 Good morning. This begins the first of two lectures on psychiatric disease. I hope everybody, each of you, had a lovely Thanksgiving holiday. I certainly did. Today, we're going to talk about mood disorders, major depression, and bipolar disease. On Wednesday, we'll talk about schizophrenia. Ralph has already talked with you about autism. A few announcements. We're going to have discussion sections this Thursday as usual. Problem set six is due Tuesday as usual. We will post the final exam on Friday, December 4th, and it will be due on Friday, December 11th, 4.30pm at the usual place. No quiz this week. Instead, or in addition, you will get extra credit, one point, for emailing Ralph or Henry a question for Friday's session. So the question for Friday's session, at which we will both preside, is what is the challenge for neuroscience in the remainder of the 21st century? At least one reference from a journal, not a website or the text, but from a contemporary journal. And we have not received any request for a final review session, so we will take that, unless there's an outcry of dismay to mean that there will be no final review session. The TQFR, I'm quoting from last year's email, the TQFR survey period will open next Monday, maybe a week from Monday. Students will have several weeks to submit their reviews. I want to remind you that TQFR, that Ralph and I do indeed appreciate your feedback and as detailed as possible. And also it's very important to give feedback on the TAs, who as you know work hard and are practicing to be professors themselves, quality of the textbook, and you can of course compliment Jonathan Lew on his wonderful presentation of the reflex hammer, which was quite interesting. And then you can email the registrar. So that I want to give a disclaimer that this lecture deals with psychiatric disease. Neither Ralph Adolph and I are psychiatrists, in fact we're not even physicians, so don't change any medical treatment that you might now be receiving on the basis of these lectures and don't give any medical advice based on these lectures or on the accompanying problem sets. This book here is abbreviated DSM-5. It is the Diagnostic and Statistical Manual of Mental Disorders. This is the fifth edition published by the American Psychiatric Association. The first two or three editions were rather thin. The fifth edition is rather thick. It still comes on one CD or one thumb drive though. It is basically the way a psychiatrist classifies and diagnosis a psychiatric disorder such as major depression or bipolar disease or schizophrenia or anxiety or autism or any of the other diseases that psychiatrists diagnose and that the National Institute of Mental Health supports research on. There is very little in DSM-5 about causality, very little about genetics, very little about any kind of prescribing or therapy. It's all descriptions, all fine grained subdivision of psychiatric disorders as has been classic for diseases for thousands of years. And in fact, there was a controversy beginning about four years ago when the then director of the National Institute of Mental Health, Thomas Insel, said, well actually DSM-5 is wonderful for psychiatrists but it's not very good for research. And he wanted, and he did in fact set up another kind of class, it wasn't a classification, it was a research framework in which one instead of diagnosing a psychiatric disease would instead talk about common characteristics of functional derangement across psychiatric diseases such as for instance aggression or mood. So that is called research domain classification. We don't have much time to talk about it in this course but it has become useful. And in the meanwhile, Tom Insel decided that after 13 years of leading the NIMH National Institute of Mental Health he was going to go and do some good for health research and for mental health research by leading a section of Google. So that's where Thomas Insel is now. But I think that the RDoC classification and the emphasis on understanding the pathophysiology of psychiatric diseases remains. Now there clearly are some brain areas that regulate mood. This is from the text, this is actually from Eric Nestler's review in Nature Reviews of Neuroscience several years ago. It remains true to this day. The frontal cortex is involved in mood regulation, the dental hippocampus, nucleus accumbens, amygdala, hypothalamus, ventral tegmental area, reward, the dorsal raffae which is mostly serotonergic, and the locus ceruleus which is mostly neuroadrenergic. So these are structures in the bottom of the brain in some ways they are also around the limbic system which is built around the ventricles. They have various transmitter systems, certainly glutamatergic, GABAergic. It is generally thought these days that monoaminergic transmitter systems, dopamineergic, serotonergic, neuroadrenergic play a greater role in mood disorder than the classical glutamate and GABA transmitters. But I'm not so sure that's true and neither are other modern neuroscientists and we will give you reasons for doubting this as we go on. So if we were reading DSM-5 or if we had graduated from medical school and we're doing now an internship in major depression, here is what we would find in psychiatry, here is what we would find for major depression. You can read from DSM-5, affective state of sadness, variety of human situations, loss of a loved one, failure to achieve goals, disappointment. Major depression which is different from depression is important and different because it differs in the intensity and duration or quality of the emotional state. DSM-5 then goes on to give some diagnostics, at least five of the symptoms that we'll discuss, each must be evident daily for at least two weeks. And most importantly as we will discuss for all psychiatric diseases that we'll discuss, you can't call a person depressed or mentally ill just because you don't like him or her or because it is as the Soviet Union used to do. It is politically convenient to get rid of a person by calling them a psychiatrically ill. The diagnosis of a psychiatric disease must include the requirement for clinically significant distress or impairment in social or job related or other important areas of life. So what are these criteria? First of all, a depressed or irritable mood. Now it's going to turn out over and over again that actually irritability plays a large role in depression. And most psychiatrists think that irritability plays a more major role in so-called depression in men than in women. Decreased interest in pleasurable activities or the ability to experience pleasure. This is also called anhedonia. Significant weight changes. Gain or loss depending on the person. This can be manifest in either way. Insomnia, sleep disorders. Some people can't sleep when they are depressed. Others sleep too much. Psychomotor agitation or retardation. This is not often seen in depression. People don't seem to be moving right. Fatigue, loss of energy. You can all think of friends who just didn't have much energy when they were depressed. Worthlessness or excessive guilt. Certainly a major aspect of major depression. Ability to think or concentrate. And the big one which we will discuss later on. Recurrent thoughts of death or suicide. So more characteristics. Untreated episodes. Major depression usually lasts about a year. Give or take a factor of two. Maybe 14 months. Most importantly, major depression is a recurring disorder which usually worsens with age if it's not treated. Again, the reported incidence of depression is three times higher in women than in men. I'm going to show you a bar graph of this later on. But in analogous situations men show more irritability than what you might call classical depression. Most importantly, and we have emphasized this in this course for years and in another course, major depression is treatable. There are treatments designed essentially for medical intervention medications which we will discuss today. There is in fact an experimental treatment called vagal nerve stimulation. There is deep brain stimulation in one of the regions we discussed in the first slide. And so just as you've learned about deep brain stimulation, which is very often employed in Parkinson's disease, deep brain stimulation for depression is much rarer but is done. And then one that is quite controversial but is very effective is electroconvulsive therapy. That is brief periods of high frequency stimulation which would cause convulsions if the patient were not protected seem to be temporarily therapeutic. And then over and over again people researchers find that in conjunction with somatic treatments psychotherapy is also very helpful. Cognitive behavioral therapy, interpersonal therapy, and then there are changes in attitude towards sleep in depression. Very nice New York Times editorial a couple of years ago claiming that some very detailed interventions in a person's attitude towards sleep helps. For instance, a person with depression should be discouraged from doing work in bed, should clearly delineate the experience of being in bed and asleep from the experience of being productive and awake. And then of course there are other treatments, diet, exercise, etc. So a major interest of my lab and of neuroscience in general is how psychiatric drugs work. The major revolution in the treatment of major depression occurred with Prozac or fluoxetine roughly 25 years ago. But very curiously the mood elevating effects don't take place right away. They require that the patient continue to use fluoxetine for several weeks. This is also true for any of the other depressants that are now on the market. Usually I don't give trademarks, but these include Xoloft and Paxil and Efexor and all of the other medications that your friends may be taking. So what's going on here? As I'm going to emphasize we know what fluoxetine in the other SSRI's selective serotonin reuptake inhibitors do on a time scale of seconds. In fact I've published several papers on this. They block serotonin reuptake mechanisms. But what is it that takes two weeks to work? Well the textbook by Heimann Nestler and Malenka, three excellent research psychiatrists, two of whom have been presidents of the Society for Neuroscience. They say well an adaptation to sustained increases in serotonin function that mediates the clinical effects of fluoxetine. Now you've heard me rave about the word adaptation or homeostasis or compensation. And you've heard me say that these words are in no sense mechanisms. They are best treated as adjectives. But where the adaptations occur and the nature of the adaptations still unknown. And yet the SSRI's and the SNRI's selective serotonin reuptake inhibitors or serotonin norepinephrine uptake inhibitors help roughly 50% of major depressive disorder patients. What do we know about SSRI's such as fluoxetine? We know that they bind tightly to and stabilize intermediate states of the serotonin transporter. I think I've showed you pictures like this. A transporter can be thought of as a channel with gates at both ends. The first gate opens, the substrates for the transporter enter the channel, the first gate closes, the second one opens up and all the gates, the second gate opens again. And the rules for binding and the rules for co-ions make it possible for a transporter to use the concentration gradient of sodium chloride potassium to reuptake neurotransporters once they have worked. And so there is a cycle of gates closing and opening, substrates binding, and fluoxetine binds tightly to and stabilizes intermediate states of the serotonin transporter so that the serotonin transporter cannot remove serotonin from the external solution, from the extracellular solution from the CSF, but in fact that serotonin remains. And as we've said, two of the three biogenic amine pathways do seem involved in antidepressant action. In part, this is because the antidepressants block their uptake. And in fact, the major argument for involvement of the biogenic amines still rests on the fact that the most clinically useful drugs, the so-called SSRIs and SNRIs, block serotonin uptake. So serotonin, 5-HT, we've discussed, norepinephrine, or noradrenaline, we've also discussed. Dopamine we're going to discuss in the next lecture on schizophrenia. So the question becomes, how does the interaction between an SSRI, a selective serotonin reuptake inhibitor, and the serotonin transporter-cert interaction relieve depression? And so most experts would say, well, how does blockade of serotonin reuptake relieve depression? And so there are possible downstream consequences of changed regulation of serotonergic systems. There's the short-term derangement of modulation of synaptic strength, possibly also of neuronal intrinsic properties. When maintained for quite a while, may cause the antidepressant effects. Long-term changes in modulation, as you know, from studying synaptic plasticity and from studying learning and memory. Long-term modulation of neuronal gene expression. And so the clinical observation that antidepressants usually take a few weeks to a month to have full efficacy suggests that modulation of gene expression plays the dominant role. But this is really unproven. The people who actually work with patients say that it takes somewhere between two and six weeks for an SSRI or another antidepressant to work. So therefore the experts say that the success of SSRIs implies participation of serotonergic systems in the brain, but in a nonspecific way. So here are the serotonin systems. There are the raffae nuclei in the midbrain. Here are all of the raffae nuclei in a sort of a washed out pink. And as usual with the monoaminergic system, the raffae nuclei project nearly all over the brain. You've seen these regions before. They all receive projections from the raffae nuclei. Now here's an interesting conundrum, which has not been solved. There are about 15 serotonin receptor genes. They have such wonderful names as 5-HD1, 5-HD2, all out through 5-HD8. But the one has six subtypes, 1A, 1B, etc. Most are GPCRs, but one 5-HD3 is a ligand gated channel. And there's only one serotonin transporter gene responsible for a reuptake of serotonin. And so you might think that if you want to manipulate mood, if you want to cause antidepressant action, then the way to do it is to find a serotonergic agonist that is selective for one subtype. A serotonin receptor, or two or three. And administer that serotonin agonist for weeks, and you would get the full benefits of antidepressant therapy with none of the side effects, which include digestive side effects, sexual side effects, etc. Despite roughly 30 years and billions of dollars and thousands of man hours spent at pharmaceutical companies and at universities, no such magic drug has been invented. Instead, the drugs that are useful are the ones that block the serotonin transporter gene, which exists all over the place. So that does not seem very selective, and it is another way of putting forth the conundrum about how antidepressants work. Because they are active, because they are effective for only 50% of patients, and because they have unwelcome side effects, it would be very helpful to be able to improve them, but nobody knows how, because nobody knows how they work. There are, in the Rathae nuclei, there are two serotonergic fiber types in the brain. Here is immunocytochemical labeling for serotonin. The small arrows are the so-called D-system. The large arrows are the so-called M-system. And these have really been confirmed, it may very well be, that the D-system activates ligand-gated channels because there are very small regions and can give precise liberation of serotonin, whereas the M-system has a more diffuse effect that activates the GPCRs. So nobody is sure what the difference is in the serotonergic systems. I think that I will skip this and go on to a possible role for a growth factor in depression. We have discussed neurotrophic factors, growth factors in this course. A particularly well-studied one is brain-derived neurotrophic factor, BDNF. And it seems to be true that SSRIs enhance, increase the expression of BDNF, mRNA, and protein. And it is also rather clear, so the treated state here would have lots of BDNF release and lots of new synapses. And those synapses would occur because the SSRI has released BDNF, brain-derived neurotrophic factor. And it is very clear that BDNF causes the enhancement of synapses. It also has several other undesirable properties, such as causing seizures. But it has been shown over and over again that SSRIs do release BDNF. How they do this is not at all clear. And that BDNF itself may be involved in the mode of action of SSRIs. Why this takes two weeks is not clear either. Or two to six weeks. So another theory about antidepressants is that they cause adult neurogenesis. Ralph has told you about adult neurogenesis. And it is fairly clear, at least in rodent models, that antidepressants, light growth factors, do increase the number of new neurons born, especially in the hippocampus. And these new neurons that are born are inhibited by some phenomena and go into the hippocampal circuitry and are influenced by inputs from other brain regions. And in turn go to influence other outputs such as the amygdala and the nucleus accompaniment. And so one answer to the puzzle of how SSRIs work may be that they cause the proliferation of neurons in restricted regions of the brain. And as Ralph has explained to you, it's now clear that even primates do have adult neurogenesis. So this would explain nicely because it takes a while for new neurons to be born, to migrate, to reach their target. This would explain rather nicely how it is that SSRIs take so long to work. In the subgranular zone of the hippocampus in the dentate gyrus, the new neurons basically are born into this particular zone. There's also a zone that gets into the olfactory system and they do differentiate and they become incorporated into neuronal circuits. So they proliferate, they differentiate, and they get into new neuronal circuits. Now the problem is of course that even in a rodent where this has been very well studied, the number of new neurons born and encouraged by SSRIs and by antidepressants is rather small. And furthermore, not all antidepressants cause neurogenesis. And the way to show that neurogenesis is necessary for SSRI action, for antidepressant action, is rather crude. You irradiate the brain, stop new neurons from being born, but you damage a whole lot of other processes with this as well. So some antidepressants are not SSRIs but SNRIs, serotonin and neurodrenaline reuptake inhibitors. And so again, most experts ask, well, how does blockade of neurodrenaline uptake relieve depression? And here are the neuroadrenergic cells in the locus ceruleus of a rodent brain. They too, like the serotonergic cells, project almost every region of the brain. There's some discussion about the hippocampus, whether actually the neuroadrenergic neurons project to the hippocampus or not. So one very exciting new set of results is the phenomenon of ketamine. Now we've discussed ketamine as a channel blocker, as a blocker of NMDA receptors, but it is found that ketamine at subanesthetic concentrations is also an antidepressant and that it exerts these antidepressant effects much more quickly than other antidepressants. It takes only a couple of hours and these effects take a couple of days, if not a week. This clinical observation has actually been known to veterinarians for decades because ketamine is used for animal surgery. The observation that you could use ketamine in low subanesthetic concentrations as an antidepressant has been in the literature for 15 years and at least one drug company is trying to make ketamine into an FDA approved drugs. What do we know about the effects of ketamine? One is that they involve BDNF synthesis and release, not surprising, in view of what we've said about BDNF. Another is that they probably occur not in the cell body, not in the nucleus, not by transcribing genes, but they do involve protein synthesis in the dendrites. And so there is the classical outside in view of how ketamine acts and there are good papers in science and nature about the fact that ketamine, a well-known blocker of NMDA channels, prevents those NMDA receptors from acting when it gets decreased calcium flux. Remember that NMDA receptors are quite calcium permeable. This decreased calcium flux acts on calcium-activated kinases. These calcium-activated kinases then change some of the proteins involved in protein synthesis, not gene activation, but protein synthesis. So new BDNF is synthesized in the endoplasmic reticulum in the dendrites, goes out through the Golgi apparatus and causes the release of BDNF. And that most people agree would be enough to change behavior maybe cause antidepressant. So that is the classical outside in theory. I published a couple of papers suggesting an inside-out idea for ketamine action. In the inside-out idea, which is very much like the ideas about nicotine, ketamine can gain and lose a proton at this immune group when it has lost the proton that becomes neutral and is quite permeable to membranes. And the question, and therefore enters the cell, and this has recently been shown by other groups. And the question is, how does this lead to BDNF secretion in two hours or so? That's an interesting problem, which one of your students, Alice Sue, is going to tackle as her rotation project. And when she's finished with that, she will conquer other problems in psychiatry. Right, Alice? Okay, so now we're going to switch to from major depression to bipolar disease. There's a clear distinction in DSM-5 and other places. We're going to follow our usual method of talking about a clinical description of a neuroscience disease, about its genetics, possible causes, about heterozygous advantage, and in fact here there is one, and about therapeutic approaches. Again, we go back to DSM-5, and bipolar disorder appears to affect between one and one and a half percent of the population in all modern societies. It's a mood disorder, which formerly turned manic depressive disorder because patients have one or more high functioning or nearly manic episodes alternating with major depressive episodes. Typically, it occurs a bit later than major depression in a person's mid-20s and unfortunately bipolar disorder often leads to suicide. So a manic episode is, again, you have to talk about the distinction between calling a person manic because he's very productive or happy and a market impairment in a person's function either in his job or in his studies or in his social life. Abnormally persistently elevated, expansive, irritable mood, including irritability, possibly patients with this disorder get hospitalized, and then there are additional symptoms, inflated self-esteem, a person has grandiose ideas. Very often patients who are manic have decreased need for sleep. You often see that patients who are manic really talk a great deal more fast than usual. There is pressure of speech. There is a flight of ideas going from one topic to the next. A person can be distractable and a very marked increased involvement in golden activities. And a person who is in a manic episode can indeed participate in pleasurable activities, sex, extreme sports, with likelihood of painful consequences. So this then would be a person with a manic episode. So DSM-5 now has the same subdivision of mood disorders as DSM-4. There are the unipolar disorders, which we discussed at the beginning of the talk today, major depression and a less severe form dysthymic disorder, and the bipolar disorders. And there are three types of bipolar disorders, and the psychiatrists have cleverly enough called them type 1 and type 2. Bipolar 1 is really the classical full-florid episode of enormous manic episodes and enormous depressive episodes. Bipolar 2 is less manic, but just as depressive, and bipolar 3 is less obvious in both directions. Now, when DSM-5 was being written, there was quite a controversy about whether patients could actually be distinguished between bipolar disorder and unipolar disorder. It was thought, for instance, that a large number of patients with major depression might be reclassified as maybe type 2 or cyclothymic bipolar disorder. In the end, that did not occur. It cares how you classify patients. Well, the reason that it's important to classify patients as either bipolar or unipolar is that most of what I have told you about medicating unipolar depression, that is, using antidepressants, using SSRIs, is pretty strongly not advised for bipolar disorder. With a bipolar patient typically giving an antidepressant precipitates a manic episode. And that is very bad. And so probably, again, Ralph and I are not psychiatrists, we don't prescribe, but a major mistake in the modern medical community is to give a patient showing signs of depression and SSRI when that patient is actually bipolar, you get a full-blown manic episode which could cause a crash and very severe consequences. So what are the genetics of bipolar disorder? I have not told you at all about the genetics of depression because they are quite complex. I will give you a whole discourse on the genetics of psychiatric disease on Wednesday when we talk about schizophrenia because that has been a successful exercise within the past year. We all thought actually that the success of genome-wide association studies for psychiatric disorders would first bear fruit for bipolar disorder and possibly then for schizophrenia. In fact, that has not occurred. Schizophrenia has been nicely mapped, although still confusing, bipolar disorder has not been mapped genetically. It is very clear that there is a strong genetic input. Concordance among twins is one way to look at a genetic input. It is not clear because in some cases concordance among twins could have to do with environment. But according to a narrow definition, that is if one member of a twin pair has bipolar disorder, does the other one also. According to one narrow definition, monozygotic twins, that is identical twins, show a 79% concordance. That is if you find a member of a twin pair who is bipolar, there is a 79% chance that his twin also has bipolar disorder. And if they are reared apart to separate the effects of nurture from nature, there is not much of a difference. The concordance drops remarkably for dizygotic twins, that is for fraternal twins rather than for identical twins. So this is a very strong indication that genetics plays a role, although it doesn't tell you how many genes are involved in what those genes do. Any questions about concordance? Again, we will talk about genetics of psychiatric disease a great deal in the next lecture. Passable causes of bipolar disease? Well, and remember here that if we took the general population and asked for concordance among members of the general population, if you find a person with bipolar disease and then wait for the next person to come by the red door or Starbucks or wherever, the chances are only one to one and a half percent that that next person will be bipolar. But if that person is a member of an identical twin and the twin walks up at 79%. Okay, so we are going to talk about schizophrenia on Wednesday and we will say that for each advance in neuroscience, somebody has, or in biology in general, somebody has tried it out on bipolar disorder as for schizophrenia and there's actually no satisfactory explanation. There are hypotheses in terms of properties of circuits and early developmental events and hypotheses no longer emphasize individual neurotransmitter systems. So, I've been promising to tell you about a heterozygid advantage for bipolar disorder and perhaps the best place to start is the writing of Kay Redfield Jamison who grew up in Pacific Palisades, went to undergraduate and graduate school at UCLA and is now a professor of psychiatry at Johns Hopkins. And so her book isn't, one of her books is entitled Touched with Fire, Manic Depressive Illness and the Artistic Temperament and basically she finds that an inordinate number of highly creative people seem to have bipolar disorder. In fact, her own biography, She is Bipolar, is entitled An Unquiet Mind. She talks about growing up as, well, not growing up as, but about her first manic episodes and about her medications and about the wonderful life she now lives, but completely medicated. And so the thinking that she has espoused and that others have espoused is that a small dose of genes leading toward bipolar activity, goal-directed behavior, fascinating behavior, interesting talks, dynamic, causes a person to get ahead in the world. It's a strong advantage if one doesn't have too many genes, but too many genes does cause bipolar behavior. So here are the writers that she lists in her book, Kay Redfield Jamison, Composers, Poets and Artists. Of course, and this means you're not responsible for this list, obviously. Of course, in a modern lecture, the person who might most typify bipolar behavior would be an artist, because we could show his pictures. And Thanh Gokha often comes to mind. He was quite productive in his rather short life. He had 750 paintings, 1600 drawings, 700 letters. Like most European artists in the 19th century, he went to Paris in order to be his most creative, and it was in his late 20s, naturally, and when he was 35, he was hospitalized first. He was so floridly manic that he cut off his own ear. He then went to the French countryside, and a couple of years later, he shot himself. So here are the self-portraits. They get more and more stylized as he comes into his own very definite impressionist, but uniquely impressionist style. Here are two pictures that he painted of his physician. At the time there were no psychiatrists. Dr. Gache would have called himself maybe a neurologist at the time. So this was an earlier one in which he get a very nice portrait of Dr. Gache. I am told, incidentally, by one of my MOOC students who identified this, that it is digitalis. So he was thinking about medications that came from plants. This is a later portrait of Dr. Gache, clearly very stylized, very emphasized one might possibly say manic. And statements like this let us know that Fengach was grandiose, to say the least. And so his paintings got more and more abstract, more and more stylized. This was one of his latest paintings. Probably his last painting, Crows in the Cornfield, one of his most famous, occurred just a couple of days before he shot himself. So it's clear that people with bipolar disorder are often fascinating in the early stages. And we provided examples from the arts. In fact, a psychiatrist once told me that everybody needs to fall in love once with a bipolar person until they learn their lesson. Also people with bipolar disorder, although we've talked about the arts, seem to be overrepresented in many high-functioning environments, including students and faculty at prestigious college campuses. So this brings us up to the topic of suicide. And Caltech counseling is very good at mental health and counseling. In the U.S. these days, there are approximately 30,000 suicides per year, more than the number of homicides. It is the third leading cause of death in adolescence. Males outnumber females by something like four to one. And this may simply be because males succeed at suicide more often than females do. And psychiatrists like to say that by definition anybody who commits suicide has a mental disorder, but to play safe they say that well, 95% of people who kill themselves have a mental disorder. Of course, if a person has not presented himself to a psychiatrist before he kills himself, you don't know. But most people have in fact presented to a psychiatrist before killing themselves. So here we have a graph that I promised you. It's called the daily, the disease associated life years. This is a statistic compiled by the World Health Organization. Sorry, disability adjusted life years. And essentially this represents the amount of productivity, the amount of production lost to disease by people in the prime of life. And so neurodegenerative disease, which mostly strikes older people, is not represented here. It's really lost working years. And the units are incomprehensible. I've never figured them out. I've tried to ask people who work for the World Health Organization. They can't help me either. But the diseases, the psychiatric diseases that we are discussing this week, unipolar depressive, bipolar depression and schizophrenia are very high on this list of disease causing lost productivity. And this is a danced society, people in the prime of their life. But you actually see the same kinds of statistics, the same kinds of results in almost every society in the world. So unipolar depressive disorder, very high, very large numbers of people. And highly apologetic, very hard to map genetically. Bipolar also very important. Schizophrenia we will discuss in the next lecture. Alcoholism, we don't have time to discuss here. And there are a couple of other neural diseases as well. Hearing loss, which causes major losses in productivity. So what about therapeutic approaches to bipolar disorder? Why is it important to have therapy for bipolar disorder? It's because many bipolar patients avoid therapy or they're partially compliant. They take their medication and primarily because they don't want to give up the pleasant feelings during the manic phase. And the problem here is of course that patients who do not comply with their medication risk suicide. So what are the therapeutic approaches? Well, there's surgical and electrical intervention, surgery to remove large portions of the brain that was done in the 50s and 60s. It was called psychosurgery. It is no longer done. I've mentioned the electroconvulsive shock therapy. I mentioned that it's not convulsive in the usual sense anymore because it's administered under anesthesia. There are various ways to put the electrodes to make the pulse widths to give to various frequencies of stimulation. There's no doubt that electroconvulsive therapy is a highly effective treatment for either major depressive disorder or bipolar disorder. We don't know how it works. There have been 100 therapies to account for the efficacy of electroconvulsive therapy. And again, you won't be responsible for this, but here is a reference to a society whose meetings I attend on theories about electroconvulsive therapy. The most basic statement that people make is, well, you're rebooting the brain. What does that make? What about, and again, I emphasize that it's usually a bad idea to treat bipolar disorder with antidepressants because this causes a manic episode. Then there are drugs for bipolar disorder. The simplest drug for bipolar disorder is lithium ion. And here we are, lithium in the periodic table, very simple, monovalent ion. The therapeutic effects of lithium also included delay, which is not explained. They occur in about five days. They require several weeks. And patients who are on lithium need to be monitored continuously because at higher doses, the typical lithium dose that's effective in the blood is a couple of millimolar. But at higher doses, lithium interferes with many ion channels, many transporters, and can typically cause seizures. So patients need to be monitored very carefully. And then there are additional treatments for bipolar disease, valproic acid, also a very simple molecule. In this case, it's an anti-convulsant. They require several weeks. So here from the early days of lithium in the 50s are notes from the first person who tried lithium on patients. He was an Australian. These patients had manic phases or manic depressive phases. He began lithium therapy, maintained it in the manic and depressive phases, were dramatically reduced. So how does lithium act? Well, we really don't know. But most ideas about lithium assume an intracellular target. And as I mentioned, lithium goes freely through some channels, freely through some ion couple transporters, typically substituting for sodium. And so most of the ideas about lithium involve inhibiting enzymes, and most of those enzymes manipulate high-energy phosphate bonds. They are ATPases or kinases. And lithium would compete for sodium binding sites at those enzymes. But this is really a very confusing field. And despite the simplicity of the lithium ion, we actually don't know how lithium works. So we have gone for the entire hour. I will be at my office hours today from 1.15 to 2. Ralph left any comments from TAs? No comments from TAs. See you Wednesday.