What affords being creative? Opportunities for novelty in light of perception, embodied activity, and imaginative skill.

An affordance perspective highlights how resourceful the ecology is for creative actions of all sorts; it captures how creativity is grounded in materiality. In contrast to "canonical affordances" (i.e., "ready-to-hand," mundane instances), creative affordances point to unconventional or surprising action opportunities that are nonetheless valued. Our initial aim is to discuss how to frame the affordance concept to make it attractive for the study of creativity. We propose a dialectic position that reconciles aspects of the realism of ecological psychology with the constructivist view more typical of creativity scholars. We stress that novel options frequently depend on constructive actions; novelty cannot always simply be "found" or just waits to be used. Many creative opportunities only emerge from how person actively engages with the ecology. Our second aim is to explore specific ways that creativity is mediated through affordances, based on illustrations from crafts and dance. These suggest that affordances span various timescales and mediate in multiple ways, from noticing existing potentials, via active affordance shaping, to background activities that indirectly invite or enable novelty. In conclusion we discuss how a person's creative "vision," imagination and combinatoric ability, all fundamental creativity mechanisms, relate to affordances and how fruitful creative directions may be perceptually hinted at.

An "in vivo" analysis of crafts practices and creativity-Why affordances provide a productive lens.

Scholars are increasingly recognizing that creativity is grounded in the active sensorimotor engagement with the environment and materiality. Affordances-recognizable pointers to action opportunities in the ecology-provide a helpful prism for analyzing how this happens. Creative practitioners, as they seek aesthetic opportunities or innovation, depend on their sensitivity toward potentialities in their action space. Presently, we apply a high-zoom lens to a crafts process, giving our micro-genetic research design an affordance focus. By investigating one of the authors, a ceramicist and a practitioner-researcher, through her process of making of a vase, we tracked how affordances are responded to, developed, shaped, invited or, where necessary, rejected, as the ceramicist "routes" her creative trajectory. Several insights emerge: (1) The ceramicist's decisions-initially about general directions, then about aesthetic details-unfold while engaging with the clay; they emerge in stepwise fashion, but with a holistic orientation. (2) Choosing among affordances requires parallel sensitivities to object functionality, aesthetics and creativity, as well as technical feasibility; adhering to the proper technical procedure that provides the very basis for creatively relevant affordances to later arise. (3) While the hands and eyes engage with short-lived affordances the ceramicist must keep in view higher-timescale affordances that ensure a good task progression for making a vase, and affordances for the material's overall "workability". (4) The ceramicist typically relates to momentary affordances in light of expected as well as imagined others, to ensure a coherent end product. (5) Affordances contribute to material creativity in more ways than typically recognized in the literature. They range from serendipitous "finds" to options developed with a large degree of creative autonomy; affordances may also be indirectly invited and practitioners strategically change probability distributions as well as providing an enabling background for generative action. Thus, a crafts practitioner brings forth unconventional affordances through active engagement, using a mix of exploration, strategy, and imaginative potential. Affordance theorists err when stressing the possibility to just "find" creative options or that perceptual acuity is the sole skill.

Childhood Comorbidity Severity Impacts Adolescent Substance Consumption in Patients With Tourette Syndrome.

BACKGROUND: This study explores the longitudinal impact of severity of Tourette Syndrome (TS), diagnosis and severity of Attention-Deficit/Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD), and guardian socioeconomic status on the level of substance use of pediatric patients with TS. METHODS: A total of 314 pediatric patients with TS participated at time 1 (T1). During these visits, the severity of the patients' TS, ADHD, and OCD symptoms were assessed, along with their guardians' socioeconomic status. At time 2 (T2), between four and eight years later (median 5.6 years), 227 patients returned for a follow-up. Here, the patients answered questions about their intake of alcohol, cigarettes, and illegal substances. The relationship between the patients' diagnoses, symptom severity, and socioeconomic status at T1 and reported substance use at T2 was then analyzed using binary logistic regression. RESULTS: Increased severity of ADHD and lower guardian socioeconomic status at T1 significantly increased the odds of later high cigarette consumption. Furthermore, both presence and increased severity of ADHD at T1 increased the odds of illegal substance consumption at T2. Conversely, increased severity of OCD at T1 significantly decreased cigarette and illegal substance consumption at T2, whereas both presence and increased severity of OCD decreased alcohol consumption. CONCLUSIONS: Pediatric patients with TS with increased ADHD severity have increased risk of consuming illegal substances and high amounts of cigarettes as adolescents, whereas increased OCD severity may act as a protective factor. Having preventative conversations about substance consumption with patients with TS with high ADHD severity is important.

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non-serious, general behaviour, and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel-group trials and first-period data from cross-over trials formed the basis of our primary analyses. We undertook separate analyses using end-of-last period data from cross-over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach. MAIN RESULTS: We included 212 trials (16,302 participants randomised); 55 parallel-group trials (8104 participants randomised), and 156 cross-over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross-over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male-female ratio was 3:1. Most trials were carried out in high-income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants. Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias. PRIMARY OUTCOMES: methylphenidate versus placebo or no intervention may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -0.88 to -0.61; I² = 38%; 21 trials; 1728 participants; very low-certainty evidence). This corresponds to a mean difference (MD) of -10.58 (95% CI -12.58 to -8.72) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD-RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68). SECONDARY OUTCOMES: methylphenidate may cause more adverse events considered non-serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher-rated general behaviour versus placebo (SMD -0.62, 95% CI -0.91 to -0.33; I² = 68%; 7 trials 792 participants; very low-certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI -0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: The majority of our conclusions from the 2015 version of this review still apply. Our updated meta-analyses suggest that methylphenidate versus placebo or no-intervention may improve teacher-rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non-serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear. Due to the frequency of non-serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials. Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.

Impact of Tourette Syndrome on Education.

BACKGROUND: Previous studies have shown that Tourette syndrome (TS) has an impact on academic achievements. The aim of this study was to investigate the association between the severity of tics and comorbidities and educational outcomes. METHODS: From 2005 to 2007, 395 participants were included in a large cohort (314 with TS and 81 controls) and the mean age was 12.60 ± 2.64 years. The cohort was re-examined after 4 to 8 years (median 5.6) where n = 276 participants (223 with TS and 53 controls) were included with a mean age of 18.52 ± 2.73 years. At both time points, severity of tics and the presence and severity of psychiatric comorbidity were assessed. Educational achievements were assessed through structured interviews. RESULTS: Children with TS had a lower passing rate at lower secondary and high school compared to healthy controls. More severe vocal tics were associated with fewer passing lower secondary school at a prospective level. At a cross-sectional level, more severe motor tics were associated with fewer passing high school. Tic severity only influenced children with TS without comorbidity. The severity of comorbidity was found to be associated with the educational level at a longitudinal view, but not cross-sectional. CONCLUSION: Overall, children with TS had a lower passing rate at lower secondary school and high school compared to healthy controls. We found that this difference was more likely driven by the severity of comorbidities than tic severity. It is important to be aware of academic achievement in children with TS in order to give them the right support and thereby optimize educational opportunities.

Predictors of the Clinical Course of Tourette Syndrome: A Longitudinal Study.

OBJECTIVE: Tourette syndrome (TS) is a chronic childhood neurodevelopmental disorder characterized by motor and vocal tics and frequent comorbidities. The clinical presentation of Tourette syndrome is heterogeneous and the prognosis for each individual child is difficult to define. This large prospective longitudinal study explores predictors in childhood of the clinical course of tics and comorbidities in early adulthood. METHODS: The cohort was recruited at the Danish National Tourette Clinic. Data were collected at baseline (N = 314; ages, 5-19 years) and follow-up 6 years later (n = 227; ages, 11-26 years) to examine changes in the expression of tics and comorbidities. Childhood clinical factors, represented by 4 binary clinical outcomes, were selected as possible predictors of the clinical course of tics and comorbidities in early adulthood; these were tic severity and diagnoses of obsessive compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and emotional disorders. RESULTS: The strongest predictors of high tic scores, OCD, or ADHD diagnoses in early adulthood were the corresponding tic (odds ratio [OR]: 1.09), OCD (OR: 1.08), and ADHD (OR: 1.13) severity scores (per scale point) in childhood. Being female (OR: 3.94) and childhood ADHD severity (OR: 1.11) predicted future emotional disorders. Special education, genetic factors, and psychosocial factors were also predictive for the clinical course of Tourette syndrome. CONCLUSION: We identified strong clinical predictors of Tourette syndrome-associated outcomes in early adulthood that are directly applicable to clinical Tourette syndrome populations and may help to guide new patients, plan early interventions, and implement preventive measures.

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events. OBJECTIVES: To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies. SEARCH METHODS: In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention. DATA COLLECTION AND ANALYSIS: Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses. MAIN RESULTS: We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants). AUTHORS' CONCLUSIONS: Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

Tourette syndrome in a longitudinal perspective. Clinical course of tics and comorbidities, coexisting psychopathologies, phenotypes and predictors.

INTRODUCTION: Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder characterised by motor and vocal tics and frequent associated comorbidities. The developmental trajectory of tic shows tic-onset in the age of 4-6, peak in the age of 10-12 and decline during adolescence, although only few and small longitudinal studies form the basis of this evidence. Recent studies suggest that comorbid obsessive-compulsive disorder (OCD), attention deficit-hyperactivity disorder (ADHD) and coexisting psychopathologies tend to persist and become more dominant in adolescence. This large prospective follow-up study want to examine the clinical course of TS: tic and comorbidities during adolescence, the prevalence of coexisting psychopathologies, the tic-related impairment, development in phenotype expression and find predictors for the expected course of TS. 
Method: This study is examining a large clinical cohort recruited at the Danish National Tourette Clinic during the period 2005-2007 and 2011-2013. At baseline, 314 participants aged 5-19 years were included and at follow-up 6 years later 227 participated, aged 11-26. All participants were uniformly clinically examined at basis and follow-up with a clinical interview and validated measurements to assess comorbidities. The Yale Global Tic Severity Scale was used to asses tic severity and tic-related impairment. At follow-up a cross-sectional diagnostic evaluation was made with the Development and Well-Being Assessment to assess coexisting psychopathologies.
 Results: A significant decline in tic and the most frequent comorbidities OCD and ADHD was found although some variation existed and some subclinical and partial remissions persisted. Tic-related impairment was not reflected in the tic-decline as expected but influenced by several parameters. The phenotype expression was found to be dynamic but overall changed toward TS without comorbidities. Several predictors were found to predict the clinical course of TS in adolescence and early adulthood. Childhood tics, OCD and ADHD severity were the strongest predictors for future symptoms of the respectively diagnoses. Comorbidities and coexisting psychopathologies were found in 63% at follow-up, whereas 37% had pure TS.
 Conclusion: The clinical course of TS during adolescence was confirmed, with solid evidence, with decline in tics, OCD and ADHD severity. We provide evidence of considerable coexisting psychopathologies requiring clinical support and partial remissions and subthreshold symptoms requiring monitoring and clinical guidance to assist the young adults in promoting a healthy transition into early adulthood. Furthermore we provide predictors for the clinical course of TS to be used in the preventive efforts, early intervention and allocation of resources improving quality of life for the children and their families.

Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: There is little evidence in the literature on the association between methylphenidate treatment and psychotic symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: We examine the occurrence of psychotic symptoms during methylphenidate treatment of children and adolescents with ADHD. The data arise from our two Cochrane systematic reviews on methylphenidate, reported elsewhere. METHODS: Electronic databases were searched up to January 2016 (for observational studies) and March 2017 (for randomized trials). We summarized data as risk ratios and pooled prevalences. Trial Sequential Analysis was used to control for random errors. We assessed the risk of bias and the quality of evidence according to Cochrane guidelines. RESULTS: Ten randomized trials (1103 participants), 17 non-randomized studies (76,237 participants) and 12 patient reports or series (18 patients) were identified. In the randomized trials, there was no significant difference in the risk of developing psychotic symptoms [10 of 654 (pooled prevalence, 2.5%) methylphenidate versus 1 of 508 (pooled prevalence, 1.7%) placebo patients; risk ratio, 2.07; 95% confidence interval, 0.58 to 7.35]. Nine of 10 trials had a high risk of bias, and according to the Trial Sequential Analysis, the required information size was not achieved, that is, the meta-analysis was considerably underpowered. There were 873 instances of psychotic symptoms in the non-randomized studies among 55,603 participants (pooled prevalence, 1.2%; 95% confidence interval, 0.7 to 2.4). In the comparative cohort study, methylphenidate significantly increased the risk for any psychotic disorder by 36% (risk ratio, 1.36; 95% confidence interval, 1.17 to 1.57). The overall risk of bias was rated as critical for this study. CONCLUSIONS: Because of sparse data and low quality of evidence, we cannot confirm or refute whether methylphenidate increases the risk of psychotic symptoms in children and adolescents with ADHD. This possible adverse event may affect 1.1% to 2.5%, and physicians, patients and caregivers should be aware of this to ensure proper treatment in case of occurrence during methylphenidate treatment.

Phenotype Development in Adolescents With Tourette Syndrome: A Large Clinical Longitudinal Study.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by frequent comorbidities and a wide spectrum of phenotype presentations. This study aimed to describe the development of phenotypes in TS and tic-related impairment in a large longitudinal study of 226 children and adolescents followed up after 6 years. The participants were clinically examined to assess tic severity and impairment, obsessive compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). The development in phenotypes changed toward less comorbidity with 40% TS-only (no OCD or ADHD) (TS without OCD or ADHD) at baseline and 55% at follow-up.Tic-related impairment was expected to improve with an age-related tic decline, but surprisingly the impairment score did not reflect the tic decline. Sex, vocal and motor tics, and OCD and ADHD severity were highly significantly correlated to the impairment score. Knowledge of TS phenotype development is used in clinical settings to guide patients and for genetic, etiological, and clinical research purposes.

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

OBJECTIVES: To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. METHODS AND FINDINGS: We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23) and weight (RR 3.89, 95% CI 1.43 to 10.59). In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04). We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. CONCLUSION: Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found.

Course of Tourette Syndrome and Comorbidities in a Large Prospective Clinical Study.

OBJECTIVE: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by tics and frequent comorbidities. Although tics often improve during adolescence, recent studies suggest that comorbid obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) tend to persist. This large prospective follow-up study describes the clinical course of tics and comorbidities during adolescence and the prevalence of coexisting psychopathologies. METHOD: The clinical cohort was recruited at the Danish National Tourette Clinic, and data were collected at baseline (n = 314, age range 5-19 years) and at follow-up 6 years later (n = 227) to establish the persistence and severity of tics and comorbidities. During follow-up, the Development and Well-Being Assessment (DAWBA) was used to diagnose coexisting psychopathologies. Repeated measures of severity scores were modeled using mixed effects models. RESULTS: Tic severity declined yearly (0.8 points, CI: 0.58-1.01, on the Yale Global Tic Severity Scale [YGTSS]) during adolescence; 17.7% of participants above age 16 years had no tics, whereas 59.5% had minimal or mild tics, and 22.8% had moderate or severe tics. Similarly, significant yearly declines in severity of both OCD (0.24, CI: 0.09-0.39, on the Yale-Brown Obsessive Compulsive Scale for Adults [Y-BOCS] and Yale-Brown Obsessive Compulsive Scale for Children [CY-BOCS]) and ADHD (0.42, CI: 0.32-0.52, DSM-IV) were recorded. At follow-up, 63.0% of participants had comorbidities or coexistent psychopathologies, whereas 37.0% had pure TS. CONCLUSION: Severity of tics, OCD, and ADHD were significantly associated with age and declined during adolescence. However, considerable comorbidities and coexisting psychopathologies persist throughout adolescence and require monitoring by clinicians.

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.

STUDY QUESTION: Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? METHODS: Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. STUDY ANSWER AND LIMITATIONS: The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) -0.77, n=1698), corresponding to a mean difference of -9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD -0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. WHAT THIS STUDY ADDS: The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events. FUNDING, COMPETING INTERESTS, DATA SHARING: Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library.

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. DATA COLLECTION AND ANALYSIS: Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. MAIN RESULTS: The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias.All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). SECONDARY OUTCOMES: Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; 5 trials, 668 participants; very low-quality evidence).A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.

A t(3;9)(q25.1;q34.3) translocation leading to OLFM1 fusion transcripts in Gilles de la Tourette syndrome, OCD and ADHD.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder with a strong genetic etiology; however, finding of candidate genes is hampered by its genetic heterogeneity and the influence of non-genetic factors on disease pathogenesis. We report a case of a male patient with GTS, obsessive compulsive disorder, attention-deficit/hyperactivity-disorder, as well as other comorbidities, and a translocation t(3;9)(q25.1;q34.3) inherited from a mother with tics. Mate-pair sequencing revealed that the translocation breakpoints truncated the olfactomedin 1 (OLFM1) gene and two uncharacterized transcripts. Reverse-transcription PCR identified several fusion transcripts in the carriers, and OLFM1 expression was found to be high in GTS-related human brain regions. As OLFM1 plays a role in neuronal development it is a likely candidate gene for neuropsychiatric disorders and haploinsufficiency of OLFM1 could be a contributing risk factor to the phenotype of the carriers. In addition, one of the fusion transcripts may exert a dominant-negative or gain-of-function effect. OLFM1 is unlikely to be a major GTS susceptibility gene as no point mutations or copy number variants affecting OLFM1 were identified in 175 additional patients. The translocation described is thus a unique event, but further studies in larger cohorts are required to elucidate involvement of OLFM1 in GTS pathogenesis.

Longitudinal Magnetic Resonance Imaging (MRI) Analysis of the Developmental Changes of Tourette Syndrome Reveal Reduced Diffusion in the Cortico-Striato-Thalamo-Cortical Pathways.

There is evidence that cortico-striato-thalamo-cortical pathways are involved in Tourette syndrome. We performed a longitudinal imaging study in 22 patients and 21 healthy controls in order to examine the development of tics and its correlation with magnetic resonance imaging (MRI) findings. Patients were divided in a group with persisting and a group with remission of tics. We found a decrease in volume of left putamen in controls, but not in patients. We found changes in mean diffusivity between patients and controls in right caudate nucleus, thalamus, and frontal lobe. In contrast to controls, parallel and perpendicular diffusivity decreased in patients and were most pronounced in the patients with persisting tics compared to those with remission. The findings suggest that the development of the brain in patients with remission resembles the normal development more than in patients with persistent tics. This could reflect a change in brain structure or compensatory mechanisms in the brain.

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome.

Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P=0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5'-exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons.