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.

Predictors of Quality of Life in Children and Adolescents with Psychiatric Disorders.

This study aimed to identify factors that predict quality of life (QoL), over and above potential improvements in QoL related to a decrease in psychopathology, in children and adolescents with psychiatric problems. Two hundred and thirty one referred children and adolescents, aged 7-19 years, were followed up across a 1-year period. QoL and psychopathology were assessed, as were a broad range of child, parent, and family/social network factors. Time 1 QoL scores and change in level of psychopathology from Time 1 to Time 2 were important predictors of Time 2 QoL scores. Lower than expected Time 2 QoL was also predicted by the presence at Time 1 of a chronic physical disease, low self-esteem, poor social skills, and stressful life events. Findings can be useful to identify children who are at risk for lower than expected levels of QoL, even after receiving help from mental health agencies.

Associations between autism traits and family functioning over time in autistic and non-autistic children.

LAY ABSTRACT: Little is known about family functioning over time when raising a child with autism traits, with or without a clinical autism diagnosis. Therefore, we asked caregivers-mostly parents-of a group of 168 children about the family functioning and the child's emotional and behavioral characteristics, as well as autistic traits, twice with about 1 year in between. For numerous reasons, the children were referred to youth mental health care centers, including child and adolescent psychiatric services. Care as usual was offered after the diagnostic assessment if a clinical diagnosis was the assessment outcome. Caregivers reported less problematic family functioning in children with fewer autism traits over time. The child's additional emotional or behavioral characteristics did not seem to influence this relation. Furthermore, we split the whole group into autistic children with a clinical autism diagnosis (58%) and non-autistic children with autism traits but without a clinical diagnosis (42%) to see whether we would find the same results in both groups. Surprisingly, the relation between family functioning and the level of a child's autism traits only held for the subgroup of non-autistic children with autism traits. Thus, raising children with autism traits without a clinical diagnosis may affect family functioning over time. We think that families might have difficulty understanding and adjusting to the autism traits of their children but are lacking the support that is exclusively offered to families of children with a clinical autism diagnosis. We must be cautious because we do not know whether there is a causal relation. Although further research is needed to explore and learn to understand this result, clinicians might consider offering support to families of children with subthreshold autism to prevent problems in family functioning. Because high autism trait levels in non-autistic children may be of a different origin than autism, for example, other neurodevelopmental or mental health problems, family training or support should be tailored to the child's underlying difficulties.

Children with Autism Spectrum Disorder in Times of COVID-19: Examining Emotional and Behavioral Problems, Parental Well-Being, and Resilience.

This longitudinal study assessed the impact of the COVID-19 pandemic on children with autism spectrum disorder (ASD; n = 62; Mage = 13 years) by measuring emotional and behavioral problems before and during the pandemic, and by comparing this change to a matched sample of children without ASD (n = 213; Mage = 16 years). Moreover, we examined whether indicators of parental well-being promoted resilience of children with ASD. Results showed that the mean change in problems did not differ between children with and without ASD. Importantly, some children showed an increase in problems, while others showed resilience. Parental well-being indicators were not related to resilience among children with ASD. The interindividual variability in responses, particularly among children with ASD, highlights the need for personalized support.

Impact of the COVID-19 pandemic on children and adolescents with autism spectrum disorder and their families: a mixed-methods study protocol.

BACKGROUND: The COVID-19 pandemic is a challenge for everyone, particularly for children and adolescents with autism spectrum disorder (ASD). ASD is a developmental disorder characterised by limitations in social communication, repetitive behavioural patterns, and limited interests, and activities. It is expected that many families with children with ASD will experience more problems due to the COVID-19 pandemic and the related public health restrictions. At the same time, some may experience improved functioning, due to fewer expectations and social demands. METHODS/DESIGN: In a mixed-method study to identify the impact of the COVID-19 pandemic, parents of children with ASD (ages 4-21) who were in care pre-COVID-19 at one of three large mental healthcare institutions in the region of Rotterdam participated (68 for T0, 57 for T1). The aims are (1) to investigate the impact of the COVID-19 pandemic on overall functioning and autistic symptoms of the child/adolescent with ASD, as well as parental and family functioning (QUANT-QUAL), in both the short term and longer term, and (2) to investigate risk and protective factors (in light of resilience) (QUANT-qual) and (3) to investigate care and informational needs (QUAL-quant). Pre-COVID-19 baseline data will be retrieved from clinical records. Participants will fill out two surveys (one during a COVID-19 peak-January-May 2021-and one thereafter). Survey participants were invited to participate in interviews (n=27). Surveys include measures thar were included pre-COVID-19 (ie, overall functioning and autism symptoms) as well as specific measures to identify family functioning and COVID-19 impact. The semistructured interviews focus on child, parent and family functioning and care-and informational needs. ETHICS AND DISSEMINATION: The Medical Ethics Committee of the Erasmus MC has approved the study. Findings will be available to families of children with ASD, their care providers, the funders, autism societies, the government and other researchers.

Quality of life in children with psychiatric disorders: self-, parent, and clinician report.

OBJECTIVE: To study the relationship between child psychiatric disorders and quality of life (QoL). METHOD: In a sample of 310 children (ages 6-18 years) referred for psychiatric problems, children, parents, and clinicians reported on psychopathology and subjective and objective QoL indicators. RESULTS: Six diagnostic categories were distinguished: attention-deficit and disruptive behavior disorders, anxiety disorders, pervasive developmental disorders, mood disorders, other disorders, and no diagnosis. In overall QoL, no differences were found between the diagnostic categories, except in clinician's ratings, who rated children with pervasive developmental disorder as having a poorer QoL than children with other diagnoses. In each diagnostic category specific QoL subdomains were affected: for children with attention-deficit and disruptive behavior disorder, school functioning and social functioning; for children with anxiety disorder, emotional functioning; for children with pervasive developmental disorder, social functioning; and for children with mood disorder, emotional functioning. CONCLUSIONS: Across multiple raters, the distinguished child psychiatric disorders had a different impact on QoL. Knowledge about domains of QoL that are affected in specific child psychiatric disorders can help clinicians to focus on particular QoL domains during the diagnostic process and to define adequate treatment goals.

Psychopathology in children: improvement of quality of life without psychiatric symptom reduction?

OBJECTIVE: The aim of this study was to assess the association between change in psychopathology and Quality of Life (QoL) across time in children with high levels of psychopathology. METHODS: A referred sample of 126 seven- to 19-year-olds was studied across a 1-year follow-up period. Information concerning QoL and psychopathology was obtained from parents. RESULTS: Overall, 38.1% of children showed neither psychiatric symptom reduction nor QoL improvement, 33.3% of children showed both a clinically significant psychiatric symptom reduction and QoL improvement, and 28.6% of children showed either psychiatric symptom reduction or QoL improvement. In 11.1% of all children, QoL improved, while the level of psychopathology remained high. Age, gender, or psychiatric diagnosis did not predict a poor outcome of persistently high psychopathology scores and poor QoL. CONCLUSION: QoL in children with psychiatric problems may be improved by reducing psychiatric symptoms in a number of children, but it is also possible to improve QoL without psychiatric symptom reduction. This implicates that QoL should become an important aim and treatment outcome measure of psychiatric treatment programs, especially since psychopathology tends to persist.

Determinants of quality of life in children with psychiatric disorders.

OBJECTIVE: To assess factors that, in addition to childhood psychopathology, are associated with Quality of Life (QoL) in children with psychiatric problems. METHODS: In a referred sample of 252 8 to 18-year-olds, information concerning QoL, psychopathology and a broad range of child, parent, and family/ social network factors was obtained from children, parents, teachers and clinicians. RESULTS: Poor child, parent, and clinician reported QoL was associated with child psychopathology, but given the presence of psychopathology, also with child factors, such as low self-esteem, and poor social skills, and family/social network factors, such as poor family functioning, and poor social support. In multiple linear regression analyses the importance of parent factors, such as parenting stress, was almost negligible. CONCLUSION: To increase QoL of children with psychiatric problems, treatment of symptoms is important, but outcome might improve if treatment is also focussed on other factors that may affect QoL. Results are discussed in relation to current treatment programs.