An Individual Participant Data Analysis: Optimizing Pharmacological Treatment in Children and Adolescents With Major Depressive Disorder

AI Summary

Individual characteristics (age, sex, ethnicity, BMI, symptom severity, family history) modify antidepressant efficacy and tolerability in paediatric major depressive disorder.
Fluoxetine showed superior efficacy for children, females, White participants, healthy weight individuals, and those with severe symptoms in acute treatment.
Findings require validation in diverse cohorts; universal suicide outcome assessment and regulatory reforms for subgroup reporting are urgently needed.

J Am Acad Child Adolesc Psychiatry. 2026 May 20:S0890-8567(26)00233-9. doi: 10.1016/j.jaac.2026.05.010. Online ahead of print.

ABSTRACT

OBJECTIVE: The influence of individual characteristics on antidepressant efficacy and tolerability in pediatric major depressive disorder (MDD) remains unclear. This study aimed to characterize subgroup-specific treatment efficacy and lay a preliminary scientific foundation for precision psychiatry in pediatric MDD management.

METHOD: An individual participant data (IPD) analysis of double-blind randomised trials (RCTs) was conducted to compare antidepressants with placebo for the acute treatment of MDD in children and adolescents. Subgroup analyses identified treatment outcome differences by participant characteristics, with mixed-effects models used to examine effect modifiers. Primary outcomes were efficacy (depressive symptom change, mean difference [MD]) and tolerability (adverse event-related withdrawals, odds ratio [OR]). Secondary outcomes included deterioration and suicide-related outcomes. The protocol is registered with PROSPERO (CRD42016051657).

RESULTS: IPD from ten RCTs (2,584 participants) on five antidepressants (fluoxetine [n=475], imipramine [n=95], paroxetine [n=413], desvenlafaxine [n=358], duloxetine [n=341]) and placebo [n=902] were analyzed. Fluoxetine demonstrated superior efficacy in children, female participants, White individuals, healthy weight participants and those with severe symptoms (MDs: -3.90 to -2.60). Paroxetine was effective in adolescents and participants with a healthy weight (MD=-2.59 and -2.92), but it was less well-tolerated among White participants, participants with mild/moderate symptoms and a family history of psychiatric disorders (ORs: 1.13 to 1.95). Fluoxetine also showed less deterioration in female participants (OR=0.55, 95% CI: 0.37 to 0.83). No significant differences in suicide-related outcomes were observed across subgroups based on individual characteristics. Most trials had “some concerns” for risk of bias.

CONCLUSION: These findings advance a preliminary understanding of the precision medicine framework for pediatric MDD, indicating that individual characteristics (age, sex, ethnicity, BMI, symptom severity, family history) may influence treatment outcomes. Exploratory subgroup analyses suggest fluoxetine’s efficacy may be more pronounced in certain populations: children, female participants, White individuals, healthy weight participants, and those with severe symptoms. These findings require validation in diverse cohorts. Universal suicide-related outcome assessment across all subgroups (regardless of individual characteristics) remains essential. The study advocates for regulatory reforms to promote subgroup analysis reporting in clinical trials, consistent with emerging precision psychiatry initiatives.

PMID:42167647 | DOI:10.1016/j.jaac.2026.05.010

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