Dose-dependent adverse events of esketamine in treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials.
Yang Qu, Shujin Li, Li Tian, Xiaoxiao Tian, Yongkang Wu
Frontiers in Pharmacology 2026 DOI: 10.3389/fphar.2026.1792570 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Meta-analysis Randomized Peer reviewed |
|---|---|
| Sample size | 1,449 |
| Population | Patients with treatment-resistant depression |
| Intervention | Esketamine |
| Dose | 28 to 84 mg for nasal spray and 0.20-0.40 mg/kg for intravenous injection |
| Topics | Depression Esketamine |
| Keywords | Dose-dependent Meta-analysis Safety |
| Key findings | Esketamine improves symptoms in treatment-resistant depression but significantly increases dose-dependent adverse events, with higher doses associated with greater risks of nausea, dissociation, and other adverse events. |
Abstract
This 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. PubMed, 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). Nine 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). Esketamine 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. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=1024830, identifier CRD420251024830.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |