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Background: Chronic tic disorders (CTD) are multifaceted disorders characterized by multiple motor and/or vocal tics. They are often associated with complex tics including echophenomena, paliphenomena, and coprophenomena as well as psychiatric comorbidities such as attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD)., Objectives: Our goal was to uncover the inter-relational structure of CTD and comorbid symptoms in children and adults and to understand changes in symptom structure across development., Methods: We used network and graph analyses to uncover the structure of association of symptoms in childhood/adolescence (n = 529) and adulthood (n = 503) and how this structure might change from childhood to adulthood, pinpointing core symptoms as a main target for interventions., Results: The analysis yielded core symptom networks in young and adult patients with CTD including complex tics and tic-related phenomena as well as touching people and objects. Core symptoms in childhood also included ADHD symptoms, whereas core symptoms in adults included symptoms of OCD instead. Interestingly, self-injurious behavior did not play a core role in the young CTD network, but became one of the central symptoms in adults with CDT. In addition, we found strong connections between complex motor and vocal tics as well as echolalia and echopraxia., Conclusions: Next to other complex tics, echophenomena, paliphenomena, and coprophenomena can be regarded core symptoms of CTD. ADHD symptoms are closely related to CTD in childhood, whereas symptoms of OCD and self-injurious behavior are closely associated with CTD in adults. Our results suggest that a differentiation between motor and vocal tics is somewhat arbitrary., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Starting in 2019, in Germany the first well documented outbreak of mass sociogenic illness induced by social media (mass social media-induced illness; MSMI) occurred presenting with functional Tourette-like behaviors (FTB). This study aimed to provide first data on the prevalence rate of MSMI-FTB in Germany between 2019 and 2021 in the general population. We conducted a large-scale representative population survey in cooperation with the USUMA market and social research institute. Between August and December 2021, n = 2.509 people (mean age: 49.5 years, range: 16-95 years, n = 1.276 females) were randomly selected, visited in their households, interviewed, and asked to answer for themselves, but also for close family members (n = 6.744). Thus, in total, we received answers for n = 9.253 people. Probable MSMI-FTB was found in n = 33 individuals (mean age at onset: 30.5 years, n = 8 females). Based on strict criteria, the diagnosis of MSMI-FTB was considered highly likely in 16/33 individuals (mean age at onset: 25.6 years, n = 2 females) corresponding to prevalence rates of 0.17% (CI lower  = 0.10, CI upper  = 0.28) and 0.36% (CI lower  = 0.25, CI upper  = 0.50), respectively. This is the first large-scale, population representative study investigating the prevalence of MSMI-FTB in the general population in Germany between 2019 and 2021. Based on the prevalence rates found, MSMI-FTB is highly relevant for health economy. Accordingly, we suggest educating healthcare professionals and the general public to avoid misdiagnosis and inefficient treatment., Competing Interests: Declaration of competing interest KRMV has received financial or material research support from National Institute of Mental Health (NIMH), Almirall, Emalex Biosciences, Inc., and Noema Pharma. She has received consultant's and other honoraria from Eurox Group, Global Praxis Group Limited, Hormosan Pharma GmbH, MCI Germany, Neuraxpharm, Noema Pharma, Sanity Group, Stadapharm GmbH, and Synendos Therapeutics AG. She is an advisory/scientific board member for Alexion, Branchenverband Cannabiswirtschaft e.V. (BvCW), CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, Ethypharm GmbH, Hormosan Pharma GmbH, IMC Germany, Leafly Deutschland GmbH, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, Syqe Medical Ltd., Therapix Biosciences Ltd., and Tilray. She has received speaker's fees from Agaplesion Frankfurter Diakonie Kliniken gemeinnützige GmbH, Almirall, Arbeitsgemeinschaft Cannabis als Medizin (ACM), Bedrocan, Branchenverband Cannabiswirtschaft e.V. (BvCW), Camurus, CEREBRO SPAIN BIDCO S.L, Cogitando GmbH, Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN), Diplomado Internacional de Endocannabinología (Programa Universitario de Investigación en Salud - PUIS, UNAM), Dresden International University (DIU), Eurox Deutschland GmbH, Georgia Medical Cannabis Project (GMCP), GROW, Hessische Landesstelle für Suchtfragen e.V. (HLS), LIO Pharmaceuticals GmbH, Medizinischer Dienst Westfalen Lippe, Swiss Alpinopharm, and Takeda GmbH. She has received royalties from Deutsches Ärzteblatt, Der Neurologie und Psychiater, Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and Kohlhammer. She is an associate editor for “Cannabis and Cannabinoid Research” and an Editorial Board Member of “Medical Cannabis and Cannabinoids” und “MDPI-Reports” and a Scientific board member for “Zeitschrift für Allgemeinmedizin”. NSZ participated in clinical trials supported by Emalex. She received scientific grants from the Polish Ministry of Health, Tourette Association of America, American Academy of Neurology and American Brain Foundation. She received speaker honoraria from Biogen. Other authors have no conflicts to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Self-injurious behavior (SIB) is a well-known phenomenon in patients with chronic tic disorders (CTD). To investigate prospectively symptomatology of SIB in adults with CTD, we developed and validated the self-injurious behavior scale for tic disorders (SIBS-T). Patients completed the SIBS-T and a variety of assessments for tics and comorbidities. We investigated SIB frequency, internal consistency of the SIBS-T, and carried out an exploratory factor analysis (EFA). We enrolled n = 123 adult patients with CTD. SIB was reported by n = 103 patients (83.7%). The most frequently reported SIB were beating/pushing/throwing and were found in 79.6% of cases. Patients with SIB had significantly higher tic severity measured with the Adult Tic Questionnaire (ATQ) (p = 0.002) as well as higher severity of psychiatric comorbidities such as obsessive-compulsive symptoms (OCS) (p < 0.001,), attention deficit/hyperactivity disorder (ADHD) (p < 0.001,), and anxiety (p = 0.001). In addition, patients with SIB had significantly lower quality of life (p = 0.002). Pearson correlations demonstrated significant associations between SIB and severity of tics (p < 0.001), depression (p = 0.005), ADHD (p = 0.008), and borderline personality traits (p = 0.014). Consequently, higher SIBS-T also correlated with greater impairment of quality of life (p < 0.001). The internal consistency of the SIBS-T was good (α = 0.88). The EFA confirmed a single factor underlying the SIBS-T., (© 2024. The Author(s).)

Background: Comorbid functional tic-like behaviors (FTB) have been described only rarely in patients with Tourette syndrome (TS)., Objectives: We present the first large sample of patients suffering from TS and FTB to raise awareness of this clinical presentation and to guide how to differentiate one from the other., Methods: We analyzed clinical data of 71 patients (n = 27 [38.0%] female, mean age: 21.5, range: 11-55) with TS + FTB., Results: In the majority of patients, FTB started abruptly on average 15 years after tic onset with "treatment-resistant" complex movements and ("coprophenomena-like") vocalizations preceded by timely related psychological stressors. Psychological evaluation revealed evidence for internal conflicts (79%), emotional dysregulation (56%), and maintaining factors (70%). About one third of patients had a positive history for further medically unexplained symptoms. Compared to a large TS sample (n = 1032), patients with TS + FTB were more likely to be female, and presented significantly more common with "coprophenomena-like" symptoms, atypical influential factors, atypical descriptions of premonitory sensations, and higher rates of comorbid obsessive-compulsive disorder and "self-injurious" behavior., Conclusions: Based on our data it can be assumed that FTB is a common comorbidity in TS, similar to functional overlay in other movement disorders and epilepsy. Before classifying a patient as suffering from treatment-resistant TS, FTB should be ruled out., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Complex tics and obsessive or compulsive behaviour can be difficult to differentiate diagnostically. The majority of adult patients with Tourette syndrome report experiencing premonitory urges before tics. Some of these experiences have been linked to non-just-right experiences (NJRE), which are frequently reported by patients with obsessive-compulsive disorder or behaviours (OCD/OCB). We aimed to assess whether NJRE are more closely related to tics and tic-associated premonitory urges or whether they are more closely associated with OCD. A total of N = 111 patients (mean age = 34.77 + /-12.93; N = 37 female) with a confirmed diagnosis of Tourette syndrome completed the premonitory urges for tic disorders scale (PUTS), the revised non-just-right experiences scale (NJRE-QR), and questionnaires regarding their tic severity, and comorbid OCD/OCB. A multi-trait-multi-methods matrix was calculated to examine associations amongst scales measuring tic-related and OCB-related phenomena. The PUTS correlated overall higher with tic questionnaires than with OCD/OCB questionnaires. The NJRE correlated higher with OCD symptoms than with tic severity. The results indicate that non-just-right experiences are more closely associated with comorbid OCB than with tics in patients with Tourette syndrome., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest This study was funded by the DFG (MU 1527/2-1). KMV has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kroner Fresenius-Stiftung, and GW, Abide Therapeutics, Lundbeck, Syneos Health, Therapix Biosciences Ltd, Almirall Hermal GmbH, GW pharmaceuticals. She has received consultant's honoraria from Abide Therapeutics, Tilray, Resalo Vertrieb GmbH, Columbia Care, Bionorica Ethics GmbH, Lundbeck and Eurox Deutschland GmbH. She is a consultant or advisory board member for Abide Therapeutics, Alirio, The Academy of Medical Cannabis Limited, CannaMedical Pharma GmbH, CannaXan GmbH, Columbia Care, Canopy Growth, Leafly Deutschland GmbH, Lundbeck, Nomovo Pharm, Nuvelution TS Pharma Inc., Resalo Vertrieb GmbH, Sanity Group, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, Wayland Group, Zynerba Pharmaceuticals, and CTC Communications Corporation. She has received speaker's fees from Tilray, Wayland Group, Emalex, Eurox group, PR Berater, Aphria, Ever pharma GmbH, and Cogitando GmbH. She has received royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer. She holds shares of Nomovo Pharm. She served as a Guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects,” is Associate editor for “Cannabis and Cannabinoid Research” and Editorial Board Member for “Medical Cannabis and Cannabinoids.” The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AM received commercial research support from Pharm Allergan, Ipsen, Merz Pharmaceuticals, Actelion, honoraria for lectures from GlaxoSmithKline, Desitin, Teva, Takeda and consultancies from Desitin, Merz Pharmaceuticals, Admedicum, PTC Therapeutics, Novartis, Barmer. He was supported by the Possehl-Stiftung (Lübeck, Germany), the Margot und Jürgen Wessel Stiftung (Lübeck, Germany), the Tourette Syndrome Association (Germany), the Interessenverband Tourette Syndrom (Germany), CHDI, and the Damp-Stiftung (Kiel, Germany). He received academic research support by the Deutsche Forschungsgemeinschaft (DFG): projects 1692/3-1, 4-1, SFB 936, and FOR 2698 (project numbers 396914663, 396577296, 396474989), by the European Reference Network – Rare Neurological Diseases (ERN – RND; Project ID No 739510). He receives royalties for the book Neurogenetics (Oxford University Press). AM is member of the advisory boards of the German Tourette syndrome Association and the alliance of patients with chronic rare diseases. RM has received financial research support from the EU (H2020 No. 754740), the Tourette Gesellschaft Deutschland e.V., Abide Therapeutics, Böhringer-Ingelheim, Emalex, Lundbeck, Nuvelution TS Pharma Inc., Otsuka Pharmaceuticals, Therapix Biosciences. He has received speakers’ honoraria from Otsuka Pharmaceuticals and Lundbeck. RM is member of the advisory board of the Tourette Gesellschaft Deutschland e.V. NS has received financial or material research support by Polish Ministry of Health, Polish Neurological Society, Foundation for Polish Science, American Academy of Neurology, Tourette Association of America, American Brain Foundation and European Stroke Organisation. She received speakers’ honoraria from Biogen and 90 Consulting and was supported to attend meetings by Biogen. She is the Secretary of the European Society for the Study of Tourette Syndrome. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Tics are intimately associated with premonitory urges (PU) but knowledge about urges is still limited, with small sample sizes often limiting the generalizability of findings., Objectives: This study addressed the following open questions: (1) is tic severity associated with urge severity, (2) how common is relief, (3) which comorbidities are associated with urges, (4) are urges, tics, and comorbidities associated with lower quality of life, and (5) can complex and simple, motor and vocal tics be differentiated based on PU?, Methods: N = 291 patients who reported a confirmed diagnosis of chronic primary tic disorder (age = 18-65, 24% female) filled out an online survey assessing demographic data, comorbid conditions, location, quality and intensity of PU, as well as quality of life. Every tic was recorded, and whether the patient experienced a PU, the frequency, intensity, and quality of that urge., Results: PU and tic severity were significantly associated, and 85% of urge-related tics were followed by relief. A diagnosis of attention deficit/hyperactivity disorder (ADHD) or depression, female gender, and older age increased the likelihood of experiencing PU, while more obsessive compulsive (OCD) symptoms and younger age were associated with higher urge intensities. PU, complex vocal tics, ADHD, OCD, anxiety, and depression were related to lower quality of life. Motor and vocal, complex and simple tics did not differ regarding PU intensity, frequency, and quality, or relief., Conclusions: The results shed light on the relationship between PU, tics, comorbidities, age, gender, and quality of life in tic disorders., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: 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., Objectives: We aimed to revise the MRVS (MRVS-R) to simplify and standardize the assessment procedure and improve the correlation with the YGTSS-TTS., Methods: 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., Results: 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., Conclusions: The MRVS-R is a simplified version of the MRVS with comparable psychometric qualities, but higher correlations with the YGTSS-TTS., (© 2023 International Parkinson and Movement Disorder Society.)

Introduction: Misophonia refers to a phenomenon in which affected individuals have a selective intolerance to sounds of mostly oral or nasal origin. This intolerance is typically associated with strong emotional reactions such as anger, irritation, and disgust. The aim of this study was to conduct the first large epidemiological survey to determine the prevalence of misophonia symptoms in the adult population in Germany., Methods: We conducted a large-scale representative population survey between December 2020 and March 2021. For this purpose, a sample of 2,519 people were visited in their households and assessed with the Misophonia Questionnaire (MQ) and the Amsterdam Misophonia Questionnaire (AMISOS-R) to document misophonic symptoms. The primary estimate of clinical misophonia symptoms prevalence was based on the MQ Severity Scale and a secondary estimate was based on the AMISOS-R. The survey further included self-ratings to measure perfectionism, not-just-right experience (NJRE), autonomous sensory meridian response (ASMR) and general health as well as demographic data., Results: Five percent of the sample scored equal or above the MQ Severity Scale threshold for clinical misophonia symptoms (5.9% based on AMISOS-R). Individuals with clinical misophonia symptoms had a higher rate of perfectionism, a higher occurrence of NJRE, higher susceptibility to ASMR, and a worse general health status than those scoring below the cut-off-score. All those factors also independently predicted the severity of misophonia symptoms in a multiple regression model., Conclusion: Misophonia is a frequent condition and should further be examined as an independent diagnostic entity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jakubovski, Müller, Kley, de Zwaan and Müller-Vahl.)

Randomized double-blind placebo-controlled trials (RCTs) are regarded as the gold standard for clinical trials. While there are established standards to avoid unblinding, in RCTs using tetrahydrocannabinol (THC) containing cannabinoids, however, accidental unblinding and intentional self-unbinding must be considered as a particular issue, since THC tests are widely available. To investigate unblinding rates in an RCT using a THC-containing cannabinoid, we re-contacted 54 out of 97 participants of the CANNA-TICS trial who had participated in our study center in Hannover. Of the 54 participants, 53 could be reached. Of these, one participant (2%) stated that she had unblinded herself intentionally during the treatment phase, and another three patients (6%) reported intentional unblinding after the end of the treatment. Noteworthy, two patients provided discrepant information and denied self-unblinding during the interview, although during study/clinic visits they had reported having done so. Thus, based on all available information, three participants (6%) unblinded themselves intentionally during the treatment phase and another three (6%) after the end of the treatment. Accidental unblinding during the treatment phase was reported by 4/54 participants (7%) (during study visits). Since one participant reported both intentional self-unblinding (during the interview) and accidental unblinding (during a study visit), the total unblinding rate was 17% ( n = 9). Of these, seven participants (13%) reported unblinding during the treatment phase. When asked in the interview whether they knew that self-unblinding would have been possible, only 34% ( n = 18/53) of participants stated that they had been aware of this possibility. Thus, altogether 33% ( n = 6/18) of those being informed about the possibility of self-unblinding did so and half of them (3/18, 17 %) during the treatment phase. It can be expected that in parallel to increasing knowledge of medicinal and recreational use of cannabinoids, more and more people will also be informed about the availability of THC tests. Hence, in future RCTs using THC-containing cannabinoids, researchers have to take the possibility of accidental and intentional unblinding into consideration, when designing the study., Competing Interests: Author KM-V has received financial or material research support from EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), DFG: GZ MU 1527/3-1 and GZ MU 1527/3-2, BMBF: 01KG1421, National Institute of Mental Health (NIMH), Tourette Gesellschaft Deutschland e.V., Else-Kröner-Fresenius-Stiftung, GW pharmaceuticals, Almirall Hermal GmbH, Abide Therapeutics, and Therapix Biosiences; has received consultant's honoraria from Abide Therapeutics, Boehringer Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Grouth, Columbia Care, CTC Communications Corp., Demecan, Ethypharm GmbH, Eurox Deutschland GmbH, Global Praxis Group Limited, Lundbeck, MCI Germany, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, and Tilray; is an advisory/scientific board member for Alexion, CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, Ethypharm GmbH, IMC Germany, Leafly Deutschland GmbH, Neuraxpharm, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, von Mende Marketing GmbH, Wayland Group, and Zambon; has received speaker's fees from Aphria Deutschland GmbH, Almirall, Camurus, Cogitando GmbH, Emalex, Eurox Deutschland GmbH, Ever pharma GmbH, Meinhardt Congress GmbH, PR Berater, Spectrum Therapeutics GmbH, Takeda GmbH, Tilray, and Wayland Group. She has received royalties from Deutsches Ärzteblatt, Der Neurologie und Psychiater, Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and Kohlhammer, all of these financial supports took place outside of this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Müller-Vahl, Jakubovski, Fremer, Lenz-Ziegenbein, Großhennig, Klages, Koch, Haas and Pisarenko.)

We report the first outbreak of a new type of mass sociogenic illness that in contrast to all previously reported episodes is spread solely via social media. Accordingly, we suggest the more specific term 'mass social media-induced illness'. In Germany, the current outbreak of mass social media-induced illness is initiated by a 'virtual' index case, who is the second most successful YouTube creator in Germany and enjoys enormous popularity among young people. Affected teenagers present with similar or identical functional 'Tourette-like' behaviours, which can be clearly differentiated from tics in Tourette syndrome. Functional 'Tourette-like' symptoms can be regarded as the 'modern' form of the well-known motor variant of mass sociogenic illness. Moreover, they can be viewed as the 21st century expression of a culture-bound stress reaction of our post-modern society emphasizing the uniqueness of individuals and valuing their alleged exceptionality, thus promoting attention-seeking behaviours and aggravating the permanent identity crisis of modern man. We wish to raise awareness of the current global Tourette-like mass social media-induced illness outbreak. A large number of young people across different countries are affected, with considerable impact on health care systems and society as a whole, since spread via social media is no longer restricted to specific locations such as local communities or school environments spread via social media is no longer restricted to specific locations such as schools or towns., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Part II of the European clinical guidelines for Tourette syndrome and other tic disorders (ECAP journal, 2011) provides updated information and recommendations for psychological interventions for individuals with tic disorders, created by a working group of the European Society for the Study of Tourette Syndrome (ESSTS). A systematic literature search was conducted to obtain original studies of psychological interventions for tic disorders, published since the initial European clinical guidelines were issued. Relevant studies were identified using computerized searches of the MEDLINE and PsycINFO databases for the years 2011-2019 and a manual search for the years 2019-2021. Based on clinical consensus, psychoeducation is recommended as an initial intervention regardless of symptom severity. According to a systematic literature search, most evidence was found for Habit Reversal Training (HRT), primarily the expanded package Comprehensive Behavioral Intervention for Tics (CBIT). Evidence was also found for Exposure and Response Prevention (ERP), but to a lesser degree of certainty than HRT/CBIT due to fewer studies. Currently, cognitive interventions and third-wave interventions are not recommended as stand-alone treatments for tic disorders. Several novel treatment delivery formats are currently being evaluated, of which videoconference delivery of HRT/CBIT has the most evidence to date. To summarize, when psychoeducation alone is insufficient, both HRT/CBIT and ERP are recommended as first-line interventions for tic disorders. As part of the development of the clinical guidelines, a survey is reported from ESSTS members and other tic disorder experts on preference, use and availability of psychological interventions for tic disorders., (© 2021. The Author(s).)

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.

Objective: In patients with Tourette syndrome and other primary tic disorders (PTDs), tics are typically preceded by premonitory urges (PUs). To date, only a few studies have investigated the location and frequency of PUs, and contrary to clinical experience, the results suggest that PUs are not located in the same anatomic region as the tics. This study aimed to further explore PU location and frequency in detail, differentiating the kind and complexity of the corresponding tics, in a large sample of patients with PTD., Methods: A total of 291 adult (≥ 18 years) patients with a confirmed diagnosis of chronic PTD were included. The study was conducted online, assement included tics and the general characterization of PUs and a sophisticated body drawing for locating PUs., Results: We found that PUs were located in the same body area as, or in direct proximity to, the corresponding tic. Most frequently, PUs were located in the face and at the head (62.1%). Compared with simple tics, complex (motor and vocal) tics were more often preceded by a PU; but there was no difference in PU frequency observed between motor tics and vocal tics. PUs were more often experienced at the front than at the back of the body (73% vs. 27%), while there was no difference between the right and left sides (41.6% vs. 41.3%)., Conclusion: The strong association between PU and tic location further supports the hypothesis that PUs represent the core of PTD. Accordingly, future therapies should focus on treating PUs to achieve greater tic reduction.

Rage Attacks (RA) represent a clinically relevant symptom in patients with different psychiatric disorders. However, only recently the Rage Attack Questionnaire Revised (RAQ-R, 22 items, range, 0-66) has been developed as a new instrument for the assessment of RA. This study aimed to validate the RAQ-R in a large mixed psychiatric and psychosomatic sample. We tested internal consistency, convergent and discriminant validity as well as factor structure. In order to further explore the relationship of RA to other psychiatric symptoms, we calculated Pearson correlations between the RAQ-R and several other self-assessments including measurements for general psychological distress, quality of life, depression, anxiety, attention deficit/hyperactivity disorder (ADHD), impulsivity, and self-regulation abilities. Most relevant predictors of RA were examined in a multiple regression with stepwise elimination. In order to assess the manifestation of RA in different psychiatric disorders, group differences between diagnostic categories and healthy controls were calculated. Additionally, psychiatric patients were compared to patients with Tourette syndrome along RAQ-R scores. Data from healthy subjects and patients with Tourette syndrome were obtained from a previous study of our group. In this study, we included 156 patients with a wide and typical spectrum of psychiatric diseases. The RAQ-R was found to have excellent internal consistency and strong construct validity in this sample (Cronbach's α = 0.97, Average Variance Extracted = 0.58). Thus, the RAQ-R was shown to be a psychometrically sound assessment of RA in patients with different psychiatric disorders. Close constructs to RA were found to be aggression and hostility ( r = 0.68) as well as low frustration tolerance and impulse control ( r = 0.69). Compared to healthy controls, RA were significantly more common in the psychiatric sample ( p < 0.001). More specifically, RAQ-R scores in all diagnostic categories assessed were higher compared to controls. Highest scores and effect sizes were found in patients with ADHD and borderline personality disorder ( p < 0.001). Our results suggest that RA are a common and relevant symptom in many psychiatric disorders. As depression and RA showed only a moderate relation, RA should be distinguished from the concept of anger attacks, which are described as a core symptom of depression., Competing Interests: In the context of other research, KM-V has received financial or material research support from EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978) DFG: GZ MU 1527/3-1 and GZ MU 1527/3-2, BMBF: 01KG1421, National Institute of Mental Health (NIMH), Tourette Gesellschaft Deutschland e.V. Else-Kröner-Fresenius-Stiftung, GW pharmaceuticals, Almirall Hermal GmbH, Abide Therapeutics, and Therapix Biosiences. She has received consultant's honoraria from Abide Therapeutics, Boehringer Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Grouth, Columbia Care, CTC Communications Corp., Demecan, Eurox Deutschland GmbH, Global Praxis Group Limited, IMC Germany, Lundbeck, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, and Tilray. She has received speaker's fees from Aphria Deutschland GmbH, Almirall, Cogitando GmbH, Emalex, Eurox Deutschland GmbH, Ever pharma GmbH, Meinhardt Congress GmbH, PR Berater, Spectrum Therapeutics GmbH, Takeda GmbH, Tilray, Wayland Group. She has received royalties from Deutsches Ärzteblatt, Der Neurologie und Psychiater, Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and Kohlhammer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Palm, Haas, Pisarenko, Jakubovski and Müller-Vahl.)

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 ( r s = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms ( r s = 0.24), obsessive-compulsive symptoms ( r s = 27) as well as internalizing symptoms ( r s = 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., Competing Interests: TJH and VT have received funding from the Guys and St Thomas' NHS Foundation Trust. IH has received research funding or support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. PM has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía. KM-V has received financial or material research support from the EU (FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kröner-Fresenius-Stiftung, and Abide Therapeutics, Almirall Hermal GmbH, GW pharmaceuticals, Lundbeck, Syneos Health, and Therapix Biosciences Ltd. She has received consultant's honoraria from Abide Therapeutics, Allmiral, Boehringer Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Grouth, Columbia Care, CTC Communications Corp., Eurox Deutschland GmbH, Global Praxis Group Limited, Lundbeck, Resalo Vertrieb GmbH, Sanity Group, STADAPHARM GmbH, Synendos Therapeutics AG, and Tilray. She was a consultant or advisory board member for Abide Therapeutics, The Academy of Medical Cannabis Limited, Alirio, Aphria Deutschland GmbH, CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, CTC Communications Corp., Leafly Deutschland GmbH, Lundbeck, Nuvelution TS Pharma Inc., Resalo Vertrieb GmbH, Sanity Group, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, and Wayland Group. She has received speaker's fees from Aphria Deutschland GmbH, Cogitando GmbH, Emalex, Eurox Deutschland GmbH, Ever pharma GmbH, PR Berater, Spectrum Therapeutics GmbH, Tilray, and Wayland Group. She has received royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer. She served as a Guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects,” and is Associate editor for “Cannabis and Cannabinoid Research,” Editorial Board Member for “Medical Cannabis and Cannabinoids” and “MDPI-Reports,” and scientific board member for “Zeitschrift für Allgemeinmedizin.” AM has received research funding or support from the Possehl-Stiftung (Lübeck, Germany), the Margot und Jürgen Wessel Stiftung (Lübeck, Germany), the Tourette Syndrome Association (Germany), Interessenverband Tourette Syndrom (Germany), CHDI, Damp-Stiftung; Deutsche Forschungsgemeinschaft (DFG): projects 1692/3-1, 4-1, SFB 936, and FOR 2698 (project numbers 396914663, 396577296, 396474989), Innovationsausschuss of the Gemeinsamer Bundesausschuss: Translate NAMSE (structural support for the Lübeck Center for Rare Diseases); European Reference Network—Rare Neurological Diseases (ERN—RND). SW has received in the last 5 years royalties from Thieme Hogrefe, Kohlhammer, Springer, Beltz. Her work was supported in the last 5 years by the Swiss National Science Foundation (SNF), diff. EU FP7s, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Thalmann, Vontobel, Unicentia, Erika Schwarz Fonds. Outside professional activities and interests are declared under the link of the University of Zurich www.uzh.ch/prof/ssl-dir/interessenbindungen/client/web/. AS has received research funding or support from University College London, National Institute of Health (NIHR), National Institute for Health Research ULCH Biomedical Research Centre, the International Parkinson and Movement Disorder Society (IPMDS), the European Commission, Parkinson's UK, GE Healthcare and the Economic and Social Research Council. Honoraria for consultancy from Biogen, Abbvie, Roche, Bial, GE Healthcare; and license fee payments from the University College London for the MSA-QoL, PSP-QoL, and PQolCarers. Royalties from Oxford University Press. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Haas, Jakubovski, Fremer, Dietrich, Hoekstra, Jäger, Müller-Vahl and the EMTICS Collaborative Group.)

Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS. Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders. Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments. Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication. Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders. Clinical Trial Registration: This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201)., Competing Interests: KM-V has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kroner Fresenius-Stiftung, and GW, Abide Therapeutics, Lundbeck, Syneos Health, Therapix Biosciences Ltd, Almirall Hermal GmbH, GW pharmaceuticals. She has received consultant's honoraria from Abide Therapeutics, Tilray, Resalo Vertrieb GmbH, Columbia Care, Bionorica Ethics GmbH, Lundbeck and Eurox Deutschland GmbH. She is a consultant or advisory board member for Abide Therapeutics, Alirio, The Academy of Medical Cannabis Limited, CannaMedical Pharma GmbH, CannaXan GmbH, Columbia Care, Canopy Growth, Leafly Deutschland GmbH, Lundbeck, Nomovo Pharm, Nuvelution TS Pharma Inc., Resalo Vertrieb GmbH, Sanity Group, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, Wayland Group, Zynerba Pharmaceuticals, and CTC Communications Corporation. She has received speaker's fees from Tilray, Wayland Group, Emalex, Eurox group, PR Berater, Aphria, Ever pharma GmbH, and Cogitando GmbH. She has received royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer. She holds shares of Nomovo Pharm. She served as a Guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects,” is Associate editor for “Cannabis and Cannabinoid Research” and Editorial Board Member for “Medical Cannabis and Cannabinoids.” The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Jakubovski, Pisarenko, Fremer, Haas, May, Schumacher, Schindler, Häckl, Aguirre Davila, Koch, Brunnauer, Cimpianu, Lutz, Bindila and Müller-Vahl.)

Background: Many children and adults with Obsessive-Compulsive Disorder (OCD) fail to respond to first-line pharmacological and behavioral treatments. Glutamate dysfunction may contribute to the development of OCD. N-acetylcysteine (NAC), a glutamate modulating drug, has shown to be a promising agent in adults with OCD. Methods: We conducted a double-blind, placebo-controlled clinical trial from July 2012 to January 2017. Children ages 8 to 17 years with OCD were assigned to receive NAC (up to 2700 mg/day) or the matching placebo for a period of 12 weeks. Children were required to be on stable psychiatric treatment (both medication and therapy) but were not required to be treatment-refractory. The primary outcome was OCD symptom severity as measured by the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). We used linear mixed models to analyze the effect of NAC compared to placebo. Results: Due to poor recruitment and eventual expiration of the study medication, enrollment was stopped at 11 children out of a planned sample size of 40. Nonetheless, NAC was associated with significant reduction in CY-BOCS total score compared to placebo (Satterthwaite's test: t (37) = 2.36, p  = 0.024) with effects separating from placebo beginning at week 8. Mean CY-BOCS total score decreased in the NAC group from 21.4 ± 4.65 at baseline to 14.4 ± 5.55 at week 12. In the placebo group, mean CY-BOCS total score remained unchanged (21.3 ± 4.65). In the NAC group, 1 out of 5 participants achieved >35% improvement in CY-BOCS total score, while none of the six patients in placebo group reached this improvement level. NAC and placebo were well tolerated. One mild adverse event was reported in each group. Conclusions: Our trial suggests that there may be some initial improvement in OCD symptom severity with NAC treatment. NAC was well tolerated in the study population. Future trials should employ multiple sites and have a larger study population to further confirm any benefits of NAC.

Introduction: Although defined by the presence of tics, most patients with Gilles de la Tourette syndrome (TS) also suffer from different psychiatric disorders. While much is known about clinical characteristics of comorbidities such as attention deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), depression, and anxiety disorders, only very little is known about rage attacks. Most of this data is based on small studies in children. Until today no larger studies have been performed in adults with TS-most likely because of the lack of validated instruments. The aim of this study was to develop a new assessment and investigate rage attacks in a large sample of adults with TS and healthy individuals., Materials and Methods: Based on a parent questionnaire for children with TS, we generated 27 items for a revised version of a rage attack questionnaire (RAQ-R) and tested factor structure, internal consistency, as well as convergent and discriminant validity. We used an online survey and included 127 patients with TS and 645 control subjects. In addition to the RAQ-R, we used several other self-assessments to measure tic severity, quality of life, as well as several psychiatric symptoms including ADHD, OCD, depression, anxiety, and impulsivity., Results: Based on expert option and statistical analyses [including item-total correlation, skewness, inter-item correlation, and principal component analysis (PCA)], we performed an item reduction resulting in a final, 22-items version of the RAQ-R (range, 0-66). Investigating internal consistency, discriminant validity, test reliability, and factor structure, the RAQ-R demonstrated good to excellent quality criteria. As assessed by RAQ-R, rage attacks were significantly more common in patients with TS compared to controls (p < 0.001). Rage attacks could be clearly differentiated from the phenomenon of impulsivity. Although rage attacks occurred more often in individuals with ADHD, they were also found in patients with "TS only", independently from comorbid ADHD, impulsivity, and OCD. Rage attacks were found to significantly influence patients' quality of life., Conclusions: Thus, from our data based on a large sample it is suggested that rage attacks represent a discrete comorbidity in adults with TS., (Copyright © 2020 Müller-Vahl, Kayser, Pisarenko, Haas, Psathakis, Palm and Jakubovski.)

Introduction: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder that is characterized by motor and vocal tics and psychiatric comorbidities, including attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive behavior/disorder (OCB/OCD). From anecdotal reports and preliminary controlled studies, it is suggested that cannabis-based medicine (CBM) may improve tics and comorbidities in adults with GTS. This study was designed to further investigate efficacy and safety of CBM in GTS and specifically compare effects of different CBM. Materials and Methods: First, we performed a retrospective data analysis including all those adult patients seen at our clinic, who had used CBM for the treatment of GTS at some time. All these patients were asked to complete an online survey (second study part) to receive more detailed data about treatment with CBM. Results: From medical records, we identified 98 patients who had used CBM (most often street cannabis followed by nabiximols, dronabinol, medicinal cannabis) for the treatment of GTS: Of the 38 patients who were able to judge, 66% preferred treatment with medicinal cannabis, 18% dronabinol, 11% nabiximols, and 5% street cannabis. Altogether, CBM resulted in a subjective improvement of tics (of about 60% in 85% of treated cases), comorbidities (55% of treated cases, most often OCB/OCD, ADHD, and sleeping disorders), and quality of life (93%). The effects of CBM appear to persist in the long term. Adverse events occurred in half of the patients, but they were rated as tolerable. Dosages of all CBM varied markedly. Patients assessed cannabis (with a preference for tetrahydrocannabinol [THC]-rich strains) as more effective and better tolerated compared with nabiximols and dronabinol. These data were confirmed by results obtained from the online survey ( n =40). Conclusion: From our results, it is further supported that CBM might be effective and safe in the treatment of tics and comorbidities at least in a subgroup of adult patients with GTS. In our sample, patients favored THC-rich cannabis over dronabinol and nabiximols, which might be related to the entourage effect of cannabis. However, several limitations of the study have to be taken into considerations such as the open uncontrolled design and the retrospective data analysis., Competing Interests: K.R.M.-V. has received consultant's honoraria from Abide Therapeutics, Fundacion Canna, and Therapix Biosiences, and speaker's fees from Tilray, and is a consultant for Zynerba Pharmaceuticals, has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), Tourette Gesellschaft Deutschland e.V., Else-Kroner-Fresenius-Stiftung, and GW, Almirall, Abide Therapeutics, and Therapix Biosiences, consultant's honoraria from Abide Therapeutics and Therapix Biosiences, and royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin. All other authors have no competing financial interests to declare., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

Although the DSM-5 chronic motor tic disorder (CMTD) and Tourette syndrome (TS) are distinct diagnostic categories, there is no genetic or phenotypic evidence that supports this diagnostic categorization. The aim of this study was to compare patients with both diagnoses along a number of clinical characteristics to provide further diagnostic clarity. Our sample consisted of 1018 patients (including adult and child patients) suffering from chronic tic disorders. Tic severity was assessed via Shapiro Tourette-Syndrome Severity Scale (STSS). Lifetime prevalence of other comorbid conditions was assessed in a semi-structured clinical interview. The data were gained through retrospective chart analysis. The two groups did not differ significantly in any of the clinical or demographic variables. Patients only differed in tic severity, with CMTD patients (n = 40) having lower mean tic severity (STSS = 2.0 vs. 2.8; p < 0.001), prevalence of complex motor tics (27.5% vs. 55.9%; p < 0.01), copropraxia (0% vs. 16.2%; p < 0.01) and echopraxia (10.0% vs. 23.8%; p < 0.05), and a markedly lower comorbidity score (1.9 vs. 2.7; p < 0.001) as compared to TS patients (n = 978). Our results suggest that both disorders exist along a symptom severity continuum of which TS constitutes a more severe and CMTD a less severe form. We therefore suggest the introduction of the term "tic spectrum disorders", instead of using different diagnostic categories.

Background: We aimed to examine the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for anxiety disorders examining overall symptom improvement, likelihood of treatment response, time course of treatment response, individual pharmacological agent, diagnostic indication dose, and tolerability., Methods: We searched PubMed and Cochrane Central Register of Controlled Trials. We included randomized placebo-controlled clinical trials of SSRIs/SNRIs in adult patients with anxiety disorders that provided data at three or more time points. Extracted data included trial duration, weekly/biweekly anxiety scores for 12 weeks., Results: Meta-analysis included 57 trials (N = 16,056). A linear mixed model analysis based on weekly outcome data suggested that for SNRI a logarithmic model offered the best fit compared to placebo (indicating the greatest incremental improvement from baseline occurred early in treatment); whereas for SSRI a linear model provided the best fit (indicating a similar improvement over the duration of the acute treatment phase). There were no significant differences in efficacy between pharmacological agents within each class or when comparing SSRIs to SNRIs. The greatest treatment benefits were observed for social anxiety disorder for both medication classes. Higher doses of SSRIs, but not SNRIs, were associated with significantly greater symptom improvement and likelihood of treatment response. For both medical classes, higher doses were associated with an increased likelihood of dropout due to side effects., Conclusions: SSRIs and SNRIs are effective in treating anxiety disorders. Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, whereas higher doses of SNRIs are not., (© 2018 Wiley Periodicals, Inc.)

Background: Antipsychotic-related weight gain is a common clinically relevant side effect when treating psychotic disorders in pediatric populations, yet few predictors and no moderators of antipsychotic-related weight gain are known., Methods: The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study randomized 119 youths (age 8-19 years) with schizophrenia or schizoaffective disorder to 8 weeks of antipsychotic treatment with molindone, risperidone, or olanzapine and assessed treatment response and side effects. In this secondary analysis, we used multivariable linear regression and receiver operating characteristic analysis to investigate predictors and moderators of weight change and percent weight change from baseline to week 8., Results: Treatment assignment was the most discriminant predictor of weight change [F(2, 66) = 17.00, p < 0.001] and percent weight change [F(2, 66) = 16.85, p < 0.001]. Mean weight gain was 0.74 (standard deviation ±3.51) kg for molindone, 4.13 ± 3.79 kg for risperidone, and 7.29 ± 3.44 kg for olanzapine. After adjusting for treatment assignment, lower pretreatment hemoglobin A1C (HgbA1C) predicted more weight gain [F(1, 55) = 4.71, p = 0.03]. Diagnosis (schizoaffective vs. schizophrenia) moderated weight change [F(2, 63) = 6.02, p = 0.004] and percent weight change [F(2, 63) = 5.26, p = 0.008] such that schizoaffective diagnosis predicted larger weight gain for youths in the risperidone treatment arm. Age, sex, family income, baseline weight, and symptoms neither predicted nor moderated weight change or percent weight change., Conclusion: We identified prognostic subgroups and novel risk factors for antipsychotic-related weight gain. We confirmed that antipsychotic choice is extremely important for predicting future weight gain. We also found that younger age did not predict greater weight gain, in contrast to prior studies. Our findings require replication in an independent sample because we did not adjust for multiple comparisons to minimize false negatives. ClinicalTrials.gov Identifier: NCT00053703.

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

This secondary analysis of the Child/Adolescent Anxiety Multimodal Study (CAMS) used baseline patient characteristics to identify prognostic subgroups of children based on likelihood of remission. We also investigated predictors and moderators of outcome. CAMS randomized 488 youths with generalized, social, and separation anxiety disorders to cognitive behavioral therapy (CBT), sertraline, both, or pill placebo. Outcomes were Week 12 child, parent, and independent evaluator (IE) ratings of child anxiety. We used receiver operating characteristics analysis and stepwise regression to identify predictors and moderators of outcome. Severe anxiety, lower socioeconomic status, and comorbid obsessive-compulsive disorder predicted higher IE-rated anxiety posttreatment; child-rated social anxiety predicted poorer outcomes reported by all informants. Regarding moderators, Hispanic ethnicity predicted higher IE-rated anxiety after CBT and higher parent-rated anxiety after sertraline. In youths with severe anxiety (Pediatric Anxiety Rating Scale ≥ 20, &lt;italic&gt;n&lt;/italic&gt; = 220), combination treatment increased remission (relative risk [RR] = 2.85, &lt;italic&gt;p&lt;/italic&gt; &lt; .001), 95% confidence interval (CI) [1.51, 5.39], whereas CBT (RR = 1.55, &lt;italic&gt;p&lt;/italic&gt; = .20), 95% CI [0.77, 3.10], and sertraline (RR = 1.27, &lt;italic&gt;p&lt;/italic&gt; = .53), 95% CI [0.59, 2.73], did not significantly increase remission relative to placebo. These are the first findings demonstrating that a combination of CBT and a selective serotonin reuptake inhibitor, not monotherapy, is likely key for achieving remission in severe anxiety. CAMS was not powered to detect treatment efficacy after stratification by anxiety severity, so further research is needed regarding effective treatments in severe anxiety. Our main effect findings suggest youth with severe anxiety (especially social phobia), low socioeconomic status and obsessive-compulsive disorder benefit less from current first-line treatments relative to other anxious youth. ClinicalTrials.gov: NCT00052078.

Background: Electroconvulsive therapy (ECT) is one of the most effective treatment options for refractory depressed patients. To date, there are only a few predictors of response., Aim: The aim was to identify predictive biomarkers of remission to ECT on a molecular level., Methods: 11 patients suffering from a major depressive episode-according to the Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-underwent 10 ECT sessions. Blood samples were taken, and the depression severity was assessed before, one hour and 24 hours after sessions 1, 4, 7, and 10 using the Montgomery Asberg Depression Rating Scale (MADRS). A MADRS total score < 12 was interpreted as remission., Results: Patients remitting under ECT had significantly higher homocysteine ( p < 0.001), S100B ( p < 0.001), and procalcitonin (PCT) ( p = 0.027) serum levels. On the contrary, serum levels of vitamin B12 ( p < 0.001) and folic acid ( p = 0.007) were significantly lower in remitters compared to those in nonremitters. Levels remained unchanged throughout the whole ECT course., Conclusions: Our findings indicate that lower levels of vitamin B12 and folic acid associated with higher levels of homocysteine, S100B, and PCT point to a subgroup of depressed patients sensitive to ECT. Due to the limited sample size, further studies are required to replicate our findings.

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F 9,115 =2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F 10,141 =0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.

Objective: This study examines predictors of later risky driving behavior in children with attention-deficit/hyperactivity disorder (ADHD)., Methods: Stepwise logistic regression and receiver operating characteristic (ROC) analysis were used to explore baseline predictors of risky driving behavior for adolescents who completed the 8-year follow-up assessment in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA)., Results: Stepwise logistic regression analysis explained 19% of the total variance in risky driving behavior. Increased likelihood of risky driving behavior was associated with parental history of conduct disorder, low parental monitoring and supervision, and increased age. ROC analysis identified discriminative predictors for adolescents older and younger than 16 years of age at follow-up. The most discriminative predictors of later risky driving behavior were parental stress at baseline (for children 16 years or older) and increased child-rated parental protectiveness (for children less than 16 years old)., Conclusion: Risky driving behavior was significantly predicted by baseline characteristics for the MTA cohort. Aspects of parenting behavior (or the child's perception of them), including parental stress levels, parental protectiveness, and parental levels of monitoring and supervision, were most informative in predicting these outcomes. Our results suggest that interventions to reduce high-risk behaviors in these high-risk children with ADHD might involve targeted parenting interventions.

The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) compared the efficacy of risperidone, olanzapine, and molindone over 8 weeks in 119 youths age 8-19 years with early-onset schizophrenia or schizoaffective disorder. From this large dataset, we examined predictors of treatment response and drop out using stepwise regression and receiver operating characteristics curve (ROC) analysis. Treatment response was defined as having both a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) score and a Clinical Global Impression-Improvement (CGI-I) score < 3. More severe baseline symptoms, having a history of being in an early education program, and previous prescription of a mood stabilizer increased the likelihood of responding to treatment. Anhedonia and poor community functioning predicted a reduction in symptom severity on the PANSS. Random assignment to different antipsychotic treatment was not predictive of outcome. Parental report of aggressive behaviors at baseline and being African American were associated with a greater likelihood of drop out. Our results suggest youth with more severe psychotic symptoms are most likely to benefit from treatment with antipsychotics and that aggressive youth may require additional support to improve treatment adherence. Further investigation is needed to understand potentially modifiable predictors of response like early education programs., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Gilles de la Tourette syndrome is a chronic neuropsychiatric movement disease with combined motor tics and at least one vocal tic for a minimum period of 1 year. It typically begins in the childhood (under 18 years of age).Most of the patients with Tourette syndrome have comorbidities, which often impair their quality of life more than the tics themselves.There are reported abnormalities in the cortico-striato-thalamo-cortical regions as well as in the neurotransmission of dopamine and other neurotransmission systems. Genetic and non genetic factors are discussed.In each patient psychoeducation is the basis of treatment. Specific treatment is only needed in more severe tic disorders which cause evident psychosocial impairment.Behavior therapy should be tried before drug treatment. For very severely affected adults, deep brain stimulation is a further treatment option., Competing Interests: Interessenkonflikt: Die Autorin Kirsten Müller-Vahl erklärt, dass sie innerhalb der letzten 3 Jahre Mitglied im Sachverständigenausschuss für Betäubungsmittel der Bundesopiumstelle und im wissenschaftlichen Beirat der Fundación CANNA war sowie 2. Vorsitzende der International Association for Cannabinoid Medicines (IACM) ist. Sie ist beratend tätig für Abide Pharmaceutics, Inc., Prahealthsciences und Therapix Biosciences und erhielt Forschungsunterstützung von der Deutschen Forschungsgemeinschaft (DFG), dem Bundesinstitut für Bildung und Forschung (BMBF), der EU, dem National Institute of Mental Health (NIMH), der Kröner-Fresenius-Stifung und Abide Pharmaceutics, Inc. Ewgeni Jakubovski wird gefördert durch das BMBF., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To explore predictors of 8-year school-based behavioral outcomes in attention-deficit/hyperactivity disorder (ADHD)., Methods: We examined potential baseline predictors of school-based behavioral outcomes in children who completed the 8-year follow-up in the multimodal treatment study of children with ADHD. Stepwise logistic regression and receiver operating characteristic (ROC) analysis identified baseline predictors that were associated with a higher risk of truancy, school discipline, and in-school fights., Results: Stepwise regression analysis explained between 8.1% (in-school fights) and 12.0% (school discipline) of the total variance in school-based behavioral outcomes. Logistic regression identified several baseline characteristics that were associated with school-based behavioral difficulties 8 years later, including being male (associated with truancy and school discipline), African American (school discipline, in-school fights), increased conduct disorder (CD) symptoms (truancy), decreased affection from parents (school discipline), ADHD severity (in-school fights), and study site (truancy and school discipline). ROC analyses identified the most discriminative predictors of truancy, school discipline, and in-school fights, which were Aggression and Conduct Problem Scale Total score, family income, and race, respectively., Conclusions: A modest, but nontrivial portion of school-based behavioral outcomes, was predicted by baseline childhood characteristics. Exploratory analyses identified modifiable (lack of paternal involvement, lower parental knowledge of behavioral principles, and parental use of physical punishment), somewhat modifiable (income and having comorbid CD), and nonmodifiable (African American and male) factors that were associated with school-based behavioral difficulties. Future research should confirm that the associations between earlier specific parenting behaviors and poor subsequent school-based behavioral outcomes are, indeed, causally related and independent cooccurring childhood psychopathology. Future research might target increasing paternal involvement and parental knowledge of behavioral principles and reducing use of physical punishment to improve school-based behavioral outcomes in children with ADHD.

Objective: Selective serotonin reuptake inhibitors are first-line treatment for major depressive disorder (MDD), but their impact on suicidal ideation is equivocal. Our goal is to examine the time course and clinical predictors of citalopram-induced suicidal ideation during phase 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial., Methods: Of the 4,041 subjects with DSM-IV nonpsychotic MDD in the STAR*D trial phase 1 (2001-2006), we included in our analysis 3,577 subjects who reported side-effect data and had received citalopram (20-60 mg/d) for 8-14 weeks. Suicidal ideation was reported on item 12 of the Quick Inventory of Depressive Symptomatology, Self-Report. Survival analysis and receiver operating characteristic analysis were used to assess baseline characteristics associated with emergence and worsening of suicidal ideation., Results: Suicidal ideation was more likely to occur early in citalopram treatment, with few subjects showing emergence or worsening occurring after 6 weeks of treatment. Clinical variables explained very little of the variance in worsening or emergence of suicidal ideation with citalopram treatment (generalized R² ≤ 2% in survival analysis). Being Hispanic, taking sedative medications, increased depression severity, absence of hypersomnia, and cardiac comorbidity were significantly (P ≤ .04) associated with greater likelihood of emergence of suicidal ideation in patients without suicidal ideation at baseline. Being widowed, better work performance, weight loss at baseline, and the presence of vascular or neurologic comorbidities were associated with a greater likelihood of worsening of suicidal ideation., Conclusions: Baseline clinical variables were poor predictors of emergence or worsening of suicidal ideation. As such, increased research focusing on clinical correlates rather than clinical predictors of suicidal ideation may be useful, as intervening events may be crucial in bringing about increased suicidality., Trial Registration: ClinicalTrials.gov identifier: NCT00021528., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objective: We conducted a meta-analysis to examine the following: the time course of response to selective serotonin reuptake inhibitors (SSRIs) and clomipramine in pediatric obsessive-compulsive disorder (OCD); whether higher doses of SSRIs are associated with an improved response in pediatric OCD; differences in efficacy among SSRI agents; differences in efficacy between SSRIs and clomipramine; and whether the time course and magnitude of response to SSRIs are different in pediatric and adult patients with OCD., Method: We searched PubMed and CENTRAL for randomized controlled trials comparing SSRIs (or clomipramine) to placebo for the treatment of pediatric OCD and using the Children's Yale-Brown Obsessive-Compulsive Scale as an outcome. We extracted weekly symptom data from trials to characterize the trajectory of pharmacological response to SSRIs. Pooled estimates of treatment effect were calculated based on weighted mean differences between the treatment and placebo groups., Results: Nine trials involving 801 children with OCD were included in this meta-analysis. A logarithmic model indicating that the greatest benefits occurred early in treatment best fit the longitudinal data for both clomipramine and SSRIs. Clomipramine was associated with a greater measured benefit compared to placebo than SSRIs. There was no evidence for a relationship between SSRI dosing and treatment effect, although data were limited. Adults and children with OCD demonstrated a similar degree and time course of response to SSRIs in OCD., Conclusion: These results suggest that the greatest incremental treatment gains in pediatric OCD occur early in SSRI treatment (similar to adults with OCD and children and adults with major depression)., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Gilles de la Tourette Syndrome (GTS) is characterized by motor and vocal tics, as well as associated comorbid conditions including obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder (ADHD), depression, and anxiety which are present in a substantial number of patients. Although randomized controlled trials including a large number of patients are still missing, aripiprazole is currently considered as a first choice drug for the treatment of tics. The aim of this study was to further investigate efficacy and safety of aripiprazole in a group of drug-free, adult patients. Specifically, we investigated the influence of aripiprazole on tic severity, comorbidities, premonitory urge (PU), and quality of life (QoL). Moreover, we were interested in the factors that influence a patient's decision in electing for-or against- pharmacological treatment. In this prospective uncontrolled open-label study, we included 44 patients and used a number of rating scales to assess tic severity, PU, comorbidities, and QoL at baseline and during treatment with aripiprazole. Eighteen out of fortyfour patients decided for undergoing treatment for their tics with aripiprazole and completed follow-up assessments after 4-6 weeks. Our major findings were (1) aripiprazole resulted in significant reduction of tics, but did not affect PU; (2) aripiprazole significantly improved OCD and showed a trend toward improvement of other comorbidities including depression, anxiety, and ADHD; (3) neither severity of tics, nor PU or QoL influenced patients' decisions for or against treatment of tics with aripiprazole; instead patients with comorbid OCD tended to decide in favor of, while patients with comorbid ADHD tended to decide against tic treatment; (4) most frequently reported adverse effects were sleeping problems; (5) patients' QoL was mostly impaired by comorbid depression. Our results suggest that aripiprazole may improve associated comorbid conditions in addition to tics in patients with GTS. It can be hypothesized that these beneficial effects are related to aripiprazole's adaptive pharmacological profile, which exhibits an influence on the dopaminergic as well as a number of other neurotransmitter systems. For the first time, our data provide evidence that patients' decision making process for or against medical treatment is influenced by other factors than tic severity and QoL.

Background: Gilles de la Tourette syndrome (TS) is a complex neuropsychiatric disorder defined by the presence of motor and phonic tics, but often associated with psychiatric comorbidities. The main objective of this study was to explore the clinical presentation and comorbidities of TS., Method: We analyzed clinical data obtained from a large sample (n = 1032; 529 children and 503 adults) of patients with tic disorders from one single German TS center assessed by one investigator. Data was collected with the help of an expert-reviewed semi-structured interview, designed to assess tic severity and certain comorbidities. Group comparisons were carried out via independent sample t-tests and chi-square tests., Results: The main findings of the study are: (1) tic severity is associated with the presence of premonitory urges (PU), copro-, echo-, and paliphenomena and the number of comorbidities, but not age at tic onset; it is higher in patients with comorbid obsessive-compulsive disorder (OCD) than in patients with comorbid attention deficit/hyperactivity disorder (ADHD). (2) PU were found to be highly associated with "not just right experiences" and to emerge much earlier than previously thought alongside with the ability to suppress tics (PU in >60% and suppressibility in >75% at age 8-10 years). (3) Self-injurious behavior (SIB) is highly associated with complex motor tics and coprophenomena, but not with OCD/obsessive-compulsive behavior (OCB). While comorbid ADHD is associated with a lower ability to suppress tics, comorbid depression is associated with sleeping problems., Discussion: Our results demonstrate that tic severity is not influenced by age at onset. From our data, it is suggested that PU represent a specific type of "not just right experience" that is not a prerequisite for tic suppression. Comorbid ADHD reduces patients' ability of successful tic suppression. Our data suggest that SIB belongs to the coprophenomena spectrum and hence should be conceptualized as a complex tic rather than a compulsion. Finally, this study strongly supports the hypothesis that TS+OCD is a more severe form of TS and that comorbid OCD/OCB, depression, and anxiety belong to the TS spectrum, while ADHD should be better conceptualized as a separate problem.

Identifying baseline characteristics associated with treatment outcome in generalized anxiety disorder, panic disorder, social anxiety disorder (SAD) or post-traumatic stress disorder. We performed two secondary analyses of the Coordinated Anxiety Learning and Management trial. Baseline characteristics and their interactions with treatment assignment were analyzed via stepwise logistic regression models and receiver-operating criterion analyses by disorder predicting remission and response for each disorder. Predictors for poor outcome across diagnoses were comorbid depression and low socioeconomic status. Good outcome was associated with positive treatment expectancy and high self-efficacy expectancy. SAD had the lowest rate of remission and response compared to the other anxiety disorders, and differed in respect to its predictors of treatment outcome. Perceived social support predicted treatment outcome in SAD. The special role of SAD among the other anxiety disorders requires further study both because of its worse prognosis and its more specific treatment needs.

Background: In recent years, behavioral therapy with comprehensive behavioral intervention for tics (CBIT) has been recognized as an effective and safe treatment in patients with Gilles de la Tourette syndrome. In Germany, however, dissemination of CBIT is restricted due to a considerable lack of well-trained therapists. The aim of this study is to overcome this deficiency by creating a new and sophisticated Internet-delivered CBIT (iCBIT) program. With this study, we want to demonstrate that iCBIT is superior to Internet-delivered psychoeducation and comparable to face-to-face CBIT., Method and Analysis: This is a multicenter, prospective, randomized, controlled, observer-blind clinical trial, which will be conducted at five sites in Germany (ONLINE-TICS). Over the course of 2 years, 160 adult patients with chronic tic disorders will be assigned to one of three treatment arms: iCBIT (n = 72), online psychoeducation (n = 72), or face-to-face CBIT (n = 16). All treatments will consist of eighty therapy sessions over a period of 10 weeks and will follow the well-established CBIT manual by Woods and colleagues. The primary outcome measure will be the change in Yale Global Tic Severity Scale (YGTSS) at 1-week posttreatment. Secondary outcome measures include YGTSS change at 3 and 6 months, video- and self-ratings of tics as well as scales for psychiatric comorbidities assessed at each visit. The primary analysis will compare iCBIT to online psychoeducation using a mixed linear model with the YGTSS change as dependent variable. Secondary analyses will look at the comparison between iCBIT and face-to-face CBIT in a non-inferiority analysis., Discussion: If iCBIT proves to be effective, it would be a considerable contribution to close the wide gap in treatment providers for tic disorders not only in Germany but also in several other countries, since this Internet-delivered therapy does not require the supervision of a therapist. In addition, iCBIT would be a cost-effective and readily available treatment alternative that guarantees high quality standard of CBIT., Ethics and Dissemination: All institutional review boards approve the protocol. All participants will provide informed consent. There are no conflicts of interest. After study completion, the results will be published., Study Registration: ClinicalTrials.gov Identifier: NCT02413216.

Background: Current pharmacological treatments for Tourette Syndrome (TS), such as antipsychotic agents and α-2 agonists, are moderately effective in the treatment of tics, but have substantial side effects that limit their use. N-acetylcysteine (NAC) modulates glutamatergic systems, and has been used safely as an antioxidant agent with minimal side effects for decades. NAC has been increasingly studied for the treatment of other obsessive-compulsive spectrum disorders. We aim to examine the efficacy of NAC for the treatment of pediatric TS in a double-blind, placebo-controlled, add-on study., Methods: Thirty-one children and adolescents 8-17 years of age with TS were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of tics as measured by the Yale Global Tic Severity Scale (YGTSS), Total tic score. Secondary measures assessed comorbid obsessive-compulsive disorder (OCD), depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD). Linear mixed models in SAS were used to examine differences between NAC and placebo., Results: Of 31 randomized subjects, 14 were assigned to placebo (two females; 11.5 + 2.8 years) and 17 to active NAC (five females; 12.4 + 1.4 years) treatment. No significant difference between NAC and placebo was found in reducing tic severity or any secondary outcomes., Conclusions: We found no evidence for efficacy of NAC in treating tic symptoms. Our findings stand in contrast to studies suggesting benefits of NAC in the treatment of other obsessive-compulsive spectrum disorders in adults, including OCD and trichotillomania, but are similar to a recent placebo-controlled trial of pediatric trichotillomania that found no benefit of NAC.

Objective: Selective serotonin reuptake inhibitors (SSRIs) are recommended as the first-line pharmacologic treatment for obsessive-compulsive disorder (OCD). SSRI response is thought to be delayed in OCD, even more so than in major depression. We conducted a meta-analysis to examine the trajectory of treatment response to SSRIs and how this trajectory is modulated by dosage., Data Sources: PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched on May 22, 2013, for randomized, placebo-controlled SSRI trials in OCD with the search terms "serotonin uptake inhibitors" [MeSH] OR "serotonin uptake inhibitors" [Pharmacologic Action] AND "obsessive-compulsive disorder" [MeSH]. There were no language limitations on the search., Study Selection: Randomized, placebo-controlled trials that examined the efficacy of SSRIs in the treatment of adults with OCD and utilized the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as an outcome were selected., Data Extraction: We extracted weekly symptom data from randomized, placebo-controlled trials of SSRIs for the treatment of adults with OCD in order to characterize the trajectory of pharmacologic response. Our primary outcome was weighted mean difference on the Y-BOCS of SSRI treatment compared to placebo. We used the PROC MIXED procedure in SAS to examine 6 possible models of SSRI response. Interaction terms were utilized to examine the effect of dose, individual agent, and year of publication on SSRI response., Results: The meta-analysis included 17 trials of SSRIs including 3,276 subjects. A statistically significant benefit of SSRIs compared to placebo was seen within 2 weeks after the start of treatment (weighted mean difference = -0.91 [95% CI, -0.54 to -1.28], P < .001). A logarithmic response curve, indicating decreasing symptom improvement over time, provided the best fit for the trajectory of OCD symptom improvement. A significantly greater response was associated with using higher doses of SSRIs (P < .0001)., Conclusions: These results suggest that the greatest incremental treatment gains in OCD are seen early on in SSRI treatment. This is consistent with a previous meta-analysis examining time course of SSRI action in major depressive disorder and contrasts with the widely held belief that SSRI response in OCD is delayed., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Deficits in implicit learning, a process by which knowledge is acquired accretively through practice independent of conscious awareness, have been implicated in Obsessive-Compulsive Disorder (OCD). The weather-prediction task (WPT) was used to assess implicit learning in 26 unmedicated patients with OCD and 23 healthy controls. An additional analysis compared these two groups with 25 medicated patients with OCD. In the comparison of unmedicated patients with healthy controls there was a subtle but statistically significant group-by-block interaction. Patients with OCD showed slower improvement in performance during the middle phase of learning. In a three-group comparison, there was no main effect of group; in post-hoc tests, medicated patients with OCD differed from unmedicated patients and were not different from healthy controls. Unmedicated patients with OCD have a subtle deficit in implicit learning in the WPT. This may be mitigated by pharmacotherapy, although prospective studies would be required to confirm this conclusion.