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

In a recent study published in the journal Natural 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) in a randomized trial placebo-controlled phase 2 study.

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 fast-acting antidepressant properties of ketamine in patients with TRD. Most research has focused on off-label intravenous racemic ketamine, with the recent approval of intranasal esketamine for TRD. Only a few randomized controlled trials of TRD have explored oral administration. Ketamine and esketamine, administered by various routes, have higher doses linked to greater improvement in depression. Prolonged exposure of oral ketamine to metabolites, such as norketamine, suggests that it acts as a prodrug. A sustained-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 the antidepressant effects of ketamine in TRD.

About the study

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

Participants aged 18 to 80 years with Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 major depressive disorder, resistant to at least two antidepressants, were eligible if they had scores on the antidepressant scale. Montgomery-Åsberg Depression Rating (MADRS) ≥20. Exclusions included serious medical conditions, contraindications to ketamine, significant laboratory 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, reduction ≥ 50%) were randomized to receive doses of R-107 (30, 60, 120, or 180 mg) or placebo twice weekly for 12 weeks. Non-respondents left the study. Randomization and blinding were maintained, with compliance monitored through logs, container returns, and telephone checks.

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

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

Study results

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

At study completion (day 92), 100 participants had discontinued treatment, including 94 due to lack of efficacy (defined as a MADRS total score ≥ 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 doses of R-107. Treatment adherence was high, with 96.4% of participants reporting adherence of 80% or greater.

Greater mean reductions in MADRS total score from baseline to day 92 were observed in all treatment groups compared to placebo. The greatest reduction was observed 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 greater in the 120 mg and 180 mg groups than in the lower dose groups. Reductions were greater for women, participants younger than 65, those taking antidepressants, and those with body weights above the median compared to their counterparts.

During the open-label enrichment phase, the average 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 response (≥50% reduction from baseline). At week 13, remission and response rates were higher in the active treatment arms than in the placebo group, with statistical significance for the 120 mg dose group in terms of treatment response (48% vs. 24%). .3%, P = 0.046).

The majority of relapses occurred during the first 4 weeks of double-blind treatment. Median times to relapse increased with higher doses of R-107, with the group receiving 180 mg having significantly longer survival times than 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 changes in blood pressure were minimal. In the double-blind phase, most adverse events were mild or moderate. Serious adverse events occurred in eight participants, none of which were considered treatment-related. Safety assessments showed no significant changes, including laboratory tests, ECGs and cognitive assessments.

Conclusions

Briefly, in this study, 231 patients with TRD received R-107 (120 mg/day) for five days, and 168 responders (72.7%) were randomized to receive various doses of R-107 in duplicate. blind 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 took place at home, improving convenience. The enrichment design reduced the impact of non-responders, showing the potential benefits of sustained-release oral ketamine over other forms.