Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial

The study addresses whether an extended-release oral formulation of racemic ketamine (R-107) can provide effective, safe, and well-tolerated antidepressant treatment for adults with treatment-resistant depression (TRD). Prior evidence supports rapid-onset antidepressant effects of ketamine, most commonly via intravenous or intranasal routes, with limited data on oral administration. The authors hypothesized that extended-release tablets, which enhance first-pass metabolism and prolong exposure to active metabolites (for example, norketamine, hydroxynorketamines), would yield antidepressant efficacy with improved tolerability (reduced dissociation and cardiovascular effects). To reduce high failure rates seen in acute antidepressant trials, they used a predictive enrichment design to randomize only initial responders into a relapse-prevention, dose-ranging, double-blind phase.

- Extensive prior research has demonstrated ketamine’s rapid antidepressant effects in TRD, with most trials using intravenous racemic ketamine and, more recently, intranasal esketamine. Only a small fraction of RCT arms have evaluated oral dosing. - Pharmacology suggests ketamine’s antidepressant activity is linked to metabolites (norketamine, hydroxynorketamines). Oral dosing produces prolonged exposure to these metabolites due to first-pass metabolism and extended absorption. - Meta-analytic and review data indicate higher ketamine doses generally produce greater antidepressant effects, and formulations maximizing first-pass metabolism with delayed Tmax may be better tolerated (less dissociation and blood pressure change). - Enrichment designs (removing nonresponders before randomized relapse-prevention) can reduce trial failure rates and increase effect sizes, and have precedent in esketamine randomized withdrawal studies.

Design: Phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging relapse-prevention trial with an initial open-label enrichment phase. Conducted at 20 psychiatric clinics in New Zealand, Australia, Singapore, and Taiwan; ethics approvals obtained; conducted per Declaration of Helsinki and GCP; CONSORT 2010 reporting. Registered: ACTRN12618001042235. Participants: Adults 18–80 years with DSM-5 major depressive disorder meeting TRD criteria (nonresponse to at least two adequately dosed, adequately long antidepressant trials). Screening MADRS ≥20. Concomitant antidepressants permitted if stable ≥4 weeks before entry and during study. Key exclusions: severe medical disorders, ketamine contraindications, clinically important findings on exam/labs/ECGs, serious suicide risk, recent substance abuse, or history of bipolar disorder, schizophrenia, or severe personality disorder. Informed consent obtained. Enrichment phase (open-label): R-107 120 mg once daily for 5 days (days 1–5). Day 8 assessment determined response (MADRS ≤12 and ≥50% reduction from baseline). Nonresponders exited; responders proceeded to randomization. Randomization and blinding: Responders randomized 1:1:1:1:1 to R-107 30 mg, 60 mg, 120 mg, 180 mg, or placebo, administered twice weekly for 12 weeks. Each dose consisted of three tablets (0, 30, or 60 mg per tablet) to achieve assigned dose; active and placebo tablets identical. Allocation via automated web response system. Patients and all trial personnel were blinded. Visits and compliance: Weekly clinic visits up to week 6, then every 4 weeks through week 13; scheduled phone checks for compliance and adverse events. Dosing often occurred at home. Compliance monitored via dosing diaries and return of containers. Patients who relapsed (MADRS ≥22) during double-blind treatment were withdrawn and could enter open-label extension. Endpoints: Primary—change in MADRS total score from baseline (day 1) to day 92 (week 13). Secondary—time to relapse (MADRS ≥22; Kaplan–Meier, restricted mean survival time), response and remission rates, CGI-S, PGI-I. Safety—AEs, vitals, labs (hematology, biochemistry), ECGs, CADSS for dissociation, BPIC-SS for cystitis symptoms, BPRS+ positive symptom subscale, Montreal Cognitive Assessment, Columbia-Suicide Severity Rating Scale. Statistical analysis: Primary analysis by ANCOVA of change in MADRS (dose as factor; baseline MADRS as covariate). Closed testing in descending dose order vs placebo. Missing day 92 MADRS imputed by last observation carried forward (LOCF) to address expected higher relapse in placebo. Time to relapse analyzed by Kaplan–Meier with restricted mean survival time differences vs placebo. Sample size targeted 26 per group (detect 6-point MADRS difference, SD 7.5, two-sided alpha 0.05, 80% power), allowing for attrition led to initial ~200 subjects for ~150 randomized.

Enrollment and disposition: 329 screened; 231 entered open-label enrichment; at day 8, 168/231 (72.7%) responders randomized; 132/231 (57.1%) achieved remission (MADRS ≤10) by day 8. By day 92, 100 discontinued; 94 due to lack of efficacy (MADRS ≥22): placebo 26; 30 mg 22; 60 mg 19; 120 mg 16; 180 mg 11. Completion to week 14 increased with dose: placebo 27.0%; 30 mg 32.4%; 60 mg 41.2%; 120 mg 48.4%; 180 mg 56.2%. Primary endpoint (MADRS change to day 92 vs placebo; LOCF): - 30 mg: +1.9 (95% CI -3.08 to 6.92), P=0.45 - 60 mg: +0.7 (95% CI -4.32 to 5.70), P=0.79 - 120 mg: +4.5 (95% CI -0.60 to 9.69), P=0.083 - 180 mg: +6.1 (95% CI 1.00 to 11.16), P=0.019 (statistically significant) Additional efficacy: - Enrichment phase mean MADRS reduction by day 8: -18.5 points (95% CI -19.69 to -17.37). - Response and remission at week 13 were numerically higher with active treatment vs placebo; response was statistically significant only for 120 mg (48.4% vs 24.3%, P=0.046). Remission not significantly different. - Time to relapse (median; higher is better): placebo 45 days; 30 mg 28; 60 mg 56; 120 mg 64; 180 mg >85. Restricted mean survival time for 180 mg vs placebo: +19.0 days (95% CI 4.9 to 33.1). Safety and tolerability: - Open-label phase: common AEs included dizziness, headache, dissociation, feeling abnormal, fatigue, nausea; dissociation reported by 11.6% (mean CADSS <3). Mean BP change after 5 days: systolic -1.2 mmHg, diastolic -0.1 mmHg. - Double-blind phase: most common AEs (≥10% in any arm): headache (up to 32.4%), dizziness (up to 19.4%), anxiety (up to 9.4%), depression, nausea, feeling abnormal, fatigue, URTI; dissociation up to 15.6% at 180 mg. Majority mild or moderate. Sedation (mild) in 5 participants (30 mg n=4; 120 mg n=1). Mean CADSS <1 at all visits; BPIC-SS <3 throughout with no differences vs placebo. No notable changes in labs, vitals, weight, ECGs, BPRS+, or MoCA. - Severe AEs: 10 events in 8 participants; SAEs in 5 subjects (3 in 180 mg group: wound dehiscence, suicidal ideation, completed suicide on day 42 in a 65-year-old male; 1 in 60 mg: noncardiac chest pain; 1 in placebo: urinary calculus). None judged treatment-related by investigators, aside from disease-related suicide; all resolved except the completed suicide. Dosing logistics: Most double-blind doses were self-administered at home; compliance high (≥80% in 96.4% of participants).

Findings support the hypothesis that extended-release oral ketamine (R-107) can maintain antidepressant effects in TRD with improved tolerability. In an enriched responder population, twice-weekly 180 mg produced a statistically significant and clinically meaningful reduction in MADRS at 13 weeks versus placebo and delayed relapse, with a clear dose–response across relapse rates and time-to-relapse. Adverse events commonly associated with parenteral or intranasal ketamine (notably dissociation, sedation, and blood pressure elevations) were minimal, suggesting that extended-release oral delivery with extensive first-pass metabolism may enhance tolerability and safety. The ability to dose at home with limited clinic monitoring indicates potential scalability and convenience. Relapse rates in both placebo and high-dose groups were higher than those in longer open-label lead-in antidepressant trials, likely reflecting the brief 5-day enrichment period that may select less stable responders. Secondary outcomes showed dose-related trends but were generally underpowered for significance. Overall, results demonstrate efficacy, safety, and practicality of extended-release oral ketamine in TRD under an enrichment design.

Extended-release ketamine tablets (R-107) were effective, safe, and well tolerated in adults with TRD enriched for initial response. The 180 mg twice-weekly dose significantly improved depressive symptoms versus placebo and prolonged time to relapse, with minimal dissociation, sedation, or cardiovascular effects, and practical at-home dosing. Extended-release oral ketamine may offer advantages over intravenous or intranasal formulations in safety, tolerability, abuse-deterrence, and community scalability. Future research should include larger, unenriched randomized trials to assess generalizability, optimize dosing, compare effectiveness with other routes, and evaluate differential effects with or without concomitant antidepressants.

- Enrichment design (randomizing only initial responders) may overestimate population-level effectiveness and limits generalizability; expectation effects during the open-label phase may inflate early response/remission rates. - Short open-label lead-in (5 days) likely contributed to relatively high relapse rates post-randomization compared with studies with longer stabilization phases. - Modest sample sizes within dose groups reduced statistical power for secondary outcomes. - Heterogeneity regarding concomitant antidepressant use; protocol did not require initiation of a new antidepressant at study start, complicating interpretation of combination effects. - Limited comparability with non-oral ketamine/esketamine studies due to differences in route, bioavailability, and exposure profiles; relatively sparse historical data for oral ketamine in TRD.