Slow-release ketamine pills have been found to prevent relapse into depression, in a trial that could pave the way for a new treatment option for patients with severe illness.
Ketamine is already used as a treatment for depression when conventional antidepressant drugs and therapy have failed. But ketamine is currently only administered intravenously, which requires supervision in a clinic, and the National Institute for Health and Care Excellence 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 more cheaply, conveniently and potentially with fewer side-effects, the researchers said.
“We’re seeing a clinically meaningful effect,” said Prof Allan Young, of King’s College London and a co-author of 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 10-hour period. The hope was that this would make the treatment more effective and reduce adverse effects such as dissociation, high blood pressure, a racing heart or feelings of numbness. The “slow peak” would also reduce the drug’s abuse potential, Young said.
For most depression treatments – including those proved to be effective – a significant subset of patients do not respond. To get around 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 responders”. Of these, the 168 who showed a significant reduction in symptoms entered the trial’s second phase, where they were randomly assigned either to continue taking ketamine tablets or to receive a placebo.
In the placebo group, 71% of patients experienced a relapse into depression after 13 weeks, compared with 43% of patients who received the tablets twice weekly. The patients had no significant changes in blood pressure and minimal reports of feeling drowsy. However, those at higher doses, who appeared to get most benefit, 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 was due to his illness rather than the treatment.
The team behind the trial hope the drug could 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 a different 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 which is safe in the long term that would be a huge advance,” he said.
However, he added that it was not yet clear whether ketamine treatments would remain an appropriate treatment only for severe cases of depression or whether trial evidence would ultimately support more mainstream applications. “Whether it’s got a place in the wider population is uncertain and this is a good way of testing this,” he said.
Dr Paul Keedwell, a consultant psychiatrist, said: “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. 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.”
The findings are published in Nature Medicine.
