Slow-release ketamine tablet reduces symptoms of severe depression

A slow-release tablet form of ketamine has been shown to effectively treat depression in a clinical trial involving 168 patients.

If eventually approved as clinical treatment, it could make ketamine cheaper and more convenient to use to treat severe depression.

Ketamine is currently administered via nasal spray and intravenous injection to treat depression. However, these forms can be expensive and must be administered within a clinic with up to 2 hours of additional monitoring.

A new study, published in Nature Medicine, found that a slow-release tablet form can be taken safely alone at home with negligible side effects.

The tablet also effectively treated trial subjects, all of whom had previously failed to treat their depression with an average of over 4 different antidepressants.

The double-blind randomised controlled trial enrolled patients with treatment-resistant depression who were randomly assigned either 30mg of ketamine, 60mg, 120mg, 180mg, or a placebo. This was administered orally twice a week for 12 weeks.

Neither the patients nor the researchers were aware of who received which intervention.

The researchers measured the intervention’s success by the reduction in a patient’s MADRS score. This measures depression symptoms, where the higher the score the more serious the depression.

They found that patients taking the strongest ketamine dose had the greatest average reduction in MADRS score (14 points down). The average reduction for those in the placebo group was just 8 points. The remaining doses of ketamine had slightly better outcomes than placebo.

Dr Paul Keedwell, a consultant psychiatrist and fellow of the Royal College of Psychiatrists who was not involved in the research, says the researchers demonstrated a major upside of oral ketamine – that side effects did not separate significantly from placebo.

“In other words, a ketamine tablet, as opposed to an infusion, is well tolerated. This is consistent with previous research,” he says.

Study co-author Colleen Loo, a clinical psychiatrist and researcher at the University of New South Wales (UNSW) and Black Dog Institute (BDI) says: “It is possible that some people may respond to one approach to treatment, such as the tablet, while others respond to another, such as the injection, so having more treatment approaches is very useful.”

The new treatment resulted in minimal symptoms of dissociation, challenging some beliefs about how ketamine works to alleviate depression.

“There’s one school of thought that says what we call dissociative effects – where you’re feeling a kind of altered reality and perception – are actually integral to the ability to improve the depression with ketamine,” says Loo.

“But with this tablet form you don’t experience that because only a tiny amount is released into the bloodstream at a time, with ongoing slow release over days, and you don’t experience the dissociation at all, and yet people are improving.

“It could be the theory that you must have these altered reality perceptions to improve may not be correct.”

This treatment has not yet been approved for clinical use. Next steps will involve reproducing the results of this study and larger phase 3 trials.

“The study 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,” says Keedwell.

“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 regimen.”

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