Clinical pharmacokinetics of antipsychotics in pediatric populations: a scoping review focusing on dosing regimen.

INTRODUCTION: Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations. AREAS COVERED: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented. EXPERT OPINION: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.

Effect of chemotherapy (with and without radiotherapy) on the intelligence of children and adolescents treated for acute lymphoblastic leukemia; a meta-analysis.

OBJECTIVE: This meta-analysis assesses cognitive functioning in children with acute lymphoblastic leukemia post-treatment who were treated with either chemotherapy-only (CT-only) or in combination with radiation therapy (CTRT). METHODS: The databases Pubmed and PsychInfo were searched between 1-1-2000 and 31-12-2021. Data were analyzed using Comprehensive Meta-Analysis (version 2). RESULTS: Mean weighted intelligence after treatment was 100.2 (number of studies n = 51, 95% CI: 98.8-101.5). For CT-only, it was 100.8 (95% CI: 99.5-102.2) and for CTRT 97.8 (95% CI: 95.9-100.2). Compared to recruited healthy controls, treated children had on average lower IQ scores (n = 23, mean difference -7.8, 95% CI: -10.7 to -5.0, p < 0.001). When looking only at studies using controls recruited from the patient's family, results remained significant (n = 5, mean difference -6.0, 95% CI: -8.6 to -3.5, p = 0.001). Meta-regressions aimed at identifying predictors of IQ after treatment failed to find an effect for sex or age. We could demonstrate an effect of time between diagnosis and IQ measurement for the CTRT treated patient (B = -0.26, 95% CI: -0.40 to -0.1, p = 0.002). CONCLUSIONS: IQ scores of patients treated with CT-only or CTRT treatment regimens did not differ from the normative population. However, compared to recruited control groups, patients showed lower mean IQ scores. The Flynn effect and/or selection effects may play a role in this discrepancy. Considering time since diagnosis may have a significant impact on IQ, at least in CTRT treated patients, long-term clinical follow-up of neurocognitive development may be prudent to detect possible (late) neurocognitive effects.

Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison.

Objective: The etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation. Methods: We assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates. Results: Overall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain. Conclusion: The syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology.

Predicting Intense Levels of Child Anxiety During Anesthesia Induction at Hospital Arrival.

In children, intense levels of anxiety during anesthetic induction are associated with a higher risk of pain, poor recovery, and emergence delirium. Therefore, it is important to identify these high-risk children at hospital arrival. The current study examined internalizing behavior (Child Behavior Checklist, CBCL) and state anxiety measures (modified Yale Preoperative Anxiety Scale, mYPAS, and State Trait Anxiety Inventory for Children, STAIC) at hospital arrival as predictors of anxiety during induction of anesthesia. One hundred children (aged 4 to 12 years) undergoing elective daycare surgery were included. The STAIC and mYPAS at hospital arrival were significant predictors of anxiety during induction, whereas CBCL was not. The STAIC state form at hospital arrival was the strongest predictor and could be used to identify children who will experience intense levels of anxiety during anesthetic induction, with sufficient to good diagnostic accuracy. Using the STAIC at hospital arrival allows targeted interventions to reduce anxiety in children.

Virtual reality exposure before elective day care surgery to reduce anxiety and pain in children: A randomised controlled trial.

BACKGROUND: Pre-operative anxiety in children is very common and is associated with adverse outcomes. OBJECTIVE: The aim of this study was to investigate if virtual reality exposure (VRE) as a preparation tool for elective day care surgery in children is associated with lower levels of anxiety, pain and emergence delirium compared with a control group receiving care as usual (CAU). DESIGN: A randomised controlled single-blind trial. SETTING: A single university children's hospital in the Netherlands from March 2017 to October 2018. PATIENTS: Two-hundred children, 4 to 12 years old, undergoing elective day care surgery under general anaesthesia. INTERVENTION: On the day of surgery, children receiving VRE were exposed to a realistic child-friendly immersive virtual version of the operating theatre, so that they could get accustomed to the environment and general anaesthesia procedures. MAIN OUTCOME MEASURES: The primary outcome was anxiety during induction of anaesthesia (modified Yale Preoperative Anxiety Scale, mYPAS). Secondary outcomes were self-reported anxiety, self-reported and observed pain, emergence delirium, need for rescue analgesia (morphine) and parental anxiety. RESULTS: A total of 191 children were included in the analysis. During induction of anaesthesia, mYPAS levels (median [IQR] were similar in VRE, 40.0 [28.3 to 58.3] and CAU, 38.3 [28.3 to 53.3]; P = 0.862). No differences between groups were found in self-reported anxiety, pain, emergence delirium or parental anxiety. However, after adenoidectomy/tonsillectomy, children in the VRE condition needed rescue analgesia significantly less often (55.0%) than in the CAU condition (95.7%) (P = 0.002). CONCLUSION: In children undergoing elective day care surgery, VRE did not have a beneficial effect on anxiety, pain, emergence delirium or parental anxiety. However, after more painful surgery, children in the VRE group needed rescue analgesia significantly less often, a clinically important finding because of the side effects associated with analgesic drugs. Options for future research are to include children with higher levels of anxiety and pain and to examine the timing and duration of VRE. TRIAL REGISTRATION: Netherlands Trial Registry: NTR6116.

Systematic Review and Meta-analysis of Virtual Reality in Pediatrics: Effects on Pain and Anxiety.

BACKGROUND: Medical procedures often evoke pain and anxiety in pediatric patients. Virtual reality (VR) is a relatively new intervention that can be used to provide distraction during, or to prepare patients for, medical procedures. This meta-analysis is the first to collate evidence on the effectiveness of VR on reducing pain and anxiety in pediatric patients undergoing medical procedures. METHODS: On April 25, 2018, we searched EMBASE, MEDLINE, CENTRAL, PubMed, Web of Science, and PsycINFO with the keywords "VR," "children," and "adolescents." Studies that applied VR in a somatic setting with participants ≤21 years of age were included. VR was defined as a fully immersive 3-dimensional environment displayed in surround stereoscopic vision on a head-mounted display (HMD). We evaluated pain and anxiety outcomes during medical procedures in VR and standard care conditions. RESULTS: We identified 2889 citations, of which 17 met our inclusion criteria. VR was applied as distraction (n = 16) during venous access, dental, burn, or oncological care or as exposure (n = 1) before elective surgery under general anesthesia. The effect of VR was mostly studied in patients receiving burn care (n = 6). The overall weighted standardized mean difference (SMD) for VR was 1.30 (95% CI, 0.68-1.91) on patient-reported pain (based on 14 studies) and 1.32 (95% CI, 0.21-2.44) on patient-reported anxiety (based on 7 studies). The effect of VR on pediatric pain was also significant when observed by caregivers (SMD = 2.08; 95% CI, 0.55-3.61) or professionals (SMD = 3.02; 95% CI, 0.79-2.25). For anxiety, limited observer data were available. CONCLUSIONS: VR research in pediatrics has mainly focused on distraction. Large effect sizes indicate that VR is an effective distraction intervention to reduce pain and anxiety in pediatric patients undergoing a wide variety of medical procedures. However, further research on the effect of VR exposure as a preparation tool for medical procedures is needed because of the paucity of research into this field.

Development of a Virtual Reality Exposure Tool as Psychological Preparation for Elective Pediatric Day Care Surgery: Methodological Approach for a Randomized Controlled Trial.

BACKGROUND: Preoperative anxiety in children is highly prevalent and is associated with adverse outcomes. Existing psychosocial interventions to reduce preoperative anxiety are often aimed at distraction and are of limited efficacy. Gradual exposure is a far more effective way to reduce anxiety. Virtual reality (VR) provides a unique opportunity to gradually expose children to all aspects of the operating theater. OBJECTIVE: The aims of our study are (1) to develop a virtual reality exposure (VRE) tool to prepare children psychologically for surgery; and (2) to examine the efficacy of the VRE tool in a randomized controlled trial (RCT), in which VRE will be compared to care as usual (CAU). METHODS: The VRE tool is highly realistic and resembles the operating room environment accurately. With this tool, children will not only be able to explore the operating room environment, but also get accustomed to general anesthesia procedures. The PREoperative Virtual reality Intervention to Enhance Wellbeing (PREVIEW) study will be conducted. In this single-blinded RCT, 200 consecutive patients (aged 4 to 12 years) undergoing elective day care surgery for dental, oral, or ear-nose-throat problems, will be randomly allocated to the preoperative VRE intervention or CAU. The primary outcome is change in child state anxiety level between baseline and induction of anesthesia. Secondary outcome measures include child's postoperative anxiety, emergence delirium, postoperative pain, use of analgesics, health care use, and pre- and postoperative parental anxiety. RESULTS: The VRE tool has been developed. Participant recruitment began March 2017 and is expected to be completed by September 2018. CONCLUSIONS: To our knowledge, this is the first RCT evaluating the effect of a VRE tool to prepare children for surgery. The VRE intervention is expected to significantly diminish preoperative anxiety, postoperative pain, and the use of postoperative analgesics in pediatric patients. The tool could create a less stressful experience for both children and their parents, in line with the modern emphasis on patient- and family-centered care. TRIAL REGISTRATION: Netherlands Trial Registry: NTR6116; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6116 (Archived by WebCite at http://www.webcitation.org/6ryke7aep).