Lithium is the most studied medication for pediatric bipolar disorder and the only FDA-approved medication for treating acute mania and bipolar disorder in patients ages 12 to 18. Approximately 40 to 50% of children and adolescents with bipolar disorder respond to lithium monotherapy.18,19
In general, lithium should be titrated to 30 mg/kg/d in two or three divided doses; this typically produces a serum level of 0.8 to 1.2 mEq/L. Common side effects in children and adolescents include nausea, polyuria, polydipsia, tremor, acne, and weight gain. Lithium levels and thyroid function should be monitored, as in adult patients.
Only one prospective, placebo-controlled study has examined lithium use in children and adolescents with bipolar disorders. Twenty-five adolescents with comorbid bipolar and substance use disorders were treated with lithium or placebo for 6 weeks. Positive urine toxicology screens decreased significantly, and global assessment of functioning improved in 46% of those receiving lithium vs. 8% of those receiving placebo.13 This study demonstrated lithium’s efficacy in treating bipolar adolescents with comorbid substance abuse but did not measure its effect on mood.
Risk factors for poor lithium response in children and adolescents with bipolar disorder include prepubertal onset and comorbid ADHD.20
Divalproex. No placebo-controlled studies of antiepileptics in pediatric bipolar disorder have been published. Open-label studies of divalproex have reported response rates of 53 to 82% in manic adolescents.18, 21-23 Several case reports and series have described successful use of carbamazepine as monotherapy and adjunctive treatment in children and adolescents with bipolar disorder.24,25
Table 4
RATES OF COMMON COMORBIDITIES IN PEDIATRIC BIPOLAR DISORDERS
| Disorder | Children (prepubertal) | Adolescents |
|---|---|---|
| ADHD | 70 to 90% | 30 to 60% |
| Anxiety disorders | 20 to 30% | 30 to 40% |
| Conduct disorders | 20 to 30% | 30 to 50% |
| Oppositional defiant disorder | 60 to 80% | 20 to 30% |
| Substance abuse | 10% | 40 to 80% |
| Learning disabilities | 30 to 40% | 30 to 40% |
One 6-week, random-assignment, prospective study compared lithium, divalproex, and carbamazepine in treating 42 acutely manic or hypomanic patients ages 8 to 18.18 In this open study, all three mood stabilizers demonstrated efficacy in treating a mixed or manic episode in youths with bipolar I or II disorder. Response rates—based on a 50% improvement in Young Mania Rating Scale baseline scores—were divalproex 53%, lithium 38%, and carbamazepine 38%.
In general, divalproex is started at 20 mg/kg/d, which typically produces a serum level of 80 to 120 μg/ml. Common side effects in children include weight gain, nausea, sedation, and tremor.
A possible association between divalproex and polycystic ovary syndrome (PCOS) has been reported in women with epilepsy.26 The mechanism for PCOS has been hypothesized to be obesity secondary to divalproex, resulting in elevated insulin and androgen levels. Recently, Rasgon et al27 reported that epilepsy—and not the anticonvulsants used to treat it—may increase the risk of PCOS. In contrast, O’Donovan et al reported higher rates of menstrual irregularities and PCOS in women with bipolar disorder who were taking divalproex than in those who were not taking divalproex and in healthy controls.28
Until we learn more about this association, clinicians should monitor bipolar female adolescents treated with divalproex for any signs of PCOS, which include menstrual abnormalities, hirsutism, and acne.
Carbamazepine is used widely for seizure management but less commonly than divalproex in pediatric bipolar disorder. This anticonvulsant must be titrated slowly and requires frequent monitoring of blood levels, which can be a problem in children with needle phobia.
Carbamazepine is usually titrated to 15 mg/kg/d to produce a serum level of 7 to 10 μg/ml. Its most common side effects are sedation, rash, nausea, and hyponatremia. Aplastic anemia and severe dermatologic reactions, such as Stevens-Johnson syndrome, occur uncommonly.28
Atypical antipsychotics. Recent case series and open-label reports suggest that atypical antipsychotics such as clozapine,29 risperidone,30 olanzapine,31-33 and quetiapine16 are effective in treating pediatric bipolar disorder. However, clinically significant weight gain may be associated with the use of olanzapine and risperidone.34 Ziprasidone may increase QTc prolongation, and safety data are limited in children and adolescents. Therefore, ziprasidone should be used with caution in pediatric bipolar disorder, and ECGs should be monitored.
In the only double-blind, placebo-controlled study of an atypical antipsychotic in pediatric bipolar disorder, manic symptoms were more greatly reduced in 15 adolescents given quetiapine plus divalproex than in 15 patients who received divalproex alone. Quetiapine was titrated to 450 mg/d across 7 days and was well-tolerated. The findings suggest that a mood stabilizer plus an atypical antipsychotic may be more effective than a mood stabilizer alone for treating adolescent mania.16
Long-term treatment
In addition to treating acute affective episodes, lithium may also help prevent recurrent affective episodes in younger patients. In the only maintenance treatment study for pediatric bipolar disorder, Strober et al prospectively evaluated 37 adolescents whose bipolar disorder had been stabilized with lithium during hospitalization.17 After 18 months of follow-up, 35% of patients had discontinued lithium, and their relapse rate was 92% (compared with 38% in patients who were lithium-compliant.