Faculty Bibliography

BACKGROUND:Raynaud syndrome (RS) is a peripheral vasculopathy characterised be impaired acral perfusion typically manifesting as skin discolouration with pallor, cyanosis and/or erythema, and increased sensitivity to cold. RS may be primary or secondary to systemic disease, lifestyle and environmental factors or medication. RS has been reported with medication to treat ADHD, but we found no recent comprehensive overview of the literature. The aim of this review is to evaluate the evidence in the published literature for Raynaud syndrome associated with medication for ADHD. METHODS:We systematically searched PubMed and Embase from inception to 12 June 2024 for articles published in English describing cases of RS in individuals treated with stimulant medication, atomoxetine, guanfacine or clonidine. Identified cases were assessed against the Naranjo Adverse Drug Reaction Scale criteria to determine the probability of a causal relationship with the medication. RESULTS:The initial search identified 197 articles. A total of 61 cases were identified from 15 case reports, 5 case series, 1 retrospective case-control study, and 1 retrospective cohort study. No randomised, controlled studies were identified. Implicated medications included methylphenidate, (dex)amfetamine and, more rarely, atomoxetine. Most cases were mild and resolved within weeks of discontinuation, dose reduction or switch to an alternative medication. A few cases associated with systemic disease were reported, leading to ulceration, gangrene and the need for amputation or revascularisation in some individuals. Assessment of 28 cases using the Naranjo criteria suggested a 'possible' causative role of ADHD medication in 13 cases, a 'probable' role in 13 cases and a 'definite' role in two cases. CONCLUSIONS:Due to the uncontrolled nature of all but one of the available studies, a causal relationship between medication for ADHD and RS could not be determined reliably. However, in view of the possibility of severe sequelae, albeit in rare cases, routine monitoring for signs of RS is recommended in individuals treated with CNS stimulants or atomoxetine, especially when initiating treatment or increasing the dose. Large database studies in which individuals act as their own controls should be conducted to clarify any association between treatment with these medications and RS, controlling for confounding factors.

OBJECTIVE:We conducted an umbrella review of systematic reviews (SRs), with or without meta-analysis (MA), of randomized controlled trials (RCTs) assessing nonpharmacological sleep interventions for children and adolescents across various clinical populations. METHOD/METHODS:We searched multiple electronic databases up to January 24, 2024. Meta-analyzable data from RCTs in the retrieved SRs/MAs were pooled using Metaumbrella. Primary outcomes were subjective/objective child sleep parameters. Additional outcomes included child health/functioning and parental sleep/health. The quality of the MAs/SRs was assessed with Assessment of Multiple Systematic Reviews (AMSTAR-2), and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). RESULTS:We included 93 SRs/MAs covering 393 RCTs, with 25 (17%, 39%, and 30%: high, moderate, and low quality) providing data for quantitative synthesis. Behavioral interventions, usually multicomponent including parent training, psychoeducation, and/or specific sleep therapy/strategies, showed beneficial effects on night waking, sleep duration, overall sleep disturbance, mood/depression, and maternal sleep quality (standardized mean difference [SMD] = 0.10-0.80) in participants with sleep problems without a formal sleep disorder diagnosis. For those with a formal diagnosis (mainly insomnia), benefits were found for night waking, sleep efficiency (subjective/actigraphically measured), and sleep onset latency (mean SMD = 0.49-0.97). Those with attention-deficit/hyperactivity disorder (ADHD) improved in bedtime resistance, night waking, parasomnias, sleep anxiety, ADHD symptoms, sleep disturbance, and quality of life (mean SMD = 0.18-0.49). For those with autism, sleep disturbance improved (mean SMD = 0.70). However, all findings were of low to very low certainty of evidence. CONCLUSION/CONCLUSIONS:Among nonpharmacological interventions for sleep difficulties in youth, only behavioral interventions are supported by meta-analytic evidence, yet with small-to-moderate effect sizes and limited certainty of evidence. STUDY PREREGISTRATION INFORMATION/UNASSIGNED:The efficacy and tolerability of nonpharmacological interventions for sleep problems in children and adolescents: protocol for an umbrella review of systematic reviews and meta-analyses of randomised controlled trials. https://osf.io; j9qna/.

Part I of this systematic review summarized the state-of-the-art of pediatric psychopharmacology for Autism Spectrum Disorder (ASD), a severe and lifelong neurodevelopmental disorder. The purpose of this Part II follow-up article is to provide a systematic overview of the experimental psychopharmacology of ASD. To this aim, we have first identified in the Clinicaltrials.gov website all the 157 pharmacological and nutraceutical compounds which have been experimentally tested in children and adolescents with ASD using the randomized placebo-controlled trial (RCT) design. After excluding 24 drugs already presented in Part I, a systematic review spanning each of the remaining 133 compounds was registered on Prospero (ID: CRD42023476555), performed on PubMed (August 8, 2024), and completed with EBSCO, PsycINFO (psychology and psychiatry literature) and the Cochrane Database of Systematic reviews, yielding a total of 115 published RCTs, including 57 trials for 23 pharmacological compounds and 48 trials for 17 nutraceuticals/supplements. Melatonin and oxytocin were not included, because recent systematic reviews have been already published for both these compounds. RCTs of drugs with the strongest foundation in preclinical research, namely arbaclofen, balovaptan and bumetanide have all failed to reach their primary end-points, although efforts to target specific patient subgroups do warrant further investigation. For the vast majority of compounds, including cannabidiol, vasopressin, and probiotics, insufficient evidence of efficacy and safety is available. However, a small subset of compounds, including N-acetylcysteine, folinic acid, l-carnitine, coenzyme Q10, sulforaphane, and metformin may already be considered, with due caution, for clinical use, because there is promising evidence of efficacy and a high safety profile. For several other compounds, such as secretin, efficacy can be confidently excluded, and/or the data discourage undertaking new RCTs. Part I and Part II summarize "drug-based" information, which will be ultimately merged to provide clinicians with a "symptom-based" consensus statement in a conclusive Part III, with the overarching aim to foster evidence-based clinical practices and to organize new strategies for future clinical trials.

The differential influence of sex on premature mortality in schizophrenia is unclear. This study assessed the differences in all-cause and specific cause mortality risks in people with schizophrenia compared to several control groups stratified by sex. We conducted a PRISMA 2020-compliant systematic review and random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) for people with schizophrenia, comparing by sex. We measured publication bias and conducted a quality assessment through the Newcastle-Ottawa scale. We meta-analyzed 43 studies reporting on 2,700,825 people with schizophrenia. Both males and females with schizophrenia had increased all-cause mortality vs. comparison groups (males, RR=2.62, 95%CI 2.35-2.92; females, RR=2.56, 95%CI 2.27-2.87), suicide (males, RR=9.02, 95%CI 5.96-13.67; females, RR=12.09, 95%CI 9.00-16.25), and natural cause mortality (males, RR=2.11, 95%CI 1.88-2.38; females, RR=2.14, 95%CI 1.93-2.38). No statistically significant differences in sex-dependent mortality risk emerged. There was an age-group-dependent increased mortality risk in females < 40 years vs. >/=40 years old (RR=4.23/2.17), and significantly higher risk of death due to neurological disorders (dementia) in males vs. females (RR=5.19/2.40). Increased mortality risks were often associated with specific modifiable risk factors. The increased mortality risk did not improve over time, calling for more studies to identify modifiable factors, and for better physical healthcare for males and females with schizophrenia.

BACKGROUND:Randomised controlled trials (RCTs) evaluating ADHD medications often use strict eligibility criteria, potentially limiting generalisability to patients in real-world clinical settings. We aimed to identify the proportion of individuals with ADHD who would be ineligible for medication RCTs and evaluate differences in treatment patterns and clinical and functional outcomes between RCT-eligible and RCT-ineligible individuals. METHODS:We used multiple Swedish national registries to identify individuals with ADHD, aged at least 4 years at the age of diagnosis, initiating pharmacological treatment between Jan 1, 2007, and Dec 31, 2019, with follow-up up to Dec 31, 2020. Hypothetical RCT ineligibility was established using exclusion criteria from the international MED-ADHD dataset, including 164 RCTs of ADHD medications. Cox models evaluated differences in medication switching and discontinuation within 1 year between eligible and ineligible individuals. Quasi-Poisson models compared eligible and ineligible individuals on rates of psychiatric hospitalisations, injuries or accidents, and substance use disorder within 1 year of initiating ADHD medications. People with lived experience of ADHD were not involved in the research and writing process. FINDINGS/RESULTS:Of 189 699 individuals included in the study cohort (112 153 men and boys [59%] and 77 546 women and girls [41%]; mean age 21·52 years [SD 12·83; range 4-68]) initiating ADHD medication, 53% (76 477 [74%] of 103 023 adults [aged >17 years], 12 658 [35%] of 35 681 adolescents [aged 13-17 years], and 10 643 [21%] of 50 995 children [aged <13 years]) would have been ineligible for RCT participation. Ethnicity data were not available. Ineligible individuals had a higher likelihood of treatment switching (hazard ratio 1·14, 95% CI 1·12-1·16) and a decreased likelihood of medication discontinuation (0·96, 0·94-0·98) compared with eligible individuals. Individuals ineligible for RCTs had significantly higher rates of psychiatric hospitalisations (ncidence rate ratio 9·68, 95% CI 9·57-9·78) and specialist care visits related to substance use disorder (14·78, 14·64-14·91), depression (6·00, 5·94-6·06), and anxiety (11·63, 11·56-11·69). INTERPRETATION/CONCLUSIONS:Individuals ineligible for ADHD medication trials face higher risks of adverse outcomes. This study provides the first empirical evidence for the limited generalisability of ADHD RCTs to real-world clinical populations, by applying eligibility criteria extracted from a comprehensive dataset of RCTs to a large real-world cohort. Triangulating evidence from RCTs and real-world studies is crucial to inform rigorous evidence-based treatment guidelines. FUNDING/BACKGROUND:National Institute of Healthcare and Research, European Union's Horizon 2020, and Swedish Research Council.

IMPORTANCE/UNASSIGNED:Amid escalating mental health challenges among young individuals, intensified by the COVID-19 pandemic, analyzing postpandemic trends is critical. OBJECTIVE/UNASSIGNED:To examine mental health care utilization and prescription rates for children, adolescents, and young adults before and after the COVID-19 pandemic. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This population-based time trend study used an interrupted time series analysis to examine mental health care and prescription patterns among the French population 25 years and younger. Aggregated data from the French national health insurance database from January 2016 to June 2023. Data were analyzed from September 2023 to February 2024. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The number of individuals with at least 1 outpatient psychiatric consultation, those admitted for full-time psychiatric hospitalization, those with a suicide attempt, and those receiving psychotropic medication was computed. Data were stratified by age groups and sex. Quasi-Poisson regression modeled deseasonalized data, estimating the relative risk (RR) and 95% CI for differences in slopes before and after the pandemic. RESULTS/UNASSIGNED:This study included approximately 20 million individuals 25 years and younger (20 829 566 individuals in 2016 and 20 697 169 individuals in 2022). In 2016, the population consisted of 10 208 277 of 20 829 566 female participants (49.0%) and 6 091 959 (29.2%) aged 18 to 25 years. Proportions were similar in 2022. Significant increases in mental health care utilization were observed postpandemic compared with the prepandemic period, especially among females and young people aged 13 years and older. Outpatient psychiatric consultations increased among women (RR, 1.13; 95% CI, 1.07-1.20), individuals aged 13 to 17 years (RR, 1.15; 95% CI, 1.06-1.23), and individuals aged 18 to 25 years (RR, 1.08; 95% CI, 1.03-1.14). Hospitalizations for suicide attempt increased among women (RR, 1.14; 95% CI, 1.02-1.27) and individuals aged 18 to 25 years (RR, 1.07; 95% CI, 1.03-1.12). Regarding psychotropic medications, almost all classes, except hypnotics, increased in prescriptions between 2016 and 2022 for females, with a particularly marked rise in the postpandemic period. For men, only increases in the prescriptions of antidepressants (RR, 1.03; 95% CI, 1.01-1.06), methylphenidate (RR, 1.09; 95% CI, 1.06-1.12), and medications prescribed for alcohol use disorders (RR, 1.08; 95% CI, 1.04-1.13) were observed, and these increases were less pronounced than for women (antidepressant: RR, 1.13, 95% CI, 1.09-1.16; methylphenidate: RR, 1.15; 95% CI, 1.13-1.18; alcohol use dependence: RR, 1.12; 95% CI, 1.08-1.16). Medications reserved for severe mental health situations, such as lithium or clozapine, were prescribed more frequently starting at the age of 6 years. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this study, an interrupted time-series analysis found a marked deterioration in the mental health of young women in France in the after the COVID-19 pandemic, accentuating a trend of deterioration that was already observed in the prepandemic period.

The directionality of the relationship between adolescent alcohol consumption and mental health difficulties remains poorly understood. This study investigates the longitudinal relationship between alcohol use frequency, internalizing and externalizing symptoms from the ages of 11 to 17. We conducted a random-intercept cross-lagged panel model across three timepoints (ages: 11yrs, 14yrs, 17yrs; 50.4% female) in the Millennium Cohort Study (N = 10,647). Survey weights were used to account for attrition. At each timepoint, past month alcohol use frequency was self-reported, parents and cohort members reported internalizing/externalizing symptoms using the Strengths and Difficulties Questionnaire. We controlled for alcohol expectancies, sex, and four cumulative risk indices (perinatal risk, early childhood adverse parenting, longitudinal parent-level risk occurrence, and persistent household socioeconomic deprivation). More frequent past month alcohol use at age 11 predicted increased internalizing symptoms at age 14 (β = 0.06; p =.01). More frequent past month alcohol use at age 14 predicted increased externalizing symptoms at age 17 (β = 0.11; p <.001). Increased internalizing symptoms consistently predicted reduced alcohol use at the next timepoint throughout the study period (11 years: β= -0.04; p =.03; 14 years: β= -0.09; p <.001). Increased externalizing symptoms at age 11 predicted increased alcohol consumption at age 14 (β = 0.06; p =.004). Frequent adolescent alcohol consumption represents a significant risk for subsequent mental health difficulties. Externalizing symptoms and alcohol use frequency appear to exacerbate one another. Internalizing symptoms may reduce the risk of frequent alcohol consumption. Incorporating routine alcohol screening into adolescent mental health treatment settings could reduce the risk of comorbid externalizing and alcohol use disorders.

Commenting on our systematic review and meta-analysis on the reporting and representation of race/ethnicity in randomized controlled trials ADHD, Jurek and Leaune thoughtfully highlighted important legal barriers that hinder the reporting of race/ethnicity data in research in some countries, focusing on France as an example. They concluded that this situation calls for a tangible action to change the status quo. Looking ahead, the question is: how should this action be implemented effectively? Given the antiracist journey that JAACAP is proudly undertaking, AACAP and JAACAP are in an ideal position to take on the challenge highlighted by Jurek and Leaune.

BACKGROUND:The comparative benefits and harms of available interventions for ADHD in adults remain unclear. We aimed to address these important knowledge gaps. METHODS:In this systematic review and component network meta-analysis (NMA), we searched multiple databases for published and unpublished randomised controlled trials (RCTs) investigating pharmacological and non-pharmacological interventions for ADHD in adults from database inception to Sept 6, 2023. We included aggregate data from RCTs comparing interventions against controls or any other eligible active intervention for the treatment of symptoms in adults (ages ≥18 years) with a formal diagnosis of ADHD. Pharmacological therapies were included only if their maximum planned doses were considered eligible according to international guidelines. We included RCTs of at least 1-week duration for medications, of at least four sessions for psychological therapies, and of any length deemed appropriate for neurostimulation. For RCTs of medications, cognitive training, or neurostimulation alone, we included only double-blind RCTs. At least two authors independently screened the identified records and extracted data from eligible RCTs. Our primary outcomes were efficacy (change in ADHD core symptom severity on self-rated and clinician-rated scales at timepoints closest to 12 weeks) and acceptability (all-cause discontinuation). We estimated standardised mean differences (SMDs) and odds ratios (ORs) using random effects pairwise and component NMA, dismantling interventions into specific therapeutic components. This study was registered with PROSPERO (CRD42021265576). People with relevant lived experience were involved in the conduct of the research and writing process. FINDINGS/RESULTS:Of 32 416 records, 113 unique RCTs encompassing 14 887 participants were eligible for analysis (6787 [45·6%] females, 7638 [51·3%] males, 462 [3·1%] sex not reported). The RCTs encompassed pharmacological therapies (63 [55·8%] of 113 RCTs; 6875 participants), psychological therapies (28 [24·8%] of 113 RCTs; 1116 participants), neurostimulatory therapy and neurofeedback (ten [8·8%] of 113 RCTs; 194 participants), and control conditions (97 [85·8%] of 113 RCTs; 5770 participants). For reduction of ADHD core symptoms at 12 weeks on both self-reported and clinician-reported rating scales, atomoxetine (self-reported scale SMD -0·38, 95% CI -0·56 to -0·21; clinician-reported scale -0·51, -0·64 to -0·37) and stimulants (0·39, -0·52 to -0·26; -0·61, -0·71 to -0·51) had higher efficacy than placebo (Confidence in Network Meta-Analysis [CINeMA] ranging between very low and moderate). Cognitive behavioural therapy (-0·76, -1·26 to -0·26), cognitive remediation (-1·35, -2·42 to -0·27), mindfulness (-0·79, -1·29 to -0·29), psychoeducation (-0·77, -1·35 to -0·18), and transcranial direct current stimulation (-0·78; -1·13 to -0·43) were better than placebo only on clinician-reported measures. Regarding acceptability, all therapeutic components were similar to placebo other than atomoxetine (OR 1·43, 95% CI 1·14 to 1·80; CINeMA moderate) and guanfacine (3·70, 1·22 to 11·19; high), which had lower acceptability compared with placebo. Baseline severity of self-reported ADHD core symptoms, year of publication, percentage of male individuals, and percentage of individuals with ADHD and another mental health condition did not explain the heterogeneity observed in unadjusted non-component models of self-reported ADHD core symptoms. Treatment length had little effect on heterogeneity. INTERPRETATION/CONCLUSIONS:Stimulants and atomoxetine were the only interventions with evidence of beneficial effects in terms of reducing ADHD core symptoms in the short term, supported by both self-reported and clinician-reported ratings. However, atomoxetine was less acceptable than placebo. Medications for ADHD were not efficacious on additional relevant outcomes, such as quality of life, and evidence in the longer term is underinvestigated. The effects of non-pharmacological strategies were inconsistent across different raters. Our network meta-analysis represents the most comprehensive synthesis of available evidence to inform future guidelines in the field. FUNDING/BACKGROUND:UK National Institute for Health and Care Research.