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Child Psychiatrist /Adult Psychiatrist

Oral Extended-Release Ketamine Promising for Treatment-Resistant Depression

An extended-release oral tablet formulation of ketamine has shown promise for treatment-resistant depression (TRD) results of a phase 2 proof-of-concept study suggest.

Resistant Depression

In the trial, twice weekly dosing of extended-release ketamine led to statistically significant and clinically meaningful improvement in depressive symptoms.

Overall tolerability was "excellent," researchers reported, and common side effects commonly associated with intravenous or intranasal ketamine such as dissociation, sedation, and increased blood pressure were "minimal."

"Having a tablet formulation makes it possible for patients to be safely dosed at home and would increase the number of patients who could be treated at any one time," study investigator Paul Glue, MBChB, MD, with University of Otago, Dunedin, New Zealand, told Medscape Medical News.

The study was published online on June 24 in Nature Medicine.

Challenging Condition

TRD poses a significant challenge. "We've known for over 20 years that ketamine, a drug originally developed as an anaesthetic, is also a fast-acting antidepressant," Glue said.

However, when injected or administered as a nasal spray, it has "quite marked side effects," which means it that has to be administered in a clinic, and patients need to remain in clinic for 2 hours or so after dosing, Glue added.

Several small studies have shown that ketamine still works as an antidepressant when taken orally, although it still produces some dissociation.

"If ketamine is formulated as an extended-release tablet (where it takes approximately 10 hours to release), most ketamine is metabolized in the liver before it can get into the circulation. It still is effective as an antidepressant because its metabolites are the main drivers of its antidepressant effects. However, the lower blood ketamine levels mean patients experience few or no side effects," said Glue.

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

During an open-label phase, 231 participants received 120 mg/d of R-107 for 5 days.

The 168 responders, identified by MADRS scores ≤ 12 and a reduction of 50% or more, were randomly assigned to double-blind twice-weekly treatment with R-107 at doses of 30, 60, 120, or 180 mg or placebo, for a further 12 weeks.

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

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

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

More Convenient, Tolerable

Several experts offered perspective on the analysis in a statement from the UK-based nonprofit Science Media Centre, which was not involved with the conduct of this study.

Paul Keedwell, PhD, consultant psychiatrist and fellow of the Royal College of Psychiatrists, said that this "novel study further underlines the impressive antidepressant effect of ketamine, but in the much more convenient and acceptable form of a slow-release tablet."

"In addition, the researchers demonstrated a major upside of oral ketamine — that side effects did not separate significantly from placebo," Keedwell said.

He added that the study also addressed the "thorny issue of maintaining improvement after the initial response. Their results suggest that many will continue to do well with longer-term treatment, provided higher doses are used, but more research is needed with higher numbers of patients."

"A potential downside of taking oral ketamine is that there are likely to be large individual differences in absorption and metabolism, so further research is needed to determine the ideal dosing regime," Keedwell noted.

Also weighing in, Rupert McShane, MD, psychiatrist at the University of Oxford, United Kingdom, said that the results are "good enough to justify the larger phase 3 trials that will be necessary for a license for the 180-mg twice weekly dose."

"Given the ease with which people may choose to take two tablets if they do not benefit from one tablet, regulators may be interested in the benefits and risks of higher doses," McShane commented.

The study was sponsored by Douglas Pharmaceuticals, which is developing R-107. Glue is named on a patent for the extended-release ketamine formulation. A complete list of author disclosures is available with the original article. Keedwell reports no relevant conflicts of interest. McShane runs a clinic in Oxford providing ketamine as a treatment for depression, runs an academic conference about ketamine, and is leading a proposal for intravenous ketamine to be repurposed as an alternative to ECT.

Note: This article originally appeared on Medscape.

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