Slow-Release Ketamine Pill Relieves Depression

A new slow-release pill form of ketamine has shown promise in treating hard-to-treat depression without the psychedelic side effects typically linked to the drug, according to early research findings. Researchers have discovered that patients taking the highest dose of ketamine tablets experienced substantial improvement in their depression compared to those on a placebo.

On a 30-point depression scale, individuals taking the ketamine pill improved by 14 points, whereas the placebo group saw an average reduction of 8 points. This new form of ketamine could be a significant advancement over existing ketamine treatments like injections and nasal sprays, said Colleen Loo, a clinical psychiatrist at the University of New South Wales in Australia.

Esketamine (Spravato), a derivative of ketamine, is already approved in the United States for treatment-resistant depression in adults. It comes in various forms, such as a pill, nasal spray, or injection. However, these methods act quickly and can produce psychedelic effects. “This is a way of administering ketamine to treat depression that's much easier to give,” Loo mentioned in a university news release. The slow-release tablet allows patients to receive treatment at home, making it as convenient as other antidepressant medications.

Extended-release ketamine does not induce the hallucinations that are typically associated with the drug. It was previously believed that the altered reality caused by ketamine was part of why it effectively treated depression. Loo noted, “That’s very similar to the psychedelic-assisted therapy model that says changing your brain circuit functioning in that very profound way gives you new insights that help you to break out of your way of thinking, and that this acute kind of dissociative, altered reality experience is necessary for you to improve.”

However, the results of the slow-release tablet challenge this theory. With the tablet form, only a minimal amount of ketamine is released into the bloodstream at a time, leading to a continuous slow release over days without dissociative effects, yet patients still show improvement. 

In the clinical trial, researchers administered a moderate dose of the time-release ketamine tablet to 231 individuals with severe depression. By the eighth day, 168 patients experienced some benefit from the tablet, and 132 saw their depression lift to the point where they could be considered in remission.

The researchers then focused on the individuals who responded to the extended-release ketamine, dividing them into five groups. Four groups received varying strengths of the ketamine pills, while one group received a placebo. The highest dose of slow-release ketamine demonstrated a significantly better effect than the placebo. Although the lower doses showed slightly better outcomes than the placebo, the results revealed a dose-response relationship—the higher the dose, the more the symptoms subsided.

Dr. Brian Barnett, clinical director of the Psychiatric Treatment Resistance Program at the Cleveland Clinic, commented on the findings, stating that a two-point drop in the depression rating scale is meaningful to patients. A six-point drop is comparable to results seen in recent clinical trials of psilocybin for treatment-resistant depression.

This trial was the first to evaluate the effectiveness of a slow-release form of ketamine against depression. Researchers indicated that it might take years of further studies before the tablet is ready for clinical approval. “Douglas Pharmaceuticals, which is the New Zealand company that has produced the drug, still needs to do further studies, and it’s important to note this is not yet approved by the FDA in the US or the [Therapeutic Goods Administration] here in Australia,” Loo said. 

Future steps include conducting similar clinical trials globally with larger patient numbers and comparing extended-release ketamine against injectable and nasal spray versions. Different patients may respond better to different treatment methods, making a variety of options valuable. Douglas Pharmaceuticals sponsored the trial, and lead researcher Paul Glue of the University of Otago in New Zealand is named on a patent for the extended-release ketamine formulation. The study was published on June 24 in the journal Nature Medicine.

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