Oral ketamine shows promise for treatment-refractory depression

Extended release oral tablet formulation Ketamine Showing promise against treatment-resistant disease depression (TRD) Phase 2 proof-of-concept study results suggest.

In this study, sustained-release ketamine administered twice weekly produced statistically significant and clinically meaningful improvements in depression symptoms.

The researchers reported that overall tolerability was “excellent,” with no significant reductions in dissociation, sedation, or pain. Increased blood pressure It was “minimal.”

“A tablet formulation would allow patients to administer the medication safely at home, potentially increasing the number of patients we can treat at one time,” said researcher Paul Grew, MD, of the University of Otago in Dunedin, New Zealand. Medscape Medical News.

This study Publish online On June 24th Nature Medicine.

A difficult situation

TRD poses a big challenge. “We’ve known for over 20 years that ketamine, originally developed as a painkiller, AnestheticIt's also a fast-acting antidepressant,” Gru says.

But when it's given as an injection or nasal spray, it has “fairly noticeable side effects” so it needs to be administered in a doctor's office, and patients must remain in the office for around two hours after administration, Grew added.

Several small studies have shown that ketamine acts as an antidepressant, although it still causes dissociation when taken orally.

“When ketamine is prescribed as an extended-release tablet (taking about 10 hours to release), most of the ketamine is metabolized in the liver before entering the blood circulation. Because metabolites are the main contributors to the antidepressant effect, it is still effective as an antidepressant. However, because blood ketamine concentrations are low, patients experience few or no side effects,” Gru said.

The current phase 2 study tested the efficacy and safety of extended-release oral ketamine tablets (R-107) in adults with TRD and Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥20.

During the open-label study period, 231 participants received 120 mg/day of R-107 for five days.

The 168 responders, judged to have a MADRS score of 12 or less and a 50% or greater reduction in symptoms, were randomly assigned to receive double-blind treatment with R-107 at doses of 30, 60, 120, or 180 mg twice weekly or placebo for an additional 12 weeks.

The study achieved its primary objective, showing a significant reduction in MADRS scores in the 180 mg R-107 group compared with the placebo group (mean difference, −6.1; P = .019).

Seventy-one percent of patients in the placebo group experienced a relapse of depression after 13 weeks, compared with 43% of patients given oral ketamine twice weekly.

There were no changes in blood pressure, and reports of sedation and dissociation were minimal. The most common adverse events were headachedizziness, anxiety, etc.

More convenient and more tolerable

Several experts commented on the analysis in a statement from the Science Media Centre, a UK-based nonprofit organization that was not involved in conducting the study.

Dr Paul Keedwell, RCP and consultant psychiatrist, said the “new study further highlights the excellent antidepressant effects of ketamine in a much more convenient and acceptable form as a sustained-release tablet.”

“Furthermore, the researchers demonstrated a major benefit of oral ketamine – side effects that were not significantly different from placebo,” Keedwell said.

He added that the study also addressed “the difficult problem of maintaining improvement after an initial response. The findings suggest that many people will do well with longer-term treatment, provided they receive higher doses, but further studies in larger numbers of patients are needed.”

“A potential drawback of taking oral ketamine is that there is likely wide individual variability in absorption and metabolism, so further research is needed to determine the ideal method of administration,” Keedwell noted.

Rupert McShane, MD, a psychiatrist at the University of Oxford in the UK, also said the results were “sufficient to justify the larger Phase 3 trials needed to approve the 180 mg twice-weekly dose.”

“Regulators may be interested in the benefits and risks of higher doses, given that someone could easily choose to take two pills if one pill doesn't work,” McShane said.

The study was sponsored by Douglas Pharmaceuticals, which is developing R-107. Glue is named on a patent for a sustained-release ketamine formulation. A full list of author disclosures can be found in the original article. Keedwell states that he has no relevant conflicts of interest. McShane runs a clinic in Oxford that provides ketamine to treat depression, hosts academic conferences on ketamine, and is leading proposals to repurpose intravenous ketamine as an alternative to ECT.