Inflammatory markers in pregnancy - surprisingly stable. Mapping trajectories and drivers in four large cohorts.

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. To translate findings from mechanistic preclinical studies to human pregnancies, studies of serum immune markers are the mainstay. The design and interpretation of human biomarker studies require additional insights in the trajectories and drivers of peripheral immune markers. The current study mapped maternal inflammatory markers (C-reactive protein (CRP), interleukin (IL)-1ß, IL-6, IL-17A, IL-23, interferon- γ ) during pregnancy and investigated the impact of demographic, environmental and genetic drivers on maternal inflammatory marker levels in four multi-ethnic and socio-economically diverse population-based cohorts with more than 12,000 pregnant participants. Additionally, pregnancy inflammatory markers were compared to pre-pregnancy levels. Cytokines showed a high correlation with each other, but not with CRP. Inflammatory marker levels showed high variability between individuals, yet high concordance within an individual over time during and pre-pregnancy. Pre-pregnancy body mass index (BMI) explained more than 9.6% of the variance in CRP, but less than 1% of the variance in cytokines. The polygenic score of CRP was the best predictor of variance in CRP (>14.1%). Gestational age and previously identified inflammation drivers, including tobacco use and parity, explained less than 1% of variance in both cytokines and CRP. Our findings corroborate differential underlying regulatory mechanisms of CRP and cytokines and are suggestive of an individual inflammatory marker baseline which is, in part, genetically driven. While prior research has mainly focused on immune marker changes throughout pregnancy, our study suggests that this field could benefit from a focus on intra-individual factors, including metabolic and genetic components.

Age Trajectories of the Structural Connectome in Child and Adolescent Offspring of Individuals With Bipolar Disorder or Schizophrenia.

Background: Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at elevated risk of developing psychiatric illness owing to both genetic predisposition and increased burden of environmental stress. Emerging evidence indicates a disruption of brain network connectivity in young offspring of patients with bipolar disorder and schizophrenia, but the age trajectories of these brain networks in this high-familial-risk population remain to be elucidated. Methods: A total of 271 T1-weighted and diffusion-weighted scans were obtained from 174 offspring of at least 1 parent diagnosed with bipolar disorder (n = 74) or schizophrenia (n = 51) and offspring of parents without severe mental illness (n = 49). The age range was 8 to 23 years; 97 offspring underwent 2 scans. Anatomical brain networks were reconstructed into structural connectivity matrices. Network analysis was performed to investigate anatomical brain connectivity. Results: Offspring of parents with schizophrenia had differential trajectories of connectivity strength and clustering compared with offspring of parents with bipolar disorder and parents without severe mental illness, of global efficiency compared with offspring of parents without severe mental illness, and of local connectivity compared with offspring of parents with bipolar disorder. Conclusions: The findings of this study suggest that familial high risk of schizophrenia is related to deviations in age trajectories of global structural connectome properties and local connectivity strength.

In this article, we show that child and adolescent offspring of parents with schizophrenia had different patterns in the development of their brain's structural connections compared with offspring of parents with bipolar disorder and offspring of parents without these conditions. The findings of this long-term study indicate that having a family history of schizophrenia is associated with changes over time during adolescence in the overall organization of the brain's structural network.

Beyond the Window of Risk? The Dutch Bipolar Offspring Study: 22-Year Follow-up.

OBJECTIVE: Adolescent offspring of parents with bipolar disorder (BD) are at high risk to develop BD and other psychopathology, yet how this risk continues into middle adulthood remains unknown. This study aimed to determine the window of risk for BD and other psychopathology in offspring of parents with BD followed from adolescence into adulthood. METHOD: This study reported on the 22-year follow-up assessment of the Dutch Bipolar Offspring Study, a fixed cohort study of 140 participants established in 1997. Offspring (n = 100; mean [SD] age = 38.28 [2.74] years) of parents with bipolar I disorder or bipolar II disorder were assessed at baseline and 1-, 5-, 12-, and 22-year follow-up. RESULTS: No new BD onsets occurred since the 12-year follow-up (lifetime prevalence = 11%-13%; bipolar I disorder = 4%; bipolar II disorder = 7%). Lifetime prevalence of any mood disorder was 65%; for major depressive disorder, prevalence was 36%; and for recurrent mood episodes, prevalence was 37%. Prevalence of major depressive disorder more than doubled in the past decade. Point prevalence of any psychopathology peaked between 20 and 25 years (38%-46%), subsiding to 29% to 35% per year after age 30. Overall, 71% of offspring contacted mental health services since the last assessment. CONCLUSION: The risk for homotypic transmission of BD in offspring of parents with BD is highest during adolescence. The heterotypic risk for mood disorder onset and recurrences continues over the life course. Severe mood disorders are often preceded by milder psychopathology, emphasizing the need for early identification and interventions. This study allows for better understanding of the onset and course of mood disorders and specific windows of risk in a familial high-risk population.

Gamification in eHealth for Chronic Disease Self-Management in Youth: A Systematic Review.

This systematic review primarily aims to provide a summary of the game mechanics implemented in eHealth tools supporting young people's self-management of their chronic diseases. This review secondarily investigates the rationale for implementing game mechanics and the effects of these tools. A systematic search was conducted in Embase, Medline, PsycINFO, and Web of Science, from inception until August 30, 2022. Studies were eligible if focus was on the utilization of gamification in eHealth self-management interventions for young people (age = 10-25 years) with chronic diseases. Primary quantitative, qualitative, and mixed-method studies written in English were included. We identified 34 eHealth tools, of which 20 (59%) were gamified tools and 14 (41%) were serious games. We found that 55 unique game mechanics were implemented. The most commonly used were rewards (50%), score (44%), creative control (41%), and social interaction (32%). In comparison with gamified tools, the number and diversity of game mechanics applied were higher in serious games. For most tools (85%), a general rationale was provided for utilizing gamification, which often was to promote engaging experiences. A rationale for using specific game mechanics was less commonly provided (only for 45% of the game mechanics). The limited availability of experimental research precludes to test the effectiveness of using gamification in eHealth to support self-management in young people with chronic diseases. In this study, we highlight the importance of reporting the rationale for utilizing specific game mechanics in eHealth tools to ensure a proper alignment with evidence-based practice and the need of conducting experimental research. PROSPERO: CRD42021293037.

Reducing behavior problems in children born after an unintended pregnancy: the generation R study.

OBJECTIVES: To examine differences in behavior problems between children from intended versus unintended pregnancies, and to estimate how much the difference in problem behavior would be reduced if postnatal depression was eliminated and social support was increased within 6 months after birth. METHODS: Data from the Generation R Study were used, a population-based birth cohort in Rotterdam, the Netherlands (N = 9621). Differences in child internalizing and externalizing behavior at ages 1.5, 3, 6, 9 and 13 years between pregnancy intention groups were estimated using linear regression. Associations of postnatal depression and social support with internalizing and externalizing problems were also estimated using linear regression. Child behavior outcomes where compared before and after modelling a situation in which none of the mothers experienced a postnatal depression and all mother experienced high social support. RESULTS: Most pregnancies (72.9%) were planned, 14.8% were unplanned and wanted, 10.8% were unplanned with initially ambivalent feelings and 1.5% with prolonged ambivalent feelings. Children from unplanned pregnancies had more internalizing and externalizing problems at all ages as compared to children from a planned pregnancy, especially when ambivalent feelings were present. Hypothetically eliminating on postnatal depression reduced the differences in internalizing and externalizing problems by 0.02 to 0.16 standard deviation. Hypothetically increasing social support did not significantly reduce the difference in internalizing and externalizing problems. CONCLUSIONS: Children from an unplanned pregnancy have more behavior problems, in particular when mothers had prolonged ambivalent feelings. Eliminating postnatal depression may help to reduce the inequality in child behavior related to pregnancy intention.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

The Mood and Resilience in Offspring (MARIO) project: a longitudinal cohort study among offspring of parents with and without a mood disorder.

BACKGROUND: One of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors. METHODS: MARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected. DISCUSSION: The MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.

Outcome measures in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. AIM: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. METHODS: The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. RESULTS: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). CONCLUSIONS: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. TRIAL REGISTRATION: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.

Applications of the experience sampling method (ESM) in paediatric healthcare: a systematic review.

BACKGROUND: With the Experience Sampling Method (ESM) participants are asked to provide self-reports of their symptoms, feelings, thoughts and behaviours in daily life. This preregistered systematic review assessed how ESM is being used to monitor emotional well-being, somatic health, fatigue and pain in children and adolescents with a chronic somatic illness. METHODS: Databases were searched from inception. Studies were selected if they included children or adolescents aged 0-25 years with a chronic somatic illness and used ESM focussing on mental health or psychosocial wellbeing, biopsychosocial factors and/or somatic health. Two reviewers extracted data of the final 47 papers, describing 48 studies. RESULTS: Most studies evaluated what factors influence medical or psychological symptoms and how symptoms influence each other. Another common purpose was to study the feasibility of ESM or ESM as part of an app or intervention. Study methods were heterogeneous and most studies lack adequate reporting of ESM applications and results. CONCLUSIONS: While ESM holds great potential for providing results and feedback to patients and caregivers, little use is being made of this option. Future studies should consider what they report in their studies, conduct a priori power analyses and how ESM can be embedded in clinical practice. IMPACT: While ESM has many clinical applications, it is currently mostly used for research purposes. Current studies using ESM are heterogeneous and lack consistent, high-quality reporting. There is great potential in ESM for providing patients and parents with personalised feedback.

Therapeutic Drug Monitoring to Optimize Risperidone Treatment in Children with Autism Spectrum Disorder.

BACKGROUND: Risperidone is an atypical antipsychotic drug used to treat irritability and aggression in children and adolescents with autism spectrum disorder. In an earlier study, the sum trough concentration of risperidone and its metabolite (9-hydroxyrisperidone) was positively correlated with weight gain and effectiveness. The aim of this study was to determine the therapeutic window for risperidone sum trough concentrations that balances weight gain with treatment effectiveness in this population. In addition, the effect of therapeutic drug monitoring (TDM) on treatment optimization was simulated. METHODS: In a retrospective cohort (n = 24 children), the target window for risperidone leading to the least increase in body mass index z-scores while retaining effectiveness as measured by the irritability subscale of the Aberrant Behavior Checklist was determined using receiver operating curve analysis. This target range was used to simulate the effect of TDM using a population PK model implemented in the software platform InsightRX. Dosing advice was based on plasma trough concentrations and the dose administered at 12 weeks to simulate whether more children would be on target at 24 weeks after the start of treatment. RESULTS: A risperidone sum trough target range of 3.5-7.0 mcg/L would minimize increase in body mass index z-score and optimize effectiveness. Dosing advice using TDM and a population PK model would lead to a larger proportion of children achieving the target concentration range (62.5% versus 16.7%). CONCLUSIONS: TDM may be a useful tool for optimizing risperidone treatment in children and adolescents with autism spectrum disorder.

Transdiagnostic risk of mental disorders in offspring of affected parents: a meta-analysis of family high-risk and registry studies.

The offspring of parents with mental disorders are at increased risk for developing mental disorders themselves. The risk to offspring may extend transdiagnostically to disorders other than those present in the parents. The literature on this topic is vast but mixed. To inform targeted prevention and genetic counseling, we performed a comprehensive, PRISMA 2020-compliant meta-analysis. We systematically searched the literature published up to September 2022 to retrieve original family high-risk and registry studies reporting on the risk of mental disorders in offspring of parents with any type of mental disorder. We performed random-effects meta-analyses of the relative risk (risk ratio, RR) and absolute risk (lifetime, up to the age at assessment) of mental disorders, defined according to the ICD or DSM. Cumulative incidence by offspring age was determined using meta-analytic Kaplan-Meier curves. We measured heterogeneity with the I2 statistic, and risk of bias with the Quality In Prognosis Studies (QUIPS) tool. Sensitivity analyses addressed the impact of study design (family high-risk vs. registry) and specific vs. transdiagnostic risks. Transdiagnosticity was appraised with the TRANSD criteria. We identified 211 independent studies that reported data on 3,172,115 offspring of parents with psychotic, bipolar, depressive, disruptive, attention-deficit/hyperactivity, anxiety, substance use, eating, obsessive-compulsive, and borderline personality disorders, and 20,428,575 control offspring. The RR and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders. The offspring's RR and lifetime risk of developing the same mental disorder diagnosed in their parent were 8.4 and 32% for attention-deficit/hyperactivity disorder; 5.8 and 8% for psychosis; 5.1 and 5% for bipolar disorder; 2.8 and 9% for substance use disorders; 2.3 and 14% for depressive disorders; 2.3 and 1% for eating disorders; and 2.2 and 31% for anxiety disorders. There were 37 significant transdiagnostic associations between parental mental disorders and the RR of developing a different mental disorder in the offspring. In offspring of parents with psychosis, bipolar and depressive disorder, the risk of the same disorder onset emerged at 16, 5 and 6 years, and cumulated to 3%, 19% and 24% by age 18; and to 8%, 36% and 46% by age 28. Heterogeneity ranged from 0 to 0.98, and 96% of studies were at high risk of bias. Sensitivity analyses restricted to prospective family high-risk studies confirmed the pattern of findings with similar RR, but with greater absolute risks compared to analyses of all study types. This study demonstrates at a global, meta-analytic level that offspring of affected parents have strongly elevated RR and lifetime risk of developing any mental disorder as well as the same mental disorder diagnosed in the parent. The transdiagnostic risks suggest that offspring of parents with a range of mental disorders should be considered as candidates for targeted primary prevention.

Alcohol exposure before and during pregnancy is associated with reduced fetal growth: the Safe Passage Study.

BACKGROUND: Prenatal alcohol exposure (PAE) is a worldwide public health concern. While PAE is known to be associated with low birth weight, little is known about timing and quantity of PAE on fetal growth. This study investigated the association between periconceptional and prenatal alcohol exposure and longitudinal fetal growth, focusing on timing and quantity in a high exposure cohort. METHODS: The Safe Passage Study was a prospective cohort study, including 1698 pregnant women. Two-dimensional transabdominal ultrasound examinations were performed to measure fetal femur length, abdominal and head circumference, and biparietal diameter, at three time points during pregnancy. Estimated fetal weight and Z-scores of all parameters were calculated. Trimester-specific alcohol exposure was assessed using the Timeline Followback method. To investigate the associations of specific timing of PAE and fetal growth, two models were built. One with alcohol exposure as accumulative parameter over the course of pregnancy and one trimester specific model, in which PAE was separately analyzed. Linear mixed models adjusted for potential confounders were applied with repeated assessments of both alcohol exposure and fetal growth outcomes. RESULTS: This study demonstrated that periconceptional and prenatal alcohol exposure were associated with reduced fetal growth. Effect sizes are displayed as estimated differences (ED) in Z-score and corresponding 95% confidence intervals (95% CIs). When investigated as accumulative parameter, PAE was related to a smaller femur length (ED30; - 0.13 (95% CI; - 0.22; - 0.04), ED36; - 0.14 (95% CI; - 0.25; - 0.04)) and a smaller abdominal circumference (ED36; - 0.09 (95% CI; - 0.18; - 0.01)). Periconceptional alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.14 (95% CI; - 0.25; - 0.02), ED36; - 0.22 (95% CI; - 0.37; - 0.06)) and a smaller estimated fetal weight (ED36; - 0.22 (95% CI; - 0.38; - 0.05)). Second trimester alcohol exposure was associated with a smaller abdominal circumference (ED30; - 0.49 (95% CI; - 0.86; - 0.12), ED36; - 0.70 (95% CI; - 1.22; - 0.17)) and estimated fetal weight (ED30; - 0.54 (95% CI; - 0.94; - 0.14), ED36; - 0.69 (95% CI; - 1.25; - 0.14)). No additional association of binge drinking was found besides the already observed association of PAE and fetal growth. CONCLUSIONS: This study demonstrated that PAE negatively affects fetal growth, in particular when exposed during the periconception period or in second trimester. Our results indicate that potential negative consequences of PAE are detectable already before birth. Therefore, healthcare providers should actively address and discourage alcohol use during pregnancy.

Functional outcomes across development in offspring of parents with bipolar disorder.

OBJECTIVE: Whereas the risk and course of psychopathology in offspring of parents with bipolar disorder (BD) have been the primary focus of high-risk offspring studies to date, functional outcomes have not been given much attention. We present a systematic review of functional outcomes and quality of life (QoL) across development in offspring of parents with BD and aim to explore the role of offspring psychopathology in these outcomes. METHOD: We searched Embase, MEDLINE, PsycINFO, Web of Science, Cochrane Central, and Google Scholar from inception to June 24, 2022, for studies referring to functional outcomes (global, social, academic or occupational) or QoL in offspring of parents with BD. RESULTS: From the 6470 records identified, 39 studies were retained (global = 17; social = 17; school = 16; occupational = 3; QoL = 5), including 13 studies that examined multiple domains. For all domains, high heterogeneity was found in study methods and quality. Only 56 % of studies adjusted for offspring psychopathology, impeding interpretation. Global and social functioning generally seemed to be impaired among older offspring (>16 years). Academic performance appeared to be unaffected. School behavior, occupational functioning, and QoL showed mixed results. Offspring psychopathology is associated with social functioning, but the relationship of offspring psychopathology with other domains is less clear. CONCLUSION: Studies on functional outcome in offspring of parents with BD show predominantly mixed results. Inconsistent adjustment of psychopathology and age limits conclusive interpretation. Functional outcomes should be prioritized as research topics in high-risk studies and the potential associations between familial risk status, offspring psychopathology, and age may inform prevention strategies.

Physical symptoms and brain morphology: a population neuroimaging study in 12,286 pre-adolescents.

Physical symptoms, also known as somatic symptoms, are those for which medical examinations do not reveal a sufficient underlying root cause (e.g., pain and fatigue). The extant literature of the neurobiological underpinnings of physical symptoms is largely inconsistent and primarily comprises of (clinical) case-control studies with small sample sizes. In this cross-sectional study, we studied the association between dimensionally measured physical symptoms and brain morphology in pre-adolescents from two population-based cohorts; the Generation R Study (n = 2649, 10.1 ± 0.6 years old) and ABCD Study (n = 9637, 9.9 ± 0.6 years old). Physical symptoms were evaluated using continuous scores from the somatic complaints syndrome scale from the parent-reported Child Behavior Checklist (CBCL). High-resolution structural magnetic resonance imaging (MRI) was collected using 3-Tesla MRI systems. Linear regression models were fitted for global brain metrics (cortical and subcortical grey matter and total white matter volume) and surface-based vertex-wise measures (surface area and cortical thickness). Results were meta-analysed. Symptoms of anxiety/depression were studied as a contrasting comorbidity. In the meta-analyses across cohorts, we found negative associations between physical symptoms and surface area in the (i) left hemisphere; in the lateral orbitofrontal cortex and pars triangularis and (ii) right hemisphere; in the pars triangularis, the pars orbitalis, insula, middle temporal gyrus and caudal anterior cingulate cortex. However, only a subset of regions (left lateral orbitofrontal cortex and right pars triangularis) were specifically associated with physical symptoms, while others were also related to symptoms of anxiety/depression. No significant associations were observed for cortical thickness. This study in preadolescents, the most representative and well-powered to date, showed that more physical symptoms are modestly related to less surface area of the prefrontal cortex mostly. While these effects are subtle, future prospective research is warranted to understand the longitudinal relationship of physical symptoms and brain changes over time. Particularly, to elucidate whether physical symptoms are a potential cause or consequence of distinct neurodevelopmental trajectories.

The Association Between Prenatal Infection and Adolescent Behavior: Investigating Multiple Prenatal, Perinatal, and Childhood Second Hits.

OBJECTIVE: Exposure to infections during pregnancy may be a potential risk factor for later psychopathology, but large-scale epidemiological studies investigating associations between prenatal infection and long-term offspring behavioral problems in the general population are scarce. In our study, we aimed to investigate the following: (1) the association between prenatal infection and adolescent behavior, (2) putative underlying pathways (mediation), and (3) "second hits" interacting with prenatal infection to increase the risk of adolescent behavior problems (moderation). METHOD: Our study was embedded in a prospective Dutch pregnancy cohort (Generation R; n = 2,213 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. At age 13 to 16 years, we assessed total, internalizing, and externalizing problems, and autistic traits using the Child Behavioral Checklist and the Social Responsiveness Scale, respectively. We investigated maternal lifestyle and nutrition, perinatal factors (placental health and delivery outcomes), and child health (lifestyle, traumatic events, infections) as mediators and moderators. RESULTS: We observed associations of prenatal infection with adolescent total behavioral, internalizing, and externalizing problems. The association between prenatal infection and internalizing problems was moderated by higher levels of maternal psychopathology, alcohol and tobacco use, and a higher number of traumatic childhood events. We found no association between prenatal infection and autistic traits. Yet, children exposed to prenatal infections and maternal substance use, and/or traumatic childhood events, had a higher risk of autistic traits in adolescence. CONCLUSION: Prenatal infection may be a risk factor for later psychiatric problems as well as a disease primer making individuals susceptible to other hits later in life. STUDY PREREGISTRATION INFORMATION: Prenatal maternal infection and adverse neurodevelopment: a structural equation modelling approach to downstream environmental hits; https://osf.io/cp85a; cp85a. DIVERSITY & INCLUSION STATEMENT: 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 and gender balance in the recruitment of human participants.

Psychotic experiences, suicidality and non-suicidal self-injury in adolescents: Independent findings from two cohorts.

BACKGROUND: Prior studies have shown that psychotic experiences are prospectively associated with an increased risk of suicidality. However, it is unclear whether this association is causal or arises from shared risk factors. Furthermore, little is known about the association between psychotic experiences and non-suicidal self-injury (NSSI). METHODS: We used data from two independent samples of young adolescents, which we analyzed separately. In a population-based cohort, data on hallucinatory experiences and suicidality were collected at ages 10 and 14 years (N = 3435). In a cross-sectional study of a population oversampled for elevated psychopathology levels, psychotic experiences, suicidality, and NSSI were assessed at age 15 years (N = 910). Analyses were adjusted for sociodemographic covariates, maternal psychopathology, intelligence, childhood adversity, and mental health problems. RESULTS: Psychotic experiences were prospectively associated with an increased risk of suicidality, even when considering self-harm ideation at baseline. Furthermore, persistent and incident, but not remittent, patterns of psychotic experiences were related to an increased burden of suicidality. Self-harm ideation was also prospectively associated with the risk for psychotic experiences, although of smaller magnitude and only by self-report. Among at-risk adolescents, psychotic experiences were cross-sectionally associated with a greater burden of suicidality and a higher frequency of NSSI events, with more extensive tissue damage. CONCLUSION: Psychotic experiences are longitudinally associated with suicidality beyond the effects of shared risk factors. We also found modest support for reverse temporality, which warrants further investigation. Overall, our findings highlight the importance of assessing psychotic experiences as an index of risk for suicidality and NSSI.

Towards precision dosing of aripiprazole in children and adolescents with autism spectrum disorder: Linking blood levels to weight gain and effectiveness.

AIMS: Aripiprazole is one of the most commonly prescribed antipsychotic drugs to children and adolescents worldwide, but it is associated with serious side-effects, including weight gain. This study assessed the population pharmacokinetics of aripiprazole and its active metabolite and investigated the relationship between pharmacokinetic parameters and body mass index (BMI) in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side-effects and drug effectiveness. METHODS: Twenty-four children and adolescents (15 males, 9 females) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side-effects and drug effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were determined. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 92 aripiprazole and 91 dehydro-aripiprazole concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-h area under the curves (AUCs) were analysed to predict outcomes using generalized and linear mixed-effects models. RESULTS: For both aripiprazole and dehydro-aripiprazole, one-compartment models best described the measured concentrations, with albumin and BMI as significant covariates. Of all the pharmacokinetic parameters, higher sum (aripiprazole plus dehydro-aripiprazole) trough concentrations best predicted higher BMI z-scores (P < .001) and higher Hb1Ac levels (P = .03) during follow-up. No significant association was found between sum concentrations and effectiveness. CONCLUSIONS: Our results indicate a threshold with regard to safety, which suggests that therapeutic drug monitoring of aripiprazole could potentially increase safety in children and adolescents with ASD and behavioural problems.

Interrelated development of autism spectrum disorder symptoms and eating problems in childhood: a population-based cohort.

Eating problems, such as food selectivity or picky eating, are thought to be an epiphenomenon of autism spectrum disorders (ASD). Yet eating problems are also common in the general pediatric population and overlap with ASD symptoms. However, the temporal association between ASD symptoms and eating problems is poorly understood. This study examines the bidirectional association between ASD symptoms and eating problems across child development, and investigates whether these associations differ by child sex. Participants (N = 4,930) were from the population-based Generation R Study. Parents reported their child's ASD symptoms and eating problems using the Child Behavior Checklist at 5 assessments from toddlerhood to adolescence (1.5 to 14 years, 50% girls). A Random Intercept Cross-Lagged Panel Model was used to examine the lagged associations between ASD symptoms and eating problems at the within-person level, controlling for stable, trait-like differences at the between-person level. At the between-person level, there was a strong correlation between ASD symptoms and eating problems (ß = .48, 95% CI: 0.38 to 0.57). Controlling for these between-person effects, there was limited evidence for consistent, predictive effects of ASD symptoms and eating problems at the within-person level. Associations did not differ by child sex. Findings suggest that ASD symptoms and eating problems may represent a cluster of traits that are highly stable from early childhood to adolescence, which have a minimal reciprocal effect at the individual-level. Future research could focus on these trait-like qualities to inform the development of supportive, family-focused interventions.

Gender Diversity and Brain Morphology Among Adolescents.

Importance: Gender-diverse youths have higher rates of mental health problems compared with the general population, as shown in both clinical and nonclinical populations. Brain correlates of gender diversity, however, have been reported only among youths with gender dysphoria or in transgender individuals. Objective: To examine brain morphologic correlates of gender diversity among adolescents from a general pediatric population who were assigned male or female at birth, separately. Design, Setting, and Participants: This cross-sectional study was embedded in Generation R, a multiethnic population-based study conducted in Rotterdam, the Netherlands. Adolescents who were born between April 1, 2002, and January 31, 2006, and had information on self-reported or parent-reported gender diversity and structural neuroimaging at ages 13 to 15 years were included. Data analysis was performed from April 1 to July 31, 2022. Exposures: Gender-diverse experiences among adolescents were measured with selected items from the Achenbach System of Empirically Based Assessment forms and the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults, as reported by adolescents and/or their parents. Main Outcomes and Measures: High-resolution structural neuroimaging data were collected using a 3-T magnetic resonance imaging scanner (at a single site). We used linear regression models to examine differences in global brain volumetric measures between adolescents who reported gender diversity and those who did not. Results: This study included 2165 participants, with a mean (SD) age of 13.8 (0.6) years at scanning. A total of 1159 participants (53.5%) were assigned female at birth and 1006 (46.5%) were assigned male at birth. With regard to maternal country of origin, 1217 mothers (57.6%) were from the Netherlands and 896 (42.4%) were from outside the Netherlands. Adolescents who reported gender diversity did not differ in global brain volumetric measures from adolescents who did not report gender diversity. In whole-brain, vertexwise analyses among adolescents assigned male at birth, thicker cortices in the left inferior temporal gyrus were observed among youths who reported gender diversity compared with those who did not. No associations were observed between gender diversity and surface area in vertexwise analyses. Conclusions and Relevance: The findings of this cross-sectional study suggest that global brain volumetric measures did not differ between adolescents who reported gender diversity and those who did not. However, these findings further suggest that gender diversity in the general population correlates with specific brain morphologic features in the inferior temporal gyrus among youths who are assigned male at birth. Replication of these findings is necessary to elucidate the potential neurobiological basis of gender diversity in the general population. Future longitudinal studies should also investigate the directionality of these associations.

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents.

OBJECTIVE: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. METHODS: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. RESULTS: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets. CONCLUSIONS: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.