Ketamine and schizophrenia

What can ketamine reveal about what causes schizophrenia?
18 July 2013

Interview with 

Paul Fletcher, University of Cambridge


Worldwide, about 1% of people are affected by schizophrenia. Paul Fletcher, from the Department of Psychiatry at Cambridge University, studies the condition and why agents like ketamine can reproduce some of the symptoms. He spoke with Hannah Critchlow.

Hannah - So Paul, the experiences that Louise just explained, are they typical for people that have Schizophrenia?

Paul - Well, one might argue that there's no absolutely typical set of symptoms, but as far as it goes, really what Louise is describing, hearing the voices, feeling very persecuted, could be considered as typical of Schizophrenia. Schizophrenia itself is a very broad description of a serious mental disorder. It means a splitting of the mind, which is not as some people have thought, a splitting of the personality, the sort of Jekyll and Hyde. It really refers to fragmentation of mental processes so that somebody has a great deal of difficulty in interacting cohesively with the world. Typically, the symptoms are divided into three broad types and a lot of what Louise was describing would be the first of these, so-called psychosis which refers to being, if you like, 'out of contact' with objective reality. So, somebody might experience often terrifying beliefs about being controlled or persecuted, just as Louise described. Those beliefs are called delusions. People may also experience what are called hallucinations, which are the perception of events or objects that are not objectively there. Now, Louise was describing them as hearing voices, but people also experience in touch by things or sometimes seeing things that aren't there, but she also describe something that probably falls into another category within the symptoms of Schizophrenia which is the sort of cognitive problems that people have feeling of being fragmented and also having difficulties with things like their attention and their memory, difficulty making sense of the world. And then there's a third group of symptoms which we often referred to as the negative symptoms which refer to difficulties in motivation and action, a tendency to disengage from the world personally, emotionally, socially, and physically.

Hannah - And do we know what's going on in the brain to give rise to this vast myriad of symptoms that are associated with Schizophrenia then?

Paul - No, we don't know the cause of Schizophrenia. It really is a broad term for what may well be a group of sub-syndromes which have a sort of common presentations such as hallucinations, but may actually have underlying different causes.

Hannah - And one avenue for researching the brain basis for Schizophrenia is to use drugs that alter perception of reality. I believe this is what you're studying here in Cambridge. Could you tell us a little bit about that?

Paul - Sure. I mean, the idea of a drug model of an illness like that is not so much that you're trying to create that illness in a healthy person who wouldn't otherwise have it. What you're trying to do is make a very specific manipulation of their brain chemistry, temporarily of course, in order to

produce some of the perceptual changes that are like those in the illness. So, in that sense, what you've got is a very highly controlled experimental situation in which you can induce things like hallucinations in healthy people and observe how their brain changes, things like that.

Hannah - And what kind of chemicals are you using to induce these changes?

Paul - Well, a number of different drugs have been used in the past to model Schizophrenia, from amphetamines to LSD. The drug that I've been very interested in is one that acts on a particular type of receptor in the brain called the NMDA receptor and that drug is ketamine.

Hannah - What kind of thing happens to people when ketamine is administered?

Paul - Well initially, people experience perceptual disturbances. Things can seem quite vivid. Things can seem strangely meaningful. So, for example, a coffee cup that's sitting on a table might somehow seem to be much more significant to them at that time. So, people describe those phenomenon - those are very similar to what a number of people describe in early Schizophrenia - this sense of changing importance of things.

Hannah - And I think you've got an audio example of how we can change, we can tweak our perception.

Paul - Most of us feel that we experience the world as passively receiving our sensory input, but actually, if we did that, we would be dysfunctional because there is so much sensory input. So much of it is noisy. So much of it is ambiguous that we can't actually do anything, unless our mind essentially takes some shortcuts.

Hannah - So, our brain is constantly being bombarded by all these information coming in through all our senses and we have to make assumptions and predictions based on our prior experiences.

Paul - That's exactly right and this is what I study under ketamine. So, an example of that would be in hearing. We have a sense that we hear words very clearly, but actually, a lot of the time, we're superimposing what we think should be there onto it. So, we've got an example here which is from Matt Davis's group in Cambridge.


Paul - So that, to most people hearing it for the first time is rather like ugly clockwork bird song. However, if you change their experience slightly by playing another clip now...

Audio - The camel is kept in a cage at the zoo.

Paul - What they now have is a different prior experience. So now, if they hear the first clip again, they should have a changed experience of it.


Paul - So, they should now be able to understand that.

Hannah - The cadence seems quite similar from the first noisy track where I didn't hear that sentence before.

Paul - Yeah, it's exactly the same track. What that tells you is that your prior experience is superimposing itself onto a highly noisy stimulus in order to make sense of that and that's great. That's what we should be doing all the time, but of course, what it also means is that your brain is creating a world. And if you're creating sensations and perceptions, what you're essentially doing under normal circumstances is hallucinating. Its balance is maintained in a very useful way in a healthy individual, but if it's shifted, then it may well be that you hallucinate in a very non-useful way. In a way, that Louise described, experiencing very unpleasant voices telling you what to do and controlling you.


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