Bipolar disorder affects approximately 1-3% of children and adolescents and is associated with substantial morbidity and an increased risk of suicide. Lithium is a first-line maintenance treatment for bipolar disorder with well-established antimanic, antidepressant, and anti-suicidal effects in adults. Despite its proven efficacy and prominent position in international treatment guidelines, its use remains limited in children and adolescents. In the Netherlands, lithium was dispensed to only 0.01% of youths in 2022. Ongoing concerns regarding thyroid dysfunction, renal impairment, cognitive adverse effects are important barriers to its use.

To address these concerns, we analyzed data from 126 children and adolescents (8–18 years) with bipolar disorder participating in the Collaborative Lithium Trials (CoLT1 and CoLT2). Together, these studies represent one of the largest prospective cohorts of children receiving lithium, with up to one year of follow-up. Individual lithium exposure was estimated using population pharmacokinetic modelling in NONMEM and related to thyroid function, renal function, and cognitive performance.

Lithium demonstrated an acceptable safety profile across the observed exposure range, including in patients with concentrations exceeding the commonly applied adult therapeutic range (>1.2 mmol/L). Higher lithium exposure was associated with modest increases in thyroid-stimulating hormone (TSH), particularly during the early phase of treatment (week 4; Kendall’s τ = 0.17–0.19, p < 0.05). These associations became less pronounced during follow-up. Furthermore, no exposure-dependent associations were observed for renal function or cognitive performance.

These findings challenge common perceptions regarding lithium toxicity in children and adolescents. Despite ongoing safety concerns, lithium was generally well tolerated across the observed exposure range, including in patients with concentrations exceeding the commonly applied adult therapeutic range. Together, these findings support a more balanced assessment of the risks and benefits of lithium and encourage greater consideration of its use in pediatric bipolar disorder.