Suicide is a leading cause of death among youth, and adverse childhood experiences (ACEs) are established risk factors for suicidality. This study is the first to investigate disparities in the cumulative impact of ACEs in individuals with suicidal ideation only (SI+) and suicide attempt (SA+) in a current, diverse, and nationally representative sample using a causal inference analysis framework. Using the 2023 National Youth Risk Behavior Survey (YRBS) (N = 20,103), adolescent demographics, suicidal thoughts and behaviors (STBs), ACEs, and confounders (eg, bullied at school) were examined. First, bivariate differences were analyzed by race/ethnicity and sex for ACE prevalence. Next, the dose-response relationship of ACEs on suicidality was estimated with a doubly robust estimation process and tested for moderation by race/ethnicity and sex. There were significant disparities by race/ethnicity in the types of ACEs that participants endorsed. Female adolescents saw higher prevalences across most ACEs compared to their male counterparts. For SI+ and SA+ outcomes, a dose-response effect of ACEs on suicidality was observed, with higher effects for SI+ compared to SA+. For both outcomes, disparities in this effect across race/ethnicity and sex were not observed. These results suggest that the number of ACEs has a similar incremental impact on the risk of youth suicidality across races/ethnicities and sex despite differences in the types of ACEs experienced (ie, emotional abuse vs physical abuse). It is critical that suicide intervention and prevention strategies better support youth experiencing ACEs; in addition, they should consider differences in prevalences of ACE types by demographics for effective risk mitigation. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.
To investigate whether age or gender moderates short-term antipsychotic efficacy, acceptability, or safety in adolescents with early-onset schizophrenia (EOS). We analyzed data from 4 placebo-controlled, randomized registration trials of antipsychotics in EOS (2003-2015). An individual patient data meta-analysis evaluated how age and gender affected efficacy (Positive and Negative Syndrome Scale [PANSS] total change, response), acceptability (all-cause discontinuations), and safety (adverse event incidence). Covariates included age at onset, body mass index, baseline negative symptoms, and study year. The study was registered in the PROSPERO database (ID: CRD42024572863). We included 949 adolescents (61% male, 39% female; mean age = 15.4 years). Neither age (β = 0.251, 95% CI= -1.561-2.064) nor gender (β = 3.057, 95% CI = -0.206-8.175) significantly altered overall antipsychotic efficacy on mean PANSS improvement or response rate. All-cause discontinuation was likewise not affected. Younger adolescents on active medication showed a higher incidence of adverse events than those on placebo, whereas older adolescents exhibited similarly low rates across arms (correlation coefficient = -0.272, p < .001). Gender did not significantly influence adverse-event incidence (aggregate β = 0,037, p = .832). The overall correlation coefficient -0.131 (p = .342) between age and 5 major side effect classes (weight gain, extrapyramidal side effects, QTc prolongation, prolactin increase, sedation) suggested no meaningful age impact, with odds ratios ranging from 0.858 (p = .691) for weight gain to 1.244 (p = .225) for sedation. Younger adolescents demonstrated greater vulnerability to antipsychotic-related adverse events despite exhibiting efficacy and acceptability comparable to those in older adolescents. These findings suggest that age-based dosing and monitoring may be warranted when treating adolescents with EOS. Influence of age and gender on short-term efficacy and safety of antipsychotic drugs in the treatment of adolescents with schizophrenia: an Individual Patients Data Meta-Analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024572863 DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.
Exposure to a modicum of stress-neither too much nor too little-may confer an adaptive advantage in the face of subsequent stress. This study tests whether there is a "sweet spot" of stress exposure in childhood. The analysis uses data from the prospective, longitudinal, representative Great Smoky Mountains Study. Childhood emotional symptoms and exposure to 32 different stressful events were assessed with a structured diagnostic interview in individuals aged 9 to 16 years (6,674 total observations). Three definitions of "moderate stress" were derived based upon the type of the prior event, the number of prior stressful events, and the severity of the stressful events. A series of planned post hoc comparisons tested whether prior exposure to moderate stress was advantageous when dealing with recent stressful life events. The majority of participants reported no/low stress (67.8.5%-77.5%). Moderate stress or exposure to one stressful event was reported at between 14.8% and 26.0% of all childhood observations. In all models, both recent stress and past stress were independently associated with current emotional symptoms. Planned post hoc comparisons, however, suggested no evidence of an advantage of prior exposure to moderate stress in participants' response to recent stressful events. Findings were most consistent with a risk saturation effect. In this cohort study, there was no evidence of an adaptive level of prior stress exposure consistent with concepts of steeling or stress inoculation. Rather, both past and current stressful events affect current functioning up to some point beyond which there is little additional vulnerability. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We actively worked to promote sex and gender balance in our author group.
The systematic review and meta-analysis by Rizzo et al.1 should be of interest to child psychiatrists and pediatricians based on its historical and contemporary relevance (Table 12-9). Historically, it addresses the 2019 COVID-19 pandemic-so far the most devastating health-related event of the 21st century-which may haunt us for decades because of post-acute sequelae of SARS-CoV-2 (PASC) or Long-COVID, which is now affecting millions of individuals. Contemporarily, it addresses an unresolved issue regarding neurodevelopment in children with a history of fetal exposure to SARS-CoV-2 during pregnancy (presumably uninfected, because vertical transmission is rare), as well as a contentious public debate regarding outcomes of children with fetal and childhood exposure to COVID-19 vaccinations. For this review, the authors applied both a narrow approach (by restricting the review to studies of neurodevelopment in children) and a broad approach (by including studies with "neurodevelopmental outcomes of the child at any age" and "any available measure of child development"). They did the following: (1) identified studies that met the exposure criteria (ie, maternal infection or vaccination) for the review ("70 studies" with 88 neurodevelopmental outcomes); (2) described basic characteristics and findings of all studies in an informative table ("which summarizes methodologies, key findings, and covariates adjustments"); (3) presented structured narrative syntheses for the studies classified into 7 outcome subdomains (with "… consistency [defined] as >70% of studies within a domain reporting effects in the same direction"): and (4) conducted meta-analyses for multiple studies with dichotomous outcomes (based on "…the number of individuals screening positive versus negative for specific auditory or developmental concerns"). As outlined in Table 1, the narrative syntheses suggested reassurances that fetal exposure did not disrupt neurodevelopment (because adverse effects of were not consistent across studies for any outcome domain), but the authors did not accept the null hypothesis (even though it was consistent with their own research). Instead, they conducted meta-analyses that suggested that there may be cause for concern (given that adverse effects were statistically significant for an initial neonatal auditory test and for some ratings of neurodevelopment).
Rising suicide rates disproportionately affect youth across racial, ethnic, and sex groups, highlighting the need to identify protective factors associated with specific suicidal behaviors in diverse populations. This study aimed to estimate and compare the effects of protective factors among youth with suicidal ideation only (SI+) and youth with suicide attempts (SA+) across race/ethnicity and sex. Data from the New Mexico Youth Risk and Resiliency Survey (N = 50,887) from 2005 to 2021 were analyzed. Using a causal inference framework, doubly robust adjusted risk ratios (aRRs) of protective factors on SI and SA were estimated through inverse probability of treatment weighting, weighted logistic regression, and G-computation. Protective factors significantly reduced suicidality with stronger effects for SA (aRRs = 0.59 [95% CI 0.54-0.64] to 0.93 [95% CI 0.85-1.01]) compared with SI (aRRs = 0.74 [95% CI 0.69-0.79] to 0.94 [95% CI 0.86-1.01]). Overall, 3 factors effectively distinguished between outcomes. There were race/ethnicity and sex differences; however, differences were more pronounced across race/ethnicity than sex and for SA compared with SI. Protective factors significantly reduced both SI and SA among adolescents, with stronger effects and more pronounced differences for SA. These findings show that protective factors are not universal, highlighting the importance of culturally and demographically tailored prevention strategies. Whereas most previous work has focused on risk factors for suicidality in adolescents, focusing on protective factors is critical for effective prevention. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.
The specific influence of individual characteristics on antidepressant efficacy and tolerability in pediatric major depressive disorder (MDD) remains unclear. This study aimed to characterize subgroup-specific treatment efficacy and to establish a preliminary scientific foundation for precision psychiatry in pediatric MDD management based on available data. An individual participant data (IPD) analysis of double-blind randomized trials (RCTs) was conducted to compare antidepressants with placebo for the acute treatment of MDD in children and adolescents. Subgroup analyses identified treatment outcome differences by participant characteristics, with mixed-effects models used to examine effect modifiers. Primary outcomes were efficacy (depressive symptom change, mean difference [MD]) and tolerability (adverse event-related withdrawals, odds ratio [OR]). Secondary outcomes included deterioration and suicide-related outcomes. The protocol is registered with PROSPERO (CRD42016051657). IPD from 10 of 40 eligible RCTs (2,584 participants) on 5 antidepressants (fluoxetine [n = 475], imipramine [n = 95], paroxetine [n = 413], desvenlafaxine [n = 358], duloxetine [n = 341]), and placebo [n = 902] were analyzed. Most trials had "some concerns" for risk of bias. There was also substantial missing data for key covariates (eg, 53% for family history of psychiatric disorders). Inconsistencies in the reporting and collection of suicide-related outcomes (ideation and attempts) limited our analyses. In the individual participant meta-analysis, subgroup analysis showed that fluoxetine was the only agent significantly more effective than placebo (MD = -2.43). Imipramine (OR = 5.43) and paroxetine (OR = 1.85) showed poor tolerability. In terms of subgroup analyses based on individual participant characteristics, fluoxetine demonstrated superior efficacy in children, female participants, White participants, healthy weight participants, and those with severe symptoms (MDs = -3.90 to -2.60). Fluoxetine also showed less deterioration in female participants (OR = 0.55, 95% CI = 0.37 to 0.83). No significant differences in suicide-related outcomes were observed across subgroups based on individual characteristics. These provide a preliminary understanding of one possible precision medicine framework for pediatric MDD, indicating that individual characteristics (age, sex, ethnicity, body mass index [BMI], symptom severity, family history) may influence treatment outcomes. Exploratory subgroup analyses suggest fluoxetine's efficacy may be more pronounced in certain populations: children, female participants, White individuals, healthy weight participants, and those with severe symptoms. These findings should be interpreted with caution as IPD was only available from a quarter of eligible clinical trials, introducing data availability bias. These findings also require further validation in more diverse cohorts. Universal suicide-related outcome assessment across all subgroups (regardless of individual characteristics) remains essential. Broader data sharing is needed to improve representativeness in future IPD analyses. Comparative efficacy and tolerability of new-generation antidepressants for major depressive disorder in children and adolescents: protocol of an individual patient data meta-analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42016051657.
Most youth in routine mental health care do not receive evidence-based treatments, and when implemented in real-world settings, their effects are typically smaller than those observed in controlled efficacy trials. Trauma-focused cognitive behavioral therapy (TF-CBT) is one of the most efficacious and widely implemented evidence-based treatments for traumatized youth worldwide, yet little is known about how it is delivered and adapted in routine practice. We examined 25,000 treatment sessions to understand the following: (1) how TF-CBT is implemented in routine care; (2) what delivery adaptations are made based on child age and the presence of complex posttraumatic stress disorder (CPTSD) symptoms; and (3) whether adaptations are associated with outcomes. Data came from an observational study of TF-CBT implementation (2018-2024) across Norwegian child and adolescent mental health services. Children and adolescents (6-18 years of age) with clinically significant posttraumatic stress symptoms (N = 1,373) received treatment from 357 therapists across 74 outpatient clinics representing 82% of such services in Norway. Overall, 66% completed treatment and 59% showed reliable improvement. Clinicians applied TF-CBT flexibly as prescribed by the model. Patients with CPTSD received more trauma processing but had less caregiver involvement than those without CPTSD. Children received more stabilization and caregiver involvement than did adolescents. More trauma experiences predicted higher dropout, whereas more caregiver sessions predicted lower dropout. CPTSD was associated with reliable improvement. Number of potentially traumatic event types were more strongly associated with dropout for children than for adolescents, and caregiver sessions more strongly predicted improvement in CPTSD cases. This study provides the first large-scale systematic documentation of TF-CBT delivery in routine care, and shows that TF-CBT can be scaled up in community clinics, with high improvement rates comparable to those in recent meta-analyses. A majority of the therapists received supervision, and future studies need to dismantle the importance of case consultation when scaling up evidence-based treatments.
Child abuse is associated with lifetime risks for psychiatric disorders. This study evaluated 30-month effects of Safer Kids, a parenting program designed for rapid implementation after suspected child abuse. In an open-label, randomized controlled trial, families reported for child abuse to 26 Swedish child welfare agencies were randomized to Safer Kids or intervention as usual. Primary outcomes were official child abuse reports (time to first new report and total number of reports) and caregiver abuse risk (the Brief Child Abuse Potential Inventory). The secondary outcome was child mental health (the Strengths and Difficulties Questionnaire). The trial was preregistered at clinicaltrials.gov (NCT04163367). The trial included 112 families (194 parents). The cumulative number of new child abuse reports was lower for Safer Kids compared with intervention as usual (incidence rate ratio 1.79; 95% CI 1.06-3.02; p = .028), although there was no difference in time to first new report (hazard ratio 0.74; 95% CI 0.31-1.76; p = .50). At 30 months, the Strengths and Difficulties Questionnaire showed a consistent effect favoring Safer Kids across analytical approaches (nonimputed data: d = 0.60; 95% CI 0.11-1.09; p = .001). For the Brief Child Abuse Potential Inventory, an effect was observed in nonimputed analyses (d = 0.41; 95% CI -0.08-0.89; p = .044) but was not supported in sensitivity analyses. Safer Kids did not reduce the time to the first new abuse report but was associated with somewhat fewer total reports and better child mental health at 30 months, suggesting preventive effects in families with suspected abuse. A Randomized Controlled Study of Safer Kids: A Manualized Intervention to Prevent Child Abuse; https://clinicaltrials.gov; NCT04163367. We worked to ensure sex and gender balance as well as ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way.
Executive function (EF) deficits are observed in externalizing disorders. However, research has yet to explore the specificity of these associations for externalizing symptom dimensions and their potential utility in identifying subgroups of youth at risk for persistent problems. The current study leverages unsupervised learning methods to investigate longitudinal relationships between EF domains of inhibitory control and working memory and externalizing dimensions of hyperactivity, impulsivity, and aggression. We include 5,501 youth from the Adolescent Brain Cognitive Development Study who participated in the baseline through 3- year follow-up (T0-T3) assessments. Youth EF was assessed with the Stop Signal and Emotional N-Back tasks. Externalizing problems were captured with the Child Behavior Checklist (CBCL) and parent-report Kiddie Schedule for Affective Disorders and Schizophrenia. A 2-cluster k-means solution optimally fit the data at T0 and T2. At both timepoints, the largest cluster (nT0= 2,927; nT2=3,089) was characterized by higher EF, while the smaller cluster (nT0= 2,574; nT2=2,412) was characterized by lower EF. Temporal stability of group membership was moderate (Cohen's k=0.41). Membership in the lower EF group at both timepoints was significantly associated with greater CBCL attention problems concurrently (T0, T2) and longitudinally (T0-T3; qs<0.05, Rank Biserial rs=0.6-0.11), and was associated with a greater proportion of ADHD diagnoses at T1 (qs≤0.001, Odds Ratios=1.65-1.71). Associations were not observed for aggressive or rule-breaking behaviors. These findings suggest multifaceted and specific cognitive performance deficits in youth attention problems that may inform tailoring and development of personalized treatment and cognitive interventions.
Following calls to formally recognize sensory differences in the autism diagnostic criteria, the DSM-5 introduced sensory features as a subdomain of restricted and repetitive behaviors (RRBs). However, this categorization was developed based on expert consensus, rather than being empirically derived. Subsequent psychometric investigations have largely examined the structure of sensory features and RRBs separately, precluding evaluation of whether these constructs are best represented by shared or distinct latent dimensions. The current study used cross-measure factor analysis with items from across the Dimensional Assessment of Repetitive Behaviors (DARB) and Sensory Experiences Questionnaire (SEQ-3) to expand coverage of sensory features and compare the DSM-5 RRB structure with alternate empirically derived structures identified in the literature. The best-fitting first-order model was then operationalized to compare different general factor solutions. Across first-order models, the four-factor DSM-aligned model showed the poorest fit, while a 10-factor empirically derived model showed the best fit. Across bifactor models, the unidimensional general RRB/sensory model showed the poorest fit. Two alternate two-bifactor structures showed superior fit. Among those bifactor models, an exploratory model - whereby Factor 1 comprised insistence on sameness, restricted interests, unusual interests, repetitive language, obsessive-compulsive behavior, self-injurious behaviors and sensory hypersensitivity, and Factor 2 comprised repetitive motor behavior, sensory seeking and sensory hyposensitivity - showed the highest internal consistency and explained the most variance in related clinical variables. Findings suggest the need to further revise the RRB DSM-5 criteria, indicating that a unidimensional general RRB/sensory domain may not be empirically valid.
Attention-deficit/hyperactivity disorder (ADHD) may lead to depression, but little is known about its underlying mechanisms. We examined whether clinical factors (irritability, anxiety), cognitive-affective processes (emotion recognition, response inhibition, working memory, sustained attention), and negative thought patterns (external locus of control, negative cognitive style) mediated ADHD-depression associations across development and whether these pathways differ by sex. Analyses were performed in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Twins Early Development Study (TEDS). In both samples, ADHD was assessed using the Strengths and Difficulties Questionnaire (SDQ) hyperactivity/inattention subscale at ages 7, 12/13, and 16/17 years. Depressive symptoms were assessed using the short Mood and Feelings Questionnaire at ages 12, 18/21, and 26/27. Mediators were assessed at ages 8-11, 16-17, and 21-25 years with counterfactual mediation models. Clinical factors were assessed and mediated the ADHD-depression effect in both cohorts across development. In ALSPAC, clinical mediators contributed most in childhood (30%) and young adulthood (25%), whereas in TEDS, they contributed most in adolescence (46%). In ALSPAC, negative thought patterns mostly contributed in adolescence (39%), whereas cognitive-affective factors did not show consistent evidence of mediating effects across development. All mediators combined explained 30%, 48%, and 29% of the total effect of ADHD on depression in childhood, adolescence, and young adulthood, respectively. In sex-stratified models, the relative contribution of mediators varied by sex and developmental stage. In childhood, mediators accounted for a greater proportion of the total effect in male (37%) than in female (25%) individuals, whereas a similar proportion of mediated effects was observed across sexes during adolescence (48% in female and 45% in male individuals). In young adulthood, the indirect effect via all mediators was evident only in female individuals (36%). Mechanisms linking ADHD and depression are developmental stage and sex specific. Irritability and anxiety in childhood and young adulthood (particularly for female individuals), and external locus of control and negative cognitive style in adolescence, might represent promising intervention targets for preventing depression in youth with ADHD. Study Preregistration: Clinical and Cognitive Mediators Underlying Subsequent Depression in Individuals With Attention-Deficit/Hyperactivity Disorder: A Developmental Approach; https://www.jaacap.org/article/S0890-8567(25)00171-6/fulltext.
Nihilistic violence has recently become a source of concern for security agencies, schools, and youth mental health clinicians. Preliminary empirical data, albeit limited, suggests that nihilistic violence is more frequent in vulnerable adolescents (10-17 years of age) referred for high risk of violence toward others than in their adult counterparts (18 years and over).1 Beyond the growing fascination with mass murderers and school shooters glorified on social media, the recent rise of multiple organized online groups that actively target and recruit vulnerable adolescents to promote, glorify, and act out extreme violence is deeply concerning and remains relatively unknown among youth practitioners. This Translation piece builds on the experience of a specialized clinical team who receives requests regarding nihilistic violence in adolescents1 to help youth mental health clinicians to recognize and address this new phenomenon. The objectives are as follows: (1) to describe key clinical manifestations of nihilistic violence; (2) to propose specific guidelines for assessment and intervention; and (3) to address countertransference and effective measures to safeguard clinicians from the emotional impact of such violence.
To test the effectiveness of group motivational interviewing (GMI) and school/parent intervention (SP) in reducing drinking among public high school students in Denmark, a region with high rates of hazardous alcohol use. This was a 3-arm, cluster-randomized controlled trial in 16 public high schools block-randomized to the following: (1) 2-session, manualized GMI coupled with SP; (2) SP-only; or (3) assessment-only control. A total of 2,766 students (65.53% female; mean age = 16.77 years, range = 15-19 years) completed online surveys during class periods at baseline and at 2, 6, 9, and 12 months. The primary outcome was past-month peak drinks per occasion at 12-month follow-up. Mixed models estimated change from baseline for each condition and mean change difference across conditions. Students in the control condition significantly increased peak drinks over time at 2.5 times the rate of the other conditions (Δmean = 1.13 [95% CI = 0.62, 1.64] vs 0.48 [95% CI = 0.03, 0.93] for GMI+SP and 0.47 [95% CI = 0.06, 0.88] for SP-only). The mean change difference in peak drinks for each GMI+SP and SP-only vs control was significant (Δmean = -0.65 [95% CI = -1.28, -0.02] and -0.66 [95% CI = -1.27, -0.04], respectively), although significance did not persist after p value correction. More robust effects were observed for the secondary outcome of past-month total drinks. GMI coupled with school-based alcohol policies and parental education represents a promising approach to mitigating drinking among high school students. This study supports the crucial roles of developmentally salient relationships (eg, peers, parents/guardians) and contexts (eg, school, home) in developing and delivering intervention programs to adolescents. Prevention of Hazardous Use of Alcohol with Danish High School Students (Our Choice); https://clinicaltrials.gov/study/NCT06018389?cond=NCT06018389.
Educational attainment (EA) is a major determinant of well-being and is influenced by genetic and environmental factors. This study investigated whether polygenic scores for EA (EA-PGSs) relate to school performance in adolescents with and without psychiatric disorders and whether associations vary by parental education and sex. We analyzed 86,122 individuals (36,659 with psychiatric disorders) from the Danish iPSYCH2015 case-cohort. Associations between EA-PGSs, psychiatric diagnoses, and ninth-grade examination outcomes (passing rates and Danish and mathematics grades) were assessed using regression models, adjusting for covariates. A higher EA-PGS was associated with lower odds of several psychiatric disorders, including attention-deficit/hyperactivity, attachment, neurotic, oppositional defiant/conduct, and substance use disorders, and intellectual disability. Regardless of case status, individuals with higher EA-PGSs were more likely to pass the examination and achieve higher grades. At comparable EA-PGS values, adolescents with psychiatric disorders performed worse than controls. For pass/fail, EA-PGS effects differed between cases and controls in attachment, eating, neurotic, mood, substance use, and tic disorders and intellectual disability (qFDR < .05), being larger in cases for all groups except intellectual disability, where effects were attenuated. Parental education, but not sex, modified the association between EA-PGSs and passing (interaction p = .008), with differences by parental education evident at lower EA-PGS levels. A higher EA-PGS was associated with better school performance, but adolescents with psychiatric disorders performed worse than controls after accounting for EA-PGSs. Performance differences persisted after accounting for EA-PGSs. Both EA-PGSs and parental education were associated with educational outcomes, indicating that genetic and familial factors are related to variation in school performance.
Catatonia was first mentioned as a subject of interest in Karl Kahlbaum's 1874 monograph "Catatonia or Tension Insanity." The German psychiatrist described catatonia as a neuropsychiatric syndrome involving motor symptoms, and identified what are now described as hypo- and hyperactive subtypes.1 Over the ensuing 150 years, the recognition and understanding of catatonia has evolved, and it is now appreciated as a syndrome associated with different psychiatric and medical diagnoses, including neurodevelopmental disorders (NDDs).2 NDDs are conditions originating in childhood that have an impact on social, personal, and academic function; they include autism spectrum disorder (ASD), intellectual disability (ID), and many genetic disorders with autistic phenotypes. Individuals with NDDs are particularly vulnerable to the development of catatonia because of shared neurobiological factors including gamma-aminobutyric acid (GABA) dysfunction.3 However, diagnosing catatonia in NDDs is challenging because of similarities in baseline developmental symptoms and core features of catatonia.4 Despite the acknowledgement of the association between catatonia and NDDs, catatonia continues to be underrecognized and underdiagnosed in this population, with resulting morbidity and mortality.
Noncommunicable or chronic illness accounts for the greatest proportion of global morbidity and mortality (burden of disease) over the past 3 decades.1 Many of the risk factors for noncommunicable diseases, such as diabetes, cancers, and mental illness including substance misuse, can be traced to environments and exposures in early life. Understanding the harms associated with air pollutants, ultra-processed foods (UPFs), excessive screen time and social media exposure, poor sleep and stress, and other factors affecting child development and well-being requires large-scale, longitudinal studies with comprehensive phenotypic characterization and the capabilities to process and make the data available to researchers. Currently, 2 studies funded by the National Institutes of Health are poised to answer pressing questions about early life exposures and vulnerability to chronic illness.
Identifying those at highest risk of making a first suicide attempt during adolescence is crucial to inform early suicide prevention. Our study aimed to predict the first ideation-to-attempt transition during adolescence among children with suicidal ideation at baseline using 187 sociodemographic, clinical, neurocognitive, functional and structural brain predictors. Data was obtained from the multisite, longitudinal Adolescent Brain Cognitive Development (ABCD) study, conducted in 21 US sites among 11,864 children aged 9-10 years at baseline with 4 follow-up waves measured between 2018-2022. The primary outcome was suicide attempt reported at any of the follow-up waves amongst children with suicidal ideation at baseline. Machine learning models were trained using 70% of the sample from 14 sites, and validated in participants from 7 holdout sites. The final sample included 660 children with suicidal ideation at baseline (no previous suicide attempt; mean[SD] age: 9.91[0.63] years; 42% female at baseline), of whom 83 children had a first suicide attempt within 4 year follow-up. The final model, which excluded the brain imaging feature as its inclusion did not improve performance, generalized well to the external holdout sites (AUC-ROC[95% CI]=0.75[0.68, 0.83], sensitivity = 0.65 [0.61, 0.75], specificity = 0.69 [0.50, 0.80], PPV = 0.23 [0.15, 0.34], NPV = 0.94 [0.88, 0.97]), p <.001) with good expected calibration error of 0.03. The model was unbiased across race and sex subgroups. The top contributing features included female sex, presence of self-harm, access to means, generalized anxiety disorder, social anxiety, impulsivity, severity of suicidal ideation, parental income and clinical treatment history. Our model using clinically accessible features predicts the first-onset suicide attempt in children. Most predictors (e.g., suicidal ideation severity, impulsivity, anxiety symptoms) are modifiable, highlighting the potential intervention targets. Findings provide longitudinal evidence for key risk factors for the ideation-attempt transition in current suicide theories.
Psychopathologies are interrelated and often co-occur, suggesting shared genetic and environmental influences. We examined the mediated associations between children's genetic predispositions for higher-order psychopathology-represented by polygenic scores (PGS)-and the development of psychopathology symptoms from childhood to adolescence via baseline levels of psychopathology symptoms in childhood. We performed the same set of analyses in 2 longitudinal birth cohorts (Generation R Study, N = 4,657; Avon Longitudinal Study of Parents and Children [ALSPAC], N = 4,368) and assessed the consistency of our results. PGS for externalizing, internalizing, and neurodevelopmental psychopathology were calculated using the LDpred2-automatic technique. Using growth curve modeling, we modeled the developmental slopes of child psychopathology symptoms into adolescence (ages 6-14 years, assessed by mothers using the Child Behavior Checklist [Generation R Study] and the Development and Well-Being Assessment [DAWBA; ALSPAC]). We next performed 3 sets of mediation analyses (one per PGS) predicting the development of psychopathological symptoms via baseline levels (at age 6 years) of psychopathology during childhood. The PGS for neurodevelopmental problems was linked to most baseline levels and developmental slopes of psychopathological symptoms through direct or mediated effects (ie, via higher levels of symptomatology at baseline). The PGS for neurodevelopmental problems could serve as a broad index of susceptibility to psychopathological symptoms in the general youth population. Direct and Indirect Developmental Pathways From Genetic Predispositions to Mental Health Symptomatology in Adolescence; https://osf.io/hwv9a/.
Early-onset schizophrenia (EOS), defined as onset before age 18, is associated with more severe symptoms, higher genetic load, and poorer functional outcomes compared to adult-onset schizophrenia (AOS). Alterations in brain network organization have been widely reported in EOS and may contribute to its distinct clinical profile, although interactive effects of age and disease on connectome topology remain poorly understood. This study included 45 first-episode drug-naïve patients with EOS, 47 first-episode drug-naïve patients with AOS, and 79 age-matched healthy controls (29 younger, 50 older), with additional exploration in medicated groups (91 EOS and 79 AOS). Using resting-state fMRI and graph theory analysis, we compared topological properties of whole-brain and subnetworks across groups. We identified significant diagnosis × age-stratum interactions specifically on clustering coefficients of the somatosensory-motor network (SMN) and auditory network (AN). EOS showed increased normalized clustering coefficients (gamma), whereas AOS exhibited reduced gamma. Crucially, these aberrant patterns in SMN persisted after antipsychotic treatment. These findings suggest that EOS and AOS may differ in the topological organization of brain networks, particularly within SMN and AN. The persistence of SMN abnormalities after antipsychotic treatment further supports the possibility that EOS has a distinct network-level pathophysiology. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.
This study evaluated the efficacy and safety of pimavanserin in children and adolescents with irritability associated with autism spectrum disorder (ASD). In this phase 2, randomized, double-masked, placebo-controlled study (NCT05523895), patients were randomized 1:1:1 to low-dose pimavanserin (5-12 years, 10 mg/d; 13-17 years, 20 mg/d), high-dose pimavanserin (5-12 years, 20 mg/d; 13-17 years, 34 mg/d), or placebo for 6 weeks, followed by a 30-day follow-up period. The primary endpoint was the change from baseline at week 6 in the caregiver-rated Aberrant Behavior Checklist-Irritability (ABC-I) subscale score. Key secondary endpoints included week 6 change from baseline in Clinical Global Impression (CGI)-Severity irritability score, CGI-Improvement irritability score, Repetitive Behavior Scale-Revised, Vineland Adaptive Behavior Scales-socialization subscale score, and the Caregiver Strain Questionnaire. Treatment-emergent adverse events were assessed. A total of 216 (93.1%) randomized patients completed double-masked treatment (low-dose pimavanserin, n = 76; high-dose pimavanserin, n = 78; placebo, n = 78). The least squares mean (LSM [95% CI]) improvement in the ABC-I subscale score was not significantly different from placebo for either pimavanserin group (placebo, -9.6 [-11.7, -7.5]; low-dose pimavanserin, -11.2 [-13.3, -9.0]; high-dose pimavanserin, -11.2 [-13.3, -9.1]). No statistically significant differences occurred between the placebo and pimavanserin groups for any secondary endpoint. Treatment-emergent adverse events (TEAEs) were similar across groups (placebo, n = 39 [50.0%]; low-dose pimavanserin, n = 36 [46.8%]; high-dose pimavanserin, n = 43 [53.1%]). No serious TEAEs or deaths occurred. Pimavanserin was well tolerated, but selected doses were not demonstrated to be efficacious compared with placebo for the short-term treatment of irritability in children or adolescents with ASD. A study to evaluate the efficacy and safety of Pimavanserin for the treatment of irritability associated with Autism Spectrum Disorder; https://clinicaltrials.gov/study/NCT05523895 DIVERSITY & INCLUSION STATEMENT: We worked to ensure that the study questionnaires were prepared in an inclusive way.