How brain scanners can help up revolutionise psychiatric drugs


WHEN it comes to treating mental health conditions, you could say we have been working in the dark. The drugs we use to treat them are notoriously problematic. Almost every one of them was developed before the advent of brain scanners, and Mitul Mehta believes these powerful machines offer an unrivalled chance to open a window onto brain conditions and see how the brain responds to treatments. This could ultimately help us find better medications. Pushing the boundaries of conventional drug discovery methods, Mehta, who is a professor of neuroimaging and psychopharmacology at King’s College London, is using scanners to explore how psychedelic drugs and even hypnosis influence the brain in an effort to find new ways to treat psychiatric and neurological conditions. What he is finding is unmasking much about the way the brain works, and causing us to reconsider the way we think about mental illness.

Clare Wilson: Why do we need to study psychiatric drugs using brain scanning?

Mitul Mehta: Pretty much every drug available in psychiatry, we don’t really know how they work in the brain. There is a huge unmet need in the treatment of psychiatric disorders. For example, we might be interested in a potential new treatment that might impact the reward system in the brain. You might have a symptom of low motivation, which is quite common across the psychiatric spectrum, for instance in schizophrenia and depression.

One of the questions is: is low motivation mediated by the same circuits in the brain? If it is, then maybe it might be responsive to the same or similar treatments. So there might be benefits in looking at symptoms and how to understand particular symptoms better, and then how to treat those symptoms better, because you might benefit more than one diagnosis.

So, rather than dealing with specific psychiatric illnesses that fit our current labelling system, you are almost looking at things that run deeper below them?

For sure. I think this is the way to go. Psychiatric diagnoses are clinically useful, but they are not based on a neurobiology, they are not based on a functional understanding of the brain. If we are going to base new treatment development on a neurobiological understanding of the brain, we want to look at processes and symptoms, and they may cross diagnostic boundaries.

Have you had any particular successes so far with your approach of using brain scanning to investigate psychiatric conditions?

The timescale that we have been working to is the timescale it takes to develop a new drug, so we wouldn’t expect big successes yet, but hope to in the next 10 years.

Take, for example, Parkinson’s disease, which is a movement disorder, but in which up to half of patients also experience psychosis. They will often experience hallucinations, and that might develop into experiencing delusions. That can cause a lot of distress, not only to the individual affected, but also to their partner or carer.

How can we reduce their symptoms? One of the models that we have been working with is using psychedelic drugs. Drugs like psilocybin [the active compound in magic mushrooms] hit a particular receptor in the brain called the 5-HT2A receptor and we think that is instrumental in its psychedelic effects.

One of the features of psychedelic effects is visual distortions or hallucinations. What’s interesting is that when you study individuals with Parkinson’s disease psychosis, you find an elevation in the number of 5-HT2A receptors, especially in a visual processing pathway in the brain. We have seen this in patients who have had PET scans, and we have seen it post-mortem as well.

We came across a drug that had been developed for cancer, but which reduces the impact of 5-HT2A receptor stimulation. It does it through a novel method, which we think might be quite successful.

Have you tested this drug in people with Parkinson’s disease?

First we have tested it in healthy volunteers given psilocybin. This is like a simpler test of our hypothesis, as we are not as sure about the role of 5-HT2A in Parkinson’s. It is also harder to work with patients than healthy volunteers. We gave the volunteers the cancer drug first, then put them in the brain scanner and then gave them psilocybin. It did reduce the impact of the psychedelic experience.

That is very promising. If it is reducing the impact of the psychedelic experience, that suggests it is getting into the brain with sufficient success to actually have an effect on the brain physiology. Now we can go into the scanner with patients who have Parkinson’s psychosis. We are running a study where they are given this drug for a couple of weeks. At the end of those two weeks, we put them in the scanner to see if the activity in this visual processing pathway has been normalised by this compound.

What made you work with psychoactive recreational drugs? Is that a useful way to shed light on how the brain works?

Oh, very much so. We are already discovering through colleagues of mine that psilocybin may be beneficial as a treatment in depression. We are learning that MDMA, also known as ecstasy, may be beneficial in helping the treatment of post-traumatic stress disorder. And we are also learning that compounds within cannabis may be beneficial in various conditions – sleep, pain and psychosis, to name just three.

“Healthy people who are highly suggestible can also experience this alien control of movement”

Ketamine is very interesting at the moment, because it appears to be successful as an antidepressant, particularly in people for whom other existing treatments just haven’t worked. But ketamine is also interesting because it produces a set of experiences which, for a long time, we thought looked a bit like psychosis – one of the main symptoms you have in schizophrenia. If you give someone ketamine and then you use a scale that you would use to measure symptoms in schizophrenia, they would score very highly on this scale.

It tells us something very important: that if you manipulate one system in the brain, and with ketamine we are manipulating mainly the glutamate system of the brain, then you can actually create a set of experiences, which you know are mediated by glutamate, that look a bit like psychosis. So we have been using ketamine to try to develop an assay to test new treatments for schizophrenia, which work on the glutamate system.

So you are using the mind-altering effects of ketamine as a proxy for schizophrenia?

You can give otherwise-healthy people ketamine, you can put them in the scanner and you can give them other drugs on top of it and see if it reverses the effects of ketamine. You can find out, first of all, if the other drugs work, if they get into the brain sufficiently to reverse the effects of ketamine, and you can find out which dose is most successful. Then you can test patients with real confidence, because if you can’t reverse the effects of ketamine, then you are probably not hitting the glutamate system enough to be beneficial to patients.

You also work with hypnosis. How can it help us understand neurological issues?

We have put hypnotised people in the scanner so we can look at the brain systems involved in hypnosis generally.

We can also give people particular suggestions in order to study certain experiences in isolation [a suggestion in hypnosis might be something simple, for instance that a person’s eyes are heavy and they feel relaxed, or more specific, such as paralysis. Some people are more suggestible than others]. One thing we did was to suggest paralysis. We would suggest to people that their left arm cannot move and is paralysed, and then we might ask them to try to move a joystick whilst they are lying in the scanner. Then we can look at their behaviour and they aren’t moving the joystick.

Fine, maybe they are being very compliant, maybe these are the best volunteers in the world and they are behaving exactly as we ask them to do [with the suggestion]. Or maybe they genuinely are experiencing a paralysis. Maybe they really want to move, but somehow their arm is not moving. That’s what they describe to us. We can believe them, but that can only take us so far.

If we can look in the brain during that experience, then we can compare that with what’s happening in the brain when we ask them to simulate not being able to move their hand.

Does it look different in the brain when they are hypnotised compared to when they are simulating it?

It is completely different. What you find is decreased activity in some of the areas involved in motor planning. This is amazing, really. It tells us that, through hypnosis and this suggestion, we are actually downregulating parts of the motor network. This experience that people are describing is matched by what we are seeing in the brain.

What we did next was we suggested that someone else is controlling their movements. So this idea that they have got agents of control or loss of agency, that it’s not actually them controlling their arm. We can have a look at the areas of the brain involved in that experience.

We can even go a step further, and we have done this as well, where we can ask people to write down the end of sentences. We can tell people that the thoughts they are having – the words they are choosing – are not their own words, but are someone else’s words that they are writing down. People do claim to have less control over the words they are selecting and they feel like someone else is giving them the words to write down. We see changes in the language areas in the brain during those experiences.

Isn’t that a symptom that is sometimes seen in schizophrenia, too?

Yes. Passivity phenomena is what we call this and that is a very common symptom in schizophrenia. So this is really an opportunity to study these phenomena in isolation. They tell us a few really important things. First of all, they tell us that otherwise-healthy people who are highly suggestible can experience passivity phenomena. They can experience this alien control of movement, these thought insertion experiences.

We can study the brain areas involved in that particular symptom. It’s also reversible, which is amazing – we can have a look at the brain circuits involved and we know it’s a safe environment in which people can have these experiences.

Do you hope to one day be able to help develop drugs to cancel out those symptoms?

Yes. We are already looking at how drugs might modulate some of them. I think with this new understanding, we can start to think about better ways to use existing drugs, but we can also start to develop the techniques to look at novel drugs and novel treatments, so we can accelerate their development., 10 june 2020