Ketamine's rapid antidepressant effects in TRD are well-established, primarily through intravenous or intranasal administration. However, oral administration, specifically via an extended-release tablet (R-107), offers potential improvements in safety and tolerability. Previous research suggests ketamine's antidepressant activity may be linked to its metabolites (norketamine and hydronorketamines), which exhibit prolonged exposure after oral dosing. Formulations maximizing first-pass metabolism and delaying peak concentrations have shown better tolerability. This phase 2 trial hypothesized that R-107, an extended-release ketamine tablet, would be an effective and well-tolerated treatment for TRD. The study employed an enrichment design to reduce the high failure rates typical of acute antidepressant trials in TRD by excluding non-responders to an initial open-label treatment phase before proceeding to a double-blind relapse-prevention phase, incorporating a dose-finding component to determine the optimal oral dose range for R-107.

A substantial body of evidence demonstrates ketamine's rapid antidepressant effects in patients with TRD, predominantly through intravenous or intranasal administration. While intranasal esketamine has received regulatory approval, oral ketamine studies remain limited. The existing literature highlights variations in ketamine's dose range and bioavailability depending on the formulation and administration route. The antidepressant action of ketamine is thought to be connected to several of its metabolites, especially norketamine and hydronorketamines. Oral administration leads to a much more extended exposure to these metabolites compared to the parent compound. Importantly, ketamine maintains its antidepressant effect even with low parent compound bioavailability via certain administration methods. Meta-analyses suggest that formulations designed to enhance first-pass metabolism and delay the time to peak concentration result in better tolerability profiles characterized by reduced dissociation and blood pressure changes.

This phase 2, multicenter, randomized, placebo-controlled trial enrolled adult patients (18-80 years) with DSM-5 TRD (defined as inadequate response to at least two antidepressant agents). Patients with MADRS scores ≥20 were included. The study comprised two phases: a 7-day open-label enrichment phase (120mg R-107 daily for 5 days) followed by a 12-week double-blind relapse-prevention phase. Responders in the enrichment phase (MADRS ≤12 and ≥50% reduction) were randomized 1:1:1:1:1 to receive placebo or 30, 60, 120, or 180 mg of R-107 twice weekly. The primary endpoint was the least squares mean change in MADRS scores from baseline to week 13, analyzed using analysis of covariance with baseline MADRS as a covariate. Secondary endpoints included remission and response rates, CGI-S, PGI-I, time to relapse (Kaplan-Meier analysis), and safety measures (adverse events, vital signs, laboratory tests, ECGs, CADSS, BPIC-SS, BPRS+). Missing data for the primary endpoint were imputed using last observation carried forward. A fixed sequence step-down closed test procedure was used for the primary objective. The sample size calculation aimed for 80% power to detect a 6-point MADRS difference between R-107 and placebo.

Between May 2019 and August 2021, 329 patients were screened, 231 entered the enrichment phase, and 168 responders were randomized. The primary objective was met, with the 180 mg R-107 group showing a statistically significant improvement in MADRS scores compared to placebo at 13 weeks (-6.1, 95% CI 1.00 to 11.16, P=0.019). Relapse rates demonstrated a dose-response relationship, ranging from 70.6% in the placebo group to 42.9% in the 180 mg group. The study observed high treatment compliance (96.4% with ≥80% compliance). Tolerability was excellent, with minimal changes in blood pressure, sedation, and dissociation. The most frequently reported adverse events were headache, dizziness, and anxiety. Secondary outcomes showed numerical improvements in remission and response rates, CGI-S, and PGI-I for the active treatment groups compared to placebo; however, these were not consistently statistically significant except for the 120 mg dose group showing a statistically significant difference in response rate at week 13 (48% vs 24.3%, p = 0.046). Median time to relapse was also longer for higher doses of R-107.

This study provides evidence supporting the efficacy and safety of extended-release oral ketamine (R-107) in treating TRD. The statistically significant improvement in MADRS scores in the 180 mg group compared to placebo, coupled with the favorable tolerability profile, suggests R-107 offers a viable alternative to other ketamine administration routes. The enrichment design successfully mitigated the risk of study failure common in TRD trials. The observed dose-response relationship in relapse rates and trends in secondary outcomes further strengthens the findings. The minimal side effects, especially concerning dissociation, sedation, and cardiovascular effects, are notable advantages of the extended-release oral formulation. The convenience of at-home dosing enhances the potential for wider community use and improved accessibility.

This phase 2 trial demonstrates that extended-release R-107 tablets are an effective and well-tolerated treatment for TRD. The superior tolerability profile compared to other ketamine formulations, along with the convenience of oral administration, suggests considerable potential for this treatment. Future studies should investigate the efficacy of R-107 in a larger, unenriched population and explore long-term treatment effects and optimal dosing strategies.

The enrichment design, while effective in reducing study failure rates, may overestimate treatment response in the broader TRD population. The relatively small sample sizes in the double-blind phase might have limited the statistical power to detect significant differences in secondary outcomes. Direct comparison with other ketamine administration routes is challenging due to limited data on oral ketamine. The inclusion of patients both on and off other antidepressants makes it difficult to assess if these populations respond differently.