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Extended-Release Ketamine Tablets May Improve Safety and Tolerability in TRD Treatment
Racemic ketamine administered as an extended-release tablet (R-107) may offer a treatment option with improved safety and tolerability for patients with treatment-resistant depression (TRD). Results from the phase 2 trial were published in Nature Medicine.
“Extended-release R-107 tablets were effective, safe, and well tolerated in an enriched patient population with TRD,” said study authors, including Paul Glue, MD, University of Otago, Dunedin, New Zealand. “Use of an extended-release oral dosage ketamine formulation may be advantageous compared with intranasal or intravenous dosing, in terms of reduced intensity of dissociation, lower risk of abuse, reduced frequency and intensity of sedative and cardiovascular side effects, and improved convenience for administration in the community.”
The phase 2 multicenter, randomized, placebo-controlled clinician trial included 231 patients with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores 20.
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To reduce failure rates (defined as the “inability to separate clinical response between active and placebo arms”), study authors included an initial open-label “enrichment” phase in which all patients received 120mg of R-107 for 5 days. Response rates were evaluated at day 8. Nonresponders exited the study, while 168 responders, described as an “enriched responder population” were randomized on a 1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120, or 180 mg, or placebo, twice weekly for the next 12 weeks.
The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 12 weeks, initiating with 180mg dose and using a fixed sequence step-down closed test procedure. The primary objective was met; the least square mean difference of MADRS score for the 180 mg tablet group and placebo was −6.1 (95% confidence interval 1.0 to 11.16, P = 0.019) at 13 weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180 mg.
Researchers also reported favorable safety and “excellent” tolerability, with minimal side effects that are usually associated with injected or intranasal ketamine (i.e. dissociation, sedation, increased blood pressure). The most common adverse events were headache, dizziness, and anxiety.
Study authors noted some limitations to the trial, including the possibility of overestimating population levels of treatment response to R-107 due to the enrichment phase.
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