Meta-analysis finds esketamine improves response in treatment-resistant depression with dose-dependent adverse events

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Frontiers in Medicine Published May 28, 2026 Medically reviewed May 28, 2026 DOI ↗ By Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

Key Takeaway

Consider personalized dosing of esketamine to balance efficacy and dose-dependent adverse events in treatment-resistant depression.

This meta-analysis of 9 randomized controlled trials involving 1,449 patients with treatment-resistant depression evaluated esketamine (nasal spray 28-84 mg or intravenous 0.20-0.40 mg/kg) versus control. The primary outcomes were incidence of adverse events, discontinuation due to adverse events, and clinical response or remission.

Esketamine significantly improved clinical response rate (RR=1.94). However, it also significantly increased the risk of nine adverse events including nausea, dissociation, dizziness, vertigo, elevated blood pressure, and somnolence (P<0.05). Risks were dose-dependent: for nausea, high-dose RR=3.72 vs low-dose RR=1.69; for dissociation, high-dose RR=10.65 vs low-dose RR=3.27. Treatment discontinuation due to adverse events increased by 2.22-fold (P=0.025).

The authors note that these are pooled estimates from a meta-analysis of RCTs, and causality is not explicitly stated. Limitations such as follow-up duration and serious adverse events were not reported.

Practice relevance: Clinical use should adopt personalized dosing strategies that balance efficacy and tolerability based on individual patient profiles. Clinicians should monitor for dose-dependent adverse events, particularly dissociation and nausea.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

IntroductionThis study systematically evaluated the safety profile of esketamine for treatment-resistant depression through a meta-analysis, focusing on dose-dependent adverse events and associated risk factors to inform precision dosing.MethodsPubMed, Embase, the Cochrane Library, the Mainland China Biomedical Literature Database (CBM), the China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched from inception to March 2025. Randomized controlled trials evaluating esketamine for treatment-resistant depression were included. Primary outcomes included the incidence of adverse events, discontinuation due to adverse events, and clinical response or remission. Statistical analysis was conducted using RevMan 5.4.1, with subgroup analyses by dosage, administration route, and geographic region (Mainland China vs. International multi-regional).ResultsNine randomized controlled trials involving 1,449 patients were included. Dosages ranged from 28 to 84 mg for nasal spray and 0.20–0.40 mg/kg for intravenous injection. Esketamine significantly increased the risk of nine adverse events, including nausea, dissociation, dizziness, vertigo, elevated blood pressure, and somnolence, compared with controls (P < 0.05). Risks were strongly dose-dependent: the high-dose group (≥56 mg or 0.40 mg/kg) showed a greater risk than the low-dose group (≤28 mg or 0.20 mg/kg), with RR for nausea of 3.72 versus 1.69 and RR for dissociation of 10.65 versus 3.27. Patients in International multi-regional studies also had higher risks of nausea, somnolence, and headache than those in Mainland China studies. Although esketamine improved the clinical response rate (RR = 1.94), it increased treatment discontinuation due to adverse events by 2.22-fold (P = 0.025).DiscussionEsketamine improves symptoms in patients with treatment-resistant depression but significantly increases dose-dependent adverse events. Clinical use should adopt personalized dosing strategies that balance efficacy and tolerability based on individual patient profiles.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1024830, identifier CRD420251024830.