Systematic Review and Network Meta-Analysis: Efficacy and Safety of Antipsychotics vs Antiepileptics or Lithium for Acute Mania in Children and Adolescents

Objective

To compare second-generation antipsychotics (SGAs) and mood stabilizers (MSs) in youth with a bipolar disorder type I (BD-I) manic/mixed episode.

Method

A systematic PubMed/Embase/PsycInfo literature search until December 31, 2023, for randomized trials of SGAs or MSs in patients ≤18 years of age with BD-I manic/mixed episode was conducted. The study included a network meta-analysis comparing treatments regarding mania symptoms and mania response (co-primary outcomes), and secondary efficacy and tolerability outcomes.

Results

Eighteen studies (n = 2844, mean age = 11.74, female participants = 48.0%, mean study duration = 5.4 weeks) comparing 6 SGAs (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and ziprasidone) and 4 MSs (lithium, oxcarbazepine, topiramate, and valproate) were meta-analyzed. All 6 SGAs outperformed placebo in reducing manic symptomatology, including risperidone (standardized mean difference [SMD] = −1.18, 95% CI = −0.92, −1.45, Confidence in Network Meta-Analysis [CINeMA] = moderate confidence), olanzapine (SMD = −0.77, 95% CI = −0.36, −1.18, low confidence), aripiprazole (SMD = −0.67, 95% CI = −0.33, −1.01, moderate confidence), quetiapine (SMD = −0.60, 95% CI = −0.32, −0.87, high confidence), asenapine (SMD = −0.54, 95% CI = −0.19, −0.89, moderate confidence), and ziprasidone (SMD = −0.43, 95% CI = −0.17, 0.70, low confidence), whereas no mood stabilizer outperformed placebo. Concerning mania response, risperidone (Risk ratio [RR] = 2.58, 95% CI = 1.88, 3.54, low confidence), olanzapine (RR = 2.42, 95% CI = 1.33, 3.54, very low confidence), aripiprazole (RR = 2.05, 95% CI = 1.44, 2.92, low confidence), quetiapine (RR = 1.89, 95% CI = 1.45n 2.47, moderate confidence), asenapine (RR = 1.81, 95% CI = 1.28, 2.55, very low confidence) and lithium (RR = 1.35, 95% CI = 1.00, 1.83, p = .049, very low confidence) outperformed placebo, without superiority of other MSs vs placebo. Individually, risperidone was more efficacious in reducing manic symptomatology than all other comparators, except olanzapine and topiramate, yet with low/very low confidence, and was associated with increased prolactin and glucose. Pooled together, SGAs outperformed both placebo and MSs for mania symptom reduction (SMD = −0.68, 95% CI = −0.86, −0.51 and SMD = −0.61, 95% CI = −0.82, −0.40, moderate confidence), and mania response (RR = 1.85, 95% CI = 1.53, 2.24 and RR = 1.65, 95% CI = 1.33, 2.04, moderate confidence) without differences between MSs and placebo. There were no significant treatment−placebo differences for all-cause discontinuation, whereas lithium, ziprasidone, and oxcarbazepine were associated with more adverse event-related drop-outs than placebo. Most SGAs were associated with more sedation, weight gain, and metabolic issues vs placebo and MSs.

Conclusion

SGAs were more efficacious than placebo and MSs in treating acute mania symptoms, however, their use must be carefully weighed against important side effects.

Plain language summary

In this systematic review, the authors compared second-generation antipsychotics and mood stabilizers in youth with bipolar disorder type I experiencing manic or mixed episodes. Drawing on data from 18 randomized trials involving 2,844 participants less than 18 years of age, the authors found that second-generation antipsychotics were more effective than both placebo and mood stabilizers in reducing manic symptoms. However, the authors recommended caution while using second-generation antipsychotics due to potential side effects such as sedation, weight gain, and metabolic issues.

Study preregistration information

Efficacy and Safety of Antipsychotics vs Antiepileptics or Lithium Used for Mood Stabilization in Bipolar Disorder in Children and Adolescents: A Systematic Review and Exploratory Network Meta-analysis of Head-to-Head Trials; https://www.crd.york.ac.uk; CRD42022370915.