Clinical Trial Finds Slow-Release Ketamine Tablet Effective for Severe Depression

A new tablet form of ketamine has shown promise in treating severe depression, offering a potential alternative to existing clinic-based treatments that can be expensive and lacking in convenience for some patients.

The study was published in the journal Nature Medicine.

Over the past twenty years, research has increasingly shown that ketamine can quickly relieve symptoms of depression in people who haven’t responded to other treatments. Most studies have looked at ketamine used in ways not originally approved by regulators, typically administered intravenously.

Recently, a nasal spray form of ketamine called esketamine has been approved for use. Both ketamine and esketamine can be given in different ways, and higher doses generally lead to greater improvements in depression than lower doses.

A study analyzing different forms of ketamine found that those designed to be processed slowly by the liver and to reach peak levels in the blood more gradually were safer and better tolerated than those that don’t have these characteristics.

In the study, scientists conducted a randomized-controlled trial to test the effectiveness of ketamine tablets in treating depression compared to a placebo. They randomly assigned 168 patients with treatment-resistant depression into five groups: four received different doses of ketamine, and one received a placebo.

The researchers found that patients taking the highest dose of ketamine—180 mg, taken orally twice a week—experienced the most significant improvements compared to the placebo group. The effectiveness was measured using the MADRS score, which assesses depression symptoms, with higher scores indicating more severe depression.

In the group receiving 180 mg of ketamine, the average MADRS score dropped by 14 points from a starting score of 30. In contrast, the placebo group saw an average reduction of 8 points. The other ketamine doses (120 mg, 60 mg, and 30 mg) also showed slightly better outcomes than the placebo.

“First, administering ketamine tablets for depression is much more convenient than clinic visits for injections and two-hour monitoring sessions. Patients can take the tablets at home, making the treatment as easy as other antidepressants. Additionally, having multiple forms of treatment—tablets and injections—can help cater to different patient responses. Second, this tablet form challenges the belief that ketamine's effectiveness relies on causing altered reality perceptions. The tablet releases ketamine slowly, with only a tiny amount entering the bloodstream at a time, preventing dissociation while still improving depression symptoms. This suggests that the dissociative effects might not be necessary for ketamine to be effective,” said the researchers.

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). https://doi.org/10.1038/s41591-024-03063-x