A phase 2 randomized placebo-controlled trial evaluated the efficacy and safety of extended-release ketamine tablets (R-107) in patients with treatment-resistant depression (TRD). Participants received open-label R-107 120 mg/day for 5 days, followed by a 12-week double-blind phase with doses of 30, 60, 120, or 180 mg twice weekly or placebo. The primary endpoint was the least square mean change in Montgomery–Asberg Depression Rating Scale (MADRS) scores at 13 weeks. The 180 mg dose showed a statistically significant improvement compared to placebo, with a mean difference of -6.1 (95% CI 1.0 to 11.16, P = 0.019). Relapse rates were lower with higher doses, with 42.9% relapse in the 180 mg group versus 70.6% in the placebo group. Tolerability was excellent, with minimal adverse events, including headache, dizziness, and anxiety. The extended-release formulation was well-tolerated, with no significant changes in blood pressure or sedation. Most dosing occurred at home, and the study showed that R-107 was effective and safe in TRD patients. The study design included an enrichment phase to exclude non-responders, improving the study's power. The results suggest that R-107 could be a viable treatment option for TRD, with a favorable safety profile and reduced risk of abuse compared to intravenous or intranasal ketamine. The study highlights the potential of oral ketamine formulations in treating TRD, with a focus on long-term relapse prevention and improved patient convenience. The findings support the use of R-107 as a safe and effective treatment for TRD, with a strong dose-response relationship observed in clinical outcomes.A phase 2 randomized placebo-controlled trial evaluated the efficacy and safety of extended-release ketamine tablets (R-107) in patients with treatment-resistant depression (TRD). Participants received open-label R-107 120 mg/day for 5 days, followed by a 12-week double-blind phase with doses of 30, 60, 120, or 180 mg twice weekly or placebo. The primary endpoint was the least square mean change in Montgomery–Asberg Depression Rating Scale (MADRS) scores at 13 weeks. The 180 mg dose showed a statistically significant improvement compared to placebo, with a mean difference of -6.1 (95% CI 1.0 to 11.16, P = 0.019). Relapse rates were lower with higher doses, with 42.9% relapse in the 180 mg group versus 70.6% in the placebo group. Tolerability was excellent, with minimal adverse events, including headache, dizziness, and anxiety. The extended-release formulation was well-tolerated, with no significant changes in blood pressure or sedation. Most dosing occurred at home, and the study showed that R-107 was effective and safe in TRD patients. The study design included an enrichment phase to exclude non-responders, improving the study's power. The results suggest that R-107 could be a viable treatment option for TRD, with a favorable safety profile and reduced risk of abuse compared to intravenous or intranasal ketamine. The study highlights the potential of oral ketamine formulations in treating TRD, with a focus on long-term relapse prevention and improved patient convenience. The findings support the use of R-107 as a safe and effective treatment for TRD, with a strong dose-response relationship observed in clinical outcomes.