Slow-release ketamine pills have been found to prevent relapse in depression, in a trial that could pave the way for a new treatment option for patients with serious illnesses.
Ketamine is already used as a treatment for depression when conventional antidepressant drugs and therapy have failed. But ketamine is currently administered only intravenously, which requires supervision in a clinic, and the National Institute for Health and Care Excellence has ruled that a ketamine-like nasal spray should not be available on the NHS.
If the apparent benefits are confirmed in a larger trial, ketamine tablets could be taken at home cheaper, more conveniently and potentially with fewer side effects, the researchers said.
“We see a clinically significant effect,” says Prof Allan Young, from King’s College London and a co-author of the findings. “This is not a definitive result, but the effect size is gratifyingly large.”
The phase 2 trial used an extended-release formulation of ketamine, designed to release the drug into the body over a period of 10 hours. The hope was that this would make the treatment more effective and reduce adverse effects such as dissociation, high blood pressure, a pounding heart or feelings of numbness. The “slow peak” will also reduce the drug’s abuse potential, Young said.
For most depression treatments—including those proven effective—a significant subset of patients do not respond. To circumvent this challenge, the latest trial used an innovative design in which all 231 were initially given the new drug formulation for five days to identify “treatment responses”. Of these, the 168 who showed a significant reduction in symptoms entered the second phase of the trial, where they were randomly assigned to either continue taking ketamine tablets or receive a placebo.
In the placebo group, 71% of patients experienced a relapse in depression after 13 weeks, compared with 43% of patients who received the tablets twice a week. The patients had no significant changes in blood pressure and minimal reports of feeling drowsy. Those with higher doses, who appeared to benefit the most, were also more likely to report feelings of dissociation and dizziness. There was also a suicide of a 65-year-old man in the treatment group, which the principal investigator considered to be due to his illness rather than the treatment.
The team behind the trial hope that the drug can become an alternative for the millions of people living with chronic depression who have not responded to conventional drugs. The most commonly used drugs, known as selective serotonin reuptake inhibitors (SSRIs), are thought to act on the brain chemical serotonin, while ketamine appears to act on another neurotransmitter called glutamate.
Dr Rupert McShane, consultant psychiatrist at Oxford Health NHS trust, said the findings were encouraging. “If a form of ketamine can be found that mimics the intravenous ketamine benefit and is safe in the long term, that would be a major advance,” he said.
However, he added that it is not yet clear whether ketamine treatments will remain an appropriate treatment only for severe cases of depression or whether trial evidence will eventually support more mainstream applications. “Whether it has a place in the wider population is uncertain and this is a good way to test it,” he said.
Dr Paul Keedwell, a consultant psychiatrist, said: “This new study further underlines the impressive antidepressant effect of ketamine, but in the much more convenient and acceptable form of a slow-release tablet. 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.”
The findings are published in Naturopathy.
