Lisa T. Ringeling

Aims: This study aimed to improve the understanding of lithium's safety profile by analysing the frequency and distribution of reported adverse drug reactions (ADRs) compared to second‐generation antipsychotics (SGAs). Methods: Individual case safety reports from VigiBase (1968–October 2023) involving individuals older than 2 years, with lithium or SGAs as a suspected or interacting drug, were included. Medical Dictionary for Regulatory Activities (MedDRA) was used for ADRs classification. Proportional reporting ratios (PRRs) with 95% confidence intervals were calculated across different age groups. Results: The lithium group contained 29 897 reported ADRs. Proportional reporting patterns varied across age groups. In children, lithium was associated with a higher proportion of renal, endocrine, gastrointestinal, skin and cardiac ADRs compared to SGAs. SGAs showed proportionally more ADRs in females, whereas lithium displayed fewer and more balanced sex‐related differences. Renal impairment accounted for a larger proportion of lithium‐related ADRs in older adults compared to children. For SGAs, type 2 diabetes and cardiovascular events showed higher proportional reporting in both younger and older adults than in children. In contrast, thyroid‐related ADRs with lithium and weight‐related ADRs with SGAs were proportionally more common in children. Conclusions: Renal, endocrine and gastrointestinal effects are observed in children using lithium, though serious outcomes like renal failure appear proportionally more often in older adults. SGAs also show age‐specific risk patterns, particularly metabolic and cardiovascular effects in adults. This emphasizes the ongoing need for individualized treatment and continued ADR monitoring and reporting to enhance the understanding of lithium's safety profile and support informed clinical decision‐making.

Objective: Bipolar disorder (BD) often emerges during mid‐adolescence and young adulthood, and leads to functional and social impairment, with a prevalence of 0.87% among Dutch youth. Lithium, the first‐line BD maintenance treatment, stabilizes mood, prevents suicide, and is well tolerated, yet its use has declined as long‐term second‐generation antipsychotics (SGAs) prescriptions increased. This study explores the prevalence, incidence, duration, prior and concurrent use of psychotropic medications, and dosage patterns of lithium dispensing in Dutch youth. Method: A retrospective cohort study using the Dutch community pharmacy‐based IADB.nl database included 567 youths (6–25 years), who were dispensed lithium between 2011 and 2022. Results: The yearly prevalence of lithium dispensing per 100,000 fluctuated between 30.3 in 2011 and 34.8 in 2022 ( p = 0.40), with the lowest prevalence in 6–12‐year‐olds and highest in 20–25‐year‐olds. Females had overall higher prevalence rates than males ( p = 0.03). Overall incidence rose from 7.9 to 9.3 ( p = 0.68). In 2011, incidence was 10.7 for both the 13–19 and 20–25 age groups. By 2022, this decreased to 4.2 in 13–19‐year‐olds and increased to 19.0 in 20–25‐year‐olds. Approximately 55% of individuals received other psychotropics before lithium, and 52% concurrently, with SGAs and antidepressants being most commonly dispensed. Conclusion: Despite lithium's efficacy and status as first‐line BD maintenance treatment, its dispensing in Dutch youth remains low compared to the BD prevalence. This may be due to misdiagnosis of BD and/or clinicians' reluctance to prescribe lithium, highlighting the need for improved diagnostics, clinician education, and further research into lithium's safety in youths.

Background: Dried blood spot (DBS) sampling offers several advantages for therapeutic drug monitoring, including minimal invasiveness, low blood volume requirements, and potential for home sampling. However, obtaining spots of sufficient quality for reliable analysis remains a key challenge of DBS. This study aimed to evaluate the impact of enhanced visual and textual guidance on the quality of DBS by analyzing data from a prospective multicenter study involving children and adolescents. Methods: In total, 108 DBS cards from 56 children were assessed for spot quality. Rejection criteria included spot diameter Pre-intervention : 47.6% of the DBS cards contained at least 1 spot qualitatively acceptable for analysis, and 25.7% of all spots qualified for analysis. Post-intervention : the acceptance rates increased to 86.6% and 64.3%, respectively. In both the pre- and post-intervention groups , the most common reason for rejection was the presence of smeared or irregularly shaped spots. Conclusions: Continued improvements in DBS quality rely on effectively addressing challenges associated with home sampling challenges, which is critical for the seamless incorporation of DBS into clinical practice.

Objective: The Youth Act, implemented by the Dutch government in 2015, aimed to provide more efficient, coherent, and cost-effective care tailored to the specific needs of children, while also reducing medicalization. Between 2003 and 2013, there was a four-fold increase in methylphenidate prescriptions among Dutch children aged 4 to 18 years. However, the impact of the Youth Act on the ADHD medication dispensing remains unassessed. This study investigated changes in ADHD medication dispensing patterns among Dutch youth following the implementation of the Youth Act. Method: A before-after retrospective cohort study was conducted using data from the Dutch community pharmacy-based IADB.nl database among 137,684 youths aged 0–19 years using ADHD medication between 2010 and 2022. Results: A significant decrease in overall ADHD medication dispensing prevalence rates per thousand youths was observed in 2022 compared to 2015 (35.2 vs. 45.7, p < 0.001). Methylphenidate accounted for approximately 87% of all ADHD medication dispensing. Incidence rates decreased significantly among children aged 7–12 from 2015 to 2022 (9 vs. 7.3, p < 0.001), while incidence rates increased significantly in adolescent youths (4 vs. 4.8, p = 0.008), particularly among adolescent females (3.5 vs. 5.3, p < 0.001). Females had lower prevalence rates and shorter durations of ADHD medication use compared to males, with no difference in daily dose observed. Conclusion: ADHD medication dispensing among Dutch youth declined following the 2015 implementation of the Youth Act. However, other factors such as the DSM-5 revision, COVID-19, and medication shortages likely contributed to this decrease, suggesting a multifactorial explanation for the observed changes in ADHD medication dispensing.

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. 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. Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, that 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.

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.