Use of lithium in pediatric bipolar disorders and externalizing childhood- related disorders: a systematic review of randomized controlled trials

Background: Lithium is the standard treatment for bipolar disorders (BD) in adults. There is dearth of data on its use in pediatric age. This review aimed to investigate the use of lithium in pediatric bipolar disorder (BD) and other externalizing childhood-related disorders. Methods: We applied the Preferred Reporting Items for Systematic Reviews and Meta- analyses criteria (PRISMA) to identify randomized controlled trials evaluating the use of lithium in pediatric (BD), conduct disorder (CD), attention deficit hyperactivity disorder, oppositional defiant disorder, and disruptive mood dysregulation disorder. The primary outcome of our study was to evaluate the efficacy of lithium compared to placebo or other pharmacological agents. Secondary outcomes were acceptability and tolerability. Results: Twelve studies were eligible, 8 on BD and 4 on CD. Overall, 857 patients were treated with lithium. No studies for externalizing disorder diagnoses were identified. Regarding BD patients (n=673), efficacy results suggested that lithium was superior to placebo in manic/mixed episode but inferior to antipsychotics. Lithium efficacy ranged from 32% to 82.4%. Results on maintenance need to be expanded. Comorbidity rates with other externalizing disorders were extremely high, up to 98.6%. Results in CD patients (n= 184) suggested the efficacy of lithium, especially for aggressive behaviors. No severe adverse events directly related to lithium were reported in BD and CD; common side effects were similar to adults. Conclusions: This systematic review supports the use of lithium in BD and CD as an efficacious and generally well-tolerated treatment in pediatric age. However, evidence is limited due to paucity of available data.