Acute Treatment of Mania in Children and Adolescents
Acute Treatment of Mania in Children and Adolescents
Traditionally, mood stabilizers with or without antipsychotics have been used in treating children and adolescents who have various phases of bipolar disorder. Evidence of their efficacy in the acute treatment of mania comes predominantly from open-label trials and a few RCTs. Efficacy of mood stabilizers in treating children and adolescents who have bipolar disorder has been the subject of recent reviews and the following summary of their efficacy in mania is derived from them and supplemented by more recent trials. We identified 20 published trials that have featured at least one mood stabilizer (lithium carbonate, sodium valproate/divalproex sodium, carbamazepine, oxcarbamazapine, lamotrigine and topiramate) in at least one treatment arm.
We found three published RCTs of mood stabilizers (one each for extended release valproate, oxcarbazepine and topiramate) for children and adolescents who have acute mania. Sample sizes ranged from 56 (topiramate) to 150 (extended release valproate). Participants were between 10 and 17 years old in the extended release valproate trial with the oxcarbazepine and topiramate trials extending down to 7 and 6 years, respectively. Participants met criteria for bipolar I and were experiencing a manic or mixed episode. The trials commonly permitted inclusion of patients who had comorbidity with ADHD, ODD, conduct disorder and anxiety, but excluded other psychiatric conditions. Trials ranged in duration from 28 to 49 days. The trials also permitted concurrent treatment with psychostimulant and rescue medications such as lorazepam. Response in two trials (extended release valproate and oxcarbazepine) was defined as a 50% reduction in scores on the Young Mania Rating Scale, whereas, in the topiramate trial, response was defined as much improved or very much improved on the Clinical Global Impression (CGI) scale. None of the trials favoured active treatment over placebo as differences in response rates failed to achieve statistical significance. Response rates to active treatment ranged from 24 to 42%, whereas response to placebo ranged from 22 to 26%. We were able to calculate NNT for each trial and they are summarized in Table 3 .
There were no RCTs examining the efficacy of other mood stabilizers (lithium, carbamazapine, standard-release valproate and lamotrigine) in the acute treatment of mania in children and adolescents. There were, however, eight monotherapy open-label trials including three with lithium, three with standard-release valproate and one each with carbamazepine extended release and lamotrigine. Sample sizes ranged from 30 to 100. Participant ages ranged from 4 to 19 years. Participants met criteria for bipolar I in most trials and were experiencing manic or mixed episodes. Trials commonly permitted ADHD, ODD, conduct disorder anxiety comorbidity but excluded other psychiatric conditions and ranged in duration from 2 to 26 weeks. The lithium trials used target serum levels of 0.6–1.2mEq/l and the divalproex sodium trials target levels at 80–125 μg/ml. Response rates (50% reduction in scores on the Young Mania Rating Scale, and in one study improved or very much improved on the CGI scale) to the mood stabilizers ranged from 44 to 73%. These trials did not report on remission rates.
The adverse effects of mood stabilizer use with children and adolescents has been the subject of recent reviews. Although the data on the side effects were sparser for mood stabilizers than for antipsychotics, mood stabilizers were found to cause less weight gain and metabolic effects than antipsychotics when used to treat bipolar disorder including acute mania in children and adolescents. In Table 4 , we report the combined data on adverse events from open-label trials and RCTs for each drug.
Three RCTs have compared mood stabilizers with each other or with SGAs in the acute treatment of mania in children and adolescents. One RCT (50 people aged 12–18 years with mania treated for 4 weeks) found an 84% response rate in patients treated with a medicine in the quetiapine group compared with a 56% response rate in those treated with divalproex. In addition, the quetiapine group showed a more rapid resolution of manic symptoms. One RCT (66 children and adolescents with mania treated for 6 weeks) found a 78.1% response/62.5% remission rate for those treated with risperidone compared with a 45.5% response/33.3% remission rate for those treated with valproate. One RCT (279 people aged 6–15 years with mania treated for 8 weeks) found response rates to risperidone, lithium or valproate of 68.5, 35.6 and 24%, respectively. We were able to calculate NNT for SGAs versus mood stabilizers and they are summarized in Table 5 .
Mood Stabilizers
Traditionally, mood stabilizers with or without antipsychotics have been used in treating children and adolescents who have various phases of bipolar disorder. Evidence of their efficacy in the acute treatment of mania comes predominantly from open-label trials and a few RCTs. Efficacy of mood stabilizers in treating children and adolescents who have bipolar disorder has been the subject of recent reviews and the following summary of their efficacy in mania is derived from them and supplemented by more recent trials. We identified 20 published trials that have featured at least one mood stabilizer (lithium carbonate, sodium valproate/divalproex sodium, carbamazepine, oxcarbamazapine, lamotrigine and topiramate) in at least one treatment arm.
We found three published RCTs of mood stabilizers (one each for extended release valproate, oxcarbazepine and topiramate) for children and adolescents who have acute mania. Sample sizes ranged from 56 (topiramate) to 150 (extended release valproate). Participants were between 10 and 17 years old in the extended release valproate trial with the oxcarbazepine and topiramate trials extending down to 7 and 6 years, respectively. Participants met criteria for bipolar I and were experiencing a manic or mixed episode. The trials commonly permitted inclusion of patients who had comorbidity with ADHD, ODD, conduct disorder and anxiety, but excluded other psychiatric conditions. Trials ranged in duration from 28 to 49 days. The trials also permitted concurrent treatment with psychostimulant and rescue medications such as lorazepam. Response in two trials (extended release valproate and oxcarbazepine) was defined as a 50% reduction in scores on the Young Mania Rating Scale, whereas, in the topiramate trial, response was defined as much improved or very much improved on the Clinical Global Impression (CGI) scale. None of the trials favoured active treatment over placebo as differences in response rates failed to achieve statistical significance. Response rates to active treatment ranged from 24 to 42%, whereas response to placebo ranged from 22 to 26%. We were able to calculate NNT for each trial and they are summarized in Table 3 .
There were no RCTs examining the efficacy of other mood stabilizers (lithium, carbamazapine, standard-release valproate and lamotrigine) in the acute treatment of mania in children and adolescents. There were, however, eight monotherapy open-label trials including three with lithium, three with standard-release valproate and one each with carbamazepine extended release and lamotrigine. Sample sizes ranged from 30 to 100. Participant ages ranged from 4 to 19 years. Participants met criteria for bipolar I in most trials and were experiencing manic or mixed episodes. Trials commonly permitted ADHD, ODD, conduct disorder anxiety comorbidity but excluded other psychiatric conditions and ranged in duration from 2 to 26 weeks. The lithium trials used target serum levels of 0.6–1.2mEq/l and the divalproex sodium trials target levels at 80–125 μg/ml. Response rates (50% reduction in scores on the Young Mania Rating Scale, and in one study improved or very much improved on the CGI scale) to the mood stabilizers ranged from 44 to 73%. These trials did not report on remission rates.
The adverse effects of mood stabilizer use with children and adolescents has been the subject of recent reviews. Although the data on the side effects were sparser for mood stabilizers than for antipsychotics, mood stabilizers were found to cause less weight gain and metabolic effects than antipsychotics when used to treat bipolar disorder including acute mania in children and adolescents. In Table 4 , we report the combined data on adverse events from open-label trials and RCTs for each drug.
Three RCTs have compared mood stabilizers with each other or with SGAs in the acute treatment of mania in children and adolescents. One RCT (50 people aged 12–18 years with mania treated for 4 weeks) found an 84% response rate in patients treated with a medicine in the quetiapine group compared with a 56% response rate in those treated with divalproex. In addition, the quetiapine group showed a more rapid resolution of manic symptoms. One RCT (66 children and adolescents with mania treated for 6 weeks) found a 78.1% response/62.5% remission rate for those treated with risperidone compared with a 45.5% response/33.3% remission rate for those treated with valproate. One RCT (279 people aged 6–15 years with mania treated for 8 weeks) found response rates to risperidone, lithium or valproate of 68.5, 35.6 and 24%, respectively. We were able to calculate NNT for SGAs versus mood stabilizers and they are summarized in Table 5 .
