The first UK study to test ketamine as a treatment for depression confirms that, when given in low intravenous doses, the "party drug" has a rapid - but short-lived - antidepressant effect in some patients with severe depression who do not respond to other treatments.
Lead investigator Dr. Rupert McShane, a researcher in the Department of Psychiatry at the University of Oxford, says:
"Intravenous ketamine is an inexpensive drug which has a dramatic, but often short-term, effect in some patients whose lives are blighted by chronic severe depression."
He and his colleagues wanted to find out if ketamine was safe if given repeatedly, and practical to administer through the NHS.
"We especially wanted to check that repeated infusions didn't cause cognitive problems," says Dr. McShane, who is also a consultant psychiatrist with Oxford Health.
The researchers report their findings in the Journal of Psychopharmacology.
Studies have already shown ketamine's potential as a fast-acting antidepressant
About 10 years ago researchers first spotted the antidepressant potential of ketamine - a drug already used as a general anesthetic and painkiller in human and animal medicine, and also as a recreational drug.
More recently, studies have drawn attention to the speed with which ketamine can alleviate symptoms of depression, and in some cases bipolar disorder, in patients for whom other treatments don't work.
In 2013, a team at the Mayo Clinic in the US, found that ketamine was effective at treating depression. They tested it on 10 patients and were surprised to find it acted very quickly - sometimes within hours - to reduce depressive symptoms and suicidal thoughts.
Also in 2012, another group of researchers at the US National Institute of Mental Health, found that bipolar depression patients benefited from ketamine within minutes. The researchers also confirmed that the drug works by interacting with the NMDA receptor complex, which is involved in strengthening and weakening synaptic connections.
'Remarkable' changes in people with many years of severe depression
However, given the drug's serious side effects, which in the short term include hallucinations, drowsiness, dizziness, impairment of memory and judgement, and in the long term, cause damage to the bladder, researchers have been looking for a safe way to administer it.
In this latest UK study, Dr. McShane and colleagues confirmed that ketamine showed a rapid antidepressant effect in some patients with severe depression who had not responded to other treatments.
Some of the patients had been suffering with severe depression for many years, and had tried several drug and talking therapies with no benefit.
The researchers say that even though many of the patients in their study relapsed within a day or two, improvement in symptoms persisted for 3 weeks in 29% of patients, and for over 2 months in 15% of them.
Dr. McShane says it was very moving to witness "remarkable changes in people who've had severe depression for many years that no other treatment has touched."
A common comment from patients was how "the flow of their thinking seems suddenly freer," he adds, noting that "For some, even a brief experience of response helps them to realize that they can get better and this gives hope."
Ketamine was safe, but did not help all patients, and effects were short-lived for many
For their study, the team treated 28 treatment-resistant depression patients over three weeks. The patients received either three or six intravenous ketamine infusions lasting 40 minutes in the recovery room of a routine treatment clinic.
The doses of ketamine the researchers used were quite different to the doses people use for recreational purposes. Users who get the drug on the street are taking doses of up to several grams a day. In the study the patients were infused with no more than 80 mg - that is 80 thousandths of a gram - a week, and they were under close medical observation.
Some patients needed a second ketamine infusion for the antidepressant response to take effect.
The patients underwent memory tests a few days after the final infusion, and reported mood symptoms every day via text or email.
In 29% of patients, their depression scores had halved by the third day after their last infusion. In those who responded to the treatment, the benefit lasted between 25 days and 8 months - the median was 2.3 months.
The ketamine did not cause memory or bladder problems. Some patients were sick and one fainted during the infusions, and some became anxious and did not finish the course because they said they could not feel any benefit.
In most cases, the patients did experience some short periods of dissociative effects, where perceptions are slightly distorted and they felt disconnected from their body, but these only happened during infusion and the researchers say they were not linked to the antidepressant effect.
Nine of the patients benefited sufficiently to continue to have further intermittent infusions. Of these, four are still receiving treatment, one is in remission without treatment and reporting no symptoms of depression, while four have relapsed and moved onto other treatments.
No evidence of addiction to ketamine with long-term use
The researchers say there is no evidence of patients becoming addicted to the ketamine, based on receiving regular doses over 2 years. This is consistent with its use as a painkiller.
They say the treatment worked well in the setting they used - an ECT clinic where all the equipment and staff necessary for the treatment were already in place.
The team has now given over 400 infusions of low-dose ketamine to 45 patients and are now working on how to make the benefits of ketamine last longer.
Dr. McShane says they now need to "build up clinical experience with ketamine in a small number of carefully monitored patients. By trying different infusion regimes and adding other licensed drugs, we hope to find simple ways to prolong its dramatic effect."
The study was sponsored by the National Institute for Health Research (NIHR) Research for Patient Benefit Programme.