This study evaluated the efficacy and safety of extended-release ketamine tablets (R-107) in treating treatment-resistant depression (TRD). The trial was a phase 2, multicenter, randomized, placebo-controlled study involving male and female adult patients with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥20. Patients received open-label R-107 tablets at 120 mg daily for 5 days, followed by a double-blind phase where responders were randomized to receive R-107 doses of 30, 60, 120, or 180 mg twice weekly for 12 weeks. The primary endpoint was the change in MADRS score at 13 weeks. The study found that the 180 mg dose group showed a statistically significant and clinically meaningful improvement in depressive symptoms compared to placebo, with a least square mean difference of −6.1 (95% CI 1.0 to 11.6, P = 0.019). The relapse rates showed a dose-response relationship, with the highest rate observed in the placebo group (70.6%) and the lowest in the 180 mg group (42.9%). Adverse events were generally mild to moderate, with minimal dissociation, sedation, and blood pressure changes. The extended-release ketamine tablets were effective, safe, and well-tolerated in patients with TRD, particularly those who responded initially to R-107 tablets.This study evaluated the efficacy and safety of extended-release ketamine tablets (R-107) in treating treatment-resistant depression (TRD). The trial was a phase 2, multicenter, randomized, placebo-controlled study involving male and female adult patients with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥20. Patients received open-label R-107 tablets at 120 mg daily for 5 days, followed by a double-blind phase where responders were randomized to receive R-107 doses of 30, 60, 120, or 180 mg twice weekly for 12 weeks. The primary endpoint was the change in MADRS score at 13 weeks. The study found that the 180 mg dose group showed a statistically significant and clinically meaningful improvement in depressive symptoms compared to placebo, with a least square mean difference of −6.1 (95% CI 1.0 to 11.6, P = 0.019). The relapse rates showed a dose-response relationship, with the highest rate observed in the placebo group (70.6%) and the lowest in the 180 mg group (42.9%). Adverse events were generally mild to moderate, with minimal dissociation, sedation, and blood pressure changes. The extended-release ketamine tablets were effective, safe, and well-tolerated in patients with TRD, particularly those who responded initially to R-107 tablets.