Update on Treatment of Pediatric Bipolar Disorder

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Lithium

Although lithium has FDA approval for bipolar I disorder in youths aged 12 years and older, there have been no controlled trials of lithium for the treatment of youth with bipolar I disorder. Findling and colleagues¹ investigated the efficacy of lithium for the treatment of youths aged 7 to 17 years with bipolar I disorder, mixed or manic episode in an 8-week double-blind, placebo-controlled trial. Fifty-three youths were randomized to treatment with lithium, and 28 youths were randomized to placebo. The mean lithium serum level at study endpoint was 0.98 mEq/L.

The lithium-treated youths had a significantly greater change in Young Mania Rating Scale (YMRS) scores than the placebo recipients. On the basis of Clinical Global Impression-Improvement scores, 47% of lithium-treated youth were very much/much improved compared with 21% of placebo-treated youth.

The most common adverse effects of lithium were vomiting (45%), nausea (43%), and headache (36%). The dose of lithium was reduced in half of the youths who experienced vomiting. For patients who received placebo, headache (32%), upper abdominal pain (32%), nausea (18%), and increased appetite (18%) were the most common adverse effects. There was no statistically significant difference in weight gain between those who received lithium (0.9 kg) and those who received placebo (1.2 kg). There was a statistically significant increase in thyrotropin concentration (3 mIU/L) with lithium compared with placebo (-0.1 mIU/L).

This is the first double-blind, placebo-controlled trial to demonstrate the efficacy of lithium in children and adolescents with bipolar I disorder. Weight gain was not a significant issue in this trial, and lithium may be an alternative for youths who experience significant weight gain when treated with an atypical antipsychotic.

Asenapine

Asenapine recently received FDA approval for the treatment of bipolar I disorder in youths aged 10 to 17 years. The findings from the controlled trial of asenapine for the treatment of pediatric bipolar disorder were recently reported (N = 403).² Youths with bipolar I disorder, manic or mixed episode participated in a 3-week double-blind, placebo-controlled trial. Youths were randomized to asenapine 2.5 mg bid, 5 mg bid, or 10 mg bid, or to placebo. In each of the asenapine groups, the initial dosage of the medication was 2.5 mg bid for 3 days. Asenapine and the placebo were administered in the same formulation: a fast-dissolving sublingual tablet.

There was a statistically significant improvement in YMRS scores from baseline to day 21 for each dose of asenapine compared with placebo. Response rates (defined as a 50% or greater decrease from baseline YMRS score at day 21) ranged from 42% to 54% in the asenapine groups compared with 28% in the placebo group.

The combination of somnolence, sedation, and hypersomnia was significantly higher in the asenapine groups: 2.5 mg (47.1%), 5 mg (52.5%), and 10 mg (48.5%) compared with placebo (11.9%). Similarly, there was a significantly higher incidence of oral hypoesthesia with dysgeusia associated with asenapine. Treatment-emergent adverse events with an incidence of 5% or higher and at least twice that of placebo were somnolence, sedation, oral hypoesthesia, oral paresthesia, and increased appetite.

There was a significantly higher incidence of 7% or more weight gain in the asenapine groups (asenapine 2.5 mg [12.0%], asenapine 5 mg [8.9%], and asenapine 10 mg [8.0%]) compared with the placebo group (1.1%). Similarly, body mass index significantly increased in the asenapine groups. The mean changes from baseline in fasting insulin, metabolic parameters, and glucose were greater for asenapine-treated youth than for youth who received placebo. The incidence of akathisia and extrapyramidal symptoms was not higher in the asenapine groups.

This study provides evidence for the efficacy of asenapine in the acute treatment of pediatric bipolar I disorder for youths aged 10 years and older. As is the case with other atypical antipsychotics, it is important to monitor metabolic parameters during treatment.

Lamotrigine

Add-on lamotrigine for maintenance treatment of bipolar I disorder in youths aged 7 to 17 years was recently examined in a placebo-controlled, randomized withdrawal study.³ The trial comprised 298 youths who received adjunctive lamotrigine during an 18-week or shorter open-label study. Those youths who met stability criteria were randomized to lamotrigine (n = 86) or placebo (n = 87). The primary efficacy endpoint was time to occurrence of a bipolar event. There was no statistically significant difference between continued lamotrigine and placebo on this outcome measure. In a subset of 13- to 17-year-olds, lamotrigine delayed the time to occurrence of a bipolar event significantly more than for the 10- to 12-year-old group.

Suicidality-related events were higher in the lamotrigine group than in the placebo group. The majority of these adverse events were suicidal ideation, although there was one suicide attempt in the lamotrigine group. The adverse effect of dermatologic rash occurred more frequently in the lamotrigine group (4% open-label study and 2% randomized phase) than in the placebo group (1% randomized phase). One patient with lamotrigine added to valproate developed a rash that required hospitalization but was not diagnosed as Stevens-Johnson syndrome or toxic epidermal necrolysis.

This study does not support adjunctive lamotrigine for maintenance treatment of pediatric bipolar I disorder. Further study is necessary to determine whether adjunctive lamotrigine would be beneficial in older adolescents with bipolar I disorder.

Valproic acid vs risperidone

There is minimal information about mood stabilizers in the treatment of bipolar disorder in young children. A recent study compared the efficacy and safety of valproic acid with that of risperidone in children aged 3 to 7 years with bipolar I disorder, manic, hypomanic, or mixed episode.⁴ Children (N = 46) were randomized to risperidone solution, valproic acid, or placebo in a 6-week, double-blind, placebo-controlled trial.

Medication and placebo were administered in liquid form. The mean dosage of risperidone at endpoint was 0.5 mg daily (range, 0.5 to 0.75 mg/d), and the mean dosage of valproic acid was 300 mg daily with a mean serum level of 81 μg/mL.

There was a significantly greater improvement in YMRS scores from baseline for children who received risperidone but not those who received valproic acid, compared with those who received placebo. Overall, 88% of children who received risperidone and 50% of children who received valproic acid were rated as much or very much improved. No improvement was seen in the children who received placebo. Clinical response for the risperidone group was demonstrated by weeks 2 to 3 and for the valproic acid group by weeks 4 to 5.

Over the 6-week period, treatment with risperidone led to increased prolactin levels, weight, and body mass index as well as higher liver function and metabolic measures. Mean prolactin levels in the risperidone group were 7.4 ng/mL at baseline and 53.9 ng/mL at endpoint; no clinical symptoms related to prolactin elevation were evident. Valproic acid treatment led to increased weight and body mass index, and decreased total red blood cells, hemoglobin level, hematocrit, and albumin level. Mood lability was associated with higher plasma levels of valproic acid.

This study showed that risperidone was more effective and produced an earlier clinical response than valproic acid in the treatment of bipolar disorder in young children. Because the study is small, the results are preliminary. The diagnosis of bipolar I disorder in young children is clinically challenging, and it is critical that the diagnosis be firmly established before treatment with mood stabilizers is considered.

The adverse effects of both risperidone and valproic acid that occurred within the 6-week timeframe demonstrate that frequent laboratory monitoring is necessary when young children are treated with mood stabilizers.

Disclosures:

Dr Wagner is Titus H. Harris Chair, Harry K. Davis Professor, Professor and Chair in the department of psychiatry and behavioral sciences at the University of Texas Medical Branch at Galveston.

References:

1. Findling RL, Robb A, McNamara NK, et al. Lithium in the acute treatment of bipolar I disorder: a double-blind, placebo-controlled study. Pediatrics. 2015;136:885-894.

2. Findling RL, Landbloom RL, Szegedi A, et al. Asenapine for the acute treatment of pediatric manic or mixed episode of bipolar I disorder. J Am Acad Child Adolesc Psychiatry. 2015;54:1032-1041.

3. Findling RL, Chang K, Robb A, et al. Adjunctive maintenance lamotrigine for pediatric bipolar I disorder: a placebo-controlled, randomized withdrawal study. J Am Acad Child Adolesc Psychiatry. 2015;54:1020-1031.

4. Kowatch RA, Scheffer RE, Monroe E, et al. Placebo-controlled trial of valproic acid versus risperidone in children 3-7 years of age with bipolar I disorder. J Child Adolesc Psychopharmacol. 2015;25:306-313.