Ketamine use in pediatric depression: A systematic review

The investigators performed a comprehensive literature search from database inception to June 2022, searching PubMed/Medline and Scopus under PRISMA guidance and supplementing the search with Google Scholar and manual reference checks. Keywords combined terms for ketamine/esketamine, depression, and child/adolescent/pediatric synonyms; no language or publication-date restrictions were applied. Screening and eligibility followed a two-step process by two independent reviewers: initial title/abstract screening followed by full-text review. Inclusion criteria required studies to (1) involve ketamine administration, (2) be in patients aged ≤18 years, (3) include participants with MDD or treatment-resistant depression (TRD), and (4) have the primary aim of treating depression. Exclusions were non-peer-reviewed abstracts, conference abstracts, unpublished datasets, systematic reviews, in vitro studies and animal studies. For each eligible manuscript the reviewers extracted year of publication, number and age of patients, ketamine dose and route, study outcomes and main findings, response definitions, comorbid medical conditions, concomitant and prior medications. The search yielded 1,966 records; after duplicate removal and title/abstract screening 12 full texts were reviewed, six of which met inclusion criteria and were included in the review. Included studies encompassed case reports, open-label trials and a single randomised clinical trial. The authors collated study characteristics (sample sizes, dosing regimens, duration, outcome measures) and reported safety/tolerability findings; the extracted text does not indicate use of a formal risk-of-bias instrument nor meta-analytic pooling, and no meta-analysis is described in the available extraction.

Six studies involving a total of 46 paediatric patients (mean age 15.7 years, range 12–18) met inclusion criteria. All included studies were conducted in the USA and published between 2017 and 2021. Study designs comprised three case reports, two open-label trials and one randomised, double-blind, single-dose crossover clinical trial. Most studies administered intravenous (IV) ketamine at 0.5 mg/kg; one study reported a continuous infusion regimen with dosing described inconsistently in the extracted text (reported variously as 2–7 mcg/kg/min or 2–7 mg/kg/min), so the exact dosing unit could not be clarified from the extraction. Treatment courses ranged from a single dose to repeated infusions over periods from 5 days to 8 weeks. Case reports (three cases) described rapid and clinically meaningful improvements in depressive symptoms and suicidality. One report described a 14-year-old female with severe depression and multiple medical comorbidities who received a continuous ketamine infusion for 5 days and experienced notable symptom improvement from day one and about five months of relief after the first infusion; the extracted text emphasises that the continuous, pain-focused infusion paradigm complicated attribution of mood benefit solely to ketamine’s antidepressant effect. A 16-year-old male received seven 0.5 mg/kg infusions across an eight-week hospitalisation and showed rapid reduction in depression and suicidal ideation after the first infusion. A 15-year-old with psychotic depression received six 0.5 mg/kg infusions over 3 weeks and was discharged one month later without depressive, psychotic or suicidal symptoms. The randomised crossover trial enrolled 17 adolescents aged 13–17 with MDD. Participants received a single IV infusion of ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), crossing over to the alternate agent two weeks later. The primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) score at 24 hours. Ketamine produced a significant reduction in depressive symptoms at 24 hours compared with midazolam, with therapeutic benefits reportedly lasting up to 14 days. Ketamine induced a higher proportion of responders in the first three days post-infusion compared with midazolam. Adverse effects were mainly brief, self-limiting dissociative symptoms; no serious adverse events were reported. One open-label trial enrolled 13 adolescents (mean age 16.9 years) who received six 0.5 mg/kg infusions over 2 weeks. Clinical response (defined as ≥50% decrease on the Children’s Depression Rating Scale–Revised, CDRS-R) was achieved by five participants (38%), and the mean CDRS-R reduction was 42.5%. At 6-week follow-up three responders remained in remission while two relapsed within two weeks. Infusions were generally well tolerated; dissociative and haemodynamic effects were transient. The second open-label study included 11 participants who also received six 0.5 mg/kg infusions over 2 weeks and combined clinical assessment with neurobiological measures. Responders showed baseline-to-post increases in nucleus accumbens resting-state fMRI (rs-fMRI) entropy and increased post-treatment insulin-stimulated activation of mTOR and GSK3β in peripheral blood mononuclear cells; these changes were reported as responder-specific rather than generalised ketamine effects. Across human studies the main adverse events were transient dissociation and transient haemodynamic changes; the extracted text reports no severe adverse events in the included paediatric studies. Animal literature cited by the authors, however, documented mixed findings: several adolescent-animal studies demonstrated antidepressant-like effects of ketamine, whereas other studies reported learning and memory impairment, increased apoptosis and neurodegenerative changes in developing rodent brains at higher or repeated doses. The extracted text also summarises small-scale paediatric work using intranasal ketamine in other psychiatric presentations (for example a ‘‘fear-of-harm’’ phenotype of bipolar disorder and behavioural dysregulation in a child with PTSD), which reported symptomatic improvements and tolerability but were not trials focused primarily on MDD.

Meshkat and colleagues interpret the assembled evidence as cautiously encouraging: paediatric studies to date suggest ketamine can produce rapid reductions in depressive symptoms and may be well tolerated without serious adverse events in the short term. The authors note consistency with adult findings that repeated and higher-dose protocols tended to yield better responses in their review. They emphasise, however, that the paediatric literature is very limited in quantity and quality—dominated by case reports, small open-label series and a single small crossover RCT—so definitive conclusions about efficacy and safety cannot be drawn. Safety concerns receive particular attention. Although the included clinical studies reported mainly transient, self-limiting adverse effects, the authors highlight animal data indicating potential neurotoxicity of high-dose ketamine on the developing brain and acknowledge that risks associated with multiple or long-term exposures in children remain insufficiently characterised. The review therefore calls for careful monitoring of misuse potential and long-term adverse effects if ketamine use becomes more widespread in paediatric practice. Methodological limitations are acknowledged: small sample sizes, heterogenous dosing and administration regimens, and all included human studies using IV administration. The authors recommend future research priorities that include larger, well-powered randomised trials, examination of non‑IV formulations (for example intranasal or oral), evaluation of ketamine’s effects on anhedonia and suicidality in youth, and further mechanistic work. They also suggest considering alternative neuroimaging modalities—functional near-infrared spectroscopy is mentioned as potentially more feasible than fMRI for some young patients. Finally, the authors point to ongoing clinical trials registered in NIH registries as evidence that the field is expanding but stress the urgent need to characterise long-term safety and misuse risk in paediatric populations.

The authors conclude that while the current paediatric ketamine literature is limited and constrained by small, non-definitive studies, the available data are promising: ketamine administration may substantially reduce depressive symptoms in children and adolescents and has a rapid onset of effect. They call for larger randomised studies, expansion to non‑intravenous formulations, and detailed characterisation of long-term safety and misuse risk before ketamine can be recommended more broadly for paediatric depression. The potential anti‑suicidal effects observed in adults are highlighted as particularly relevant for youth and warrant targeted investigation.