 Division is a debilitating illness, typicly life long. Sometimes people just get one episode. But in many people it comes and goes for the rest of their life and it becomes more difficult to treat with every episode. And of course we all have moods, that go up and down, and that's not necessarily unhealthy. Ond yna, mae'r syndrach cynlluniaid, gallw'r syniad mewn cyfnodol maen nhw. Felly, mae'r syniad cyffredinol yn benhefn y cyfnodol. Mae'r syniad honnol yn cyfnodol yn dweud yng nghymru, ond mae'r syniad yn y myfyrdd cyffredinol gyda'r myfyrdd. i'w ddweud o gwyfnol i'r ddeunedol. Y ddweud y oeddiol yn ymwyfodol o'u ddweud o'r gwaith o'r gwaith o'r ffordd o'r ffordd i addysg. Y dros ymddorol, os ymgyrch ar y cyd-af, mae oedd o'n cyd-af gwaith o'r dros ymgyrch yn y ddau, ac oedd o'n cyd-af gan eu cyfnodol. A'r ddweud o'r ddweud o'r ddweud o'r ddweud o'r ddweud o'r credu I think the view of the general public is that depression is people just feeling a bit melancholic, a bit sad, a bit fed up. But what isn't appreciated is that it's actually a major cause of premature death near the suicide rate is enormous. About 20% of people with depression attempt suicide and about 12% to 15% of them succeed. What's particularly worrying is that that rate is increasing in young people. The very first anti-depressant was actually being used to treat tuberculosis and a side effect of that drug was to induce euphoria. But then someone had the bright idea of saying, well, if this drug makes ordinary people who are otherwise well euphoric, maybe it will cheer up depressed people if we give it to them and it worked. And that led to the whole portfolio of drugs that we have as anti-depressants today. But there's no doubt that anti-depressants are useful, there's no doubt that talking therapies are useful, but they are not the ideal treatment. The first thing to be remembered or to be emphasised is that depression is extremely common. It's one of the leading causes of virgin disease so-called by the WHO. Because depression is common, anyone time perhaps 5-10% of people may be suffering from depression, it's twice as common in women. But because people can have depression off and on for decades, that means the burden of disease, the morbidity and indeed the early mortality, just like expectancy are extremely important. So we crucially do need better treatments to try and improve the outcome of people with depression. Only about 30% of depressed people actually respond to the first anti-depressant they're given. About 30% more patients respond to some treatment eventually. About 30% of depressed patients don't respond to any drug treatment at all. And they are often the patients who go for electric convulsive therapy because everything else has failed. The other reason we need new ones is because most anti-depressants take weeks or months before they start to work. They're not like antibiotics where if the patient isn't feeling better in a couple of days, try another antibiotic. They do have side effects which cannot be ignored and those side effects can be really quite dangerous in overdose. And of course depressed patients are just the sort of people who are likely to attempt suicide and you don't want to give them drugs that are actually dangerous in overdose. We'd ideally want a treatment that would remove depression very quickly with minimal side effects and it wouldn't come back. Depression is often thought of as a uniquely human experience but depression is a very complex disease with lots of different symptoms. So some of those symptoms, like the loss of interest or pleasure, we can look at in mice so we can look at how mice change their interest in food or water. But more complicated symptoms around suicidal thoughts, feelings of worthlessness and guilt, you can't ask a mouse how it's feeling. So those are the sort of elements that we can't really address in animal models. But we use behaviours that put the mice in mildly stressful situations so one of the ones that we typically use is something called the forced swim test. So when we do the forced swim test with mice, they're gently placed in a cylinder of warm water for six minutes and they spend time swimming and climbing, which we think of as escape-related behaviours, and they also spend time immobile. And then at the end of the six minutes, they're taken out of the test, they're warmed, they're dried and they're returned to their home cage where they show a full range of home cage behaviours, which indicates that the animals are not experiencing any long-lasting harm as a result of the forced swim test. With rats and mice are naturally born, so they don't sink, they float on the surface of the water and they float with their noses above the water and their bodies hanging down and they just carry out the occasional movement of their legs and their feet. So they give up swimming and climbing. What is clear is that all antidepressant drugs delay the onset of that floating posture. So animals do tend to swim around and explore the perimeter of the tank for much longer. It's presumably longer, two or three times longer, when they've been given an antidepressant drug before the test. It was first introduced as for screen and antidepressant, so as a quick screen for antidepressant activity. And I think that that's an important point to make about it. It's a bit overstated if we want to say that it's a model of depression. And that's a very important point to make is that do we have in our laboratory animals, do we have models of depression, or do we have screening tests for antidepressants? Or do we have models that might purport to be both? And in my opinion, the forced swim test has been a screening test for antidepressant activity. Many of the symptoms of depression, you cannot recapitulate in animals basically. But what we can try to do in animals is actually try to mimic some of the aspects of depression. We can look in on other aspects that are associated with depression, like just open eyes sleep. That we can definitely do with the animals. So you need to diversify your tests and not just rely on one read out. One test is not going to do it. It's the same for humans. One test is not going to tell you if a human is depressed or not. So you definitely need to diversify. Well, I can absolutely say with 100% confidence that no animal has ever drowned in the forced swim test. Not only would they not drown because they float naturally, they also wouldn't drown because if they showed any signs of drowning, they would have to be pulled out of the tank immediately. So when we're developing new medicines, we start off by testing them in cultured cells and isolated tissues so that we can learn as much about the effects of the medicine before we get to doing any testing in an animal. But fundamentally, if you want to know how a new potential medicine is going to work in a human, you have to start by looking at a whole behaving organism. So we're also required by the Home Office to use the animal species with the lowest capacity to experience pain, suffering and distress. And yet they have to still be capable of having the same brain structures that we have in our mammalian brains. So for us that leads us to mice and to rants. Other models for looking at antidepressant activity and the effectiveness of antidepressants in animals are being developed, but at the moment there are none that are as well validated across a wide range of antidepressant medicines as the forced swim test. The antidepressant medicines that are available are effective for those for whom they work, but they are limited so less than half of the people who take an antidepressant will get completely well after that. So there is still a need for new and better antidepressants and at the moment there is no alternative to using animals in that research.