Incidence, prevalence, and global burden of ADHD from 1990 to 2019 across 204 countries: data, with critical re-analysis, from the Global Burden of Disease study.

Data on incidence, prevalence and burden of ADHD are crucial for clinicians, patients, and stakeholders. We present the incidence, prevalence, and burden of ADHD globally and across countries from 1990 to 2019 from the Global Burden of Disease (GBD) study. We also: (1) calculated the ADHD prevalence based on data actually collected as opposed to the prevalence estimated by the GBD with data imputation for countries without prevalence data; (2) discussed the GBD estimated ADHD burden in the light of recent meta-analytic evidence on ADHD-related mortality. In 2019, GBD estimated global age-standardized incidence and prevalence of ADHD across the lifespan at 0.061% (95%UI = 0.040-0.087) and 1.13% (95%UI = 0.831-1.494), respectively. ADHD accounted for 0.8% of the global mental disorder DALYs, with mortality set at zero by the GBD. From 1990 to 2019 there was a decrease of -8.75% in the global age-standardized prevalence and of -4.77% in the global age-standardized incidence. The largest increase in incidence, prevalence, and burden from 1990 to 2019 was observed in the USA; the largest decrease occurred in Finland. Incidence, prevalence, and DALYs remained approximately 2.5 times higher in males than females from 1990 to 2019. Incidence peaked at age 5-9 years, and prevalence and DALYs at age 10-14 years. Our re-analysis of data prior to 2013 showed a prevalence in children/adolescents two-fold higher (5.41%, 95% CI: 4.67-6.15%) compared to the corresponding GBD estimated prevalence (2.68%, 1.83-3.72%), with no significant differences between low- and middle- and high-income countries. We also found meta-analytic evidence of significantly increased ADHD-related mortality due to unnatural causes. While it provides the most detailed evidence on temporal trends, as well as on geographic and sex variations in incidence, prevalence, and burden of ADHD, the GBD may have underestimated the ADHD prevalence and burden. Given the influence of the GBD on research and policies, methodological issues should be addressed in its future editions.

The genetics of trichotillomania and excoriation disorder: A systematic review.

BACKGROUND: Trichotillomania (TTM) and excoriation disorder (ED) are impairing obsessive-compulsive related disorders that are common in the general population and for which there are no clear first-line medications, highlighting the need to better understand the underlying biology of these disorders to inform treatments. Given the importance of genetics in obsessive-compulsive disorder (OCD), evaluating genetic factors underlying TTM and ED may advance knowledge about the pathophysiology of these body-focused repetitive behaviors. AIM: In this systematic review, we summarize the available evidence on the genetics of TTM and ED and highlight gaps in the field warranting further research. METHOD: We systematically searched Embase, PsycInfo, PubMed, Medline, Scopus, and Web of Science for original studies in genetic epidemiology (family or twin studies) and molecular genetics (candidate gene and genome-wide) published up to June 2023. RESULTS: Of the 3536 records identified, 109 studies were included in this review. These studies indicated that genetic factors play an important role in the development of TTM and ED, some of which may be shared across the OCD spectrum, but there are no known high-confidence specific genetic risk factors for either TTM or ED. CONCLUSIONS: Our review underscores the need for additional genome-wide research conducted on the genetics of TTM and ED, for instance, genome-wide association and whole-genome/whole-exome DNA sequencing studies. Recent advances in genomics have led to the discovery of risk genes in several psychiatric disorders, including related conditions such as OCD, but to date, TTM and ED have remained understudied.

The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis.

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.

Meta-Analysis: Efficacy and Tolerability of Vesicular Monoamine Transporter Type 2 Inhibitors in the Treatment of Tic Disorders.

Vesicular 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.

ADHD and autism symptoms in youth: a network analysis.

BACKGROUND: Previous research investigating the overlap between attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (henceforth, autism) symptoms in population samples have relied on latent variable modeling in which averaged scores representing dimensions were derived from observed symptoms. There are no studies evaluating how ADHD and autism symptoms interact at the level of individual symptom items. METHODS: We aimed to address this gap by performing a network analysis on data from a school survey of children aged 6-17 years old (N = 7,405). ADHD and autism symptoms were measured via parent-report on the Swanson, Nolan, Pelham-IV questionnaire and the Childhood Autism Spectrum test, respectively. RESULTS: A relatively low interconnectivity between ADHD and autism symptoms was found with only 10.06% of possible connections (edges) between one ADHD and one autism symptoms different than zero. Associations between ADHD and autism symptoms were significantly weaker than those between two symptoms pertaining to the same construct. Select ADHD symptoms, particularly those presenting in social contexts (e.g. 'talks excessively', 'does not wait turn'), showed moderate-to-strong associations with autism symptoms, but some were considered redundant to autism symptoms. CONCLUSIONS: The present findings indicate that individual ADHD and autism symptoms are largely segregated in accordance with diagnostic boundaries corresponding to these conditions in children and adolescents from the community. These findings could improve our clinical conceptualization of ADHD and autism and guide advancements in diagnosis and treatment.

Parental age and the risk of bipolar disorder in the offspring: A systematic review and meta-analysis.

OBJECTIVES: Whether parental age, i.e., paternal or maternal, at childbirth is associated with the risk of bipolar disorder (BD) in offspring remains unclear. We conducted a meta-analysis of observational studies to address this gap. METHODS: PubMed, PsycINFO, Embase, and Web of Science were searched up to June 2021. Studies investigating the associations between parental age at childbirth (exposure) and the risk of BD in offspring (outcome) were eligible for inclusion in our study. Paternal and maternal age were examined separately. Odds ratio (OR) was used as the effect size index. Data were pooled through random-effects meta-analyses. RESULTS: Seven studies involving 3,183,539 participants and 23,253 individuals with BD were included in our meta-analyses. Meta-analyses indicated an increased risk of BD in the offspring of the older paternal age groups (35-44 years old [k = 5; OR = 1.09; 95% CI 1.05, 1.14; p < 0.0001] and ≥45 years old [k = 5; OR = 1.44; 95% CI 1.19, 1.14; p = 0.0001]) in comparison with the reference category (25-34 years old). Meta-analysis also indicated an increased risk of BD in the offspring of the older maternal age group (≥40 years old [k = 3; OR = 1.20; 95% CI 1.10, 1.31; p < 0.0001]) in comparison with the reference category (20-29 years old). CONCLUSIONS: Advanced paternal and maternal age were both associated with an increased risk of BD in offspring. Further studies are needed to investigate the mechanisms behind this association.

Casino Gambling in Adolescents: Gambling-Related Attitudes and Behaviors and Health and Functioning Relationships.

Recreational and problem gambling have been linked with adverse health and functioning outcomes among adolescents. Youth may gamble and engage in other risk-taking behaviors in casinos. There are limited data available regarding casino gambling in high-school students, and factors linked to adolescent gambling in casinos have yet to be systematically investigated. To address this gap, we analyzed cross-sectional data from 2010 Connecticut high-school students with chi-square tests and logistic regression models to examine casino gambling in relation to at-risk/problem gambling (ARPG) with respect to sociodemographic characteristics, gambling perceptions & attitudes, health/functioning measures and gambling behaviors. Approximately 11 % of adolescents acknowledged gambling in casinos. ARPG was more frequent and gambling perceptions were more permissive among adolescents endorsing casino gambling. Stronger relationships between ARPG and heavy alcohol and drug use and weaker relationships between ARPG and engagement in extracurricular activities, gambling with friends, gambling with strangers and gambling for financial reasons were observed among adolescents endorsing casino gambling. In conclusion, gambling in casinos was endorsed by a sizable minority of adolescents who gamble, and prevention efforts should consider targeting permissive attitudes towards gambling, adolescent drinking and participation in extracurricular activities when addressing underage casino gambling.

Commentary: Identifying individualized predictions of response in ADHD pharmacotherapy - a commentary on Rodrigues et al. (2020).

In this issue, Rodrigues et al. (2020) present a systematic review with meta-analyses that reports the efficacy of five treatments for children with attention-deficit hyperactivity disorder symptoms in the context of autism spectrum disorder - (a) methylphenidate; (b) atomoxetine; (c) guanfacine; (d) aripiprazole; and (e) risperidone. In this commentary, we highlight the contrast between the scarce evidence base of treatment for ADHD in the context of autism and other subpopulations, such as tic disorders and intellectual disability, and the extensive evidence base of treatment for ADHD in general. The commentary weighs about the conundrum clinicians face of whether to rely on the limited evidence base of treatment for ADHD in subpopulation, or to derive conclusions from the larger body of evidence of treatment for ADHD in general. The commentary also discusses potential avenues for future research to address this clinical problem.

Excitement-Seeking Gambling in Adolescents: Health Correlates and Gambling-Related Attitudes and Behaviors.

Motivational characteristics such as excitement-seeking are key components of models of addiction, including problem gambling. Previous studies have established associations between excitement-seeking and problem gambling in youth. However, these studies have employed dimensional psychological assessments which are unlikely to be routinely administered. Other approaches to conceptualize excitement-seeking could be of value. In the present study, we employed a single question (What are the reasons that you gamble?) to identify adolescents who reported excitement-seeking motivation for gambling. Cross-sectional data from 2030 adolescent gamblers who participated in a Connecticut high-school survey were examined. Gambling perceptions and correlates of problem-gambling severity were examined relative to excitement-seeking and non-excitement-seeking gambling. Gambling perceptions were more permissive and at-risk/problem gambling was more frequent among adolescents with excitement-seeking gambling versus non-excitement-seeking gambling. A weaker relationship between problem-gambling severity and moderate and heavy alcohol use was observed for excitement-seeking versus non-excitement-seeking gambling. Excitement-seeking gambling is associated with more permissive gambling-related attitudes and riskier gambling behaviors and may account for some variance in adolescent risk of heavy alcohol use. A single question may provide important information for identifying adolescents who are at elevated risk of problem gambling and associated negative outcomes, although the utility of the question in specific settings warrants direct examination, especially given the observed high prevalence of excitement-seeking motivations for gambling.

Pharmacological and behavioral treatment for trichotillomania: An updated systematic review with meta-analysis.

BACKGROUND: Trichotillomania (TTM) is a difficult-to-treat psychiatric condition with no first-line medications approved by the Food and Drug Administration. Individuals with TTM often feel that clinicians know little about this disorder. Here, we present an updated meta-analysis of randomized controlled trials (RCTs) examining treatments for TTM. METHODS: Pubmed, PsychINFO, Embase, and CENTRAL were searched with the terms "Trichotillomania OR Hair Pulling Disorder" to identify randomized controlled clinical trials evaluating treatments for TTM. RESULTS: Twenty-four trials involving 26 comparisons and 857 participants were included in this meta-analysis. Behavioral therapy with habit-reversal training components (BT-HRT) demonstrated a large benefit compared to control conditions (standardized mean difference [SMD] [95% CI] = -1.22 [-1.71, -0.73], p < .0001) for improving TTM symptoms. Clomipramine (SMD [95% CI] = -0.71 [-1.38, -0.05], p = .036), N-acetylcysteine (SMD [95% CI] = -0.75 [-1.36, -0.13], p = .017) and olanzapine (SMD [95% CI] = -0.94 [-1.77, -0.12], p = .025) demonstrated significant benefits compared to placebo in RCTs. CONCLUSIONS: BT-HRT has demonstrated the largest treatment effects and has the strongest evidence base for reducing TTM symptoms. In contrast, several pharmacological agents have demonstrated efficacy in single randomized clinical trials that would benefit from replication. Additional trials are needed to identify other effective medications for TTM and determine the relative efficacy of available agents.

Cognitive behavioral rehabilitation for bipolar disorder patients: A randomized controlled trial.

OBJECTIVES: Bipolar disorder is frequently associated with cognitive impairment even during euthymia. Previous studies have reported significant impairments in functional and quality of life outcomes and a possible relationship between these variables and cognitive performance. Cognitive rehabilitation interventions have been proposed to address these outcomes but positive results are still scarce. The objective of the present study is to evaluate the efficacy of a new intervention developed to address both cognitive and functional impairment. METHODS: Thirty-nine individuals were included in this randomized controlled trial. All participants were evaluated by the Cambridge Neuropsychological Test Automated Battery (CANTAB) and completed functional and quality of life (QOL) scales. Patients were randomized to either treatment as usual (TAU) or Cognitive Behavior Rehabilitation (CBR), an add-on treatment delivered in 12 weekly group sessions. All individuals were revaluated after 12 weeks. RESULTS: A total of 39 bipolar type I or II patients were included in the analysis, 19 in the TAU group and 20 in the CBR condition. At the entrance of the study, both groups were statistically similar regarding clinical, socio-demographics and cognitive variables. After the end of the intervention, CBR individuals had significantly improved reaction time, visual memory and emotion recognition. In contrast, individuals in the CBR did not present a statistically change in functional and QOL scores after the 12-week intervention. CONCLUSIONS: CBR intervention showed promising results in improving some of the commonly impaired cognitive domains in BD. A longer follow-up period may be necessary to detect changes in functional and QOL domains.

Are prematurity and environmental factors determinants for developing childhood-onset systemic lupus erythematosus?

OBJECTIVE: The objective of this study is to evaluate the influence of exposure to air pollutants and inhalable environmental elements during pregnancy and after birth until childhood-onset systemic lupus erythematosus(cSLE) diagnosis. METHODS: This case-control study comprised 30 cSLE patients and 86 healthy controls living in the Sao Paulo metropolitan area. A structured and reliable questionnaire (kappa index for test-retest was 0.78) assessed demographic data, gestational and perinatal-related-factors, and exposure to inhalable elements during pregnancy and after birth (occupational exposure to inhalable particles and/or volatile vapor, and/or tobacco, as well as, the presence of industrial activities or gas stations near the home/work/daycare/school). Tropospheric pollutants included: particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3) and carbon monoxide (CO). RESULTS: The median current age was similar between cSLE patients and healthy controls [16.0 (5-21) versus 15.0 (4-21) years, p = .32], likewise the frequency of female gender (87% versus 78%, p = .43). The frequencies of prematurity (30% versus 6%, p = .001), maternal occupational exposure during pregnancy (59% versus 12%, p < .001), exposure to volatile vapor (48% versus 8%, p < .001) and fetal smoking (maternal and/or secondhand) (37% versus 19%, p = .008) were significantly higher in cSLE patients compared with controls. In a multivariate analysis regarding the gestation period, maternal occupational exposure (OR 13.5, 95% CI 2.5-72.4, p = .002), fetal smoking (OR 8.6, 95%CI 1.6-47, p = .013) and prematurity (OR 15.8, 95%CI 1.9-135.3, p = .012) remained risk factors for cSLE development. Furthermore, exposure to secondhand smoking during pregnancy and after birth (OR 9.1, 95%CI 1.8-42.1, p = .002) was also a risk factor for cSLE development. CONCLUSIONS: Prematurity and environmental factors were risk factors for developing cSLE.

Treatment Outcomes With Licensed and Unlicensed Stimulant Doses for Adults With Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis.

Importance: Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. Objective: To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. Data Sources: Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. Study Selection: Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. Data Extraction and Synthesis: Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. Main Outcome Measures: Change in ADHD symptoms and discontinuations due to adverse events. Results: A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). Conclusions and Relevance: Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Prevalence and gender distribution of excoriation (skin-picking) disorder: A systematic review and meta-analysis.

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.

Efficacy of stimulants for preschool attention-deficit/hyperactivity disorder: A systematic review and meta-analysis.

Background: Robust synthesis of evidence to support treatment recommendations for preschoolers with attention-deficit/hyperactivity disorder (ADHD) is lacking. The aim of this systematic review and meta-analysis was to review currently available evidence to evaluate the efficacy and acceptability of stimulants for preschool children with ADHD. Methods: We searched electronic databases (CENTRAL, Embase, PubMed) from the database inception to March, 2022; and clinical trial registries through WHO ICTRP from the database inception to July, 2022, and selected double-blinded randomized controlled trials (RCTs) that compared stimulants against placebo for the treatment of preschoolers (age ≤ 7 years) with ADHD. Change in ADHD symptom severity was the primary outcome (efficacy) and all-cause dropout rates (acceptability) was the secondary outcome. Data were pooled with random-effects models weighted by the inverse of the variance. Risk of bias of individual studies were assessed with the Cochrane Risk of Bias tool version 2. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the quality of evidence. This study is registered with PROSPERO (CRD42022348597). Results: Five RCTs (three methylphenidate immediate-release, one methylphenidate extended-release, and one lisdexamfetamine) were included. The analysis of efficacy was based on 489 participants. Meta-analysis of change in ADHD symptom severity demonstrated a significant effect in favor of stimulants over placebo (standardized mean difference = -0.59; 95% CI -0.77, -0.41; p < 0.0001). There was no evidence of heterogeneity but some concerns about publication bias. Regardless, the confidence of evidence was considered moderate. For acceptability, stimulants did not lead to an increased rate of all-cause discontinuation rates in comparison to placebo (OR = 0.59; 95% CI 0.15, 2.37; p = 0.45) but the confidence of estimate was very low. Conclusions: Our findings demonstrated that stimulants are efficacious in reducing ADHD symptoms among preschool children. Clinicians should consider the use of stimulants when making treatment recommendations for preschoolers with ADHD.

BDNF blood levels after electroconvulsive therapy in patients with mood disorders: An updated systematic review and meta-analysis.

OBJECTIVES: Studies have suggested Brain-Derived Neurotrophic Factors (BDNF) increase after electroconvulsive therapy (ECT) although they were methodologically limited and enrolled small sample sizes. We aimed at updating a systematic review and meta-analysis to explore BDNF changes after ECT for the treatment of depression. METHODS: PubMed, PsycInfo, Embase and Global health were searched (March, 2021). Clinical trials that measured BDNF in the blood before and after ECT in adults (≥ 18 years old) with depression (major depressive disorder or bipolar disorder) were eligible. Data were pooled through random-effects meta-analyses. RESULTS: Twenty-eight studies involving 778 participants were included. Meta-analysis showed a significant increase in BDNF levels after ECT (Hedges' g = 0.28; 95% CI: 0.10, 0.46) while there was evidence of significant heterogeneity (I2 = 67.64%) but not publication bias/small-study effect. Subgroup analyses and meta-regressions were underpowered to detect significant differences. Meta-analysis of depression severity scores demonstrated a considerable larger treatment effect in reducing depressive symptoms after ECT (Hedge's g = -3.72 95% CI: -4.23, -3.21). CONCLUSION: This updated review showed that BDNF blood levels increased after ECT treatment. However, there was still evidence of substantial heterogeneity and there were limited sample sizes to investigate factors driving the variability of effects across studies. Importantly, the increase in BDNF levels was substantially smaller than the observed in depressive symptomatology, which could be indicative that the former was independent than the latter. Additional studies with larger sample sizes are currently required.

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

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

Characteristics of trichotillomania and excoriation disorder across the lifespan.

Trichotillomania (hair-pulling disorder) and excoriation (skin-picking) disorder are body-focused repetitive behaviors, which often first present in adolescence and cause distress and impairment into adulthood. Few studies have examined the clinical characteristics of the co-occurrence of these conditions across the lifespan. We examined cross-sectional survey responses collected from April 2018-February 2020 to evaluate the relationship between trichotillomania, excoriation disorder, and their co-occurrence. Responses from individuals with trichotillomania (n = 50), excoriation disorder (n = 52), and both conditions (n = 50) ages 4-67 years old were compared for co-occurring conditions and current symptoms. Self-report measures of hair-pulling and skin-picking severity and subtypes were assessed. Gender, race, and co-occurring conditions were generally similarly distributed across the three groups with high rates of self-reported anxiety (63-82%), depression (34-50%), obsessive-compulsive disorder (16-29%), and attention-deficit/hyperactivity disorder (12-32%). Among individuals with both trichotillomania and excoriation disorder, significant positive correlations were observed between hair-pulling and skin-picking severity scores as well as hair-pulling and skin-picking subtypes. Hair-pulling and skin-picking severity peaked at the transition from adolescence to adulthood and hair-pulling/skin-picking styles appeared to shift across the lifespan. Our results support several similarities between trichotillomania and excoriation disorder, providing new insight into the clinical characteristics of these conditions.

Networks of Neurodevelopmental Traits, Socioenvironmental Factors, Emotional Dysregulation in Childhood, and Depressive Symptoms Across Development in Two U.K. Cohorts.

OBJECTIVE: Previous population-based studies have identified associations between childhood neurodevelopmental traits and depression in childhood, adolescence, and young adulthood. However, neurodevelopmental traits are highly correlated with each other, which could confound associations when traits are examined in isolation. The authors sought to identify unique associations between multiple neurodevelopmental traits in childhood and depressive symptoms across development, while taking into account co-occurring difficulties, in multivariate analyses. METHODS: Data from two U.K. population-based cohorts, the Twins Early Development Study (TEDS) (N=4,407 independent twins) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (N=10,351), were independently analyzed. Bayesian Gaussian graphical models were estimated to investigate pairwise conditional associations between neurodevelopmental traits (autism and ADHD symptoms and general cognitive, learning, and communication abilities), socioenvironmental stressors (academic performance and peer relations), and emotional dysregulation in childhood (ages 7-11) and depressive symptoms across development (ages 12, 16, and 21). RESULTS: In both cohorts, bivariate correlations indicated several associations between neurodevelopmental traits and depressive symptoms across development. However, based on replicated findings across cohorts, these pairs of variables were mostly conditionally independent, and none were conditionally associated, after accounting for socioenvironmental stressors and emotional dysregulation. In turn, socioenvironmental stressors and emotional dysregulation were conditionally associated with both neurodevelopmental traits and depressive symptoms. Based on replicated findings across cohorts, neurodevelopmental traits in childhood could be associated only indirectly with depressive symptoms across development. CONCLUSIONS: This study indicates that associations between childhood neurodevelopmental traits and depressive symptoms across development could be explained by socioenvironmental stressors and emotional dysregulation. The present findings could inform future research aimed at the prevention of depression in youths with neurodevelopmental disorders.