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

In a recent study published in the journal Medicine of nature, 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: Ketamine extended-release tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial.  Image Credit: Djavan Rodríguez/ShutterstockStudy: Ketamine extended-release tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial. Image Credit: Djavan Rodríguez/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 by various routes, show higher doses associated with greater improvement in depression. Prolonged exposure of oral ketamine to metabolites, such as norketamine, suggests that it acts as a prodrug. An extended-release tablet formulation could be effective and well tolerated for TRD. More 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 nonresponders, a 12-week double-blind phase evaluated responders. The trial met ethical standards and was registered (ACTRN12618001042235).

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

Eligible patients received open-label R-107 (120 mg/day) for five days. Responder patients (MADRS ≤12, reduction ≥50%) were randomly assigned to doses of R-107 (30, 60, 120, or 180 mg) or placebo twice weekly for 12 weeks. Those who did not respond dropped out of the study. Randomization and blinding were maintained, and compliance was monitored through diaries, container returns, and telephone checks.

The primary endpoint was the change in MADRS score from baseline to day 92, analyzed by analysis of covariance. Safety assessments included laboratory testing, electrocardiograms (ECG), cognitive testing, and adverse event reporting. The sample size pointed to a significant improvement in MADRS score with R-107 compared to placebo, involving 200 initial participants to ensure 150 randomized.

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

Study results

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

At the end of the study (day 92), 100 participants had discontinued treatment, 94 of which were due to lack of efficacy (defined by a MADRS total score ≥22). The interruptions 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 compliance was high, with 96.4% of participants reporting 80% or greater compliance.

Greater mean reductions in MADRS total score were observed from baseline to day 92 in all treatment groups compared to placebo. The greatest reduction occurred 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 compared to the lower dose groups. The reductions were greater for women, participants younger than 65, those taking antidepressants and those above average 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 to placebo, with statistical significance for the 120 mg dose group in treatment response (48% vs 24.3% , P = 0.046).

Most relapses occurred within the first 4 weeks of double-blind treatment. Median relapse times increased with higher doses of R-107, and the 180 mg group showed significantly longer survival times compared to 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 and none were considered related to treatment. Safety evaluations showed no significant changes, including laboratory tests, ECGs, and cognitive evaluations.

Conclusions

In summary, in this study, 231 patients with TRD received R-107 (120 mg/day) for five days, and 168 responding patients (72.7%) were randomly assigned to various doses of R-107 or placebo in a double-blind study 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 doses were administered at home, increasing convenience. The enrichment design reduced the impact in non-responders, demonstrating the potential advantages of extended-release oral ketamine over other forms.

Magazine reference:

  • Glue, P., Loo, C., Fam, J. et al. Extended-release ketamine tablets for treatment-resistant depression: a randomized, placebo-controlled phase 2 trial. Nat Med (2024), DOI – 10.1038/s41591-024-03063-x, https://www.nature.com/articles/s41591-024-03063-x

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