Ketamine for Treatment-Resistant Depression in Adolescents: A Systematic Review of Efficacy and Safety

Abstract

Introduction: Treatment-resistant depression (TRD) in adolescents—failure of ≥2 antidepressants—lacks evidence-based pharmacological options. Off-label ketamine shows rapid antidepressant effects in adults, but pediatric data are sparse. This review synthesizes available evidence on ketamine for adolescent TRD.

Methods: We searched PubMed, PsycINFO, ClinicalTrials.gov for prospective studies (RCTs, open-label, case series) of intravenous or intranasal ketamine/esketamine in adolescents (12–17 years) with TRD. Primary outcome: change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to 24 hours post-infusion. Secondary: response (≥50% reduction) and dissociative/adverse effects. No meta-analysis due to heterogeneity.

Results: Four studies (n=112 adolescents) were included: 2 small RCTs (placebo-controlled), 1 open-label, 1 retrospective case series. At 24 hours, MADRS reduction ranged from 12–18 points in ketamine groups vs. 2–5 points in placebo. Response rates: 55–65% for ketamine vs. 20–25% for placebo. Effects peaked at 24 hours and decayed by day 7. Dissociative symptoms occurred in 70–80% of ketamine recipients but resolved within 2 hours. Transient blood pressure increases (>20 mmHg) in 30%. No severe adverse events or emergence of psychosis.

Discussion: Ketamine shows rapid but transient antidepressant effects in adolescent TRD, with effect sizes comparable to adult data. The high dissociation rate is limiting, though no prolonged psychotomimetic effects were reported. Limitations: small samples, short follow-up (maximum 4 weeks), absence of repeated-dose protocols.

Conclusions: Evidence supports ketamine's acute efficacy for adolescent TRD, but effects are short-lived. Repeated-dose studies and longer-term safety monitoring are urgently needed before clinical adoption.