Five recent randomized controlled trials (RCTs) have demonstrated the efficacy of atypical antipsychotics for treating bipolar disorder in children and adolescents, but 4 of these 5 trials remain unpublished. The lag time between the completion of these trials and publication of their results—typically 4 to 5 years1—leaves psychiatrists without important evidence to explain to families and critics2 why they might recommend using these powerful medications in children with mental illness.
This article previews the preliminary results of these 5 RCTs of atypical antipsychotics, offers a treatment algorithm supported by this evidence, and discusses how to manage potentially serious risks when using antipsychotics to treat children and adolescents with bipolar disorder (BPD).
Where do atypical antipsychotics fit in?
Details of the 5 industry-sponsored RCTs of atypical antipsychotics in children and adolescents with bipolar I manic or mixed episodes are summarized in Table 1.3-7 Only the olanzapine study4 has been published; data from the other 4 trials were presented at medical meetings in 2007 and 2008.
Change in Young Mania Rating Scale (YMRS) score was the primary outcome measure in these 5 trials, and each compound was more effective than placebo. The trials demonstrated statistically significant and clinically relevant differences between each antipsychotic and placebo. The number needed to treat (NNT)—how many patients need to be treated for 1 to benefit in a controlled clinical trial—ranged from 2 to 4. For comparison, the NNT for statins in the prevention of coronary events is 12 to 22,8 and the NNT in an analysis of trials of selective serotonin reuptake inhibitors for pediatric major depressive disorder was 9.9 Thus, an NNT of ≤4 represents a clinically significant effect.
Risperidone is FDA-approved for short-term treatment of acute bipolar I manic or mixed episodes in patients age 10 to 17. Aripiprazole is approved for acute and maintenance treatment of bipolar I manic or mixed episodes (with or without psychosis) as monotherapy or with lithium or valproate in patients age 10 to 17. In June, an FDA advisory committee recommended pediatric bipolar indications for olanzapine, quetiapine, and ziprasidone.
‘Mood stabilizers’ such as lithium, valproate, and carbamazepine have been used for years to treat bipolar mania in adults, adolescents, and children, despite limited supporting evidence. Preliminary results of a National Institute of Mental Health-funded double-blind RCT provide insights on their efficacy.10
The 153 outpatients age 7 to 17 in a bipolar I manic or mixed episode were randomly assigned to lithium, divalproex, or placebo for 8 weeks. Response rates—based on a Clinical Global Impressions-Improvement score of 1 or 2 (very much or much improved)—were divalproex, 54%; lithium, 42%; and placebo, 29%. Lithium showed a trend toward efficacy but did not clearly separate from placebo on the primary outcome measures. Effect sizes for lithium and divalproex were moderate.10
Only 1 study has compared a mood stabilizer with an atypical antipsychotic for treating mania in adolescents. In a double-blind trial, DelBello et al11 randomly assigned 50 patients age 12 to 18 with a bipolar I manic or mixed episode to quetiapine, 400 to 600 mg/d, or divalproex, serum level 80 to 120 μg/mL, for 28 days. Manic symptoms resolved more rapidly, and remission rates measured by the YMRS were higher with quetiapine than with divalproex. Both medications were well tolerated.
Combination therapy. BPD as it presents in children and adolescents is often difficult to treat because of the disorder’s various phases (manic, depressed, mixed), frequent psychotic symptoms, and high rate of comorbidity. Pediatric BPD patients frequently require several psychotropics, including mood stabilizers and atypical antipsychotics.
In a double-blind, placebo-controlled study, 30 adolescents in a bipolar I manic or mixed episode initially received divalproex, 20 mg/kg/d, then were randomly assigned to 6 weeks of adjunctive quetiapine, titrated to 450 mg/d in 7 days (n=15), or placebo (n=15). Those receiving divalproex plus quetiapine showed a statistically significant greater reduction in manic symptoms (P=.03) and a higher response rate (87% vs 53%, P=.05), compared with those receiving divalproex and placebo. This suggests that a mood stabilizer plus an atypical antipsychotic is more effective than a mood stabilizer alone for adolescent mania. Quetiapine was well tolerated.12
Treatment. The American Psychiatric Association’s outdated 2002 practice guideline for acute bipolar I manic or mixed episodes in adults recommends lithium, valproate, and/or an antipsychotic.13 The more recent Texas Medication Algorithm Project (TMAP) guidelines recommend monotherapy with lithium, valproate, aripiprazole, quetiapine, risperidone, or ziprasidone for adults with euphoric or irritable manic or hypomanic symptoms.14