Ketamine and psilocybin alter depression-tinted memories

New research suggests that mood-altering drugs such as the anaesthetic ketamine and the hallucinogen psilocybin can help alleviate symptoms in difficult to treat cases of depression. The experiments - which were carried out on rats by a team at the University of Bristol - suggest that people with depression tend to attach negative emotions to memories. Breaking those associations, which the experimental drugs seem to do, appears to boost mood for extended periods of time. Professor Emma Robinson conducted the research...

Emma - People with depression tend to think about things and remember things in a negative or pessimistic way. And we think that this is important in contributing to why they have a low mood and perpetuating the illness. We also think the treatments for depression might actually be affecting these pathways in the brain that generate this sort of negative thinking. And so this project was all about asking that question. Do these drugs specifically interact with this kind of negative thinking and these pathways involved in negative thinking?

Chris - Are these new drugs or are they old drugs that we're finding a new way to use?

Emma - No, they're not new. That's what's really interesting. I mean, one of the drugs is ketamine. It's been used as an anaesthetic. It's a well-known drug of abuse. And the other drug that we've particularly been interested in is psilocybin, which is a psychedelic, and it's something which we've known about probably for millennia.

Chris - And how did it come to light that they had these interesting properties then?

Emma - About 20 years ago, somebody thought it would be interesting to see what would happen if they gave people a single dose of ketamine and what would happen to patients who had treatment resistant depression. And I think everybody was really surprised when the drug had this very rapid and long lasting effect after single treatment. People were feeling better within 24 hours and they stayed better for many days.

Chris - So how have you tried to unpick what you think is going on then?

Emma - So what we're doing is we're forming specific memories and then we're using different treatments to shift those memories by a virtue of the emotion at the time they learn it. So if you imagine you find something that's worth £10. When you experience that in a negative emotion, it's valued a bit less. So it's like when people have depression, they can experience positive things, but they value them less and that means that they're less likely to remember them positively. The drugs seem to have quite a specific effect on the part of the brain that creates that sort of emotional part of a memory. So it doesn't change the memory itself, but where a memory might have been not very valued because it was learned during a depression--like state. When they've had the drug and we ask them to retrieve the memory, it's actually become more positive.

Chris - How did you do this in your rats though, to reach that conclusion?

Emma - So we just give them very specific memories and the memories are that a particular thing that they dig in has food in it, and they had to remember that. And rats are brilliant at it. And then we ask them the simple question, which of these memories do you prefer? And when they've experienced the memory after a negative or a depression-like state, they don't like that experience as much as they like the one in a neutral state. And so we're asking them to say, which one do you prefer? And we can manipulate that with the drug treatments.

Chris - So you've got your food item in different things. They can dig in and they've dug in one when they're feeling in a low mood and they've dug in another when they're feeling in a good mood and you present them with the choice and you say which ones you want, whereas you can break that association with these drugs.

Emma - We can break that, yeah. And what's particularly exciting was that we didn't just break it, but actually a day later, that previously negative memory had actually become more positive. So it had shifted to the other side. So it was actually better than what they'd learned on the neutral day.

Chris - And you can prove it's not just these drugs having an amnesic effect. They're not just forgetting that they were depressed because they still remember there was food. It was in that particular material and have to dig for it. So they've still got a memory there, but they're regarding it as less negative than they used to.

Emma - Yeah, that's right. So we actually do a control experiment. So we do a different type of memory test where we use exactly the same treatments, but this time there's no emotional component to it. And these drugs have no effect on that at all. So it's not just amnesia, it's a very specific effect on this sort of emotional part of the memory.

Chris - Do these experiments give you any insight into why people tend to, if they have a tendency towards depression and negative mood, that they have this problem in the first place, why they are emotionally loading their memories in this bad way? So they tend to overemphasise the negatives and underemphasise the contribution of the good things

Emma - We don't yet. So that's very much where we want to see this work going. We have the potential now to use this same sort of approach to now ask questions. So in someone who has depression. So can we, if we model depression itself in a rat, can we actually see these changing in that way? So we did some work a few years ago where we found that actually if animals experience adversity early in their lives, then they actually become more pessimistic in their thinking. So a bit like what we see in depressed people. So we do think that perhaps in depression there's this sort of adaptive change in these parts of the brain making people sort of become more pessimistic.