Faculty Bibliography

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.

The diagnosis of autism is currently based on the developmental history, direct observation of behavior, and reported symptoms, supplemented by rating scales/interviews/structured observational evaluations-which is influenced by the clinician's knowledge and experience-with no established diagnostic biomarkers. A growing body of research has been conducted over the past decades to improve diagnostic accuracy. Here, we provide an overview of the current diagnostic assessment process as well as of recent and ongoing developments to support diagnosis in terms of genetic evaluation, telemedicine, digital technologies, use of machine learning/artificial intelligence, and research on candidate diagnostic biomarkers. Genetic testing can meaningfully contribute to the assessment process, but caution is required when interpreting negative results, and more work is needed to strengthen the transferability of genetic information into clinical practice. Digital diagnostic and machine-learning-based analyses are emerging as promising approaches, but larger and more robust studies are needed. To date, there are no available diagnostic biomarkers. Moving forward, international collaborations may help develop multimodal datasets to identify biomarkers, ensure reproducibility, and support clinical translation.

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.

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 coexistence of mental and physical health illnesses could be accounted for by an underlying general disease factor (termed d-factor), reflecting theoretical underpinnings based on possible genetic and pathophysiological overlapping mechanisms. This study evaluated whether the d-factor underlies mental and physical health illnesses in adolescents. A series of confirmatory factor analyses were conducted using data from 1120 adolescents. The proposed common underlying factor, we believe is the d-factor, was consistently present across different modeling approaches, including unidimensional, correlated-factor, and bifactor models. The best model fit was achieved with the bifactor model represented by mental, neurological, and psychical conditions tested. The first compelling evidence was provided supporting the existence of the transdiagnostic d-factor in youth, opening the door to innovative research of comorbid mental and physical health conditions.

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.

Weighing risks and benefits of the use of psychotropic medications during pregnancy remains a challenge worldwide. We systematically assessed the strength of associations between psychotropic medication use in pregnant people with mental disorders and various adverse health outcomes in both pregnant people and foetuses. Systematic reviews with meta-analyses of observational studies investigating the association between exposure to psychotropic medication in pregnancy and any adverse health outcomes were included. Credibility was graded into convincing, highly suggestive, suggestive, weak or not significant. Quality of the meta-analyses and of individual studies were assessed with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) the Newcastle-Ottawa Scale (NOS), respectively. We considered 21 meta-analyses encompassing 17,290,755 participants (AMSTAR 2 high = 1, low = 12, or critically low = 8). Evidence was suggestive for: (1) preterm birth in pregnant people with either any mental disorder (equivalent odds ratio 1.62 (95% confidence interval 1.24-2.12) or depression (1.65 [1.34-2.02]) receiving antidepressants during any trimester of pregnancy; (2) small for gestational age for pregnant people with depression receiving a SSRI during any trimester of pregnancy (1.50 [1.19-1.90]); and (3) major congenital malformation (1.24 [1.09-1.40]) or cardiac malformations (1.28 [1.11-1.47]) in babies for pregnant people with depression or anxiety receiving paroxetine during first trimester of pregnancy. Additional associations were supported by weak evidence, or were not statistically significant. This umbrella review found no convincing or highly suggestive level of evidence of adverse health outcomes associated with psychotropic medication use in pregnant people with mental disorders.

Systematic reviews and meta-analyses have become crucial for evidence-based decision-making in recent decades. However, it is common for the results of multiple reviews on the same topic to be inconsistent, and it is widely recognised that the results of the reviews are not always effectively communicated to healthcare professionals and the lay public. This manuscript proposes a strategy to summarise and communicate the findings of previous systematic reviews and meta-analyses to wider audiences. The proposed approach couples the findings of umbrella reviews with the creation of open-access online platforms that present the results of these umbrella reviews in an accessible way to various stakeholders. The key potential methodological avenues of this approach are presented, and specific examples from the author's own works and those from other teams are provided. An accompanying website (https://u-reach.org/) has been designed to present this Umbrella-Review, Evaluation, Analysis, and Communication Hub (U-REACH) approach and to overcome the technical challenges associated with this type of project (by sharing the code used to build existing U-REACH projects). The present document is intended to serve as a methodological and technical guide for the creation of large-scale projects designed to synthesise and disseminate scientific information to a broad audience.