Study in young patients confirms value of short-term use; results on long-term use forthcoming.
A multicenter randomized, placebo-controlled trial now offers some of the strongest evidence to date that lithium — a long-established treatment for adults with bipolar disorder — can be both effective and generally safe for children and adolescents in the short term. The study, led by researchers associated with Johns Hopkins Children’s Center and published in Pediatrics, supports clinicians’ long-standing observations and gives physicians greater confidence in prescribing lithium for pediatric bipolar illness during acute episodes.
Lithium is one of the oldest and most well-known mood stabilizers for bipolar disorder, a chronic brain illness characterized by alternating manic and depressive episodes. While lithium’s efficacy in adults is well documented, rigorous clinical data for children and teens have been limited. Historically, children and women of childbearing potential have often been excluded from drug trials for ethical reasons and safety concerns, but that practice can leave clinicians without reliable evidence for treating these groups.
Robert Findling, M.D., M.B.A., professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine and director of child and adolescent psychiatry at Johns Hopkins Children’s Center, led the study after initiating the work while at Case Western Reserve University School of Medicine. The trial evaluated whether lithium would reduce manic symptoms in pediatric patients without producing the weight gain commonly linked to many antipsychotic medications used in youth.
The study enrolled 81 children and adolescents, ages 7 to 17, diagnosed with bipolar I disorder experiencing manic or mixed episodes. Conducted across nine academic centers in the United States, the trial followed a randomized, double-blind, placebo-controlled design. After washout of ineffective prior medications, 53 participants received lithium, titrated to a tolerated therapeutic dose over eight weeks; 28 received placebo. Symptoms were monitored weekly for the first month and biweekly thereafter using the Young Mania Rating Scale (YMRS) and other standard assessments. Investigators also recorded side effects, performed physical exams, and tracked weight.
Over the eight-week treatment period, participants randomized to lithium showed significantly greater reductions in manic symptoms than those on placebo. On the Clinical Global Impressions–Improvement scale, 47 percent of children receiving lithium were rated as “very much improved” or “much improved,” versus 21 percent of the placebo group. On the YMRS, lithium-treated patients dropped nearly six more points on average than those on placebo, a meaningful clinical difference.
Importantly, lithium in this trial was not associated with the substantial weight gain frequently seen with several antipsychotic agents such as risperidone or olanzapine, and no participants experienced serious adverse events directly attributed to lithium during the acute study period. The trial did detect a statistically significant increase in thyrotropin (TSH) concentrations among lithium-treated participants, a known potential effect of lithium that warrants monitoring. There was no statistically significant between-group difference for weight change.
Findling and colleagues conclude that lithium was superior to placebo for reducing manic symptoms in pediatric bipolar I disorder and was generally well tolerated over the acute eight-week treatment period. These findings provide clinicians with controlled-trial evidence to inform treatment decisions for youth with acute mania or mixed episodes, especially when concerns about metabolic side effects influence medication choice.
Longer-term safety and effectiveness remain important questions. The authors note that further analyses are underway to evaluate potential long-term effects of lithium in young patients, including monitoring for changes in kidney function, thyroid function, and weight over time — key considerations when a medication may be needed for years.
Bipolar disorder affects about 1 percent of adolescents and is a leading cause of disability in this age group. The illness often begins in adolescence or young adulthood, and early-onset bipolar disorder is frequently associated with a more severe course. Having evidence-based medication options for children and teens is therefore critical for effective, long-term management of the disorder.
Funding: The research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development under the Best Pharmaceuticals for Children Act Pediatric Off-Patent Drug Study: “Lithium in the Treatment of Pediatric Mania” (contract HHSN275200503406C).
Source: Taylor Graham – Johns Hopkins Medicine
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Original Research: Abstract for “Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study” by Robert L. Findling and colleagues, published in Pediatrics (online October 12, 2015).
Abstract
Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study
BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults, but definitive studies in pediatric bipolar I disorder (BP-I) have been lacking.
METHODS: This multicenter, randomized, double-blind, placebo-controlled trial enrolled participants ages 7–17 years with BP-I manic or mixed episodes. Lithium (n = 53) was compared with placebo (n = 28) for up to eight weeks. The primary efficacy measure was change from baseline to week 8 in Young Mania Rating Scale (YMRS) score, using last-observation-carried-forward analysis.
RESULTS: After adjusting for baseline YMRS, age group, weight group, sex, and site, the reduction in YMRS score was significantly greater in lithium-treated participants (adjusted difference 5.51; 95% CI: 0.51 to 10.50; P = .03). Clinical Global Impression–Improvement ratings favored lithium: 47% of lithium-treated patients were rated very much/much improved versus 21% on placebo (P = .03). Lithium treatment was associated with an increase in thyrotropin concentration compared with placebo (mean change 3.0 ± 3.1 mIU/L vs −0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant difference between groups in weight gain.
CONCLUSIONS: In this clinical trial, lithium was superior to placebo for reducing manic symptoms in pediatric patients with bipolar I disorder and was generally well tolerated without the weight gain commonly seen with other agents used to treat youth with bipolar disorder.
“Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study” by Robert L. Findling et al., Pediatrics. Published online October 12, 2015. doi:10.1542/peds.2015-0743