conclusivo. CONCLUSÕES: O presente estudo identificou benefícios com o uso do antipsicóticos. O estudo também identificou que a TRH e a ICAT apresentaram melhora na redução da gravidade dos tiques, além de não apresentarem efeitos adversos. Essas terapias mostraram importante melhora clínica, mas não há comparação entre o uso dessas abordagens isoladas em relação ao seu uso associado com medicamentos. Diante das diferentes formas de terapia, mais estudos são necessários para identificar a eficácia e o perfil de efeitos adversos dessas intervenções.

Comprehensive behavioural intervention for tics: a neurophysiological intervention.

BACKGROUND: Gilles de la Tourette Syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterised by motor and vocal tics. While Comprehensive Behavioural Intervention for Tics (CBIT) is an effective, non-pharmacological treatment for patients with GTS, the underlying neurophysiological basis of this intervention has not been investigated. METHODS: To investigate the clinical effectiveness of CBIT in reducing tic severity in young people with GTS and explore neurophysiological mechanisms associated with clinical change. RESULTS: There was a significant overall improvement in tic severity of large effect size. The Cortical Silent Period (CSP) to motor evoked potential (MEP) ratio (CSP/MEP ratio) increased after the intervention with a small effect size. Other neurophysiological measures of inhibition were not significantly related to the change in tic severity. CONCLUSIONS: Alongside significant clinical improvements, these results suggest a role for motor cortical Gamma-aminobutyric acid (GABA)-ergic inhibitory circuitry in the neurophysiological changes underlying CBIT treatment. These findings need to be replicated in larger studies using control samples.