The Biologic Basis of Bipolar Disorder:

Five mini-chapters on the brain chemistry of mania and depression

(revised 8/2008) The biologic basis of depression is described in a 1. The genetic basis of bipolar disorder separate section on this website. It is a rather long story. Over time, this story about bipolar disorder will likely become longer as well. I will try to keep 2. Brain differences this page updated with new findings. 3. The central role of the biological As of 2008, treatment of bipolar disorder is roughly clock [updated 8/2008] equivalent to when diabetes was treated without insulin. We do not know the fundamental cause and 4. The biological basis of depression cannot therefore target our treatments accordingly. 5. Big picture -- there must be some However, our understanding is growing very evolutionary advantage? quickly. I used to hope that a Nobel prize would be awarded someday to someone who made the key discovery. But it now appears that the tapestry of manic symptoms is extremely complex. Many threads have been identified, and they are just beginning to come together. This is a very exciting time in the history of bipolar understanding. Even if no single researcher wins a Nobel, major breakthroughs seem likely within the next 5-10 years.

PsychEducation.org (home) Biologic Basis of Bipolar Disorder (start)

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Chapter 1: The Genetic Basis of Bipolar Disorder

Summary: Whereas 10 years ago it was hoped that a single gene for bipolar disorder might be found, it is

now clear that many genes are involved. Indeed, the diagram below tells this story well, and our task in this chapter is to explain that diagram. In the process we will examine a few particular genes which are best understood in terms of their roles in bipolar disorder. Bipolar Disorder Shared Genes Schizophrenia

Link to Chapter 2 The master diagram Of course this is not the end of the story about the genetics of bipolar disorder, but it represents a very good beginning. Don't worry, I won't snow you with too much basic biology. But you do remember, you knew this once: there are 23 human chromosomes; 22 pairs, one of each from mom and dad, plus the X and the Y sex chromosomes -- unless you have two X's and no Y, in which case you have more genetic material overall and therefore more responsibility to save the planet (that's the female of the species, guys). At least one psychiatric illness is caused by a single gene: Huntington's disease. But so far, nothing else in psychiatry has proved to be that simple. And unfortunately, bipolar disorder seems to be an opposite story, in which many genes are involved. Worse yet, it appears that any given individual can have one of many different combinations of these genes, so that there are many different bipolar disorders, quite literally. The gene diagram below illustrates this theme well. In the left column are represented genes known to be associated with bipolar disorder. Actually, these are not individual genes, but rather positions on the various chromosomes. At these positions are found particular gene sequences which appear to differ in people with bipolar disorder. In the right column are chromosome positions known to be associated with schizophrenia. In the middle column are chromosome positions in which particular genetic sequences are associated with symptoms shared by both conditions, such as delusions, hallucinations, and abnormal thought processes (as you probably know from reading elsewhere on this website, these are symptoms of

Bipolar I, not Bipolar II. The latter shares some of the genes of Bipolar I, but clearly not all of them, because it does not share these psychosis genes at all). Bipolar Disorder Shared Genes Schizophrenia

As you can see, any given individual (shown here by the black ellipticals circles) could have one of many different combinations of genes. You would expect that different combinations would produce different manifestations. And that is the current thinking on why there appeared to be so many different variations of bipolar disorder. You can see in this diagram that some of those variations share genes with schizophrenia. For example, someone who had several genes from the left column, but one or two from the middle column, might have symptoms that look a bit more like someone with schizophrenia than someone whose bipolar disorder was associated with genes from the left-hand column only. in other words, the genes in the left column represent relatively "pure" bipolar disorder. With my apologies both to you and to the researchers who originally created this diagram, I confess that I have lost the reference for this picture. However, it is at least three years old now and so quite out of date. A more up-to-date list of genes associated with particular conditions is shown below. In this table, we are looking at individual genes, not positions on a chromosome. In other words, the table below shows a very precise location of gene differences in people with these conditions. Indeed, in the third column of the table you see that an exact difference in the DNA sequence is known for these particular genes. Don't worry, you don't need to understand any of the details. The point is to show off how well some of these gene differences are now understood. You could substitute the genes shown in purple below into the left-hand column of the black and white diagram above for a more upto-date picture. Gene SERT COMT Name Serotonin Transporter Catechol-Omethyltransferase Variant Gene length polymorphism Val-158-met Effects Depression, anxiety, alcohol Intelligence, BP, schizophrenia

Dopamine receptor 48 base pair repeat ADHD D4 DRD4 Dopamine receptor 120 base pair ADHD D4 insertion/deletion DAT Dopamine Base pair repeat Schizophrenia transporter BDNF Brain derived Val-66-met BP, cognitive performance neurotrophic factor MAO Monoamine oxidase Promoter region base BP, cognitive performance pair repeat ApoE Cholesterol transport Epsilon E4 allele Alzheimers, late-life cognitive system performance Particular genes As I have watched this story unfold, two genes in particular have been particularly striking: one because it seems central to the story, and the other because it represents such an advance in our understanding. They are not shown in the table above because their exact gene sequence difference has not been determined yet. GSK3-Beta Glycogen synthase kinase 3-beta is an enzyme which appears repeatedly at the crossroads between pathways associated with mood problems. Exactly how it works in creating mood symptoms is not yet known. But many of the known treatments for mood disorders work through pathways that pass through this enzymatic step, as shown in the following diagram (note the pink rectangle in the lower left-hand corner):

DRD4

If you read all the way through this story about what causes bipolar disorder, you are going to run into this enzyme again in the section on the biological clock. Recently it was discovered that lithium works by inhibiting GSK3-beta and thereby restoring normal cycling of the biological clock. (Lithium works in other ways as well, but this may be one of the most important). Link to Chapter 2: Brain differences

PsychEducation.org (home) Biologic Basis of Bipolar Disorder (start)

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Chapter 2: Brain Differences

Summary: This is a hard chapter. If there are any in this series of five chapters you might wish to skip, this would probably be it. The others lead more directly to implications for treatment. This chapter is for those people who would like to see with their own eyes what is going on in the brain of people with bipolar disorder that might be different from what is going on in those who do not have this condition. The bottom line: psychiatry is making progress. Although it is hard to spot differences in the brain by doing simple tests like a CT scan, or even an MRI, there are now consistent differences which are being shown that confirm the working hunch about bipolar disorder -namely, that this is a condition in which emotions gain too much power over behavior. I know, is that not obvious? True, we already knew that just from experience, as you surely know as well. But what we can now see is at least a glimpse of the brain mechanisms by which this occurs: too much activity in emotional centers, and too little in the frontal lobes that are supposed to be able to inhibit action. Moreover, these differences are present even when no symptoms are present.

Differences in Size Differences in Function: facial recognition Differences in Function: making quick decisions The Upside of Bipolar Disorder

Link to Chapter 3: The central role of the biological clock Differences in size First the good news: many of the differences in brain size which have been shown in many studies of patients with mood problems can be reversed at least in part with effective treatment. Second, the take-home message for now: growing evidence suggests that each episode of severe mood symptoms is associated with increases in these brain size differences, and therefore aggressive pursuit of good symptom control may be associated with preventing some of the brain changes that unfortunately seem to progress in at least some forms of bipolar disorder. Although it has taken years to be certain, because not all studies have shown the same results, there is now fairly good agreement that the frontal cortex (which is associated with decisionmaking and controlling impulsive behavior) shrinks in size when bipolar disorder is allowed to progress. This is basically the same result which has been seen in severe forms of depression which remain untreated, as shown in my essay on frontal atrophy in depression. Several studies have now shown that lithium appears to be capable of reversing this trend toward frontal atrophy (the studies are referenced in the essay on treatment effects in depression).

Differences in Function: Facial Recognition Tasks People with bipolar disorder make mistakes when interpreting the expressions on people's faces, at least in an experimental setting. This has been shown several times, including in children,McClure where the following results were obtained:

As you can see, given the pictures that were shown in this study, everybody makes mistakes and interpreting them, but people with bipolar disorder make those mistakes more often. Interestingly, their mistake rate was even greater than patients with anxiety disorders, who did not differ greatly from controls. When the faces shown exhibited more dramatic expressions, people with bipolar disorder made over twice as many mistakes as people without a mood or anxiety problem. all of the above findings were seen even in children who were not symptomatic at the time of the study. In other words, this difficulty with facial expression recognition may be one of the more lasting, permanent parts of the illness, not a symptom. However, the error rate may be particularly evident during mania.Altshuler, Fleck Interestingly, these mistakes in facial recognition appear to be reduced by treatment, at least with one of the standard treatment for bipolar disorder, lamotrigine.Haldane Making quick decisions about emotional matters If you aren't familiar with reading one of these pictures, and don't want to learn (not too tough, but maybe not necessary), the bottom line here is: people with bipolar disorder, even when they don't have any symptoms, don't seem to use the front part of their brain when making decisions under time pressure. In this particular task, at least, they were not using the part of the brain known to inhibit impulsive action (not as much as were the control subjects).

Researchers are homing in on regions of the brain which act differently in people with bipolar disorder compared to those without the illness. Evidence is growing quite strong that a region of the brain called the medial prefrontal cortex is underactive in people with bipolar disorder even when they are having no symptoms at all. However, to see this difference show up, the the brain image study must be done when participants are working on a task that requires making decisions quickly about something with an emotional overtone. In a recent study, a team from AustraliaLagopoulos found the following result:

The red region is the medial prefrontal cortex. You see here the portion of it which is more active during the task in people without bipolar disorder, compared to those with the illness (the task required a complex sorting of words, some of which had emotional implications). The blue/green region is the hippocampus, which was more active during the task in people with bipolar disorder. The authors note that this region of the frontal cortex is thought to be important in being able to change one's behavior from a routine response to a new, flexible response based on circumstances. One of my patients to whom I showed this picture asked about her sense that she is no longer able to "multitask". She cannot rely on her brain to make choices between routine or flexible responses unless she really concentrates. She pointed out that people often take up the ability to multitask as a marker of intelligence; and unfortunately, the opposite as well: if you cannot multitask, you aren't "smart". Increasingly, this somewhat subtle cognitive impairment is being recognized as one of the unfortunate consequences of bipolar disorder. Medications may make a difference, however, at least somewhat. In a study similar to the one shown above,Strakowski researchers compared patients who were not receiving medications with those who were. The following series of MRI slices shows regions of the brain which were more active in those taking medications. As you can see, a region of the brain similar to that emphasized above, the medial frontal cortex, became more active with treatment. Another region which changes substantially is the anterior cingulate gyrus, which has been shown in other studies to play a central role in emotion control.

In general the picture which seems to be developing here is that people with bipolar disorder are working harder with their emotional centers when doing basic thinking work, compared to those without the illness. This may be some form of compensation for decreased activity in more frontal regions of the brain.

The Upside of Bipolar Disorder Isn't there some good news to go along with all this? This is a popular line of thought, lately. Several authors have written recently about the benefits of hypomania (The Hypomanic Edge; Exuberance; The Bipolar Advantage; an article by a NY Times science writer). In general, these authors emphasize the high degree of productivity and creativity associated with bipolar-like traits. In the last chapter of my little miniseries here, you'll see a science-based speculation on how bipolar genes might lead to these very positive social outcomes. Unfortunately, I fear that for many people with bipolar disorder, this line of thought is not going to help much, and could be harmful -- if people look at this supposed benefit of bipolar disorder and wonder why they never saw any kind of benefits like that in their own lives. However, I must admit that one of the reasons why I have specialized in bipolar disorder is because it seems like nearly every single person with bipolar disorder I see is unusually

creative or intelligent or charismatic or something. Quite a few have been really profoundly intelligent to the point where I have trouble keeping up with their minds. Perhaps the following might serve as the metaphorical "other side" of the story in the images above: Robert Schumann

To listen to some of his works, take this link to Wikipedia and scroll to the bottom of the page.

Link to Chapter 3: The central role of the biological clock

Junkpile to be sorted out later (OCT 12, 2007) led by Dr. Stephen Strakowski at the University of Cincinnati, patients were asked to make quick decisions that required maintaining focused attention. In particular, they had to inhibit the impulse to answer quickly in order to think through their options before responding (using a test called the Stroop).Strakowski Reading from left to right and top to bottom, these 18 MRI slices show us activity in different regions of the brain. Blue regions are less active in patients with bipolar disorder than and control subjects; yellow and red areas are more active. The researchers emphasize the blue regions, which are nearly all associated with controlling impulsive behavior (except for the cerebellum, in the first three slices; the role of the cerebellum in all this is still not clear, although it does keep showing up in most studies like this): in particular, the regions I have circled in red:

PsychEducation.org (home) Biologic Basis of Bipolar Disorder (start)

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Chapter 3: The Central Role of the Biological Clock

(Written 9/2007; updated 10/2007) Summary: The first two parts of this story are summaries of material explained in detail elsewhere on my website (links below). The last two sections here, about night shift work, and sleep apnea, arise very directly from an understanding of the biological clock story.

Update: sleep deprivation activates emotional brain centers The Biological Clock and Bipolar Disorder How does the biological clock work? Sleep and light and darkness and the biological clock Should I get off night shift? Can sleep apnea cause or look like bipolar disorder?

Link to Chapter 4 Update: sleep deprivation activates emotional brain centers Only a month after the essay below was written, a major new result arrived which is very consistent with everything therein. Indeed, it strongly reinforces the importance of this whole story. Here is that stunning result. When people do not sleep, activity increases in a brain center which is responsible for fear and emotional interpretation of events -- the amygdala. In some ways, this is not news: doesn't everyone know that when you don't sleep, you get grouchy, and more agitated? But imagine if a person who is already prone to overactivity in their amygdala goes without sleep. This sleep loss will have more impact on them, one might expect, than on the average person. As you saw in the previous chapter on brain differences, evidence is increasing that people with bipolar disorder have overactivity in regions of their brain associated with emotional processing. In chapter 2, you saw pictures depicting this "limbic" hyperactivity, focusing on the hippocampus. In the picture below, we see hyperactivity in the amygdala, which sits right next door to the hippocampus and is very tightly functionally linked to it.

Participants in the study (by Matthew Walker and colleagues at UC Berkeley) were shown pictures with negative emotional overtones. In the top panel, you see a slight increase in activity in the amygdala amongst study subjects who were allowed their normal sleep pattern prior to this brain scan. In the bottom panel, however, you see a much greater level of activity in the amygdala on both sides of the brain; these subjects, who did not have bipolar disorder ("normal" graduate students), were deprived of sleep all night before this scan, which came about 36 hours after their last sleep. What's the point? In these images we see direct evidence that sleep deprivation increases activity in brain centers you do not want to have running your emotional show.as you'll see on the rest of this page, sleep is a crucial ingredient in health for people with bipolar disorder (and probably for everyone else). The Biological Clock and Bipolar Disorder Bipolar disorder is a disruption of the biological clock. Well, that's almost true: clock disruption is an important part of the story in the majority of people with bipolar disorder. Once in a while I see a patient whose sleep is completely normal but who is still having bipolar symptoms. This is very unusual but not impossible. That tells us the biological clock story is not common to every version of bipolar disorder. However, for most people with this illness, sleep abnormalities are a central part of the problem: when sleep gets worse, symptoms get worse; and when it gets better, symptoms often get better. Obviously, this means your sleep is important -- which means you need to be careful about getting it! This is one of the most important messages which emerges from understanding the

biological clock story. The good news is that by being careful with sleep -- and darkness too, as you'll see -- you can potentially improve your symptom control without relying entirely on medications. You will also see that at least in one particular individual, nearly complete symptom control was possible without medications are all, just by very strategic use of darkness and sleep. Unfortunately, it is not easy to have a normal life while using that treatment approach, so this is not for everyone. Wow, have I got your attention now? You'll find details about that particular patien tin the essay about dark therapy, and how to apply this whole story to your version of bipolar disorder in the essay entitled Light and Darkness and Bipolar Disorder: Treatment Implications. The latter is my attempt to tell the whole story as implied by the title. In it you will find details on how dark therapy may be possible using a simple $7 device while leaving your lights on. How does the biological clock work? Here's the short answer -- a link to the long version iscoming up. In brief: in a particular region of the brain called the hypothalamus (here is a Brain Tour) contains a collection of neurons which function as a clock. These neurons "know" when it is morning, and start many of the biologic rhythms your body depends on during the day. Likewise, they know when it is nighttime: they then turn off daytime rhythms, and turn on nighttime functions including the secretion of melatonin which is associated with sleep. Therefore your inclination to sleep is very directly controlled by the biological clock. Likewise, your daytime wakefulness also depends on the clock. The individual molecules associated with this biological clock function have been worked out in remarkable detail. Originally this was done using the biological clock in a fruit fly has the model, but the mechanism in humans turns out to be remarkably similar. A recent study showed that by manipulating one of the genes responsible for a protein in this clock process, a behavioral change very much like maniac could be produced in a mouse. It even got better when they gave the mouse lithium, causing a return to normal mouse function. Here is a picture of the normal mouse. Can you imagine what a manic mouse looks like? Hint: it does not crouch in the corner!

Whoops, wrong picture, that's the manic mouse. Here is normal mouse behavior:

Here is the full essay about how the biological clock works. Sleep and light and darkness and the biological clock Well, at this point you've seen links to this story enough times that by now I hope you've gone off to read it! The "bottom line": sleep is not the only thing that matters. Just as we use light as a therapy for depression, it may be possible to use darkness as mood stabilizer treatment for bipolar disorder. In fact, the whole story makes you wonder whether our use of electric light, particularly televisions and computers, might be part of why bipolar disorder seems to be such a problem in our society right now. But the good news is that we can use this understanding as part of treatment, at least as a reminder about the importance of regular sleep -- and perhaps by making sure that we get enough darkness, as well as enough light (and all at the proper time, in order to preserve our natural biological clock function). Here again, one last time, is the remarkable story about Light and Darkness In Bipolar Disorder. (Sorry if I'm leading you around in circles here) Should I get off night shift? Clearly sleep deprivation can be a trigger for manic episodes. This can occur from travel across time zones, or shift work, for example. I routinely write letters for my patients who work a "graveyard" shift indicating that they need at least a "swing" shift and preferably a day shift to keep from making their bipolar disorder worse by sleep deprivation. (At least our local Corvallis, OR employers have been excellent about going along with this recommendation. That probably would not be the case everywhere; although a case could be made that shift changes would be "reasonable accommodation" as required by the Americans with Disabilities Act. I have not had to invoke that legal issue; for more on the Act, try these legal resources: Bazelon, basics of the ADA; Boston University's How to's (use their navigation bar)). Can sleep apnea cause or look like bipolar disorder? Sleep apnea refers to a form of snoring which leads to closure of the breathing tube, the airway to the lungs. people wake up because they are not getting any air. Sometimes this is marked by a pattern of snoring, a "crescendo" from mild snoring to very loud and effortful -almost gasping -- snoring followed by a momentary waking. These brief moments of waking are usually not remembered. They are sometimes accompanied by a repositioning motion in bed. Then the pattern begins again.

If you snore or if you are overweight, then you probably need to understand sleep apnea, so you can make sure you do not have it. Here is a sleep disorders resource center you can use to learn more about apnea and other problems. I have had several patients who report substantial improvement in the control of their symptoms after their sleep apnea (described in the above link) was treated, so this definitely warrants more attention than it is now getting. Thanks to Dr. Robert Clark for providing the link (he does have some proprietary interest, but the basics on the site are clear and straightforward and you will probably find them useful). One of my colleagues, Dr. Tam Kelly, thinks that every patient who comes in with bipolar symptoms should have a test for sleep apnea. He uses a paper and pencil test for this that he's about to give me [Under construction, August 8, 2008]. For now, it is not routine to get a sleep study looking for sleep apnea in every patient with bipolar symptoms. If you have good insurance, where plenty of money, and your partner says you snore, you should consider such a test. If you have no partner to tell you, but you have severe daytime sleepiness and fatigue, you should also consider it.

Link to Chapter 4 PsychEducation.org (home) Biologic Basis of Bipolar Disorder (start) The

Chapter 4: The Biologic Basis of Depression

Summary: In contrast to mania, depression is now quite well understood at a molecular and cellular level. Even some of the genes which are associated with susceptibility to depression have been connected into this molecular-cellular story. A general mechanism by which many antidepressant treatments work, even exercise, has been mapped out. In brief, this turns out to be a story about cell growth and cell death. The brain is highly "plastic", a jargon term meaning that the brain is very changeable in response to the demands placed upon it. Brand-new cells can grow in certain regions of the brain. (I know, that's not what you learned once upon a time, it is a recent discovery). The bad news is that a sustained depression appears to be associated with a decrease in the number of brain cells, and in the number of connections each brain cell makes with others. The good news is that treatment appears to be able to halt and even reverse this decrease in neuron number and connections. Indeed, this seems to be the fundamental way that effective treatments work. We have come a long way from understanding depression to be a problem with neurotransmitters like serotonin and norepinephrine. The story is vastly more complicated, and yet a good portion of that complexity is now understood. This is an amazing success story of modern research, and one of my favorite stories to demonstrate that psychiatry can do science too! I hope that this brief summary will make you want to know more, and see more details about all this. You'll find them presented step-by-step in a series of mini-chapters that are part of

my essay about the brain chemistry of depression (each chapter is only about one long page). The story above begins in Chapter 6 of that series. Alternatively, you might want to start with the introduction to the entire 12- chapter series, then choose to jump to Chapter 6 if you wish.

Link to Chapter 5 (in this series on bipolar mechanism): The Big Picture PsychEducation.org (home) Biologic Basis of Bipolar Disorder (start) The

Chapter 5: The Big Picture -There Must Be Some Evolutionary Advantage?

Summary: Evolution did not select out bipolar disorder because the genes which lead to bipolar disorder have, in low "doses", significant value. The traits to which they lead were valuable in society when humans were evolving by natural selection, and may be acted upon by social selection pressures even now. one theory about depression, which can be extended to understanding mania, this suggests that depression is similar to being at the bottom of the latter in a social hierarchy. The best thing to do is keep a low profile and save your energy. Similarly, mania might be akin in some way to being at the top of a social hierarchy, where aggressive use of available resources can lead to significant accomplishments.

Why didn't evolution "select out" bipolar disorder? Fitness and bipolar disorder Possible evolutionary value of mania Recommended reading: Kay Jamison

Why didn't evolution "select out" bipolar disorder? (You don't believe in evolution? Here's some brief help with that) Ten to twenty thousand years ago humans were still strongly affected by evolutionary selection. Only highly "fit" individuals could survive and prosper. If they did prosper, they could help their children survive and reproduce. So genes that created increased "fitness" would be preserved, and amplified: more children with these genes would survive to reproduce -- and prosper enough to help their children survive, and so forth. The opposite is also true: genes that decreased "fitness" -- the ability to survive and prosper -would be reduced in every generation, as the humans with those genes struggled and failed to reproduce, or their children struggled without prosperous parents to help them. Severe bipolar disorder clearly reduces "fitness". In bipolar I, an individual who has delusions that his wife is unfaithful and kills her, loses her support for their children and his opportunity to reproduce (to put the matter in blunt evolutionary terms). Becoming "manic" and giving away all one's grain because of a belief that more can easily be harvested, when actually it's all been harvested already -- this too would decrease survival and reproduction of the individual and probably his children.

So why wasn't the "gene", or genes, for bipolar disorder eliminated by evolution many thousands of years ago? Surprisingly, there are numerous genes that appear to decrease an individual's reproductive success yet still have not disappeared. The most common explanation for this puzzle is that the gene causes some change that in small doses provides increased fitness, and only with a "large dose" of this gene, and its effects, does the individual function less well than average. Fitness in bipolar disorder One of the classic examples of this is "sickle cell anemia". When an individual gets two copies of the gene that causes this condition, she has a crippling anemia and will die young. However, if she gets only one copy of this gene, and a normal gene from her other parent, she can actually have increased survival success. If she lives in an area with lots of malaria, she will have a lower risk contracting this lethal infection (her red blood cells contract into a sickle shape in which the malaria bug cannot survive -- but only some of her cells do this, because half of them are being governed by a "normal" gene, so she doesn't get the crippling effect of many cells doing this at once). The bipolar geneticists are thinking this same kind of thing has happened in bipolar disorder. There must be some advantage that getting a "small dose" of bipolar genes provides. And that's not too hard to imagine. What is a person like in a manic phase? What if you could have just a little of that? For example: Gene A B C D Gene Effect Connect unrelated ideas Seek novelty Take risks Creativity Fascinated by change, curious Courageous Just a little Too much Tangential, disorganized Jumping from project to project Bad judgment about harm Anxious, suspicious, paranoid Can't stop, slow down Racing thoughts Unable to focus Scattered activity

Be aware of others' opinions Socially polished

High energy level

Very productive

If there are multiple genes that cause bipolar symptoms, then having a few was probably a good thing, in terms of one's reproductive success 10,000 years ago. Later, human evolution became dominated by social selection: those who rose up the social ladder, or started there by being born of social leader, were more reproductively successful. This pattern has been diminished in the last several hundred years as more and more humans are able to reproduce regardless of their position in the social hierarchy. But until then, a genetic selection process probably still had major effects on bipolar gene "frequency" -- how many individuals, in the total population, carried one or more genes that in large doses cause illness. So our model looks like this:

Having a few too many genes begins to decrease reproductive success, because the behaviors they cause are becoming too extreme -- in other words, a person with that many genes is becoming "symptomatic". If you get a few more genes than that, you may have so many symptoms that you cannot function well. This is what we regard as "mental illness". Possible evolutionary value of mania itself Does anyone have even a hunch as to what mania is? The most compelling guess I've heard also falls in well with a long-standing guess about what depression is. The guess presumes that somehow these mood changes must have some evolutionary benefit, at least when they are not so extreme (otherwise we'd have to wonder why these potentially lethal mood changes wouldn't have led to the removal of the genes associated with them, whatever those genes are). So what might be the benefit of depression? When faced with overwhelming stress, perhaps it might have been "smart", at one point in our evolutionary history-- reproductively speaking, anyway -- to be able to "shut down" and save resources for better times. Give up on climbing the social ladder; give up on trying to start new projects or even complete the current ones (if you're really at the bottom of the heap already, anything you manage to make or gather might very likely be stolen anyway). Just hunker down and wait. Turn off your motivational engines. Heck, turn off your engines themselves as much as possible and go into a sort of hibernation if you can manage to do so. Wait for better times. Sleep a lot. Hoard your calories, because you may not get much to eat during this time. If you can grab any easy calories, eat a bunch of them, who knows when more are coming. "Perceptions of defeat" are the key ingredient leading to this state, according to one researcher (Gilbert). That's the depression side of the hunch, obviously. Somehow mania must be "opposite" in some ways? (even though it probably has a different mechanism, because we know that manic and depressive symptoms can occur at the same time, as you've learned about bipolar "mixed states") So the mania-side hunch goes like this: what if it is caused by the brain chemistry associated with the opposite social experience, namely being on top of the social ladder, somehow goes to an extreme in mania? In our primate ancestors, these social ladders are very distinct and very obvious, even to researchers chasing them around their natural environments. Much of what we know about stress hormones and social ladders comes from the work of Robert Sapolsky and colleagues,

for example, who did indeed literally chase baboons around the African Savannah routinely for years, gathering information on the chemistry of animals at the top and the bottom of their social "hierarchies". Based on and reasoning forward from such research, several mood experts have speculated that mania might be "too much of a good thing", where the good thing is the confidence, the drive, the ability to motivate oneself and get things done, the decrease in need for sleep, and even the increased sexual activity, of the top-of-the-heap animals in a social hierarchy. Go ahead, take risks; you've already established that you're the top baboon, so who's going to beat you up for bragging? Just strut right up to the top female in the hierarchy; she'll recognize that you're the alpha guy, and something good will happen. Take on that pack of hyenas? Sure, the pack is behind you, they'll follow your lead and you'll get rid of these pests for a while. Doesn't everyone see what is possible? Let's get going. The pickings are there for the taking. Everything will work out (believing all this may be necessary to work up the kind of confidence it takes to be the leader in this pack; and if it works, you'll have some great privileges it really does make sense to take risks for). This line of thought has been around a long time (e.g. 1982). But it is still very active; a recent resurgence in this reasoning (e.g. Wilson, 2002) is associated with the rise of "evolutionary psychology", now a field unto itself and growing stronger. A classic explanation of depression as an adaptation was provided by a leader in this field, Randolph Nesse. Not all mood scientists agree with this model, however; e.g. Dubrovsky, 2002. I've cited this line of thought here because it helps me to have at least some working guess as to what bipolar disorder might be, some idea on where it came from -- just in case there might emerge some suggestion on how to treat it. So far, the latter is lacking. Keep watching. (If you keep stumbling over the apparent emphasis on evolution here, perhaps my little essay on evolution might help.) Recommended reading Dr. Kay Jamison is a professor at Johns Hopkins University. She has written extensively on the connection between creativity and bipolar disorder. Her book Touched with Fire is a good starting place on this subject. So is her newer work, Exuberance.