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Anorexia nervosa (AN) entails many uncertainties regarding the clinical outcome, due to large heterogeneity in the disease course. AN is associated with global decrease in brain volumes and altered brain functioning during acute illness. However, it is unclear whether structural and functional brain alterations can predict clinical outcome. We aimed to systematically review the predictive value of volumetric and functional brain outcome measures of structural and functional brain magnetic resonance imaging (MRI) on the disease course of AN. Four databases (Embase, Medline, Psycinfo, and Cochrane Central Register) were systematically searched. A total of 15 studies (structural MRI: n = 6, functional MRI: n = 9) were reviewed. In total 464 unique AN patients, and 328 controls were included. Follow-up time ranged between 1 and 43 months. Structural neuroimaging studies showed that lower brain volumes of the cerebellum, subcortical grey matter, and cortical white matter at admission predicted a worse clinical outcome. A smaller increase of the anterior cingulate cortex volume in the early phase of the disease predicted a worse clinical outcome. Lower overall gyrification, and a higher clustering coefficient predicted a worse clinical outcome. Functional MRI studies showed that frontal, parietal and temporal activity during task-based algorithms predicted follow-up body mass index, although results were bidirectional possibly due to the large heterogeneity in methodological approaches. Neuroimaging measures may predict the clinical outcome of AN. However, there is a lack of replication studies. Future studies are needed to validate the prognostic utility of neuroimaging measures in AN patients, and should harmonize demographic, clinical and neuroimaging features in order to enhance comparability.

The first aim of this study was to construct/validate a subscale—with cut-offs considering gender/age differences—for the school-age Child Behavior CheckList (CBCL) to screen for Autism Spectrum Disorder (ASD) applying both data-driven (N = 1666) and clinician-expert (N = 15) approaches. Further, we compared these to previously established CBCL ASD profiles/subscales and DSM-oriented subscales. The second aim was to cross-validate results in two truly independent samples (N = 2445 and 886). Despite relatively low discriminative power of all subscales in the cross-validation samples, results indicated that the data-driven subscale had the best potential to screen for ASD and a similar screening potential as the DSM-oriented subscales. Given beneficial implications for pediatric/clinical practice, we encourage colleagues to continue the validation of this CBCL ASD subscale.

Background: Psychiatric traits are heritable, highly comorbid and genetically correlated, suggesting that genetic effects that are shared across disorders are at play. The aim of the present study is to quantify the predictive capacity of common genetic variation of a variety of traits, as captured by their PRS, to predict case-control status in a child and adolescent psychiatric sample including controls to reveal which traits contribute to the shared genetic risk across disorders. Method: Polygenic risk scores (PRS) of 14 traits were used as predictor phenotypes to predict case-control status in a clinical sample. Clinical cases (N = 1,402), age 1–21, diagnostic categories: Autism spectrum disorders (N = 492), Attention-deficit/ hyperactivity disorders (N = 471), Anxiety (N = 293), disruptive behaviors (N = 101), eating disorders (N = 97), OCD (N = 43), Tic disorder (N = 50), Disorder of infancy, childhood or adolescence NOS (N = 65), depression (N = 64), motor, learning and communication disorders (N = 59), Anorexia Nervosa (N = 48), somatoform disorders (N = 47), Trauma/stress (N = 39) and controls (N = 1,448, age 17–84) of European ancestry. First, these 14 PRS were tested in univariate regression analyses. The traits that significantly predicted case-control status were included in a multivariable regression model to investigate the gain in explained variance when leveraging the genetic effects of multiple traits simultaneously. Results: In the univariate analyses, we observed significant associations between clinical status and the PRS of educational attainment (EA), smoking initiation (SI), intelligence, neuroticism, alcohol dependence, ADHD, major depression and anti-social behavior. EA (p-value: 3.53E-20, explained variance: 3.99%, OR: 0.66), and SI (p-value: 4.77E-10, explained variance: 1.91%, OR: 1.33) were the most predictive traits. In the multivariable analysis with these eight significant traits, EA and SI, remained significant predictors. The explained variance of the PRS in the model with these eight traits combined was 5.9%. Conclusion: Our study provides more insights into the genetic signal that is shared between childhood and adolescent psychiatric disorders. As such, our findings might guide future studies on psychiatric comorbidity and offer insights into shared etiology between psychiatric disorders. The increase in explained variance when leveraging the genetic signal of different predictor traits supports a multivariable approach to optimize precision accuracy for general psychopathology.

Brain morphology is altered in both anorexia nervosa and obesity. However, it is yet unclear if the relationship between Body Mass Index-Standard Deviation Score (BMI-SDS) and brain morphology exists across the BMI-SDS spectrum, or is present only in the extremes. The study involved 3160 9-to-11 year-old children (50.3% female) who participate in Generation R, a population-based study. Structural MRI scans were obtained from all children and FreeSurfer was used to quantify both global and surface-based measures of gyrification and cortical thickness. Body length and weight were measured to calculate BMI. Dutch growth curves were used to calculate BMI-SDS. BMI-SDS was analyzed continuously and in two categories (median split). The relationship between BMI-SDS (range − 3.82 to 3.31) and gyrification showed an inverted-U shape curve in children with both lower and higher BMI-SDS values having lower gyrification in widespread areas of the brain. BMI-SDS had a positive linear association with cortical thickness in multiple brain regions. This study provides evidence for an association between BMI-SDS and brain morphology in a large sample of children from the general population and suggests that a normal BMI during childhood is important for brain development. Future studies could determine whether lifestyle modifications optimize BMI-SDS result in return to more typical patterns of brain morphology. Supplementary Information The online version contains supplementary material available at 10.1007/s00429-020-02209-0.

Purpose Young people transitioning from child to adult mental health services are frequently also known to social services, but the role of such services in this study and their interplay with mental healthcare system lacks evidence in the European panorama. This study aims to gather information on the characteristics and the involvement of social services supporting young people approaching transition. Design/methodology/approach A survey of 16 European Union countries was conducted. Country respondents, representing social services’ point of view, completed an ad hoc questionnaire. Information sought included details on social service availability and the characteristics of their interplay with mental health services. Findings Service availability ranges from a low of 3/100,000 social workers working with young people of transition age in Spain to a high 500/100,000 social workers in Poland, with heterogeneous involvement in youth health care. Community-based residential facilities and services for youth under custodial measures were the most commonly type of social service involved. In 80% of the surveyed countries, youth protection from abuse/neglect is overall regulated by national protocols or written agreements between mental health and social services, with the exception of Czech Republic and Greece, where poor or no protocols apply. Lack of connection between child and adult mental health services has been identified as the major obstacles to transition (93.8%), together with insufficient involvement of stakeholders throughout the process. Research limitations/implications Marked heterogeneity across countries may suggest weaknesses in youth mental health policy-making at the European level. Greater inclusion of relevant stakeholders is needed to inform the development and implementation of person-centered health-care models. Disconnection between child and adult mental health services is widely recognized in the social services arena as the major barrier faced by young service users in transition; this “outside” perspective provides further support for an urgent re-configuration of services and the need to address unaligned working practices and service cultures. Originality/value This is the first survey gathering information on social service provision at the time of mental health services transition at a European level; its findings may help to inform services to offer a better coordinated social health care for young people with mental health disorders.

Introduction: The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known. Areas covered: This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between drug concentrations and side-effects and/or effectiveness was evidenced in reasonably reported and executed studies, but these findings were barely replicated. Expert opinion: In order to better support routine TDM in child- and adolescent psychiatry, future work must improve in aspects of study design, execution and reporting to demonstrate drug concentration-effect relationships. The quality criteria proposed in this work can guide future TDM research. Systematic review protocol and registration PROSPERO CRD42018084159.

BACKGROUND: Minimally invasive sampling methods are important to facilitate therapeutic drug monitoring and pharmacokinetic research in children with behavioral problems. This study assessed the feasibility and pain of dried blood spot (DBS) sampling in this population. METHODS: Repeated DBS sampling was performed in children with autism spectrum disorder (ASD) and severe behavioral problems using antipsychotic drugs, aged between 6 and 18 years. The child, guardian, and DBS performer assessed pain using the numeric rating scale (NRS-11) or 5-face Faces Pain Scale. The influence of age, sex, and the fingerprick performer on the child's pain intensity was analyzed using linear mixed models. RESULTS: Overall, 247 fingerpricks were performed in 70 children. Seven children refused all DBS sampling. The median (interquartile range) NRS-11 pain scores were 2 (3) rated by children, 3 (2.5) by guardians, and 2 (2) by fingerprick performers. The child's age and sex, and fingerprick performer had no significant influence on pain intensity. CONCLUSIONS: DBS sampling could be performed in most children with ASD and severe behavioral problems. However, 1 in 5 children refused one or more DBS fingerpricks owing to distress. Most expressed minimal pain (NRS < 4). Repeated sampling with DBS is feasible in children with ASD and severe behavioral problems.

Antipsychotic-induced weight gain is a major health concern in children and adolescents. The aim of this study was to identify risk factors for weight gain during short-, middle- and long-term treatment with antipsychotic drugs in this young population. We analysed a combined prospective and a retrospective observational cohort of Dutch children and adolescents, starting with risperidone, aripiprazole or pipamperone treatment. Linear mixed models were used to test whether sex, age, baseline body-mass-index (BMI) z score, type of antipsychotic, dose equivalent/kg, duration of use, previous antipsychotic use, ethnicity, physical exercise, IQ, concomitant medication, and psychiatric classification predicted the BMI z score for a follow-up of 52 weeks. A total of 144 patients were included with a median [interquartile range ([IQR)] age of 9 (4) years and median follow-up of 30 (73) weeks. During the complete follow-up, the median (IQR) weight gain was 0.37 (0.95) BMI z score points. Antipsychotic-induced weight gain was found to be most pronounced during the first 15 weeks of use (BMI z score increase per week β = 0.02, 95% CI 0.01–0.03, p = 0.002). A higher baseline BMI z score and the absence of stimulant use were associated with a higher BMI z score during the entire follow-up and after 15 weeks, respectively. Previous treatment with an antipsychotic drug was associated with less weight gain during the first 15 weeks of treatment. Our findings underscore the importance of close patient monitoring during the first weeks of antipsychotic treatment with a focus on patients with a high baseline BMI z score.

Neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable and influenced by many single nucleotide polymorphisms (SNPs). SNPs can be used to calculate individual polygenic risk scores (PRS) for a disorder. We aim to explore the association between the PRS for ADHD, ASD and for Schizophrenia (SCZ), and ADHD and ASD diagnoses in a clinical child and adolescent population. Based on the most recent genome wide association studies of ADHD, ASD and SCZ, PRS of each disorder were calculated for individuals of a clinical child and adolescent target sample (N = 688) and for adult controls (N = 943). We tested with logistic regression analyses for an association with (1) a single diagnosis of ADHD (N = 280), (2) a single diagnosis of ASD (N = 295), and (3) combining the two diagnoses, thus subjects with either ASD, ADHD or both (N = 688). Our results showed a significant association of the ADHD PRS with ADHD status (OR 1.6, P = 1.39 × 10−07) and with the combined ADHD/ASD status (OR 1.36, P = 1.211 × 10−05), but not with ASD status (OR 1.14, P = 1). No associations for the ASD and SCZ PRS were observed. In sum, the PRS of ADHD is significantly associated with the combined ADHD/ASD status. Yet, this association is primarily driven by ADHD status, suggesting disorder specific genetic effects of the ADHD PRS. Electronic supplementary material The online version of this article (10.1007/s10519-019-09965-8) contains supplementary material, which is available to authorized users.

The transition from child and adolescent to adult mental health services for young people with mental health problems is of international concern. Despite the high prevalence of mental disorders during adolescence and their tendency to continue during adulthood, the majority of young people do not experience continuity of care. The aim of this review paper is to unravel the complexity of transitional mental healthcare to clinicians, policy makers and mental health service managers, and to address challenges to a smooth transition process at all levels. ispartof: BJPSYCH BULLETIN vol:44 issue:4 pages:163-168 ispartof: location:England status: published

Aim: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. Methods: Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. Results: A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P

ObjectiveYoung people moving from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS) are faced with significant challenges. To improve this state of affairs, there needs to be a recognition of the problem and initiatives and an urgent requirement for appropriate tools for measuring readiness and outcomes at the transfer boundary (16–18 years of age in Europe). The objective of this study was to develop and validate the Transition Readiness and Appropriateness Measure (TRAM) for assessing a young person’s readiness for transition, and their outcomes at the transfer boundary.DesignMILESTONE prospective study.SettingEight European Union (EU) countries participating in the EU-funded MILESTONE study.ParticipantsThe first phase (MILESTONE validation study) involved 100 adolescents (pre-transition), young adults (post-transition), parents/carers and both CAMHS and AMHS clinicians. The second phase (MILESTONE cohort study and nested cluster randomised trial) involved over 1000 young people.ResultsThe development of the TRAM began with a literature review on transitioning and a review of important items regarding transition by a panel of 34 mental health experts. A list of 64 items of potential importance were identified, which together comprised the TRAM. The psychometric properties of the different versions of the TRAM were evaluated and showed that the TRAM had good reliability for all versions and low-to-moderate correlations when compared with other established instruments and a well-defined factor structure. The main results of the cohort study with the nested cluster randomised trial are not reported.ConclusionThe TRAM is a reliable instrument for assessing transition readiness and appropriateness. It highlighted the barriers to a successful transition and informed clinicians, identifying areas which clinicians on both sides of the transfer boundary can work on to ease the transition for the young person.Trial registration numberISRCTN83240263 (Registered 23 July 2015), NCT03013595 (Registered 6 January 2017); Pre-results.

Background Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. Objectives The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. Methods Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM®). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. Results In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th–75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0–180.5 µg/L]) than in non-responders (58.0 µg/L [14.9–105.5 µg/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. Conclusions Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100–400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account. Electronic supplementary material The online version of this article (10.1007/s40262-020-00894-y) contains supplementary material, which is available to authorized users.

Introduction Transitioning into adulthood and from pediatric services to adult healthcare are both challenging processes for young adults with rare chronic disorders such as tuberous sclerosis complex (TSC) and their parents. Adult healthcare systems are often less family-oriented and lack multidisciplinary care and experience with TSC, which can result in increased health risks and morbidity. Patient-driven data on care needs are necessary to optimize support for this vulnerable patient group. Aim The aim of this study was to explore the concerns and care needs of young adult patients with TSC in medical, psychological, and socioeconomical domains. Method A qualitative study was performed using semistructured interviews with 16 patients (median age: 21 years; range: 17 to 30) and 12 parents. Concerns and care needs were organized using the International Classification of Functioning, Disability, and Health (ICF). Results Main concerns involved mental and physical health, participation, self-management skills, family planning, and side effects of medications. Patients expressed the need for multidisciplinary care that is well-informed, easily accessible, and focused on the patient as a whole, including his/her family. Parents reported high stress levels. Conclusion The current study provides patient-driven information, allowing recommendations to facilitate the (transition of) care for young adults with TSC. In addition to seizures, tumor growth, and TSC-associated neuropsychiatric disorders (TAND), more attention is needed for concerns and care needs specific to the transitional period, participation, and environmental factors. Adult healthcare providers should offer expert multidisciplinary care for adult patients with TSC, including attention for parental stress.

Objectives: The use of antipsychotic drugs by youth is associated with serious side effects, especially when prescribed in higher dosages and for a longer period. Despite this, little is known about recent trends in the dosages and duration of use of antipsychotic drugs in children and adolescents. The aim of this study was to describe trends in prevalence, incidence, dosages, duration of use, and preceding psychotropic medication in Dutch youth who had been prescribed antipsychotic drugs from 2005 to 2015. Methods: We analyzed 84,828 antipsychotic prescriptions of youths aged 0-19 years between 2005 and 2015, derived from a large Dutch community pharmacy-based prescription database (IADB.nl). Results: Since a peak of 9.8 users per 1000 youths in 2009, prevalence rates stabilized. Dosages in milligram per kilogram declined for the most frequently prescribed antipsychotic drugs during the study period. The median duration of use was 6.0 (95% CI 5.4-6.6) months. Boys used antipsychotic drugs significantly longer than girls, with a median of 6.9 (95% CI 6.1-7.7) versus 4.6 (95% CI 3.9-5.3) months (p

International audience; Transition-related discontinuity of care is a major socioeconomic and societal challenge for the EU. The current service configuration, with distinct Child and Adolescent Mental Health (CAMHS) and Adult Mental Health Services (AMHS), is considered a weak link where the care pathway needs to be most robust. Our aim was to delineate transitional policies and care across Europe and to highlight current gaps in care provision at the service interface. An online mapping survey was conducted across all 28 European Countries using a bespoke instrument: The Standardized Assessment Tool for Mental Health Transition (SATMEHT). The survey was directed at expert(s) in each of the 28 EU countries. The response rate was 100%. Country experts commonly (12/28) reported that between 25 and 49% of CAMHS service users will need transitioning to AMHS. Estimates of the percentage of AMHS users aged under 30~years who had has previous contact with CAMHS were most commonly in the region 20-30% (33% on average).Written policies for managing the interface were available in only four countries and half (14/28) indicated that no transition support services were available. This is the first survey of CAMHS transitional policies and care carried out at a European level. Policymaking on transitional care clearly needs special attention and further elaboration. The Milestone Study on transition should provide much needed data on transition processes and outcomes that could form the basis for improving policy and practice in transitional care.

Autism spectrum disorder (ASD) is a heterogeneous group of disorders characterized by problems with social interaction, communication, and repetitive and restricted behavior. Despite its high heritability and the substantial progress made in elucidating genetic associations, the corresponding biological mechanisms are largely unknown. Our objective is to investigate the contribution of common genetic variation to biological pathways functionally involved in ASD. We conducted gene-set analyses to identify ASD-associated functional biological pathways using the statistical tools MAGMA and INRICH. Gene-set selection was based on previously reported associations with psychiatric disorders and resulted in testing of specific synaptic and glial sets, a glutamate pathway gene-set, mitochondrial gene-sets and gene-sets consisting of fragile X mental retardation protein (FMRP) targets. In total 32 gene-sets were tested. We used Psychiatric Genomics Consortium genome-wide association studies summary statistics of ASD. The study is based on the largest ASD sample to date (N=5305). We found one significantly associated gene-set consisting of FMRP-targeting transcripts (MAGMA: p corr.=0.014, INRICH: p corr.=0.031; all competitive P-values). The results indicate the involvement of FMRP-targeted transcripts in ASD in common genetic variation. This novel finding is in line with the literature as FMRP has been linked to fragile X syndrome, ASD and cognitive development in whole-exome sequencing and copy number variant studies. This gene-set has also been linked to Schizophrenia suggesting that FMRP-targeted transcripts might be involved in a general mechanism with shared genetic etiology between psychiatric disorders.

Objective: The objective was to estimate the age of onset (AOO) for all anxiety disorders and for specific subtypes. Gender differences in the AOO of anxiety disorders were examined, as were the influence of study characteristics on reported AOOs. Methods: Seven electronic databases were searched up to October 2014, with keywords representing anxiety disorder subtypes, AOO, and study design. The inclusion criteria were studies using a general population sample that provided data on the AOO for all anxiety disorders, or specific anxiety disorders, according to DSM-III-R, DSM-IV, or ICD-10 criteria. Results: There were 1028 titles examined, which yielded 24 studies meeting the inclusion criteria. Eight studies reported the AOO and gender. Meta-analysis found a mean AOO of all anxiety disorders of 21.3 years (95% CI 17.46 to 25.07). Separation anxiety disorder, specific phobia, and social phobia had their mean onset before the age of 15 years, whereas the AOO of agoraphobia, obsessive-compulsive disorder, posttraumatic stress disorder, panic disorder, and generalized anxiety disorder began, on average, between 21.1 and 34.9 years. Meta-analysis revealed no difference in the AOO between genders. A prospective study design and higher developmental level of the study country were associated with an earlier AOO. Conclusions: Results from this meta-analysis indicate that anxiety disorder subtypes differ in the mean AOO, with onsets ranging from early adolescence to young adulthood. These findings suggest that prevention strategies of anxiety disorders should be directed towards factors associated with the development of anxiety disorder subtypes in the age groups with the greatest vulnerability for developing those disorders.

Background: Risperidone, aripiprazole, and pipamperone are antipsychotic drugs frequently prescribed for the treatment of comorbid behavioral problems in children with autism spectrum disorders. Therapeutic drug monitoring (TDM) could be useful to decrease side effects and to improve patient outcome. Dried blood spot (DBS) sample collection seems to be an attractive technique to develop TDM of these drugs in a pediatric population. The aim of this work was to develop and validate a DBS assay suitable for TDM and home sampling. Methods: Risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone were extracted from DBS and analyzed by ultra–high-performance liquid chromatography–tandem mass spectrometry using a C18 reversed-phase column with a mobile phase consisting of ammonium acetate/formic acid in water or methanol. The suitability of DBS for TDM was assessed by studying the influence of specific parameters: extraction solution, EDTA carryover, hematocrit, punching location, spot volume, and hemolysis. The assay was validated with respect to conventional guidelines for bioanalytical methods. Results: The method was linear, specific without any critical matrix effect, and with a mean recovery around 90%. Accuracy and imprecision were within the acceptance criteria in samples with hematocrit values from 30% to 45%. EDTA or hemolysis did not skew the results, and no punching carryover was observed. No significant influence of the spot volume or the punch location was observed. The antipsychotics were all stable in DBS stored 10 days at room temperature and 1 month at 4 or −80°C. The method was successfully applied to quantify the 3 antipsychotics and their metabolites in patient samples. Conclusions: A UHPLC-MS/MS method has been successfully validated for the simultaneous quantification of risperidone, 9-OH risperidone, aripiprazole, dehydroaripiprazole, and pipamperone in DBS. The assay provided good analytical performances for TDM and clinical research applications.

The parents of children with psychopathology are at increased risk for psychiatric symptoms. To investigate which parents are mostly at risk, we assessed in a clinical sample of families with children with psychopathology, whether parental symptom scores can be predicted by offspring psychiatric diagnoses and other child, parent and family characteristics. Parental depressive, anxiety, avoidant personality, attention-deficit/hyperactivity (ADHD), and antisocial personality symptoms were measured with the Adult Self Report in 1805 mothers and 1361 fathers of 1866 children with a psychiatric diagnosis as assessed in a child and adolescent psychiatric outpatient clinic. In a multivariate model, including all parental symptom scores as outcome variables, all offspring psychiatric diagnoses, offspring comorbidity and age, parental age, parental educational attainment, employment, and relationship status were simultaneously tested as predictors. Both 35.7% of mothers and 32.8% of fathers scored (sub)clinical for at least one symptom domain, mainly depressive symptoms, ADHD symptoms or, only in fathers, avoidant personality symptoms. Parental psychiatric symptoms were predicted by unemployment. Parental depressive and ADHD symptoms were further predicted by offspring depression and offspring ADHD, respectively, as well as by not living together with the other parent. Finally, parental avoidant personality symptoms were also predicted by offspring autism spectrum disorders. In families with children referred to child and adolescent psychiatric outpatient clinics, parental symptom scores are associated with adverse circumstances and with similar psychopathology in their offspring. This signifies, without implying causality, that some families are particularly vulnerable, with multiple family members affected and living in adverse circumstances. Electronic supplementary material The online version of this article (10.1007/s00787-018-1156-6) contains supplementary material, which is available to authorized users.

Backgrounds Reports of increasing incidence rates of delirium in critically ill children are reason for concern. We evaluated the measurement properties of the pediatric delirium component (PD-scale) of the Sophia Observation Withdrawal Symptoms scale Pediatric Delirium scale (SOS-PD scale). Methods In a multicenter prospective observational study in four Dutch pediatric ICUs (PICUs), patients aged ≥ 3 months and admitted for ≥ 48 h were assessed with the PD-scale thrice daily. Criterion validity was assessed: if the PD-scale score was ≥ 4, a child psychiatrist clinically assessed the presence or absence of PD according to the Diagnostic and statistical manual of mental disorders (DSM)-IV. In addition, the child psychiatrist assessed a randomly selected group to establish the false-negative rate. The construct validity was assessed by calculating the Pearson coefficient (rp) for correlation between the PD-scale and Cornell Assessment Pediatric Delirium (CAP-D) scores. Interrater reliability was determined by comparing paired nurse-researcher PD-scale assessments and calculating the intraclass correlation coefficient (ICC). Results Four hundred eighty-five patients with a median age of 27.0 months (IQR 8–102) were included, of whom 48 patients were diagnosed with delirium by the child psychiatrist. The PD-scale had overall sensitivity of 92.3% and specificity of 96.5% compared to the psychiatrist diagnosis for a cutoff score ≥4 points. The rp between the PD-scale and the CAP-D was 0.89 (CI 95%, 0.82–0.93; p

Knowledge is lacking regarding current psychopathology in parents whose children are evaluated in a psychiatric outpatient clinic. This especially accounts for fathers. We provide insight into the prevalence rates of parental psychopathology and the association with their offspring psychopathology by analyzing data on psychiatric problems collected in 701 mothers and 530 fathers of 757 referred children. Prevalence rates of parental psychopathology were based on (sub)clinical scores on the adult self report. Parent–offspring associations were investigated in multivariate analyses taking into account co-morbidity. Around 20 % of the parents had a (sub)clinical score on internalizing problems and around 10 % on attention deficit hyperactivity (ADH) problems. Prevalence rates did not differ between mothers and fathers. Parent–offspring associations did not differ between girls and boys. Maternal anxiety was associated with all offspring problem scores. In addition, maternal ADH problems were associated with offspring ADH problems. Paternal anxiety and ADH problems scores were specifically associated with offspring internalizing and externalizing problem scores, respectively. Associations with offspring psychopathology were of similar magnitude for mothers and fathers and were not influenced by spousal resemblance. Our study shows that both fathers and mothers are at increased risk for psychiatric problems at the time of a child’s evaluation and that their problems are equally associated with their offspring problems. The results emphasize the need to screen mothers as well as fathers for psychiatric problems. Specific treatment programs should be developed for these families in especially high need.

OBJECTIVE: Parental psychiatric symptoms can negatively affect the outcome of children's psychopathology. Studies thus far have mainly shown a negative effect of maternal depression. This study examined the associations between a broad range of psychiatric symptoms in mothers and fathers and the child's outcome.METHOD: Internalizing and externalizing psychiatric symptoms were assessed in 742 mothers, 440 fathers, and their 811 children at the first evaluation in 3 child and adolescent psychiatric outpatient clinics and at follow-up (on average 1.7 years later). Predictions of child's symptoms scores were tested at follow-up by parental symptom scores at baseline, parental scores at follow-up, and offspring scores at baseline.RESULTS: Children whose mother or father scored above the (sub)clinical threshold for psychiatric symptoms at baseline had higher symptom scores at baseline and at follow-up. Offspring follow-up scores were most strongly predicted by offspring baseline scores, in addition to parental psychiatric symptoms at follow-up. Offspring symptom scores at follow-up generally were not predicted by parental scores at baseline. Maternal and paternal associations were of similar magnitude.CONCLUSION: Higher symptom scores at follow-up in children of parents with psychopathology were mainly explained by higher symptom scores at baseline. Continuing parent-offspring associations could be a result of reciprocal effects, ie, parental symptoms influencing offspring symptoms and offspring symptoms influencing parental symptoms. Nevertheless, the results show that these children are at risk for persisting symptoms, possibly indicating the need to treat maternal and paternal psychopathology.

Dried blood spot (DBS) sampling offers a minimally invasive sampling method for therapeutic drug monitoring of antipsychotics. To facilitate implementation in clinical practice, the aim of this study was to perform a clinical validation study of a DBS method for quantification of risperidone, aripiprazole, pipamperone, and their major metabolites 9-OH risperidone and dehydro-aripiprazole in a real-life, clinical setting.Paired DBS and venous plasma samples were analyzed (n = 35 for risperidone, n = 21 for aripiprazole, n = 21 for pipamperone). Estimated plasma concentrations were calculated from DBS concentrations based on hematocrit and/or Deming regression formulas. Deming regression and Bland-Altman analyses were used to determine the agreement between the calculated and measured plasma concentrations. For Bland-Altman analysis, the following acceptance limit was used: for a minimum of 67% of the samples, the difference of the 2 measurements should be within 20% of their mean.The median venous plasma levels were 0.9 mcg/L for risperidone, 14.8 mcg/L for 9-OH risperidone, 135.4 mcg/L for aripiprazole, 54.9 mcg/L for dehydro-aripiprazole, and 56.4 mcg/L for pipamperone. All antipsychotics required different correction formulas of DBS concentrations for best agreement. Subsequently, no constant or proportional bias was observed using Deming regression analysis. With Bland-Altman analyses, for risperidone, 45% of the samples were within the 20% limits; for 9-OH risperidone, 36%; for aripiprazole, 45%; for dehydro-aripiprazole, 35%; and for pipamperone, 43%.The DBS method to quantify risperidone, aripiprazole, pipamperone, and their major metabolites did not meet the acceptance criteria in the Bland-Altman analyses. Therefore, this DBS method was not clinically valid. This study shows the importance of a clinical validation study with use of Bland-Altman plots before clinical implementation.

Background Anxiety disorders are highly prevalent during adolescence. Although literature points out that anxiety symptoms are related to problems in social and academic functioning, the extent of these problems among adolescents with clinical anxiety disorders has not been systematically reviewed before. Methods Electronic databases were searched up to October 2017, with keywords representing anxiety disorders, adolescents, and social or academic functioning. The inclusion criteria were studies with a sample of adolescents (10–19 years) with anxiety disorders that provided data regarding their social or academic functioning. 3431 studies were examined, of which 19 met the inclusion criteria. Results Adolescents with anxiety disorders had a lower social competence relative to their healthy peers. They reported more negativity within interpersonal relationships, higher levels of loneliness, and victimization. Most adolescents with anxiety disorders felt impaired at school, however, findings of their average school results, compared to peers, were mixed. In addition, they had a higher risk for school refusal and entered higher education less often. Impairments in social and academic functioning differed across type and the number of anxiety disorders. Limitations Most studies examined social phobia or anxiety disorders in general and methodological approaches varied widely between studies. Conclusions This systematic review indicates that adolescents with anxiety disorders experience a range of significant problems in both social and academic functioning. These findings suggest that the assessment and treatment of anxiety disorders in adolescence should focus on improving functioning across domains.

The antipsychotics risperidone, aripiprazole and pipamperone are frequently prescribed for the treatment in children with autism. The aim of this study was to validate an ultra-high performance liquid chromatography-mass spectrometry method for the quantification of these antipsychotics in plasma. An ultra-high performance liquid chromatography-mass spectrometry assay was developed for the determination of the drugs and metabolites. Gradient elution was performed on a reversed-phase column with a mobile phase consisting of ammonium acetate, formic acid in methanol or in Milli-Q ultrapure water at a flow rate of 0.5 mL/min. The method was validated according to the US Food and Drug Administration guidelines. The analytes were found to be stable enough after reconstitution and injection of only 5 μL improved the accuracy and precision in combination with the internal standard. Calibration curves of all five analytes were linear. All analytes were stable for at least 72 h in the autosampler and the high quality control of 9-OH-risperidone was stable for 48 h. The method allows quantification of all analytes. The advantage of this method is the combination of a minimal injection volume, a short run-time, an easy sample preparation method and the ability to quantify all analytes in one run. Copyright © 2015 John Wiley & Sons, Ltd.

To conduct international comparisons of parent-adolescent cross-informant agreement in clinical samples, we analyzed ratings on the Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) for 6,762 clinically referred adolescents ages 11-18 from 7 societies (M = 14.5 years, SD = 2.0 years; 51% boys). Using CBCL and YSR data, we asked the following questions: (a) Do parents report more problems for their adolescent children than the adolescents report about themselves? (b) How do cross-informant correlations (rs) for scale scores differ by problem type and by society? (c) How well do parents and adolescents, on average, agree regarding which problems they rate as low, medium, or high? (d) How does within-dyad item agreement vary within and between societies? (e) How do societies vary in dichotomous cross-informant agreement with respect to the deviance status of the adolescents? CBCL and YSR scores were quite similar, with small and inconsistent informant effects across societies. Cross-informant rs averaged .47 across scales and societies. On average, parents and adolescents agreed well regarding which problem items received low, medium, or high ratings (M r = .87). Mean within-dyad item agreement was moderate across all societies, but dyadic agreement varied widely within every society. In most societies, adolescent noncorroboration of parent-reported deviance was more common than parental noncorroboration of adolescent-reported deviance. Overall, somewhat better parent-adolescent agreement and more consistency in agreement patterns across diverse societies were found in these seven clinical samples than in population samples studied using the same methods.

The original version of this article contained an error in Table 1. The correct table is presented below.

Depression during pregnancy is a common and high impact disease. Generally, 5–10 % of pregnant women suffer from depression. Children who have been exposed to maternal depression during pregnancy have a higher risk of adverse birth outcomes and more often show cognitive, emotional and behavioural problems. Therefore, early detection and treatment of antepartum depression is necessary. Both psychotherapy and antidepressant medication, first choice treatments in a non-pregnant population, have limitations in treating depression during pregnancy. Therefore, it is urgent and relevant to investigate alternative treatments for antepartum depression. Bright light therapy (BLT) is a promising treatment for pregnant women with depressive disorder, for it combines direct availability, sufficient efficacy, low costs and high safety, taking the safety for the unborn child into account as well. In this study, 150 pregnant women (12–18 weeks pregnant) with a DSM-V diagnosis of depressive disorder will be randomly allocated in a 1:1 ratio to one of the two treatment arms: treatment with BLT (9.000 lux) or treatment with dim red light therapy (100 lux). Both groups will be treated for 6 weeks at home on a daily basis for 30 min, within 30 min of habitual wake-up time. Follow-up will take place after 6 weeks of therapy, 3 and 10 weeks after end of therapy, at birth and 2, 6 and 18 months postpartum. Primary outcome will be the average change in depressive symptoms between the two groups, as measured by the Structured Interview Guide for the Hamilton Depression Scale – Seasonal Affective Disorder version and the Edinburg Postnatal Depression Scale. Changes in rating scale scores of these questionnaires over time will be analysed using generalized linear mixed models. Secondary outcomes will be the changes in maternal cortisol and melatonin levels, in maternal sleep quality and gestational age, birth weight, infant behaviour, infant cortisol exposure and infant cortisol stress response. If BLT reduces depressive symptoms in pregnant women, it will provide a safe, cheap, non-pharmacological and efficacious alternative treatment for psychotherapy and antidepressant medication in treating antepartum depression, without any expected adverse reactions for the unborn child. Netherlands Trial Register NTR5476 . Registered 5 November 2015.

Prevalence and severity of childhood behavioral problems differ between boys and girls, and in psychiatry, testing for gender differences is common practice. Population-based studies show that many psychopathology scales are (partially) Measurement Invariance (MI) with respect to gender, i.e. are unbiased. It is, however, unclear whether these studies generalize towards clinical samples. In a psychiatric outpatient sample, we tested whether the Child Behavior Checklist 6-18 (CBCL) is unbiased with respect to gender. We compared mean scores across gender of all syndrome scales of the CBCL in 3271 patients (63.3% boys) aged 6-18. Second, we tested for MI on both the syndrome scale and the item-level using a stepwise modeling procedure. Six of the eight CBCL syndrome scales included one or more gender-biased items (12.6% of all items), resulting in slight over- or under-estimation of the absolute gender difference in mean scores. Two scales, Somatic Complaints and Rule-breaking Behavior, contained no biased items. The CBCL is a valid instrument to measure gender differences in problem behavior in children and adolescents from a clinical sample; while various gender-biased items were identified, the resulting bias was generally clinically irrelevant, and sufficient items per subscale remained after exclusion of biased items. Copyright © 2016 John Wiley & Sons, Ltd.

BackgroundSpouses resemble each other for psychopathology, but data regarding spousal resemblance in externalizing psychopathology, and data regarding spousal resemblance across different syndromes (e.g. anxiety in wives and attention deficit/hyperactivity disorder [ADHD] in husbands) are limited. Moreover, knowledge is lacking regarding spousal resemblance in parents of children with psychiatric disorders. We investigated and compared spousal resemblance within and across internalizing and externalizing symptom domains in parents of children with and without psychopathology.MethodsSymptoms of depression, anxiety, avoidant personality, ADHD, and antisocial personality were assessed with the Adult Self Report in 728 mothers and 544 fathers of 778 children seen in child and adolescent psychiatric outpatient clinics and in 2075 mothers and 1623 fathers of 2784 children from a population-based sample. Differences in symptom scores and spousal correlations between the samples were tested.ResultsParents in the clinical sample had higher symptom scores than in the population-based sample. In both samples, correlations within and across internalizing and externalizing domains of psychopathology were significant. Importantly, correlations were significantly higher in the clinical sample (P = 0.03). Correlations, within and across symptoms, ranged from 0.14 to 0.30 in the clinical sample and from 0.05 to 0.23 in the population-based sample.ConclusionsThis large study shows that spousal resemblance is not only present within but also across symptom domains. Especially in the clinical sample, ADHD symptoms in fathers and antisocial personality symptoms in mothers were correlated with a range of psychiatric symptoms in their spouses. Clinicians need to be alert of these multiple affected families.

The antipsychotics risperidone, aripiprazole and pipamperone are frequently prescribed for the treatment in children with autism. The aim of this study was to validate an ultra-high performance liquid chromatography-mass spectrometry method for the quantification of these antipsychotics in plasma. An ultra-high performance liquid chromatography-mass spectrometry assay was developed for the determination of the drugs and metabolites. Gradient elution was performed on a reversed-phase column with a mobile phase consisting of ammonium acetate, formic acid in methanol or in Milli-Q ultrapure water at a flow rate of 0.5 mL/min. The method was validated according to the US Food and Drug Administration guidelines. The analytes were found to be stable enough after reconstitution and injection of only 5 μL improved the accuracy and precision in combination with the internal standard. Calibration curves of all five analytes were linear. All analytes were stable for at least 72 h in the autosampler and the high quality control of 9-OH-risperidone was stable for 48 h. The method allows quantification of all analytes. The advantage of this method is the combination of a minimal injection volume, a short run-time, an easy sample preparation method and the ability to quantify all analytes in one run. Copyright © 2015 John WileySons, Ltd.

Background: It is of debate whether or not childhood anxiety disorders (AD) can be captured by one taxonomic construct. This study examined whether perceived arousal (PA), autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis measures can distinguish children with different primary diagnoses of clinical anxiety disorders (AD) from each other, and from a general population reference group (GP). Methods: The study sample consisted of 152 AD children (comparing separation anxiety disorder, generalized anxiety disorder, social phobia and specific phobia), aged 8- to 12-years, and 200 same-aged reference children. HPA-axis functioning was measured by a diurnal cortisol profile. ANS functioning was measured by continuous measures of skin conductance level in rest and during a mental arithmetic task and high frequency heart rate variability in rest. PA was assessed by a questionnaire. Results: The AD sample showed lower high frequency heart rate variability during rest, heightened anticipatory PA, higher basal and reactive skin conductance levels and lower basal HPA-axis functioning compared to the GP sample. The existence of three or more clinical disorders, i.e. a high clinical 'load', was associated with lower basal HPA-axis functioning, higher skin conductance level and lower posttest PA. Specific phobia could be discerned from social phobia and separation anxiety disorder on higher skin conductance level. Conclusions: Our findings indicated that children with AD have specific psychophysiological characteristics, which resemble the psychophysiological characteristics of chronic stress. A high clinical 'load' is associated with an altered ANS and HPA-axis functioning. Overall, ANS and HPA-axis functioning relate to AD in general, accept for specific phobia. (C) 2014 Elsevier Ltd. All rights reserved.

WorkshopAge of onset of mental disorders: etiopathogenetic and treatment implications.BackgroundAge of onset (AOO) of anxiety disorders could serve as a vital statistic in the formulation of mental health policy. Previous reviews have reported on the AOO of anxiety disorders in the general population. However, these review studies did not systematically estimate the AOO of different anxiety disorder subtypes, and did not examine factors that might have influenced reported AOO.ObjectiveThe aims of the present study were (1) to estimate the AOO for all anxiety disorders and for specific subtypes, (2) to examine gender differences in AOO of anxiety disorders, and (3) to examine the influence of study characteristics on reported AOO.MethodSeven electronic databases were searched with keywords representing anxiety disorder subtypes, AOO and study design. The inclusion criteria were studies using a general population sample that provided data on AOO for all anxiety disorders, or specific anxiety disorders, according to DSM-III-R, DSM-IV or ICD-10 criteria. Meta-analysis was used to estimate AOO and gender differences, while meta-regression was used to examine the influence of study characteristics.ResultsA total of 1028 titles were examined, which yielded 24 studies meeting the inclusion criteria. Meta-analysis found an average AOO of all anxiety disorders of 21.3 years (95% CI: 17.46 to 25.07). Separation anxiety disorder, specific phobia and social phobia had their mean onset before the age of 15 years, whereas AOO of agoraphobia, obsessive compulsive disorder, post-traumatic stress disorder, panic disorder and generalized anxiety disorder began on average between 21.1 and 34.9 years. Anxiety disorder is more common in women, but meta-analysis revealed no difference in AOO between genders. Prospective study design and higher developmental level of the study country were associated with earlier AOO.ConclusionResults from this meta-analysis indicate that anxiety disorder subtypes differ in mean AOO, with onsets ranging from early adolescence to young adulthood. These findings suggest that prevention strategies of anxiety disorders should be directed towards the factors associated with the development of subtypes of anxiety disorder in the age groups with the greatest vulnerability for developing those disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.