Emerging psychopathology and clinical staging in adolescent offspring of parents with bipolar disorder or schizophrenia-A longitudinal study.

OBJECTIVES: Offspring of parents with bipolar disorder (BDo) and schizophrenia (SZo) are at increased risk for these disorders and general psychopathology. Little is known about their (dis)similarities in risk and developmental trajectories during adolescence. A clinical staging approach may help define the developmental course of illness. METHODS: The Dutch Bipolar and Schizophrenia Offspring Study is a unique cross-disorder and prospective cohort study, established in 2010. In total, 208 offspring (58 SZo, 94 BDo, and 56 control offspring [Co]) and their parents participated. Offspring were 13.2 years (SD = 2.5; range: 8-18 years) at baseline and 17.1 years (SD = 2.7) at follow-up (88.5% retention rate). Psychopathology was assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version, and Achenbach System of Empirically Based Assessment parent-, self- and teacher-reports. Groups were compared on (1) the presence of categorical psychopathology, (2) timing and development of psychopathology using a clinical staging perspective, and (3) dimensional psychopathology using a multi-informant approach. RESULTS: SZo and BDo showed more categorical psychopathology and (sub)clinical symptoms, as compared to Co. SZo have, compared to BDo, an increased risk for developmental disorders, a younger age of onset, and more (sub)clinical symptoms of the mood and behavioral spectrum as reported by multiple informants. CONCLUSIONS: Our study shows that the phenotypical risk profile overlaps between SZo and BDo, although an earlier onset of developmental psychopathology was found specifically in SZo, suggesting of a potentially different ethiopathophysiology. Longer follow-up and future studies are needed.

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.

Exposure to prenatal infection and the development of internalizing and externalizing problems in children: a longitudinal population-based study.

BACKGROUND: A large body of work has reported a link between prenatal exposure to infection and increased psychiatric risk in offspring. However, studies to date have focused primarily on exposure to severe prenatal infections and/or individual psychiatric diagnoses in clinical samples, typically measured at single time points, and without accounting for important genetic and environmental confounders. In this study, we investigated whether exposure to common infections during pregnancy is prospectively associated with repeatedly assessed child psychiatric symptoms in a large population-based study. METHODS: Our study was embedded in a prospective pregnancy cohort (Generation R; n = 3,598 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. Child total, internalizing, and externalizing problems were assessed repeatedly using the parent-rated Child Behavioral Checklist (average age: 1.5, 3, 6, 10, and 14 years). Linear mixed-effects models were run adjusting for a range of confounders, including child polygenic scores for psychopathology, maternal chronic illness, birth complications, and infections during childhood. We also investigated trimester-specific effects and child sex as a potential moderator. RESULTS: Prenatal exposure to infections was associated with higher child total, internalizing, and externalizing problems, showing temporally persistent effects, even after adjusting for important genetic and environmental confounders. We found no evidence that prenatal infections were associated with changes in child psychiatric symptoms over time. Moreover, in our trimester-specific analysis, we did not find evidence of significant timing effects of prenatal infection on child psychiatric symptoms. No interactions with child sex were identified. CONCLUSIONS: Our research adds to evidence that common prenatal infections may be a risk factor for psychiatric symptoms in children. We also extend previous findings by showing that these associations are present early on, and that rather than changing over time, they persist into adolescence. However, unmeasured confounding may still explain in part these associations. In the future, employing more advanced causal inference designs will be crucial to establishing the degree to which these effects are causal.

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.

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.

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 implications of the COVID-19 pandemic on eating disorder features and comorbid psychopathology among adolescents with anorexia nervosa and matched controls: a comparative cohort design study.

PURPOSE: To examine implications of the COVID-19 pandemic on eating disorder (ED) features and psychopathology in female adolescents with anorexia nervosa (AN). METHOD: In total 79 females with first-onset AN (aged 12-22 years) were included and were followed up across a period of 1 year. We assessed AN participants recruited pre-pandemic (n = 49) to those recruited peri-pandemic (n = 30). Pre- (n = 37) and peri-pandemic (n = 38) age-, and education-matched typically developing (TD) girls (n = 75) were used as a reference cohort. ED features and psychopathology were assessed at baseline. After 1 year of follow-up the association between pandemic timing and clinical course was assessed. Analyses of covariance were used to examine differences in ED features and psychopathology. RESULTS: Peri-pandemic AN participants experienced less ED symptoms at baseline compared to pre-pandemic AN participants. In particular, they were less dissatisfied with their body shape, and experienced less interpersonal insecurity. In addition, the peri-pandemic AN group met fewer DSM-IV criteria for comorbid disorders, especially anxiety disorders. In contrast, peri-pandemic AN participants had a smaller BMI increase over time. In TD girls, there were no differences at baseline in ED features and psychopathology between the pre- and peri-pandemic group. CONCLUSION: Overall, peri-pandemic AN participants were less severely ill, compared to pre-pandemic AN participants, which may be explained by less social pressure and peer contact, and a more protective parenting style during the pandemic. Conversely, peri-pandemic AN participants had a less favorable clinical course, which may be explained by reduced access to health care facilities during the pandemic. LEVEL OF EVIDENCE: Level III: Evidence obtained from well-designed cohort or case-control analytic studies.

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.

The gut microbiome and child mental health: A population-based study.

The link between the gut microbiome and the brain has gained increasing scientific and public interest for its potential to explain psychiatric risk. While differences in gut microbiome composition have been associated with several mental health problems, evidence to date has been largely based on animal models and human studies with modest sample sizes. In this cross-sectional study in 1,784 ten-year-old children from the multi-ethnic, population-based Generation R Study, we aimed to characterize associations of the gut microbiome with child mental health problems. Gut microbiome was assessed from stool samples using 16S rRNA sequencing. We focused on overall psychiatric symptoms as well as with specific domains of emotional and behavioral problems, assessed via the maternally rated Child Behavior Checklist. While we observed lower gut microbiome diversity in relation to higher overall and specific mental health problems, associations were not significant. Likewise, we did not identify any taxonomic feature associated with mental health problems after multiple testing correction, although suggestive findings indicated depletion of genera previously associated with psychiatric disorders, including Hungatella, Anaerotruncus and Oscillospiraceae. The identified compositional abundance differences were found to be similar across all mental health problems. Finally, we did not find significant enrichment for specific microbial functions in relation to mental health problems. In conclusion, based on the largest sample examined to date, we do not find clear evidence of associations between gut microbiome diversity, taxonomies or functions and mental health problems in the general pediatric population. In future, the use of longitudinal designs with repeated measurements of microbiome and psychiatric outcomes will be critical to identify whether and when associations between the gut microbiome and mental health emerge across development and into adulthood.

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.

Cognitive performance in children and adolescents with psychopathology traits: A cross-sectional multicohort study in the general population.

Psychopathology and cognitive development are closely related. Assessing the relationship between multiple domains of psychopathology and cognitive performance can elucidate which cognitive tasks are related to specific domains of psychopathology. This can help build theory and improve clinical decision-making in the future. In this study, we included 13,841 children and adolescents drawn from two large population-based samples (Generation R and ABCD studies). We assessed the cross-sectional relationship between three psychopathology domains (internalizing, externalizing, dysregulation profile (DP)) and four cognitive domains (vocabulary, fluid reasoning, working memory, and processing speed) and the full-scale intelligence quotient. Lastly, differential associations between symptoms of psychopathology and cognitive performance by sex were assessed. Results indicated that internalizing symptoms were related to worse performance in working memory and processing speed, but better performance in the verbal domain. Externalizing and DP symptoms were related to poorer global cognitive performance. Notably, those in the DP subgroup had a 5.0 point lower IQ than those without behavioral problems. Cognitive performance was more heavily affected in boys than in girls given comparable levels of psychopathology. Taken together, we provide evidence for globally worse cognitive performance in children and adolescents with externalizing and DP symptoms, with those in the DP subgroup being most heavily affected.

Maternal sensitivity in early childhood and body mass index in adolescence: A population-based study on the role of self-regulation as a mediator.

Maternal sensitivity has been implicated in various aspects of child health and development, including overweight. However, long-term effects, the role of paternal sensitivity and the explanatory pathways are unclear. This study examined whether maternal sensitivity in early childhood is prospectively associated with adolescent body mass index and whether children's self-regulation mediates this relation. Data from 540 children and their mothers were available from a large cohort study in the Netherlands. Maternal sensitivity was assessed at child ages 1, 3, and at 4 years paternal sensitivity was also included. Children's self-regulation skills were observed at age 3, eating behaviour was assessed at 10 years, and child BMI was measured at 13 years. Longitudinal structural equation modelling was applied. The cross-sectional association between maternal sensitivity and child self-regulation was significant, while lower levels of self-regulation and higher levels of food responsiveness and restrained eating predicted a higher child BMI at 13 years. Furthermore, a direct association of paternal sensitivity at 4 years with BMI at 13 years was found, but only in girls. Maternal sensitivity was not directly associated with child BMI after adjusting for covariates. Our findings showed the importance of self-regulation in the early years for subsequent weight development. Nevertheless, as self-regulation could not explain the relationship between parenting and child weight, research should focus on the contribution of other contextual factors, such as feeding styles and the social environment, to this relationship.

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.

Adolescent gender diversity: sociodemographic correlates and mental health outcomes in the general population.

BACKGROUND: Gender diversity in young adolescents is understudied outside of referral clinics. We investigated gender diversity in an urban, ethnically diverse sample of adolescents from the general population and examined predictors and associated mental health outcomes. METHODS: The study was embedded in Generation R, a population-based cohort of children born between 2002 and 2006 in Rotterdam, the Netherlands (n = 5727). At ages 9-11 and 13-15 years, adolescents and/or their parents responded to two questions addressing children's contentedness with their assigned gender, whether they (a) 'wished to be the opposite sex' and (b) 'would rather be treated as someone from the opposite sex'. We defined 'gender-variant experience' when either the parent or child responded with 'somewhat or sometimes true' or 'very or often true'. Mental health was assessed at 13-15 years, using the Achenbach System of Empirically Based Assessment. RESULTS: Less than 1% of the parents reported that their child had gender-variant experience, with poor stability between 9-11 and 13-15 years. In contrast, 4% of children reported gender-variant experience at 13-15 years. Adolescents who were assigned female at birth reported more gender-variant experience than those assigned male. Parents with low/medium educational levels reported more gender-variant experience in their children than those with higher education. There were positive associations between gender-variant experience and symptoms of anxiety, depression, somatic complaints, rule-breaking, and aggressive behavior as well as attention, social, and thought problems. Similar associations were observed for autistic traits, independent of other mental difficulties. These associations did not differ by assigned sex at birth. CONCLUSIONS: Within this population-based study, adolescents assigned females were more likely to have gender-variant experience than males. Our data suggest that parents may not be aware of gender diversity feelings in their adolescents. Associations between gender diversity and mental health symptoms were present in adolescents.

Child mental health problems as a risk factor for academic underachievement: A multi-informant, population-based study.

OBJECTIVE: To investigate whether child mental health problems prospectively associate with IQ-achievement discrepancy (i.e., academic under- and over-achievement) in emerging adolescence. The secondary aims were to test whether these associations are specific to certain mental health problems, to assess potential sex differences, and to examine whether associations are robustly observed across multiple informants (i.e., maternal and teacher-reports). METHODS: This study included 1,577 children from the population-based birth cohort the Generation R Study. Child mental health problems at age 6 were assessed by mothers and teachers using the Child Behavior Checklist and the Teacher's Report Form. The IQ-achievement discrepancy was quantified as the standardized residuals of academic achievement regressed on IQ, where IQ was measured with four tasks from the Wechsler Intelligence Scale for Children-Fifth Edition around age 13 and academic attainment was measured with the Cito test, a national Dutch academic test, at the end of elementary school (12 years of age). RESULTS: Mental health problems at age 6 were associated with IQ-achievement discrepancy at age 12, with more problems associating with greater academic underachievement. When examining specific mental health problems, we found that attention problems was the only mental health problem to independently associate with the IQ-achievement discrepancy (adjusted standardized difference per 1-standard deviation, mother: -0.11, p < 0.001, 95% CI [-0.16, -0.06]; teacher: -0.13, p < 0.001, 95% CI [-0.18, -0.08]). These associations remained after adjusting for co-occurring mental health problems. The overall pattern of associations was consistent across boys and girls and across informants. CONCLUSION: Mental health problems during the transition from kindergarten to elementary school associate with academic underachievement at the end of elementary school. These associations were primarily driven by attention problems, as rated by both mothers and teachers-suggesting that strategies targeting attention problems may be a particularly promising avenue for improving educational performance irrespective of IQ, although this should be established more thoroughly through further research.

The effect of therapeutic drug monitoring of risperidone and aripiprazole on weight gain in children and adolescents: the SPACe 2: STAR (trial) protocol of an international multicentre randomised controlled trial.

BACKGROUND: Antipsychotic drugs are an important part of the treatment of irritability and aggression in children with an autism spectrum disorder (ASD). However, significant weight gain and metabolic disturbances are clinically relevant side effects of antipsychotic use in children. In the SPACe study, we showed positive correlations between both risperidone and aripiprazole plasma trough concentrations and weight gain over a 6-month period. The trial SPACe 2: STAR is designed as a follow-up study, in which we aim to research whether therapeutic drug monitoring in clinical practice can prevent severe weight gain, while retaining clinical effectiveness. METHODS: SPACe 2: STAR is an international, multicentre, randomised controlled trial (RCT). One hundred forty children aged 6 to 18 who are about to start risperidone or aripiprazole treatment for ASD related behavioural problems will be randomised into one of two groups: a therapeutic drug monitoring (TDM) group, and a care as usual (CAU) group. Participants will be assessed at baseline and 4, 10, 24, and 52 weeks follow-up. In the TDM group, physicians will receive dosing advice based on plasma levels of risperidone and aripiprazole and its metabolites at 4 and 10 weeks. Plasma levels will be measured in dried blood spots (DBS). The primary outcome will be BMI z-score at 24 weeks after start of antipsychotic treatment. Among the secondary outcomes are effectiveness, metabolic laboratory measurements, levels of prolactin, leptin and ghrelin, extrapyramidal side effects, and quality of life. DISCUSSION: This will be the first RCT evaluating the effect of TDM of antipsychotic drugs in children and adolescents. Thus, findings from SPACe 2: STAR will be of great value in optimising treatment in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05146245. EudraCT number: 2020-005450-18. Sponsor protocol name: SPACe2STAR. Registered 8 June 2021. Protocol Version 6, Protocol date: 18 august 2022.

The association of early life stress with IQ-achievement discrepancy in children: A population-based study.

Early life stress (ELS) is associated with lower IQ and academic achievement; however, it remains unclear whether it additionally explains their discrepancy. In 2,401 children (54% girls, 30.2% migration background) from the population-based study Generation R Study, latent factors of prenatal and postnatal (age 0-10) ELS were estimated, and IQ-achievement discrepancy (age 12) was quantified as variance in academic achievement not explained by IQ. ELS was prospectively associated with larger IQ-achievement discrepancy (ßprenatal  = -0.24; ßpostnatal  = -0.28), lower IQ (ßprenatal  = -0.20; ßpostnatal  = -0.22), and lower academic achievement (ßprenatal  = -0.31; ßpostnatal  = -0.36). Associations were stronger for latent ELS than for specific ELS domains. Results point to ELS as a potential prevention target to improve academic potential.

Clustering of characteristics associated with unplanned pregnancies: the generation R study.

BACKGROUND: Unplanned or unintended pregnancies form a major public health concern because they are associated with unfavorable birth outcomes as well as social adversity, stress and depression among parents-to-be. Several risk factors for unplanned pregnancies in women have previously been identified, but studies usually take a unidimensional approach by focusing on only one or few factors, disregarding the possibility that predictors might cluster. Furthermore, data on predictors in men are largely overlooked. The purpose of this study is to determine predictors of unplanned versus planned pregnancy, to determine predictors of ambivalent feelings regarding pregnancy, and to investigate how characteristics of men and women with an unplanned pregnancy cluster together. METHODS: This study was embedded in Generation R, a multiethnic population-based prospective cohort from fetal life onwards. Pregnancy intention was reported by 7702 women and 5367 partners. Information on demographic, mental, physical, social, and sexual characteristics was obtained. Logistic regression, multinomial regression and cluster analyses were performed to determine characteristics that were associated with an unplanned pregnancy, with ambivalent feelings regarding the unplanned pregnancy and the co-occurrence of characteristics in women and men with unplanned pregnancy. RESULTS: Twenty nine percent of the pregnancies were unplanned. Logistic regression analyses showed that 42 of 44 studied predictors were significantly associated with unplanned pregnancy. The most important predictors were young age, migration background, lower educational level, lower household income, financial difficulties, being single, lower cognitive ability, drug use prior to pregnancy, having multiple sexual partners in the year prior to the pregnancy, younger age of first sexual contact and a history of abortion. Multinomial regression analyses showed that a Turkish or Moroccan background, Islamic religion, little financial opportunities, being married, having ≥3 children, high educational level, more mental health and social problems and older age of first sexual contact were associated with prolonged ambivalent feelings regarding pregnancy. Different combinations of characteristics were observed in the four clusters of women and men with unplanned pregnancy. CONCLUSIONS: Many predictors are related with unplanned pregnancies, ambivalent feelings toward the pregnancy, and we identified very heterogeneous groups of women and men with unplanned pregnancies. This calls for heterogeneous measures to prevent unplanned pregnancies.

Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene-environment correlation.

Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities.