Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

The negative effects of the COVID-19 pandemic on youth mental health have been significant.1,2 The impact of the pandemic on eating disorders has been particularly notable, given the numerous risk factors exacerbated during the pandemic, such as increased social isolation and body image concerns associated with amplified virtual and social media exposure.3 Although the rise of eating disorder presentations have been documented by increased pediatric hospital admissions4 at an earlier ages of onset,5 there has, until this time, not been a meta-analytical approach to understanding the full scope of this impact on health care use. In our ever-burdened pediatric mental health care systems, it is crucial for the field to understand how health care use for eating disorders has been affected. As such, we read with keen interest the article by Madigan et al.6 This meta-analysis fills a gap in the field, analyzing the health care visits of close to 150,000 children and adolescents across more than 300 sites. This study highlights an important theme that has been observed across our mental health systems: there has been a significant increase in severe eating disorder symptom expression since the start of the pandemic. This article provides the empirical evidence to support what has been anecdotally and qualitatively observed across sites-namely, an increased use of higher levels of care, such as emergency rooms and inpatient units, in addition to outpatient care. This increase in service use for eating disorders has been particularly sharp among girls, adolescents, and those presenting with restricting presentations such as anorexia nervosa.6.

Objective: Ketamine has proved effective as a rapid-acting antidepressant agent, but treatment is not effective for everyone (approximately a quarter to a half of patients). Some adult studies have begun to investigate predictors of ketamine's antidepressant response, but no studies have examined this in adolescents with depression. Methods: We conducted a secondary data analysis of adolescents who participated in a randomized, single-dose, midazolam-controlled crossover trial of ketamine for adolescents with treatment-resistant depression. We examined the relationship between 19 exploratory demographic and clinical variables and depression symptom improvement (using the Montgomery-Åsberg Depression Rating Scale [MADRS]) at 1 and 7 days postinfusion. Results: Subjects who had fewer medication trials of both antidepressant medications and augmentation treatments were more likely to experience depression symptom improvement with ketamine. Subjects with shorter duration of their current depressive episode were more likely to experience depression symptom improvement with ketamine. Subjects currently being treated with selective serotonin reuptake inhibitor medications, and not being treated with serotonin-norepinephrine reuptake inhibitor medications, also experienced greater symptom improvement with ketamine. When receiving the midazolam control, less severe depressive symptoms, as measured by the Children's Depression Rating Scale (CDRS) (but not MADRS), and a comorbid attention-deficit/hyperactivity disorder diagnosis were associated with increased response. Conclusions: Findings should be viewed as preliminary and exploratory given the small sample size and multiple secondary analyses. Identifying meaningful predictors of ketamine response is important to inform future therapeutic use of this compound, however, considerably more research is warranted before such clinical guidance is established. The trial was registered in clinicaltrials.gov with the identifier NCT02579928.

Physician explicit and implicit biases involving race and sexual orientation (SO) affect patient and provider experiences in healthcare settings. An anonymous survey was disseminated nationally to graduating medical students, residents, and practicing physicians to evaluate SO and racial biases across medical specialties. SO explicit and implicit bias were measured with the Attitudes toward Lesbians and Gay Men Scale, short form (ATLG-S) and Gay-Straight Implicit Association Test (IAT). Racial explicit and implicit bias were measured with the Quick Discrimination Index (QDI) and the Black-White IAT. Medical specialty was associated with racial explicit bias and specialty prestige with Black-White IAT score. Medical specialty and specialty prestige were not associated with SO bias. Female sex, sexual and gender minority (SGM) identity, and decreased religiosity were associated with reduced SO and racial bias. Provider race was associated with racial implicit and explicit bias.

Post-event rumination, the extent to which one engages in persistent, detailed, and negative thinking following social situations, serves as a risk process in the pathophysiology of social anxiety. Although a substantial body of research has assessed post-event rumination and social anxiety, this literature has produced inconsistent results. We conducted a systematic review and meta-analysis to examine whether the magnitude of the association between post-event rumination and social anxiety varied as a function of questionnaire and/or task utilized. We included all studies reporting a correlation between post-event rumination and social anxiety symptomatology. Fisher 's z correlation coefficients were calculated through random-effect meta-analyses. Results indicated a moderate association between post-event rumination and social anxiety symptomatology ( r = 0.45, p < 0.001, 95%CI [0.40 -0.50]). Subgroup meta-analyses indicated that the type of questionnaire used to assess post-event rumination ( Q = 44.36, df = 3, p < 0.001) and social anxiety ( Q = 26.44, df = 8, p < 0.001), as well as the task conducted prior to assessing post-event rumination ( Q =14.31, df = 2, p < 0.001), influenced the effect size. This study demonstrates a moderate relation between post-event rumination and social anxiety across the anxiety spectrum, illustrating the importance of treatments specifically targeting post-event rumination. Moreover, we highlight the importance of taking care when designing studies to explore relations between post-event rumination and social anxiety.

This article describes the protocol for a randomized, controlled clinical trial of a neurofeedback (NF) intervention for Tourette Syndrome (TS) and chronic tic disorder. The intervention involves using functional magnetic resonance imaging (fMRI) to provide feedback regarding activity in the supplementary motor area: participants practice controlling this brain area while using the feedback as a training signal. The previous version of this NF protocol was tested in a small study (n = 21) training adolescents with TS that yielded clinically promising results. Therefore, we plan a larger trial. Here we describe the background literature that motivated this work, the design of our original neurofeedback study protocol, and adaptations of the research study protocol for the new trial. We focus on those ideas incorporated into our protocol that may be of interest to others designing and running NF studies. For example, we highlight our approach for defining an unrelated brain region to be trained in the control group that is based on identifying a region with low functional connectivity to the target area. Consistent with a desire for transparency and open science, the new protocol is described in detail here prior to conducting the trial.

Trichotillomania and excoriation disorder are common psychiatric conditions classified as obsessive-compulsive–related disorders. These body-focused repetitive behaviors (BFRBs) frequently onset in adolescence and can be difficult to treat. Affected individuals often feel that their clinicians know little about these disorders. The goal of this presentation will be to systematically review evidence of the efficacy of treatments for trichotillomania and excoriation disorder in both children and adults. We conducted systematic reviews and meta-analyses of randomized controlled trials examining treatments for trichotillomania and excoriation disorder. Electronic databases (PubMed, PsycINFO, Embase, Cochrane Central Register of Controlled Trials [CENTRAL]) were searched to identify relevant articles for extraction. Eligible articles compared pharmacological or behavioral interventions with a control group or between active treatments. The primary outcome was mean improvement in symptom severity determined by standardized mean difference. Results demonstrate that behavioral therapy with habit-reversal training components has the largest benefit compared to controls for improving BFRB symptoms in clinical trials of both adults and children. A few pharmacologic agents have demonstrated some benefit in randomized control trials of adults, including clomipramine, n-acetylcysteine, and olanzapine. A single randomized controlled study of pediatric trichotillomania has demonstrated that n-acetylcysteine was not superior to placebo. Results will be reviewed and discussed in the context of the clinical practice of child and adolescent psychiatry. Currently, behavioral therapies with habit-reversal training components are an effective treatment strategy for both trichotillomania and excoriation disorder in children and adults. A few medications show some promise in adults, but more research is needed in children to identify effective pharmacological treatments in large-scale clinical trials.

Epidemiological studies of excoriation disorder have reported different prevalence estimates for this condition, limiting our understanding of its public health impact. We performed a systematic review and meta-analysis to collate epidemiological studies of excoriation disorder. We aimed to estimate the pooled prevalence and the female-to-male ratio of excoriation disorder in the general population. We searched Embase, PsycInfo, and PubMed up to May 2020 and updated the PubMed search in October 2021. Studies which reported the frequency of excoriation disorder in a sample from the general population were included in our meta-analyses. We made no restrictions regarding the definition or assessment of excoriation disorder. Data were pooled through random -effects meta-analyses. Of the 677 records identified through database searches, 19 studies involving 38,038 participants met our inclusion criteria. Meta-analyses demonstrated that excoriation disorder has an overall prevalence of 3.45% (95% CI 2.55, 4.65%) and impacts women more than men (female-to-male OR = 1.45; 95% CI 1.15, 1.81, p = 0.001). These findings underscore the public health impact of excoriation disorder, which will hopefully motivate future research focused on advancing our understanding and management of this condition.

The first systematic review and meta-analysis of obsessive-compulsive disorder (OCD) genetic epidemiology was published approximately 20 years ago. Considering the relevance of all the studies published since 2001, the current study aimed to update the state-of-art knowledge on the field. All published data concerning the genetic epidemiology of OCD from the CENTRAL, MEDLINE, EMBASE, BVS, and OpenGrey databases were searched by two independent researchers until September 30, 2021. To be included, the articles had to fulfill the following criteria: OCD diagnosis provided by standardized and validated instruments; or medical records; inclusion of a control group for comparison and case-control, cohort or twin study designs. The analysis units were the first-degree relatives (FDRs) of OCD or control probands and the co-twins in twin pairs. The outcomes of interest were the familial recurrence rates of OCD and the correlations of OCS in monozygotic compared with dizygotic twins. Nineteen family, twenty-nine twin, and six population-based studies were included. The main findings were that OCD is a prevalent and highly familial disorder, especially among the relatives of children and adolescent probands, that OCD has a phenotypic heritability of around 50%; and that the higher OCS correlations between MZ twins were mainly due to additive genetic or to non-shared environmental components.

The deleterious impact of the COVID‐19 pandemic on youth mental health has garnered much attention (Newlove‐Delgado et al., 2023). It has been a topic of interest in both research and academic writing, as well as in the public press (e.g., Tanner, 2023). Disorders and mental health concerns of focus have been wide‐ranging, with some of the most severe presentations, such as suicidality, highlighted (Asarnow and Chung, 2021). Eating disorders are among the most life‐threatening and prominent mental health concerns that have been exacerbated by the pandemic, and our current models of youth mental health care cannot keep up. Given this context, our team read and reviewed the manuscript, ‘Shifting age of child eating disorder hospitalizations during the Covid‐19 pandemic’ (Auger et al., 2023), eagerly. While the increasing severity of eating disorder presentations and increase in pediatric hospitalization has been an area of research (Asch et al., 2021), including at our own institution (Shum et al., 2022), the impact of age of onset, and the consequential impact on current systems of care, requires much greater attention.

Objective: Ketamine has proven effective as a rapid-acting antidepressant agent. Several adult studies have investigated the association between ketamine's acute dissociative effects and depression response, but no studies have examined the association in adolescents with treatment-resistant depression (TRD). Methods: We conducted a secondary data analysis of 16 adolescent participants who participated in a randomized, single-dose, midazolam-controlled crossover trial of ketamine in adolescents with depression. We examined the association between the acute dissociative symptoms (measured at 60 minutes following start of infusion using the Clinician-Administered Dissociative States Scale [CADSS], and its three subscales: depersonalization, derealization, amnesia) and response and depression symptom improvement at 1'day (using the Montgomery-Åsberg Depression Rating Scale). Results: Within the ketamine group, there were no significant associations between dissociation symptoms or CADSS subscale scores and magnitude of depression symptom improvement or likelihood of ketamine response. When receiving midazolam, there was no significant association between overall dissociation symptoms and magnitude or likelihood of response of depressive symptoms. Higher levels of symptoms on the 'depersonalization' CADSS subscale when receiving midazolam were associated with less improvement in depression symptoms at 1 day following infusion. Conclusions: In contrast to some adult literature, the current data do not show a relationship between acute dissociative effects and antidepressant response to ketamine in pediatric patients with TRD. Interpretation may be limited by the small sample size, reducing the power to detect small or medium associations. Future research should utilize larger samples to more definitively measure the magnitude of association between acute dissociative symptoms and later antidepressant response to ketamine and to assess the relationship to trial design (e.g., crossover vs. parallel trial, comparison condition utilized and number of infusions) within both adult and pediatric populations. ClinicalTrials.gov identifier: NCT02579928.

ABSTRACTVesicular monoamine transporter type 2 (VMAT2) inhibitors may be an effective therapy for chronic tic disorders (CTD), including Tourette syndrome (TS), but there has not been a meta‐analysis compiling available evidence from randomized controlled trials (RCTs). We performed a systematic review and meta‐analysis to evaluate the efficacy, acceptability, and tolerability of VMAT2 inhibitors for CTD/TS. PubMed, CENTRAL, and Embase were searched for double‐blinded RCTs of VMAT2 inhibitors versus placebo for the treatment of CTD/TS. Change in tic severity measured by the Yale Global Tic Severity Scale (efficacy) and rates of discontinuation attributed to adverse effects (tolerability) or all causes (acceptability) were extracted closest to 12 weeks. Mean difference (MD) and odds ratio (OR) were the effect size indexes for efficacy and acceptability/tolerability, respectively. Data were pooled through random‐effects meta‐analysis weighted by inverse variance. Five RCTs involving eight comparisons were included. Meta‐analysis found a nonsignificant effect on efficacy (k = 8; N = 583; MD = −0.71; 95% confidence interval [CI], −1.93 to 0.50; P = 0.24), and there was certainty that the true effect is nonclinically meaningful (high quality of evidence). Meta‐analysis found decreased tolerability (k = 7; N = 626; OR = 2.67; 95% CI, 1.21–5.92; P = 0.01) and decreased acceptability (k = 8; N = 626; OR = 1.90; 95% CI, 1.14–3.18; P = 0.01), although those comparisons were limited because of the relatively small number of events across trials. Meta‐analyses did not support the efficacy of VMAT2 inhibitors in the short‐term treatment of tic disorders and suggested no clinically meaningful effect of these agents on tic symptoms. © 2022 International Parkinson and Movement Disorder Society

Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose–response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose–response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice.

Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested an impaired medial ganglionic eminence fate and a decreased differentiation of cholinergic and GABAergic interneurons. Transcriptome analyses revealed organoid mispatterning in TS, with a preference for dorsolateral at the expense of ventromedial fates. Our results point to altered expression of GLI transcription factors downstream of the Sonic Hedgehog signaling pathway with cilia disruption at the earliest stages of BG organoid differentiation as a potential mechanism for the BG mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.

Abstract The origin of tics may be related to a heightened and selective sensitivity to cues from within the body or from the outside world, possibly as a result of a reduced ability to suppress irrelevant information in sensory, motor, and cognitive domains. The temporal pattern of tics, which are known to occur in bouts and wax and wane in severity, and their long-term outcome might represent important clues to the neurobiology of tics. Moreover, the role played by the environmental context in modulating tic expression may be key to developing and refining novel behavioral interventions. The association of tics with comorbid behavioral problems has a very strong impact on social, emotional, and academic outcomes in adulthood. This chapter introduces the reader to the wide phenomenological spectrum of Tourette syndrome and other tic disorders. The key phenomenological features of Tourette syndrome and related disorders represent crucial educational objectives for clinicians, teachers, parents, and peers that may lead to better clinical, social, and academic outcomes.

The world has experienced an unprecedented mental health crisis associated with the COVID-19 pandemic (Liu et al., 2020). After more than two years navigating the associated uncertainty and distress, the impact on youth mental health continues to be a pressing concern. Those in the mental health field, as well as the children and families plagued by its impact, are inundated with seeing firsthand the impact on youth's functioning. This includes increases in depression and suicide (Asarnow & Chung, 2021; Manzar et al., 2021), and having to navigate siloes in care and often even an inability when in crisis to access a continuum of services (Zhai, 2021). This has highlighted the significant issues with accessibility of mental health care and inequitable access to care for youth mental health both in the United States and globally. We continue to experience daily the impact of insufficient resources for youth behavioral health. For those in the field who prioritize the need for more robust intervention approaches, the child mental health crisis associated with the pandemic has highlighted the need for us to develop more novel and innovative interventions.