New Treatments: Ketamine
In the first in a series on novel treatments, Anorexia Myths speaks to consultant psychiatrist Dr Rupert McShane about the pros and cons of using ketamine in the treatment of anorexia nervosa
AM: When was ketamine first used, and what was it originally used for?
RM: Around 60 years ago, as an anaesthetic.
AM: I understand that there was a trial in anorexia nervosa patients that showed promise back in 1995. What were the results, and why was the treatment not revisited for another 30 years?
RM: Professor Ivor Mills in Cambridge showed that nine of 15 patients who were admitted did well with long duration infusions. I don’t know why it was not revisited. Perhaps he was just too far ahead of his time for people to believe him and so he couldn’t get further funding — but that’s pure conjecture. Or maybe people at that time just weren’t terribly interested in a disorder that affects predominantly young women.
AM: How did you become interested in ketamine as a potential treatment for anorexia nervosa?
RM: When we published a case series about ketamine treatment of resistant depression, I got a call one day from a patient who had been in Ivor Mills’s study. She said it had transformed her life. That’s what got us thinking again about this. To this day, I’m cross that I managed to lose her number!
AM: Ketamine is described as a dissociative anaesthetic. Can you explain to a lay person what this means?
RM: Dissociation is the sensation that mind and body are separate. Patients may look at their feet and not feel like they are part of them. As this intensifies, people can have the experience of being ‘out of body’, ie floating. At its most intense, people’s sense of self can feel obliterated or dissipated, as if they are a drop of water dropped into a river. This is known as ‘ego dissolution’.
AM: How is it hypothesised that ketamine works on a patient with anorexia nervosa?
RM: There are several theories. Mills reasoned that ketamine blocks the NMDA glutatmate receptor, that these are crucially involved in creating new memory, and he thought that disrupting anorexic ideas/memories about shape and weight might be useful. That’s still a plausible theory. He also clearly showed a reduction in depression in these patients but did not appear to be very interested in that. Given the known effect of ketamine on depression, it seems also possible that the effect of ketamine on depression might help people with anorexia feel better able to deal with their eating psychopathology. The main theories about how blocking NMDA receptors helps can be summarised as: putting a brake on the brake; blocking the centre in the brain that fires when you are disappointed; and helping neurons to turn from being like a tree in winter to a tree in spring — with lots of new twigs that can form new connections.
AM: How effective has it been shown to be?
RM: No one has proven that it is helpful: there are no randomised controlled trials. In 30 patients, we found that 42 per cent appeared to be much or very much improved. A few patients have told us that they believe it saved their life. Personally, I believe them — but, in clinical trials, the placebo effect of ketamine is very strong so I could easily be wrong.
AM: What can you tell us about your patients with anorexia nervosa who are currently receiving this treatment?
RM: Most of the patients we are still treating continue to have some symptoms of anorexia. Ketamine treatment, if it works, usually needs to be given repeatedly. In AN, this is between every two to eight weeks.
AM: Can ketamine result in remission of the disorder?
RM: I don’t know. A few of our patients have remitted, but this may have happened without the ketamine.
AM: Is ketamine treatment safe, and what, if any, are the downsides of this drug?
RM: Yes, it is a safe drug. It is on the WHO Model List of Essential Medicines. Tolerance sometimes develops — perhaps at the same rate as with wine. Occasionally, this is problematic. Overuse can definitely be a problem if people try to treat themselves.
AM: How do you guard against a patient developing a tolerance to the drug?
RM: Take it in a supervised medical setting with a specialist team overseeing it.
AM: Do you have an opinion on the combination of ketamine with other treatments, for example zinc or a ketogenic diet?
RM: I don’t know about the effect of zinc. Ketogenic diets tend to result in weight loss but are an efficient way of delivering energy. It would be a brave person to suggest it in patients who are already underweight. As you know, there is a case series of five cases where ketamine was combined with ketogenic diet. The two treatments may be synergistic, but someone needs to do a study of ketogenic diet on its own first.
AM: Any effective treatment to date has required full nutritional rehabilitation before thinking around food/weight gain can change. Do you think it’s possible to change the thinking around eating/body shape prior to nutritional rehabilitation with the use of ketamine, and how do you think this might work?
RM: Our experience is that treating the depression is helpful, but that changes in the ideas about shape and weight come second.
AM: If it proves effective for anorexia, are there any barriers to this treatment being widely used? If so, what are they?
RM: I don’t think I can say it is effective for anorexia. It may be helpful for depression in anorexia. Cost, availability, lack of formal evidence and lack of a licence are obvious barriers.
AM: I’m sure that many of our readers, particularly those who have had a lengthy illness, would be interested in this novel area of treatment. Are you or others recruiting for any trials at present? If so, how can people get involved?
RM: I understand that the team at King’s led by Hubertus Himmerich are hoping to start a trial soon. Our focus in Oxford is on developing a clinical service, improving access and trying to show how such a service could be structured.
AM: Thank you for taking the time to answer these questions and for all the fantastic work you are doing for people with anorexia nervosa and other mental illnesses.
Dr Rupert McShane is a consultant psychiatrist at Oxford Health NHS Foundation Trust and Associate Professor of Psychiatry at the University of Oxford