Antipsychotics in Children and Adolescents with Schizophrenia-Spectrum Disorders: A Systematic Review, Meta-Analysis, and Long-Term Prospective Evidence

Objective: To compare the short-term efficacy and tolerability of second-generation antipsychotics (SGAs) versus placebo for schizophrenia-spectrum disorders in children and adolescents using pairwise meta-analysis of randomized trials, and to summarize prospective long-term evidence.

Methods: We pooled acute double-blind randomized controlled trials (RCTs) (<= 12 weeks; participants <= 19 years; Diagnostic and Statistical Manual of Mental Disorders [DSM]/International Classification of Diseases [ICD] schizophrenia-spectrum) with random-effects models. Efficacy was change in Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale [BPRS] total score, expressed as standardized mean difference (SMD) versus placebo. Short-term tolerability was defined as adverse event-related outcomes and expressed as risk ratios (RRs) for potentially drug-related treatment-emergent adverse events (TEAEs) versus placebo. Trials without a placebo arm and long-term prospective studies were synthesized narratively.

Results: Seventeen acute RCTs were identified; ten were placebo-controlled and entered pooling (agents: olanzapine [OLZ], risperidone [RSP], asenapine [ASP], aripiprazole [APZ], brexpiprazole [BRX], blonanserin [BNS], quetiapine [QTP], lurasidone [LUR], paliperidone [PAL], ziprasidone [ZPD]); seven head-to-head or open-label trials were not pooled. Placebo-referenced efficacy favored several agents: OLZ -1.12 [-1.44 to -0.81], RSP -0.93 [-1.22 to -0.63], BNS -0.50 [-0.89 to -0.11], ASP -0.41 [-0.65 to -0.17], APZ -0.37 [-0.61 to -0.13], BRX -0.34 [-0.61 to -0.07], QTP -0.33 [-0.61 to -0.06], LUR -0.31 [-0.54 to -0.08], PAL -0.25 [-0.57 to -0.07], and ZPD -0.06 [-0.31 to -0.19]. For tolerability, most drugs showed numerically higher TEAE risk versus placebo with wide confidence intervals (typical RR approximate to 2-3); APZ showed a statistically higher risk (RR 2.34 [1.42-3.86]), whereas the point estimate for LUR was below 1 (0.47 [0.18-1.17]). One randomized maintenance study and 12 open-label extensions were reviewed narratively and were not meta-analyzed.

Conclusions: Several SGAs produce short-term symptom reductions versus placebo in children and adolescents with schizophrenia-spectrum disorders, with heterogeneity in TEAE risk across agents. Evidence for long-term maintenance and continuation remains limited, underscoring the need for adequately powered randomized continuation trials to guide sustained treatment in this population.