Faculty Bibliography

OBJECTIVE:Prenatal maternal depression (PMD) is a common public health concern, affecting up to 20% of pregnancies worldwide. Children exposed to PMD exhibit early self-regulatory and emotional difficulties, although its impact on the developing fetal brain remains largely unexplored. The amygdala and cerebellum are both implicated in emotion regulation and psychiatric vulnerability, are densely interconnected, and undergo rapid maturation in utero. Characterizing the relationship of PMD symptoms to amygdala-cerebellar connectivity before birth offers a unique opportunity to isolate in utero mechanisms of risk. METHOD/METHODS:In a sample of 123 pregnant participants (61% male fetuses, n = 75), PMD symptoms were assessed between the second to third trimester using the Center for Epidemiologic Studies-Depression Scale. Fetuses underwent functional MRI, and region-to-voxel analyses examined amygdala-cerebellar functional connectivity. Statistical tests focused on an emerging hypothesis regarding fetal amygdala-cerebellar connectivity, while also addressing potential amygdala connectivity effects across the full fetal cerebrum. RESULTS:Higher PMD symptoms were associated with significantly increased functional connectivity between the fetal amygdala and cerebellum. This effect remained significant following small volume correction within the cerebellum and after adjusting for covariates. CONCLUSION/CONCLUSIONS:This is the first study to demonstrate altered amygdala-cerebellum connectivity in the human fetal brain in relation to prenatal maternal depression. These findings extend models of prenatal programming by addressing the earliest stages of human brain development and by highlighting the cerebellum's role in emotional network development. Enhanced amygdala-cerebellar coupling in utero may represent an early neural marker of risk for later emotional dysregulation.

Prior studies suggest fluoride exposure in drinking water above 1500 μg/L is associated with lower child cognition, but evidence is limited at lower exposure levels and in U.S. populations. We evaluated whether prenatal exposure to fluoride in regulated public drinking water was associated with cognition in a pooled U.S. cohort. We analyzed observational data from the Environmental influences on Child Health Outcomes (ECHO) Cohort, including 2514 children born 2006-2019 across 17 sites in 23 states. Individual prenatal time-weighted average public water fluoride concentrations were estimated by linking census tract-level concentrations to residential addresses across pregnancy. Fluid and crystallized cognition were assessed using NIH Toolbox scores. Generalized estimating equation models estimated adjusted mean differences using restricted cubic spline and linear change-point models. Individual prenatal time-weighted average water fluoride concentrations ranged from < 1.0-1940.0 μg/L (mean = 396.9 μg/L). Cubic spline models showed significant inverse associations for fluid cognition above 1107.0 μg/L. Linear change-point models identified 675 μg/L as the best-fitting change-point for fluid cognition; above this value, fluid scores were 0.67 points lower (95% CI, -0.92, -0.42) per 100 μg/L higher fluoride. These findings indicate that prenatal fluoride exposure in regulated public water is nonlinearly associated with lower fluid cognition scores in U.S. children at concentrations below current WHO and U.S. EPA thresholds.

BACKGROUND/UNASSIGNED:Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood, negatively impacting occupational, social, and economic outcomes. The Adult ADHD Investigator Symptom Rating Scale (AISRS) is a clinician-administered tool designed to evaluate ADHD symptom severity and treatment response. However, a validated Japanese version is not available. This study evaluated the reliability and convergent validity of the Japanese version of the AISRS (AISRS-Japanese) in adults with ADHD. METHODS/UNASSIGNED:Following linguistic validation procedures, the AISRS was translated into Japanese and reviewed by clinicians for conceptual and clinical equivalence. This was a multicenter, longitudinal, non-interventional study assessing the psychometric properties of the AISRS-Japanese. The evaluation instruments were the AISRS-Japanese, the Adult ADHD Self-Report Scale (ASRS-Japanese version), and the Clinical Global Impressions-Severity (CGI-S) scale. Reliability assessments included internal consistency (Cronbach's alpha), test-retest, intra-rater, and inter-rater reliability (intraclass correlation coefficient [ICC] and G(q,k) coefficients). Convergent validity was evaluated via Pearson's correlation between AISRS-Japanese and ASRS-Japanese version scores. RESULTS/UNASSIGNED:In total, 61 adults with ADHD were included in the analysis. The mean age of the study participants was 34 years, 52.5% (32/61) were male, and 75.4% (46/61) were moderately ill (CGI-S score of 4). The AISRS-Japanese demonstrated internal consistency for the total scale (Cronbach's alpha = 0.83) and the hyperactivity/impulsivity and inattention subscales (0.76 and 0.75, respectively). Test-retest reliability was good (ICC: total, 0.77; hyperactivity/impulsivity, 0.79; inattention, 0.83), as was intra-rater reliability (ICC: total, 0.76; hyperactivity/impulsivity, 0.77; inattention, 0.83). Inter-rater reliability was excellent (G(q,k): total, 0.96; hyperactivity/impulsivity, 0.97; inattention, 0.96). Convergent validity of the ASRS-Japanese version was high (correlation coefficient: total, 0.89; hyperactivity/impulsivity, 0.88; inattention, 0.84). CONCLUSION/UNASSIGNED:These results provide evidence supporting the reliability and convergent validity of AISRS-Japanese as a semi-structured tool for assessing ADHD symptoms in Japanese adults.

OBJECTIVES/OBJECTIVE:To systematically evaluate the certainty of evidence for treatment strategies across age groups and mood phases in bipolar disorder, and develop an open access web platform to facilitate shared decision making. DESIGN/METHODS:Living umbrella review, evaluation, analysis, and communication hub (U-REACH) project. DATA SOURCES/METHODS:PubMed, PsycInfo, and Cochrane library databases, from inception to 19 November 2024. ELIGIBILITY CRITERIA FOR SELECTING STUDIES/METHODS:Systematic reviews with network or pairwise meta-analyses of randomised controlled trials of pharmacological, nutraceutical, psychosocial, brain stimulation, or circadian rhythm based treatments, administered as monotherapy (without concurrent interventions), augmentation treatment (interventions added to an ongoing treatment regimen), or combination treatment (simultaneous initiation of two different interventions), examining any age group, bipolar disorder phase (ie, acute bipolar depression, mania or mixed episodes, or maintenance), treatment, control, or outcome. RESULTS:77 studies met the inclusion criteria (21 network meta-analyses and 56 pairwise meta-analyses), including 116 unique pharmacological (n=74), brain stimulation (n=18), nutraceutical (n=13), psychosocial (n=8), and circadian rhythm based (n=3) treatments as monotherapy, augmentation, or combination therapy, along with five control interventions. These studies covered 133 unique outcomes (45 efficacy outcomes and 88 safety outcomes) resulting in 2510 meta-analyses with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) ratings of the certainty of the evidence as high (n=236), moderate (n=827), low (n=986), and very low (n=461). A communication hub, the Evidence Based Interventions for Bipolar Disorder (EBI-BD) platform, was developed and the full results are freely available (https://ebibd-database.org), including the preference based tool (12 interventions and 17 safety outcomes). Interventions effective across outcomes varied by phases. For bipolar depression, effective interventions in adults were cariprazine, divalproex or valproate, fluoxetine, ketamine (augmentation), lamotrigine, lumateperone, lurasidone, olanzapine, olanzapine with fluoxetine, and quetiapine, whereas effective interventions in children and adolescents were lurasidone and olanzapine with fluoxetine. For mania episodes, effective interventions in adults were aripiprazole, asenapine, carbamazepine, cariprazine, divalproex or valproate, haloperidol, lithium, olanzapine, paliperidone, quetiapine (also augmentation), risperidone (also as augmentation), tamoxifen, and ziprasidone, whereas effective interventions in children and adolescents were aripiprazole, asenapine, olanzapine, quetiapine, and risperidone. For maintenance, interventions effective across outcomes in adults were aripiprazole (also the long acting injectable formulation), asenapine, divalproex or valproate, lithium, olanzapine, group psychoeducation (augmentation), quetiapine, and risperidone long acting injectable formulation. Interventions effective across phases were aripiprazole (also as augmentation and as a long acting injectable formulation), asenapine, cariprazine, cognitive behavioural therapy (augmentation), divalproex or valproate, lamotrigine, lithium, olanzapine (also as augmentation), paliperidone, quetiapine (also as augmentation), and risperidone (also as augmentation and the long acting injectable formulation) (adults). Treatment effects by neuroscience based nomenclature classes are also reported. CONCLUSIONS:The EBI-BD tool can help clinicians make evidence based, personalised treatment decisions for bipolar disorder. This resource can inform clinical guidelines and provides a foundation for continuously improving bipolar disorder care as new evidence emerges. TRIAL REGISTRATION/BACKGROUND:Open Science Framework https://osf.io/pjmvn/ READERS' NOTE: This is a living systematic review and may be updated in the next two years if additional evidence emerges.

Decades of research on the developmental origins of health and disease highlight how prenatal and perinatal conditions are associated with long-term neurocognitive development. Exposures such as maternal stress, substance use, metabolic disorders, obstetric complications, low birthweight, and preterm birth have been linked to differences in brain, cognition, and mental health. Yet, most prior studies have been limited by small sample sizes, narrow exposure measures, or isolated outcomes. The Adolescent Brain Cognitive Development (ABCD) Study provides an unparalleled opportunity to overcome these limitations with nearly 12,000 children recruited at ages 9-10 across the United States, followed longitudinally with harmonized multimodal MRI, cognitive and behavioral testing, biospecimens, genetic data, and rich environmental measures in a diverse cohort. Retrospective caregiver reports provide key prenatal and perinatal information, which can be prospectively related to neurodevelopmental outcomes across adolescence. This review synthesizes findings from 111 ABCD-based studies published from 2017 to 2026. Results implicate maternal health conditions, substance use, birth outcomes, and cumulative adversity as being associated with variation in brain, cognitive, and behavioral development. Leveraging its size and diversity, ABCD has fostered advanced analytic approaches, such as multimodal integration of imaging and behavioral data, and longitudinal tracking of developmental trajectories, rarely possible elsewhere. While methodological challenges remain, including retrospective reporting and imaging site variability, ABCD offers unique opportunities to clarify pathways of vulnerability and resilience within an observational framework. Insights from this work can inform public health strategies and guide policies to reduce prenatal risks and strengthening early-life environments to optimize developmental outcomes.

PURPOSE/OBJECTIVE:Few studies have examined the increased risk for pregnancy complications in women with autism spectrum disorder (ASD) diagnosis. The autism genetic propensity in relation to the complications of pregnancy and birth remains unknown, and is an area critical for informing maternal health and reproductive guidance. Here, we assessed whether maternal genetic liability to ASD is associated with pregnancy complications. METHODS:The study comprised 28,985 females with at least one pregnancy-related record from the UK Biobank (UKB) cohort. Individual polygenic risk scores (PRS) for ASD were calculated, and pregnancy complications were defined using ICD-10 diagnostic codes. Associations between ASD PRS and pregnancy outcomes were evaluated using logistic regression models adjusted for maternal age at first conception. In the secondary analyses, we used schizophrenia (SCZ) PRS, and analyzed broader, ICD-based clusters of pregnancy outcomes. RESULTS:Maternal ASD PRS showed no nominally significant associations with pregnancy outcomes. Maternal SCZ PRS was nominally associated with a reduced risk of spontaneous delivery (O80) and forceps/vacuum delivery (O81); however, no associations remained significant after FDR correction. CONCLUSION/CONCLUSIONS:Higher genetic liability to ASD was not significantly associated with an increased risk of pregnancy complications in the UKB sample. Findings should be interpreted with caution, given the limitations of PRS, potential selection bias in UKB, and the relatively small sample size of females with pregnancy outcomes in the UKB.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Randomised controlled trials (RCTs) have demonstrated that pharmacotherapy reduces symptoms of attention-deficit/hyperactivity disorder (ADHD) at a group level, but efficacy and tolerability vary across individuals. Clinico-demographic characteristics may act as predictors and/or moderators of treatment efficacy and tolerability, but systematic evidence remains limited. Therefore, we systematically analysed RCTs of ADHD medications to identify potential demographic and clinical predictors/moderators of efficacy and tolerability across the lifespan. METHODS:Randomised controlled trials were identified from the MED-ADHD database ( https://med-adhd.org/ ), a repository of RCTs of medications for ADHD in children, adolescents and adults. The database is based on systematic searches of multiple electronic sources, including PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Registry of Controlled Trials and EMBASE, and is also complemented by unpublished data obtained from manufacturers and study authors. We used the most recent (2026) version of MED-ADHD. The risk of bias was assessed using the revised Cochrane risk-of-bias tool (RoB 2). RESULTS:Among the 171 RCTs screened, 62 assessed clinico-demographic factors as possible predictors or moderators of treatment efficacy and tolerability. Age was the most examined characteristic (56.4%) followed by, among the top five, psychiatric comorbidities (53.2%), sex (46.8%), baseline ADHD symptom severity (27.4%), and ADHD presentation (24.2%). Most RCTs reported no significant findings although there was preliminary evidence of associations with age (17.7%), psychiatric comorbidities (17.7%), baseline ADHD symptom severity (16.1%), sex (11.3%), and ADHD presentation (4.8%). Risk of bias was rated high in 37% of RCTs. CONCLUSIONS:Stringent sample selection and reliance on group-level analyses may limit the power to detect predictors and moderators of treatment efficacy and tolerability in classical RCTs. Consequently, the current evidence provides limited and inconsistent guidance on clinically meaningful predictors/moderators. However, variables such as age, psychiatric comorbidities, sex, baseline severity and ADHD presentation have been the most frequently examined with positive findings and may hold promise. Future research should prioritise individual participant data meta-analyses of RCTs, alongside well-powered analyses of a comprehensive observational dataset, to more robustly investigate these associations and support treatment stratification through predictive models.

BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) medications can reduce ADHD symptom severity in individuals with comorbid autism spectrum disorder (ASD). However, clinical guidance on pharmacological treatment of ADHD in this clinical population remains limited and inconsistent. Characterising real-world treatment patterns (ie, initiation timing, medication choices, switching, discontinuation) and the impact of alternative medication choices on clinical outcomes is critical for informing evidence-based management strategies. OBJECTIVE:To (1) characterise ADHD pharmacological treatment patterns in youth with ADHD+ASD versus ADHD alone and (2) assess whether using alternative ADHD medications versus methylphenidate is associated with differential changes in negative clinical outcomes among youth with ADHD+ASD. METHODS:This is a population-based cohort study using Swedish national registers. The study included children (<13 years) and adolescents (13-17 years) with an incident ADHD diagnosis between 2007 and 2018 and followed-up until 2021, comparing youth with co-occurring ASD (n=24 117) and ADHD alone (n=79 830). Descriptive outcomes included time to pharmacological treatment initiation, medication type, number of medication switches and discontinuations. The primary outcome was changes in rates of inpatient psychiatric hospitalisations, accidental injuries and specialist care visits for substance use, depressive or anxiety disorders in the 1 year after versus the 1 year before medication initiation. FINDINGS/RESULTS:Individuals with ADHD+ASD experienced longer delays to treatment initiation (12-14% initiated >12 months after diagnosis vs 7-8% in ADHD alone). Children with ADHD+ASD were slightly more likely to discontinue treatment within 3 months (16% vs 12%) and had the highest average number of medication switches within 3 years (2.6; IQR 0.0-2.0). In within-individual analyses, comparisons of alternative ADHD medications versus methylphenidate did not yield statistically significant differences after correcting for multiple comparisons. CONCLUSIONS:Children with ADHD+ASD experienced longer delays to treatment initiation and more frequent medication switching compared with those with ADHD only. The effects of alternative ADHD medication options on key negative clinical outcomes appeared similar to those of methylphenidate. CLINICAL IMPLICATIONS/CONCLUSIONS:These findings suggest that, rather than recommending fixed first-line and second-line treatments for individuals with ADHD-ASD, clinical guidelines should emphasise appropriate training as well as prompt and individualised treatment based on a shared decision-making process.

Youth with developmental disabilities (DD) are often at increased suicide risk. However, clinician guidance on suicide prevention practices specific to the DD population is rarely available, which may result in care disparities. The current study examined whether rates of standard suicide risk screening in two pediatric emergency departments (ED) differed for youth with and without DD. Then, using data from a NIMH-funded initiative, we compared youth with and without DD on demographic, visit, and clinical characteristics to identify possible factors related to differences in screening rates. Disparities in the completion of suicide risk screening with youth with DD were identified in standard care but few differences were found across groups to suggest a rationale, holding important clinical and research implications.