Dealing with depression

15:16David Nutt:If they do have the indication for it and we can manage it without medication, we'll look to do that first. But yes, sometimes medication is indicated. The patient does want it and we do see benefits a lot of the time. I wouldn't say that these medications are addictive, but we do have to be clear that if you take them for any length of time and you stop them suddenly you can get withdrawal symptoms and that we need to be clear with patients as being careful not to stop them suddenly and not thinking that you're addicted when you have side effects from stopping it or withdrawal effects from stopping it it's just that we need to do it gradually.

15:53Jackie Rogers:And those withdrawal effects is that basically the mirror image of how you feel when you are taking them So if you feel more centred, if you feel a bit like you're on an even keel and you suddenly stop, there's a risk it'll upset the apple cart and you feel all wobbly again.

16:07David Nutt:Yes, you can do. People will talk about feeling a bit shaky. They might have a recurrence of their symptoms. Some people talk about funny electric shock type feelings in their head. Stomach upset would be another common one. And it can be very unpleasant to have withdrawal symptoms, which people can then fear means that they're stuck on medications, but it doesn't.

16:31Jackie Rogers:What about the downside in terms of just physically taking that pill? What side effects does it have?

16:37David Nutt:We'll always mention the side effects. Common ones that I would mention, the delayed onset. It might take four to six weeks to have full effect of the medication. we would mention that it can sometimes instead of giving you the normal highs and lows of being reactive to your day it can leave you a bit unreactive a bit flat in the middle with your mood which can be strangely unpleasant actually we see anorgasmia quite commonly so a lack of ability to have an orgasm stomach upset often settles down within the first few days and I do mention that if you take these very long term there is some evidence that it can impair your brain function.

17:17David Nutt:The biggest risk is in young people of having more suicidal thoughts. In fact it's not just young people but it's more commonly seen in young people that you'll have more suicidal thoughts so there is oddly a slightly higher risk of suicide at times when starting antidepressants.

17:35Jackie Rogers:Mumro Stewart at the Royal College of General Practitioners and trials show that about half of the people who try antidepressant medication will report that they feel better subsequently, although it can take significant amounts of time.

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18:56Jackie Rogers:This is the Naked Scientist podcast with me Chris Smith and today we're examining why it's hard to treat depression and how some new innovations offer some fresh hope. Now diagnosis and medicine are usually only part of the treatment for someone who's diagnosed with depression with people usually also being offered therapy. The concept of healing through words dates back in fact thousands of years but it wasn't until the 19th century that we shifted towards diagnosing and treating mental health conditions through actually talking. It was this development that helped to establish the Foundation for Modern Psychology.

19:31Jackie Rogers:Jackie Rogers is an accredited psychotherapist at the British Association for Counselling and Psychotherapy. And I began by asking her who might come to see her and what that involves.

19:41David Nutt:A person that referred themselves because they want to go privately, or sometimes an employment-assisted programme that they've contacted me and they want to work with their depression. So the tools I would have would be counselling skills. I can use counselling, so allowing somebody to talk, exploring their feelings, and then I also can do a bit of interpersonal therapy, so that would be looking at who have they got around them that can support them.

20:08Jackie Rogers:Do you actually find yourself also seeking to try and validate the self-diagnosis that someone may have made? Because someone might come to you and say, well, I'm depressed. Do you question that and make sure that they really are, or whether there might be something else going on?

20:22David Nutt:Yes and no. So I would acknowledge what they're saying when people say I'm depressed. It's a word that's used quite a lot. It may be just low mood. So I'd explore what does depression look like to you? Get them to tell me about their depression.

20:35Jackie Rogers:Well, and that enables you to then validate that's definitely what's going on here. Therefore, the right way to perhaps attack this would be X, Y and Z.

20:43David Nutt:It's through exploring their feelings and stuff like that. So it may be a session or a couple of sessions. So sometimes I've got a measure called a PHQ-9. That is a depression score. And I'll ask the client if they want to go through that and measure that. But I treat the client rather than the depression. Does that make sense? Because a depression could be a label. So I look at the person rather than the depression.

21:08Jackie Rogers:And what does success look like to you? What are you trying to achieve for that person?

21:13David Nutt:The first session would be asking them what their best hopes for therapy would be. And how do you know when you get there? So they'd say something like, I want to be happy. How do you know what happiness looks like? When I look at success as such, when somebody's depressed, they'll have no motivation. So by the end of therapy or near the end of treatment, they're going to have some sort of spark in them. They're going to be doing more. So that will be my goal or a marker that they've recovered or recovering from depression.

21:40Jackie Rogers:Has anyone asked, or presumably they have, how it compares when you do the sorts of interventions that you offer compared with the sorts of benefits people might or might not get from a packet of pills? What's the comparison?

21:55David Nutt:Well, there's no side effects from therapy for a start. I'm not against medication, but medication can obviously give side effects. But also the serotonin that you get in some antidepressants, you can create your own serotonin by doing things that you enjoy doing, like getting outside or doing some sport or some movement, some exercise or mixing with other people. You can create those chemicals yourself. But again, I am not dissing any medication because it has its place, certainly.

22:24Jackie Rogers:and when you take people through the various maneuvers that you as a psychotherapist have to try to bolster people's mood make them more resilient reduce their anxieties and get them feeling more positive how do you think that's actually working or what are you helping to achieve in their mind and in their brain that they are not able to do themselves i think when

22:46David Nutt:you're depressed you've got a very negative internal dialogue and i think that our loved ones will be saying, will be telling them that, you know, you can make it, you're fine, but they won't believe them. So I think it's a stranger, which I will be as a therapist. I'm hopefully reinforcing more compassionate, a more compassionate rather than a critical voice. Depression is very critical, whereas compassion, so I'll be validating what they're feeling, but also that depression is an illness and they will get better. And they're not the only ones that are depressed. it is recoverable from, you know, so it's more encouraging compassion.

23:24Jackie Rogers:How do you actually measure success then? Because one of the things that must be difficult is if you're just asking a person subjectively, how do you feel? Everyone feels different day to day. So how do you gauge that people are moving in the right direction in general?

23:40David Nutt:Their body is lighter, it's less tense, the muscles aren't so tense and they feel lighter and they can see more of a solution.

23:47Jackie Rogers:because psychiatrists the first thing they write down in the history when they see someone is appearance and behavior isn't it so i suppose you're doing exactly the same thing you're saying

23:55David Nutt:how does this person look when they walk in the door absolutely are they looking disheveled got no respect in your appearance in a way but when you're feeling better they're standing up straight there's a difference about the way they're presenting their voice will be more clearer they won't be talking to the feet you know they're possibly making more eye contact and they're becoming with a sort of like spring in the step completely different and indeed about half

24:19Jackie Rogers:of people with depression who talk to someone like Jackie Rogers will see improvements in their symptoms and their quality of life by the end of the treatment nevertheless that does mean that some people and it can be as many as 30 percent just don't get better with any of these sorts of interventions both first-line medications and also talking therapies they have what's been broadly dubbed treatment-resistant depression. And neuroscientists think that at a basic level, this might be because in some people, the brain learns to be depressed and it becomes very good at it, optimising certain pathways that lead to relentless intrusive negative thoughts that end up drowning out the positives in life.

24:59Jackie Rogers:And it's in this context where more invasive and dramatic interventions like ECT, electroconvulsive therapy, and even psychosurgery, cutting nerve pathways in the brain have emerged. More recently, electrical brain implants as well as drugs like ketamine and hallucinogenic agents have begun to be explored with thankfully encouraging results. I asked David Nutt, who's Professor of Neuropsychopharmacology at Imperial College London, to take us through some of these treatments, both past and present, and how they're thought to give relief.

25:30Trevor Robbins:Well the first real innovation in treatment resistant depression was the development of ECT, electroconvulsive therapy, which actually was invented to treat schizophrenia where it has marginal effects. But it was discovered that it definitely lifted depression in people who had chronic illness. And it was a revolution at the time, because before then, there weren't therapies for treatment-resistant depression. ECT involves essentially giving someone a seizure. So you put electrodes either side of their head, you pass a current through, and they have a fit. The fit itself lasts about 30 seconds or more to have a therapeutic benefit.

26:07Trevor Robbins:The problem with ECT, of course, is after the fit, it takes a while to come round. And also, fit can incur muscle spasms. And also, if you get a lot of them, you can have fractures of the bones, etc. So ECT was quite rapidly modified so that people didn't have muscle spasm. They put muscle relaxants in so that it was much more tolerable. And then it became the mainstay of treatment resistant to present therapy and still is in the uk for instance the nice is it not dangerous though

26:35Jackie Rogers:making people have a seizure in an uncontrolled neurological activity for a reasonable period of

26:42Trevor Robbins:time is that not bad for your brain well it definitely heals depression it's not particularly good for memory and that's one of the downsides of ect which is that they lose bits of long-term memory it improves short-term memory which is badly affected in depression but yes it's not It's not an ideal treatment for those reasons. But it is safe because it's done in a hospital with an anaesthetist. So it's not an uncontrolled seizure. And the seizures rarely last more than a minute.

27:07Jackie Rogers:So when you're making someone have a seizure, why does that lift depression, do we think?

27:12Trevor Robbins:Well, that was obviously a topic of enormous research interest, including some of my very earliest work. And it turns out that ECT turns on, in a progressive way, different neurotransmitters. The first thing ECT does is turn on the dopamine system. And then after a few more seizures, it turns on the noradrenaline system. And in the end, it turns on the serotonin system. So three of the main monoamine neurotransmitters, which are necessary for appropriate levels of mood and different aspects of mental functioning, are enhanced by ECT.

27:45Jackie Rogers:Is that effect indefinite or do you have to keep doing this to get the relief?

27:50Trevor Robbins:You can see in an immediate effect for a few hours after the first seizure, people are eating and drinking. But to get what you might call a full antidepressant effect normally takes between about 6 and 12 seizures. And they're normally given twice a week. And then the effects can be very enduring. The effect can last for months or years. But often depression does come back. And then people are given a choice either of having some more ECT. Very often we put people on a mood stabilizer to try to keep their mood improved after ECT.

28:20Jackie Rogers:We also hear people talking about the question of brain stimulation, putting electrodes into the brain chronically and delivering impulses, which also has a mood lifting effect. Is that a sort of modern counterpart or a safer alternative to ECT? Does it work the same way, but is basically a bit kinder?

28:42Trevor Robbins:Yes, it does. And in fact, the idea of deep brain stimulation came in part from the work on ECT, showing that ECT enhanced dopamine function in the brain. And most of the experimental work on deep brain stimulation happened in Parkinson's disease, which of course is a disorder of dopamine function with dopamine levels falling. So the technology of deep brain stimulation was developed and about 120 ,000 people in the world now have electrodes in their brain to help them overcome the symptoms of Parkinson's disease. That technology was then developed for depression by a lady called Helen Mayberg, who realized that in depressed people, there was overactivity in a certain part of the brain in the prefrontal cortex.

29:29Trevor Robbins:And that was a very important paradoxical finding because until she discovered that, which she did using brain imaging, we had assumed that depression was a loss of the ability to feel pleasure.

29:41Jackie Rogers:Where does that part of the prefrontal cortex project to? So when it's becoming too active, what is it doing to downstream brain areas and which downstream brain areas and why does that translate into this profound dark mood that when you turn that single cluster of nerve cells off immediately lifts the depression?

30:01Trevor Robbins:That's a question that we're all still trying to resolve. In part, it seems to project down and suppress the serotonin system. But in part, it also seems to lock higher cortical regions, cortical regions in which we do our sort of thinking about ourselves when we reflect on our capacities and our competencies, and we challenge our decisions. it seems to change the tone of those and put people into a negative mood state and it seems to lock people into that state of what we call rumination where they cannot stop thinking about mistakes they've made they cannot stop having beliefs of guilt or incompetence etc is it that

30:46Jackie Rogers:that is what lies upstream of the depression because they ruminate on the bad stuff and and If I spent all day thinking about bad things and things I thought I'd done wrong or not done as well as I could, I think I would end up with a low mood. So is it because it relieves people of those intrusive thoughts that it breaks that cycle?

31:05Trevor Robbins:That is exactly right. Absolutely. But the thing with the deep brain stimulation is you've got to keep doing it. It's a sort of tonic shift in belief about oneself. What we would like and where modern research is going is to try to avoid having to continually stimulate a system, but to rectify those abnormal thought processes. And that's where the modern treatments of depression, such as ketamine and psychedelics, come in, because they can profoundly disrupt networks of negative thinking after maybe one or just a few doses.

31:41Jackie Rogers:Is the effect persistent? Because obviously those things do have significant side effects. patients who have been in trials have had some quite negative experiences doing it, not least because one of them, ketamine, is quite sedating. Psychedelics can give people unpleasant experiences as well as hopefully relieving their depression. So is this again like ECT? You do it a bit and then you get some long-term relief or do you have to keep doing it?

32:07Trevor Robbins:I'll start with the easy answer. Psychedelics like psilocybin, where there have now been over 10 RCTs of psilocybin in depression, largely treatment-resistant depression, a single dose of psilocybin, a single trip, can produce enduring benefits, which in the latest German study, which is not yet published, persist up to one year. So you can, in a sense, in some cases, reset those abnormal thinking processes. Ketamine is more complicated because ketamine initially developed as a way of lifting mood, the effects of ketamine last for two or three days and then are repeated. So current ketamine therapy relies on giving it twice a week or three times a week for a period of weeks or months until eventually the depression lifts or it doesn't.

32:56Trevor Robbins:However, what we and others are doing is saying, well, ketamine has brain effects which are rather similar to those of psychedelics. And maybe if we use ketamine like a psychedelic, give a bigger dose and have therapy around the trip, we might get better outcomes. And so the current debate is between whether you use ketamine as a sort of prophylactic over weeks and months, or whether you use it three or four or five times over, say, a month and try to get a bigger benefit, which then is enduring.

33:29Jackie Rogers:Thought-provoking stuff. Thanks very much to David Nutt at Imperial College London. Well it's nice of course to end on a positive note but the reality is that more people than ever are ending up with mental illness. Rates are up nearly 50 % in the last 30 years and government figures say that one person in six in the UK is now using antidepressants. So although we've looked at how to manage this problem this week, as ever prevention is always is better than cure. So we must keep asking what lies beneath this dramatic increase in mental ill health and what we need to do to stop it. We're back on Friday with the latest in science news including how new mRNA vaccines might help to break the back of the Ebola outbreak which is kicking off in the Democratic Republic of the Congo.

34:15Jackie Rogers:We'll also have our usual updates on LinkedIn, on X and on Instagram and if you would like to support our work please do head over to nakedscientist.com forward slash donate we are really grateful I'm Chris Smith, thank you for listening and until next time, from all of us here at The Naked Scientist goodbye Bye.

35:02David Nutt:Donald Trump presidency, it can be easy to lose sight of his most troubling legacy. The U.S. Supreme Court has reshaped the country's legal landscape on abortion, guns, religion, and more. In Slate's new season of Slow Burn, we're taking on Trump's first Supreme Court pick. He is the most unpredictable vote on this court. Slow Burn, becoming Justice Gorsuch. Out now, wherever you get your podcasts.

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