 something that sometimes people think you know well depression just snap out of it etc it's obviously much more than that and takes a big toll there's a lot as you heard from doctor hen we need to do better this slide tries to capture what I think are some of the things we really need to try and address the first one is the delayed onset of action if anyone in this room was in physical pain you would expect a painkiller to work within minutes or hours you wouldn't be willing to accept wait eight weeks and then your pain will go away and yet we're asking people with mental pain anguish which is worse than any physical pain they've had to put up with waiting for weeks you know that's sort of unacceptable got to do something about that the second thing is you know we talked about suicide and right now we don't have any treatments for suicidal ideation so if you're suicidal you basically get hospitalized to sort of prevent you from committing suicide until the treatments kick in so could you have something that worked rapidly on suicide the third one um doctor hen also touched on often will talk about response and responses often defined as a fifty percent reduction in your depression so you could be here and we get you fifty percent better which is great but you may not be well so we really need to get people well not just somewhat better the fourth point is a very recurrent illnesses of bipolar disorder is very recurrent most people with depression don't just have one depression it's recurrent and we need to do something about the long-term course of the illness and the last point one that says biomarkers that's something that's also very important because as you know doctor hen alluded to you know maybe there's at least five types of depression and there's bipolar you don't treat them all the same necessarily but we don't have a good test you can't just do an x-ray and say aha you have this type of depression so you should get this treatment or you're a bipolar disorder patient and the bipolar and depression distinction is very important because often people who have bipolar illness will have several depressive episodes before they have a manic episode you might have this young individual in front of you who's depressed are they depressed or are they bipolar waiting to have their first manic episode and it's not just an academic distinction because the treatment for depression might trigger mania so you really would like to know that better is there a blood test or something you could do a brain imaging that would help you distinguish because that would really help you with treatments this slide again we don't need a lot of details but I think doctor hen sort of covered a lot of it is the idea that you know we used to think that you know depression was you know your lower court of serotonin now we know that that's not the case so serotonin, dopamine, noradrenaline are all very important but it's more complex than that and we think that it's these plasticity cascades and when I use the term plasticity you know every single person in this room is going to remember this lecture you know a year from now you'll know this lecture took place you may not remember every single detail but somehow your brains are changing as we speak to remember this information and that's what the brain does for a living it adapts to the environment and today we know that there's these plasticity pathways that are very important there and we think these plasticity pathways could be related in treating both the signs and symptoms what's your mood like, what's your energy like, what's your sleep like etc as well as the long term course of the illness what I mentioned the recurrences that I'll be touching on so again you know some of these diagrams have a lot of you know words on them you don't need all of them but this is an important area of science and cold spring harbor labs is actually one of the pioneers here it was discovered that doctor hen mentioned that you know this is a synapse what we've learned is you make the information that flows through synapses stronger or weaker and that allows you to you know remember things, think certain ways etc and there are some of these molecules called amper receptors or NMDA receptors that move in or out of the synapse to make it stronger or weaker and that's shown here so what you're looking at here is one nerve cell the white color indicates this amper receptor so it's an amper receptor which has a fluorescence label on it then what the investigators have done is electrically stimulate this nerve cell over and over and what you see is that now the amper receptors have actually moved to the synapse these things physically move into the synapse and we know that now that's a very important process in various types of plasticity what does it have to do with depression well people started to wonder you know why do antidepressants take so many weeks to work these antidepressants you heard from doctor hen increased the level of serotonin or norepinephrine in the synapse but maybe what you need to do is affect the amper or the NMDA receptors and so the antidepressants have to go through all these steps before they can get there and that might be one of the things that results in the delay and secondly if you've got to go through this twenty steps if you've got a problem at any one of those steps you're not going to respond to the antidepressant because the road is damaged so that was an interesting idea but why you know ideas are you know a dime a dozen it begs the question if that's true if you directly affected these receptors would you A get an antidepressant that worked rapidly because you're going exactly where you're supposed to go and secondly would it work in people in whom available medications didn't work because you're bypassing a lot of those steps and that's what doctor hen alluded to and that's shown on the left here these were treatment resistant depressive patients so they had failed six different antidepressants some had failed electroconvulsive therapy they were admitted to the NIH and administered intravenous placebo sort of sugar pill or low doses of this anesthetic ketamine very low doses and what you see in this very refractory population you see this rapid antidepressant effect starting at two hours at one day almost seventy percent of people could be classified as responding and that is shown there to compare to traditional drugs you know medications like prozac or well-butterned or medications like that those have something like a sixty percent response at eight weeks in people who are not refractory so this was mind-boggling that you could treat depression so rapidly in people who hadn't responded to anything else I mentioned already suicide is a big problem so we wondered okay is it treating the core symptoms of depression and we looked at a lot of the symptoms we also asked the question what about suicidality and so what this slide shows is a group that had a high suicidality at the beginning or a low suicidality and you see that the suicidal thinking drops dramatically rapidly as well and you know many people in this room might find this you know sort of difficult to understand you know surely something like suicide is a very complex psychological adaptation that you make how can it go in thirty minutes and yet it may well be that there are certain circuits involving the habanula etc that are driving this and if you hit it it goes so based on these results the NIH is actually trying an emergency room study to see if people come into the ER suicidal can you get the suicidal ideation under control right then or you know relatively rapidly so that's a very exciting area for further research one other I think interesting area is the area of what we call cytokines and cytokines have traditionally been thought of as being involved in inflammation so when you have allergies or other inflammatory conditions rheumatoid arthritis psoriasis etc these cytokines are thought to be involved but more and more data suggesting that they might be involved in depression and what is that data one is that if you take depressed patients and you measure their cytokines in the blood or the spinal fluid there's something like fifty studies that show that many of these things are elevated in depressed patients the second thing is if you administer some of these cytokines to animals you can make them depressed somewhat similar to what dr hen showed you in that learned helplessness model you give these cytokines to animals and you make them depressed the third one is that if you give interferon alpha to humans almost forty percent of humans become depressed so it suggests that you know there may be something going on here and finally there's data in animals that if you manipulate these receptors you can either cause or treat depression and in fact there's already some human data so a tannercept is a medication which is a TNF alpha antagonist it's used to treat psoriasis and what this group at Duke did was they treated the patients with psoriasis with this drug and they wanted to look at the improvement in psoriasis but they also asked the question does their depression if they have depression also improve and they saw an improvement in with the drug compared to placebo and it didn't seem to be related to how much better their psoriasis got because you could obviously well wouldn't you feel better if your psoriasis got better they were able to sort of dissociate this so this is a very intriguing pathway that is very new interestingly it affects these amper receptors we were talking about earlier and it won't get into all the details and in humans you can't measure amper receptor currents you know like you can in animals but using things like magnetoencephalography you can start to look at this sort of synaptic potentiation in certain brain areas and I think this is going to turn out to be a very exciting area in all fields of medicine ideally what you want to do is identify the genes that are involved in your disease whether certain kind of say breast cancer diabetes etc once you have the gene then you can make some sort of animal model usually mouse but you can make fly models etc then you can try and understand how does that gene cause problems is the nerve cell not firing properly are the cells in the habanula reduced etc then you could try and develop okay this is the circuit where do I want to intervene and then come up with the pathway so that's what you want to do in all fields of medicine unfortunately in psychiatry the genetics isn't far enough cold spring harbor and many other institutions are doing some very elegant work and I think there's almost no question we will have real genes but we don't have them today so does that mean that we stop everything today and you know sort of wait for the genes to come about and then start things and I think obviously not and I think one area that's been utilized is depicted somewhat on this slide so this is kind of what bipolar illness looks like for many patients you have these depressions and you have these manias and for many individuals they'll have ten or more episodes a year we we have many treatments none of them great but one treatment that caught our attention is this thing which is lithium this is the oldest treatment for bipolar disorder sixty years old it looks like table salt so if you look in the chemical you know table it's in the same area as table salt and yet at a very low concentration compared to table salt for the people in whom it works it can often be very beneficial it's got lots of side effects lots of nuisance etc but it seems to help people and not shown here from some of the data from Dr. Baldessarini at Harvard where what he's looked at is people the amount of time they spent in manic episodes before lithium and after lithium and it's about a four and a half fold reduction and same thing with depression amount of time they spent in depression before lithium and after and it's about two and a half fold reduction and interestingly bipolar disorder is thought to have the highest suicide rate of any illness and lithium treatment seems to normalize it so it's something like a six to ten fold reduction so that begs the question how does something that look this simple do this again it doesn't work for everyone it's got side effects but if we could understand how we did it maybe we could come up with better drugs Dr. Han alluded to this already now we know that all the time we're turning on and turning off certain genes so when you go to exercise say you're lifting weights you're actually turning on genes in your muscle cells that then allow you to lift heavier weights you're doing that in your brain you're turning on and turning off genes that allow you to adapt to situations so it seemed fairly clear that these drugs which often take weeks to work must be turning on and turning off certain genes but the question was which one and until about fifteen years ago you'd literally have to look at them one by one you'd have to say I think it's the serotonin gene or I think it's a cortisol gene or I think it's that but some of the technological advances things called differential display or microarray allow you to look at all the genes in the body and say let's look at what's different in bipolar compared to control or control versus lithium treatment and when you do some of these studies to summarize something like fifteen years of work it was very surprising that some of the genes which were turned on the most were genes whose job we thought was to help nerve cells grow and withstand insults so to make the nerves more resilient and you think what the you know what the hell does that have to do with bipolar disorder and unfortunately we think a lot so Dr. Henn alluded to this this was so nature is thought of as you know the leading scientific journal one of the leading scientific journals this was a study that was done which took bipolar patients or unipolar patients and did MRI scans to try and look at the size of a part of the brain the anterior cingulate and they were astounded to find that bipolar patients or these recurrent unipolar patients had almost forty percent shrinkage of this part of the brain and you know that was you know eye-opening at the time and I think it's a bad news good news picture the bad news is that obviously you know we don't know if it happens in every individual or you know some individuals etc but obviously you don't want it to happen but the good news is that the nerve cells aren't dead they're there but they seem to be shrunk and not shown in this cartoon where if this is a healthy nerve cell you've got all these branches in mood disorder patients or at least some patients you see you've got fewer of those branches that sort of shriveled up a bit same thing here these knobs represent something called