Table 1.
Characteristics of randomized controlled studies and open-label studies included in the systematic review.
| Author, Year | Study Design | Population Study | Primary Outcome | Duration | Study Drugs | Main Findings |
|---|---|---|---|---|---|---|
| MDD patients with TRD | ||||||
| Chen et al., 2023 [30] |
Placebo-controlled RCT | 250 MDD patients with TRD | Change in MADRS total score from baseline to week 4 | 4 weeks | IN ESK 56–84 mg vs. placebo | No statistical difference in MADRS score was observed between ESK and placebo groups from baseline to week 4. |
| Reif et al., 2023 [41] |
Active-controlled RCT (ESCAPE-TRD) | 676 MDD patients with TRD | Remission rate at week 8 | 32 weeks | IN ESK 28–84 mg vs. quetiapine | A significantly greater remission rate was observed in the ESK group compared to the quetiapine group at week 8 (27.1% vs. 17.6%, p = 0.003, respectively). |
| Takahashi et al., 2021 [32] |
Placebo-controlled RCT | 202 MDD patients with TRD | Change in MADRS score from baseline to week 4 | 4 weeks (DB phase) 24 weeks (OL phase) |
IN ESK 28, 56, and 84 mg vs. placebo | No statistical difference in MADRS score was observed between ESK and placebo groups from baseline to week 4. |
| Ochs Ross et al., 2020 [34] | Placebo-controlled RCT (TRANS FORM-3) | 138 MDD patients with TRD and ≥65 years old | Change in MADRS score from baseline to week 4 | 4 weeks | IN ESK 28–84 mg vs. placebo | No statistical difference in MADRS score was observed between ESK and placebo groups from baseline to week 4. |
| Wajs et al., 2020 [42] |
OL trial (SUSTAIN-2) | 802 MDD patients with TRD | Change in MADRS score from baseline to week 4 (IND phase) and from week 5 to week 52 (OP/MAINT phase) | 52 weeks | IN ESK 28–84 mg | MADRS score decreased in the IND phase (baseline to week 4) (mean [SD] change: −16.4 [8.76]) and persisted during the OP/MAINT phase (week 5 to week 52) (mean [SD] change: 0.3 [8.12]). |
| Daly et al., 2019 [36] |
Placebo-controlled RCT | 297 MDD patients with TRD | Time to relapse in patients with stable remission after IND phase (week 4) | Until relapse | IN ESK 56–84 mg vs. placebo | Significant delay to relapse was observed in the ESK group compared to the placebo group (HR, 0.49; 95% CI 0.29–0.84; p = 0.003). |
| Fedgchin et al., 2019 [37] | Placebo-controlled RCT (TRANS FORM-1) | 342 MDD patients with TRD | Change in MADRS score from baseline to week 4 | 4 weeks | IN ESK 56 and 84 mg vs. placebo | No statistical difference in MADRS score was observed between ESK and placebo groups from baseline to week 4. |
| Popova et al., 2019 [38] | Placebo-controlled RCT (TRANS FORM-2) | 227 MDD patients with TRD | Change in MADRS score from baseline to week 4 | 4 weeks | IN ESK 56–84 mg vs. placebo | Significantly greater improvement in MADRS score was observed in the ESK group compared to the placebo group from baseline to week 4 (LS mean difference [SE]: −4.0 [1.69], p = 0.02). |
| Daly et al., 2018 [39] |
Placebo-controlled RCT | 67 MDD patients with TRD | Change in MADRS score from baseline to week 1 and week 2 | 2 weeks (DB phase) d15–d74 (OL phase) |
IN ESK 28, 56, and 84 mg vs. placebo | Significantly greater improvement in MADRS score was observed in ESK groups compared to the placebo group in both periods (mean difference from placebo [SE]: ESK 28 mg: −4.2 [2.09], p = 0.02; ESK 56 mg: −6.3 [2.07], p = 0.001; ESK 84 mg: −9.0 [2.13], p < 0.001). |
| Galves et al., 2018 [40] | Active-controlled RCT | 5 MDD patients with TRD | Feasibility and safety of repeated IN ketamine | 4 weeks | IN ketamine 100 mg vs. midazolam 4.5 mg | The study was stopped early due to poor tolerability after the inclusion of five patients. |
| Lapidus et al., 2014 [23] | Placebo-controlled RCT | 20 MDD patients with TRD | Change in MADRS score from baseline to 24 h | 7 days | IN ketamine 50 mg vs. placebo | Significantly greater improvement in MADRS score was observed in the ketamine group compared to the placebo group from baseline to 24 h (t-test = 4.39, p < 0.001). |
| MDD patients with active suicidal ideation | ||||||
| Ionescu et al., 2021 [31] | Placebo-controlled RCT (ASPIRE II) | 230 MDD patients with ASI | Change in MADRS score from baseline to 24 h | 4 weeks | IN ESK 84 mg vs. placebo | Significantly greater improvement in MADRS score was observed in the ESK group compared to the placebo group from baseline to 24 h (LS mean difference [SE]: −3.9 [1.39]; −1.11; p = 0.006). |
| Fu et al., 2020 [33] |
Placebo-controlled RCT (ASPIRE I) | 226 MDD patients with ASI | Change in MADRS score from baseline to 24 h | 4 weeks | IN ESK 84 mg vs. placebo | Significantly greater improvement in MADRS score was observed in the ESK group compared to the placebo group from baseline to 24 h (LS mean difference [SE]: −3.8 [1.39]; p = 0.006). |
| Canuso et al., 2019 [35] | Placebo-controlled RCT | 68 MDD patients with imminent suicide risk | Change in MADRS score from baseline to 4 h | 4 weeks | IN ESK 84 mg vs. placebo | Significantly greater improvement in MADRS score was observed in the ESK group compared to the placebo group from baseline to 4 h (LS mean difference [SE]: −5.3 [2.10], p = 0.015). |
Abbreviations: ASI: active suicidal ideation; d: days; ESK: esketamine; HR: hazard ratio; IN: intranasal; IND phase: induction phase; LS: least-squares; MADRS: Montgomery–Asberg Depression Rating Scale; MDD: major depressive disorder; OL: open-label; OP/MAINT phase: optimization/maintenance phase; RCT: randomized controlled trial; SE: standard error; SD: standard deviation; TRD: treatment-resistant depression.