Extended-release ketamine tablets offer new hope for treatment-resistant depression

In a recent study published in the journal Nature Medicine, an international team of researchers evaluated the efficacy, safety, and tolerability of extended-release ketamine tablets (R-107) in adult patients with treatment-resistant depression (TRD) through a randomized placebo-controlled phase 2 trial.

Study: Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Image Credit: Djavan Rodriguez / Shutterstock

Background 

Over the past two decades, substantial evidence has demonstrated the rapid-onset antidepressant properties of ketamine in patients with TRD. Most research has involved off-label intravenous racemic ketamine, with the recent approval of intranasal esketamine for TRD. Only a few randomized controlled trials for TRD have explored oral dosing. Ketamine and esketamine, administered via various routes, show higher doses linked to greater depression improvement. Oral ketamine’s prolonged exposure to metabolites, such as norketamine, suggests it acts as a prodrug. An extended-release tablet formulation could be effective and well-tolerated for TRD. Further research is needed to optimize dosing, evaluate long-term efficacy and safety, and understand the mechanisms underlying ketamine’s antidepressant effects in TRD.

About the study 

The present phase 2 multicenter clinical trial was conducted across 20 psychiatric clinics in New Zealand, Australia, Singapore, and Taiwan. Following a 1-week open-label phase to exclude nonresponders, a 12-week double-blind phase assessed responders. The trial adhered to ethical standards and was registered (ACTRN12618001042235).

Participants aged 18-80 with Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 major depressive disorder, resistant to at least two antidepressants, were eligible if they had Montgomery-Åsberg Depression Rating Scale (MADRS) scores ≥20. Exclusions included severe medical disorders, ketamine contraindications, significant lab findings, serious suicide risk, recent substance abuse, and certain psychiatric conditions.

Eligible patients received open-label R-107 (120 mg/day) for five days. Responders (MADRS ≤12, ≥50% reduction) were randomized to R-107 doses (30, 60, 120, or 180 mg) or placebo twice weekly for 12 weeks. Nonresponders exited the study. Randomization and blinding were maintained, with compliance monitored through diaries, container returns, and phone checks.

The primary endpoint was the change in MADRS score from baseline to day 92, analyzed using analysis of covariance. Safety assessments included lab tests, Electrocardiograms (ECGs), cognitive tests, and adverse event reports. The sample size aimed for significant MADRS score improvement with R-107 compared to placebo, involving 200 initial participants to ensure 150 randomized.

Time to relapse and other efficacy measures were analyzed, with conservative imputation for missing values to ensure robust primary endpoint analysis.

Study results 

Between May 2019 and August 2021, 329 individuals were screened for eligibility, with 231 entering the open-label enrichment phase (days 1–5). On day 8, 132 out of 231 participants (57.1%) were in remission, and 168 out of 231 (72.7%) were responders. After excluding nonresponders, 168 responders were randomized to double-blind treatment. 

By the end of the study (day 92), 100 participants had discontinued, 94 of whom were due to a lack of efficacy (defined by a MADRS total score of ≥22). Discontinuations were distributed as follows: placebo (26), 30 mg (22), 60 mg (19), 120 mg (16), and 180 mg (11). Completion rates ranged from 29.7% in the placebo group to 56.2% in the 180 mg group, with higher completion rates associated with higher R-107 doses. Treatment compliance was high, with 96.4% of participants reporting 80% or more compliance.

Greater mean reductions in MADRS total score from baseline to day 92 were observed in all treatment groups compared with placebo. The largest reduction was in the 180 mg treatment group (6.1 points; 95% CI 1.00 to 11.16; P = 0.019), which was statistically significant. Mean reductions in MADRS scores were generally higher in the 120 mg and 180 mg groups compared to lower-dose groups. Reductions were greater for females, participants under 65 years, those taking antidepressants, and those above median body weight compared to their counterparts.

During the open-label enrichment phase, the mean reduction in MADRS total score was 18.5 points (95% CI 17.37 to 19.69). On day 8, 57.1% achieved remission (MADRS ≤10), and 72.7% achieved a response (≥50% reduction from baseline). At week 13, remission and response rates were higher in the active treatment arms compared with placebo, with statistical significance for the 120 mg dose group in treatment response (48% vs. 24.3%, P = 0.046).

The majority of relapses occurred within the first 4 weeks of double-blind treatment. Median relapse times increased with higher R-107 doses, with the 180 mg group showing significantly longer survival times compared with placebo.

Adverse events were monitored throughout the study. During the open-label phase, common adverse events included dizziness, headache, dissociation, fatigue, and nausea, with 11.6% reporting dissociation. Mean blood pressure changes were minimal. In the double-blind phase, most adverse events were mild or moderate. Serious adverse events occurred in eight participants, with none considered treatment-related. Safety assessments showed no significant changes, including lab tests, ECGs, and cognitive assessments.

Conclusions 

To summarize, in this study, 231 patients with TRD received R-107 (120 mg/day) for five days, and 168 responders (72.7%) were randomized to various double-blind R-107 doses or placebo for 12 weeks. The 180 mg dose showed significant improvement in depressive symptoms compared to placebo, with minimal side effects such as dissociation and sedation. Most dosing occurred at home, enhancing convenience. The enrichment design reduced nonresponder impact, showing the potential advantages of extended-release oral ketamine over other forms.