Lithium Effective for Bipolar Disorder in Children

Pam Harrison

October 21, 2015

Lithium is as effective for the treatment of manic or mixed episodes in pediatric patients with bipolar I disorder as it is in adults, as indicated by the first large, randomized, double-blind study of its kind.

"Lithium is the gold standard or benchmark treatment for adults with bipolar illness, but prior to this study, there have not been any methodologically rigorous studies that have looked at the efficacy of lithium in young patients with bipolar illness," Robert Findling, MD, the Johns Hopkins University/Kennedy Krieger Institute, Baltimore, Maryland, told Medscape Medical News.

"And we found that the treatment effect size was about the same in this study as has been previously described in adults, so this suggests that the efficacy of lithium transfers across the life cycle."

The study was published online October 12 in Pediatrics.

Randomized Trial

The first multicenter, randomized, double-blind, placebo-control acute efficacy trial of lithium in children with bipolar I disorder currently in a manic or mixed episode involved a total of 81 patients aged 7 to 17 years.

Fifty-three patients were assigned to receive lithium; 28 were assigned to receive placebo.

Initially, the use of a concomitant psychostimulant was precluded, but to enhance recruitment and retention, participants with comorbid attention-deficit/hyperactivity disorder were allowed to receive psychostimulants after 4 weeks of double-blind therapy, at the treating physician's discretion.

The starting dose of lithium was either 600 or 900 mg/day of regular-release capsules.

For participants weighing less than 30 kg, therapy was initiated at the lower dose, but for all other participants, therapy was initiated at the 900 mg/day dose.

Doses could be increased by 300 mg/day during the middle of the first week of randomization if the patient met dosing response criteria.

The mean daily dose for patients aged 7 to 11 years was 1292 mg; for patients aged 12 to 17 years, the mean daily dose was 1716 mg.

Adherence rates were higher than 90% in both treatment groups.

The primary outcome was change from baseline to study end point at week 8 on the Young-Mania Rating Scale (YMRS) score, as determined on the basis of last-observation-carried-forward analysis.

Change in the YMRS score was significantly greater at 8 weeks in patients who received lithium after adjusting for baseline YMRS, age group, weight group, sex, and study site (P = .03), the investigators note.

Numerically, the mean YMRS score at week 8 was 17.8 for patients receiving lithium vs 22.3 for those receiving placebo.

After adjusting for baseline YMRS score, age, weight group, sex, and study site, the treatment effect size was 5.51.

The mean decrease in the Children's Depression Rating Scale–Revised from baseline was 5.5 for patients receiving lithium vs 6.8 for patients receiving placebo (P = .49). The Children's Global Assessment Scale score increased to 9.5 for those receiving lithium compared with 8.5 for those receiving placebo, suggesting an improvement in global functioning.

Scores on the Clinical Global Impression–Severity scale (CGI-S) for overall illness severity decreased by at least two points from baseline to week 8 in 42% of the lithium group compared with 21% of the patients receiving placebo.

Thirty-two percent of patients receiving lithium met the response criteria of a 50% or greater reduction in the YMRS score from baseline and a Clinical Global Impression–Improvement scale score of 1 or 2 compared with 21% for patients receiving placebo.

Twenty-six percent of patients receiving lithium achieved remission at week 8 compared with 14% for patients receiving placebo.

Adverse Events

The most common adverse events (AEs) with lithium were vomiting, seen in 45% of patients; nausea, in 43%; and headache, in 36%.

The most common AEs among patients receiving placebo were headache, upper abdominal pain, nausea, and increased appetite.

As Dr Findling noted, making sure patients do not take lithium on an empty stomach and giving patients their highest dose of lithium in the evening helps mitigate any nausea and vomiting that patients may experience.

Weight gain of 0.9 kg was reported in the lithium group; this compares with weight gain of 1.2 kg in patients receiving placebo.

It is possible that longer-term treatment with lithium may affect weight more significantly, and researchers are in the process of following up this possibility further, said Dr Findling.

"No participants discontinued the study due to lack of tolerability," the investigators note.

The mean number of AEs per participant was 6.4 to 7.7 in the lithium group and 4 in the patients receiving placebo. Only two patients receiving lithium discontinued the study because of persistent psychosis.

In addition, there was a statistically significant increase in thyrotropin concentrations with lithium, at 3.0 mIU/L, compared with -0.1 mIU/L (P < .001).

"We know that lithium can affect thyroid function, so we wanted to make sure that lithium's impact on thyroid function we see in adults occurred in this patient population as well," said Dr Findling.

If thyroid production is affected in patients taking lithium, the dose of lithium can be decreased or the drug discontinued, or patients may be treated with thyroid hormone.

This work was sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Findling has consulted for Bristol-Myers Squibb, Lilly, Merck, Osaka, Pfizer, Sunovion, and Validus and has received research support from AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, Lilly, Merck, Otsuka, Pfizers, Sunovion, and Validus.

Pediatrics. Published online October 12, 2015. Abstract

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