the biologic basis of bipolar disorder.doc

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now clear that many genes are involved. Indeed, the diagram below tells this story well, andour 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 itrepresents a very good beginning.

Don't worry, I won't snow you with too much basic biology. But you do remember, you knewthis once: there are 23 human chromosomes; 22 pairs, one of each from mom and dad, plusthe X and the Y sex chromosomes -- unless you have two X's and no Y, in which case youhave more genetic material overall and therefore more responsibility to save the planet (that'sthe 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 disorderseems to be an opposite story, in which many genes are involved. Worse yet, it appears thatany given individual can have one of many differentcombinations of these genes, so thatthere are many different bipolar disorders, quite literally.

The gene diagram below illustrates this theme well. In the left column are represented genesknown to be associated with bipolar disorder. Actually, these are not individual genes, butrather positions on the various chromosomes. At these positions are found particular genesequences which appear to differ in people with bipolar disorder. In the right column arechromosome positions known to be associated with schizophrenia. In the middle column arechromosome positions in which particular genetic sequences are associated with symptomsshared 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
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Bipolar I, not Bipolar II. The latter shares some of the genes of Bipolar I, but clearly not allof 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 haveone of many different combinations of genes. You would expect that different combinationswould produce different manifestations. And that is the current thinking on why thereappeared 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 hadseveral genes from the left column, but one or two from the middle column, might havesymptoms that look a bit more like someone with schizophrenia than someone whose bipolardisorder was associated with genes from the left-hand column only. in other words, the genesin the left column represent relatively "pure" bipolar disorder.

With my apologies both to you and to the researchers who originally created this diagram, Iconfess that I have lost the reference for this picture. However, it is at least three years oldnow and so quite out of date. A more up-to-date list of genes associated with particularconditions is shown below. In this table, we are looking at individual genes, not positions ona 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 seethat an exactdifference in the DNA sequence is known for these particular genes. Don'tworry, you don't need to understand any of the details. The point is to show off how wellsome 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 up-to-date picture.

Gene Name Variant Effects

SERT SerotoninTransporter

Gene lengthpolymorphism

Depression, anxiety, alcohol

COMT Catechol-O-methyltransferase

Val-158-met Intelligence, BP, schizophrenia


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DRD4 Dopamine receptorD4

48 base pair repeat ADHD

DRD4 Dopamine receptorD4

120 base pairinsertion/deletion

ADHD

DAT Dopaminetransporter

Base pair repeat Schizophrenia

BDNF Brain derivedneurotrophic factor

Val-66-met BP, cognitive performance

MAO Monoamine oxidase Promoter region basepair repeat

BP, cognitive performance

ApoE Cholesterol transportsystem

Epsilon E4 allele Alzheimers, late-life cognitiveperformance

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 advancein our understanding. They are not shown in the table above because their exact genesequence difference has not been determined yet.

GSK3-Beta

Glycogen synthase kinase 3-beta is an enzyme which appears repeatedly at the crossroadsbetween pathways associated with mood problems. Exactly how it works in creating moodsymptoms is not yet known. But many of the known treatments for mood disorders workthrough pathways that pass through this enzymatic step, as shown in the following diagram(note the pink rectangle in the lower left-hand corner):

If you read all the way through this story about what causes bipolar disorder, you are going torun into this enzyme again in the section on the biological clock. Recently it was discoveredthat 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
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PsychEducation.org (home) TheBiologic Basis of Bipolar Disorder (start)

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. Thischapter 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 thosewho do not have this condition.

The bottom line: psychiatry is making progress. Although it is hard to spot differences in thebrain by doing simple tests like a CT scan, or even an MRI, there are now consistentdifferences 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. Iknow, is that not obvious? True, we already knew that just from experience, as you surelyknow as well. But what we can now see is at least a glimpse of the brain mechanisms bywhich this occurs: too much activity in emotional centers, and too little in the frontal lobesthat are supposed to be able to inhibit action. Moreover, these differences are present evenwhen 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 manystudies of patients with mood problems can be reversed at least in part with effectivetreatment. Second, the take-home message for now: growing evidence suggests that eachepisode 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 ofbipolar 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 decision-making and controlling impulsive behavior) shrinks in size when bipolar disorder is allowedto progress. This is basically the same result which has been seen in severe forms ofdepression which remain untreated, as shown in my essay onfrontal 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 indepression).
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Differences in Function: Facial Recognition Tasks

People with bipolar disorder make mistakes when interpreting the expressions on people'sfaces, at least in an experimental setting. This has been shown several times, including inchildren,McClure where the following results were obtained:

As you can see, given the pictures that were shown in this study, everybody makes mistakesand 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 didnot 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 oranxiety 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 themore lasting, permanent parts of the illness, not a symptom. However, the error rate may beparticularly evident during mania.Altshuler,Fleck Interestingly, these mistakes in facial recognitionappear to be reduced by treatment, at least with one of the standard treatment for bipolardisorder, 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 tootough, 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 whenmaking 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).
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Researchers are homing in on regions of the brain which act differently in people with bipolardisorder compared to those without the illness. Evidence is growing quite strong that a regionof the brain called the medial prefrontal cortex is underactive in people with bipolar disordereven when they are having no symptoms at all. However, to see this difference show up, thethe brain image study must be done when participants are working on a task that requiresmaking 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 moreactive 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 peoplewith bipolar disorder.

The authors note that this region of the frontal cortex is thought to be important in being ableto change one's behavior from a routine response to a new, flexible response based oncircumstances. One of my patients to whom I showed this picture asked about her sense thatshe 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 oftentake up the ability to multitask as a marker of intelligence; and unfortunately, the opposite aswell: if you cannot multitask, you aren't "smart". Increasingly, this somewhat subtle cognitiveimpairment 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 oneshown above,Strakowskiresearchers compared patients who were not receiving medications withthose who were. The following series of MRI slices shows regions of the brain which weremore active in those taking medications. As you can see, a region of the brain similar to thatemphasized above, the medial frontal cortex, became more active with treatment. Anotherregion which changes substantially is the anterior cingulate gyrus, which has been shown in

other studies to play a central role in emotion control.
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In general the picture which seems to be developing here is that people with bipolar disorderare working harder with their emotional centers when doing basic thinking work, compared tothose without the illness. This may be some form of compensation for decreased activity inmore 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 thebenefits of hypomania (The Hypomanic Edge;Exuberance; The Bipolar Advantage; an articleby a NY Times science writer). In general, these authors emphasize the high degree ofproductivity and creativity associated with bipolar-like traits. In thelast chapterof my littleminiseries here, you'll see a science-based speculation on how bipolar genes might lead tothese very positive social outcomes.

Unfortunately, I fear that for many people with bipolar disorder, this line of thought is notgoing to help much, and could be harmful -- if people look at this supposed benefit of bipolardisorder 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 isbecause it seems like nearly every single person with bipolar disorder I see is unusually
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creative or intelligent or charismatic or something. Quite a few have been really profoundlyintelligent 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 imagesabove:

Robert Schumann

To listen to some of his works, take thislink to Wikipedia and scroll to the bottom of thepage.

Link to Chapter 3: The central role of the biological clock
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Junkpile to be sorted out later (OCT 12, 2007)

led by Dr. Stephen Strakowski at the University of Cincinnati, patients were asked to makequick decisions that required maintaining focused attention. In particular, they had to inhibitthe impulse to answer quickly in order to think through their options before responding (usinga test called the Stroop).Strakowski Reading from left to right and top to bottom, these 18 MRIslices show us activity in different regions of the brain. Blue regions are less active in patientswith bipolar disorder than and control subjects; yellow and red areas are more active. Theresearchers emphasize the blue regions, which are nearly all associated with controllingimpulsive behavior (except for the cerebellum, in the first three slices; the role of thecerebellum 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:
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Participants in the study (by Matthew Walker and colleagues at UC Berkeley) were shownpictures with negative emotional overtones. In the top panel, you see a slight increase inactivity 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 activityin 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 cameabout 36 hours after their last sleep.

What's the point? In these images we see direct evidence that sleep deprivation increasesactivity in brain centers you do not want to have running your emotional show.as you'll see onthe 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: clockdisruption 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 clockstory is not common to every version of bipolar disorder. However, formostpeople with thisillness, 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 meansyoursleep is important -- which means you need to be careful aboutgetting it! This is one of the most important messages which emerges from understanding the
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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 onmedications. You will also see that at least in one particular individual, nearly completesymptom control was possible without medications are all, just by very strategic use ofdarkness and sleep. Unfortunately, it is not easy to have a normal life while using thattreatment approach, so this is not for everyone.

Wow, have I got your attention now? You'll find details about that particular patien tin theessay aboutdark therapy, and how to apply this whole story to your version of bipolardisorder in the essay entitled Light and Darkness and Bipolar Disorder: TreatmentImplications. The latter is my attempt to tell the whole story as implied by the title. In it youwill find details on how dark therapy may be possible using a simple $7 device while leavingyour 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 particularregion of the brain called the hypothalamus (here is aBrain Tour) contains a collection of

neurons which function as a clock. These neurons "know" when it is morning, and start manyof the biologic rhythms your body depends on during the day. Likewise, they know when it isnighttime: they then turn off daytime rhythms, and turn on nighttime functions including thesecretion of melatonin which is associated with sleep. Therefore your inclination to sleep isvery directly controlled by the biological clock. Likewise, your daytime wakefulness alsodepends on the clock.

The individual molecules associated with this biological clock function have been worked outin remarkable detail. Originally this was done using the biological clock in a fruit fly has themodel, but the mechanism in humans turns out to be remarkably similar. A recent studyshowed 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 betterwhen 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 doesnot crouch in the corner!

Whoops, wrong picture, that's the manic mouse. Here is normal mouse behavior:
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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 goneoff to read it! The "bottom line": sleep is not the only thing that matters. Just as we use lightas 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 sucha problem in our society right now. But the good news is that we can use this understandingas 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 theproper time, in order to preserve our natural biological clock function).

Here again, one last time, is the remarkable story about Light and Darkness In BipolarDisorder. (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 travelacross time zones, or shift work, for example. I routinely write letters for my patients whowork a "graveyard" shift indicating that they need at least a "swing" shift and preferably a dayshift to keep from making their bipolar disorder worse by sleep deprivation. (At least ourlocal Corvallis, OR employers have been excellent about going along with this

recommendation. That probably would not be the case everywhere; although a case could bemade that shift changes would be "reasonable accommodation" as required by the Americanswith Disabilities Act. I have not had to invoke that legal issue; for more on the Act, try theselegal resources: Bazelon, basics of the ADA; Boston University's How to's (use theirnavigation 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, theairway to the lungs. people wake up because they are not getting any air. Sometimes this ismarked 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 wakingare usually not remembered. They are sometimes accompanied by a repositioning motion in

bed. Then the pattern begins again.
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If you snore or if you are overweight, then you probably need to understand sleep apnea, soyou can make sure you do not have it. Here is a sleep disorders resource centeryou can useto learn more about apnea and other problems. I have had several patients who reportsubstantial improvement in the control of their symptoms after their sleep apnea (described inthe 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 bipolarsymptoms should have a test for sleep apnea. He uses a paper and pencil test for this that he'sabout 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 withbipolar symptoms. If you have good insurance, where plenty of money, and your partner saysyou snore, you should consider such a test. If you have no partner to tell you, but you havesevere daytime sleepiness and fatigue, you should also consider it.

Link to Chapter 4


Chapter 4: The Biologic Basis of Depression

Summary:In contrast to mania, depression is now quite well understood at a molecular and cellularlevel. 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 manyantidepressant 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 notwhat you learned once upon a time, it is a recent discovery). The bad news is that a sustaineddepression 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 inneuron number and connections. Indeed, this seems to be the fundamental way that effectivetreatments work.

We have come a long way from understanding depression to be a problem withneurotransmitters 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 successstory of modern research, and one of my favorite stories to demonstrate that psychiatry can doscience too!

I hope that this brief summary will make you want to know more, and see more details aboutall this. You'll find them presented step-by-step in a series of mini-chapters that are part of
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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 withtheintroduction 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


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 disorderhave, in low "doses", significant value. The traits to which they lead were valuable in societywhen 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 understandingmania, this suggests that depression is similar to being at the bottom of the latter in a socialhierarchy. The best thing to do is keep a low profile and save your energy. Similarly, maniamight be akin in some way to being at the top of a social hierarchy, where aggressive use ofavailable 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 somebrief help with that)

Ten to twenty thousand years ago humans were still strongly affected by evolutionaryselection. Only highly "fit" individuals could survive and prosper. If they did prosper, they

could help theirchildren survive and reproduce. So genes that created increased "fitness"would be preserved, and amplified: more children with these genes would survive toreproduce -- and prosper enough to help theirchildren 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 toreproduce, or their children struggled without prosperous parents to help them.

Severe bipolar disorder clearly reduces "fitness". In bipolar I, an individual who hasdelusions that his wife is unfaithful and kills her, loses her support for their children and hisopportunity 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, whenactually it's all been harvested already -- this too would decrease survival and reproduction ofthe individual and probably his children.
http://www.psycheducation.org/mechanism/6atrophy.htmhttp://www.psycheducation.org/mechanism/introduction%20to%20mechanism.htmhttp://www.psycheducation.org/mechanism/introduction%20to%20mechanism.htmhttp://www.psycheducation.org/mechanism/introduction%20to%20mechanism.htmhttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htmhttp://www.psycheducation.org/http://www.psycheducation.org/BipolarMechanism/introduction.htmhttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#selection%23selectionhttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#fitness%23fitnesshttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#value%23valuehttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#Jamison%23Jamisonhttp://www.psycheducation.org/mechanism/evolution.htmhttp://www.psycheducation.org/mechanism/6atrophy.htmhttp://www.psycheducation.org/mechanism/introduction%20to%20mechanism.htmhttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htmhttp://www.psycheducation.org/http://www.psycheducation.org/BipolarMechanism/introduction.htmhttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#selection%23selectionhttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#fitness%23fitnesshttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#value%23valuehttp://www.psycheducation.org/BipolarMechanism/5BigPicture.htm#Jamison%23Jamisonhttp://www.psycheducation.org/mechanism/evolution.htm


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So why wasn't the "gene", or genes, for bipolar disorder eliminated by evolution manythousands of years ago? Surprisingly, there are numerous genes that appear to decrease anindividual's reproductive success yet still have not disappeared. The most commonexplanation for this puzzle is that the gene causes some change that in small doses providesincreased fitness, and only with a "large dose" of this gene, and its effects, does the individualfunction less well than average.

Fitness in bipolar disorder

One of the classic examples of this is "sickle cell anemia". When an individual gets twocopies 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, shecan actually have increasedsurvival success. If she lives in an area with lots of malaria, shewill have a lower risk contracting this lethal infection (her red blood cells contract into asickle 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 cripplingeffect 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. Andthat's not too hard to imagine. What is a person like in a manic phase? What if you couldhave just a little of that? For example:

Gene Gene Effect Just a little Too much

A Connect unrelated ideas Creativity Tangential, disorganized

B Seek novelty Fascinated by change, curiousJumping from project to

project

C Take risks CourageousBad judgment aboutharm

D Be aware of others' opinions Socially polishedAnxious, suspicious,

paranoid

E High energy level Very productive

Can't stop, slow downRacing thoughtsUnable to focusScattered activity

If there are multiple genes that cause bipolar symptoms, then having a few was probably agood 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 bybeing born of social leader, were more reproductively successful. This pattern has beendiminished in the last several hundred years as more and more humans are able to reproduceregardless 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 thetotal population, carried one or more genes that in large doses cause illness.

So our model looks like this:


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Having a few too many genes begins to decrease reproductive success, because the behaviorsthey 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 manysymptoms 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 heardalso falls in well with a long-standing guess about what depression is. The guess presumesthat somehow these mood changes must have some evolutionary benefit, at least when theyare not so extreme (otherwise we'd have to wonder why these potentially lethal mood changeswouldn't have led to the removal of the genes associated with them, whatever those genesare). 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-- reproductivelyspeaking, anyway -- to be able to "shut down" and save resources for better times. Give up onclimbing the social ladder; give up on trying to start new projects or even complete the currentones (if you're really at the bottom of the heap already, anything you manage to make orgather might very likely be stolen anyway). Just hunker down and wait. Turn off yourmotivational engines. Heck, turn off your engines themselves as much as possible and go intoa 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 easycalories, eat a bunch of them, who knows when more are coming. "Perceptions of defeat" arethe 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" insome ways? (even though it probably has a different mechanism, because we know that manicand depressive symptoms can occur at the same time, as you've learned about bipolar "mixedstates") So the mania-side hunch goes like this: what if it is caused by the brain chemistryassociated 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 toresearchers chasing them around their natural environments. Much of what we know aboutstress hormones and social ladders comes from the work of Robert Sapolsky and colleagues,
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for example, who did indeed literally chase baboons around the African Savannah routinelyfor years, gathering information on the chemistry of animals at the top and the bottom of theirsocial "hierarchies". Based on and reasoning forward from such research, several moodexperts have speculated that mania might be "too much of a good thing", where the goodthing is the confidence, the drive, the ability to motivate oneself and get things done, thedecrease 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 thetop baboon, so who's going to beat you up for bragging? Just strut right up to the top female inthe 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'llget 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 benecessary to work up the kind of confidence it takes to be the leader in this pack; and if itworks, 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 recentresurgence 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 depressionas an adaptation was provided by a leader in this field, Randolph Nesse. Not all moodscientists agree with this model, however; e.g. Dubrovsky, 2002. I've cited this line ofthought here because it helps me to have at leastsome working guess as to what bipolardisorder might be,some idea on where it came from -- just in case there might emerge somesuggestion 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 essayon evolutionmight help.)

Recommended reading

Dr. Kay Jamison is a professor at Johns Hopkins University. She has written extensively onthe connection between creativity and bipolar disorder. Her bookTouched with Fire is a goodstarting place on this subject. So is her newer work,Exuberance.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7149905&query_hl=4&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9875952&query_hl=11&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9875952&query_hl=11&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10632228&query_hl=17&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11853097&query_hl=17&itool=pubmed_docsumhttp://www.psycheducation.org/mechanism/evolution.htmhttp://www.psycheducation.org/mechanism/evolution.htmhttp://www.psycheducation.org/mechanism/evolution.htmhttp://www.amazon.com/Touched-Fire-Manic-Depressive-Artistic-Temperament/dp/068483183Xhttp://www.amazon.com/Exuberance-Passion-Kay-Redfield-Jamison/dp/0375701486/ref=pd_bbs_sr_1/105-8077424-1106831?ie=UTF8&s=books&qid=1192230374&sr=1-1http://www.amazon.com/Exuberance-Passion-Kay-Redfield-Jamison/dp/0375701486/ref=pd_bbs_sr_1/105-8077424-1106831?ie=UTF8&s=books&qid=1192230374&sr=1-1http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7149905&query_hl=4&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9875952&query_hl=11&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10632228&query_hl=17&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11853097&query_hl=17&itool=pubmed_docsumhttp://www.psycheducation.org/mechanism/evolution.htmhttp://www.psycheducation.org/mechanism/evolution.htmhttp://www.amazon.com/Touched-Fire-Manic-Depressive-Artistic-Temperament/dp/068483183Xhttp://www.amazon.com/Exuberance-Passion-Kay-Redfield-Jamison/dp/0375701486/ref=pd_bbs_sr_1/105-8077424-1106831?ie=UTF8&s=books&qid=1192230374&sr=1-1

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