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
2.  Brain differences
3.  The central role of the biological
clock [updated 8/2008]
4.  The biological basis of depression
5.  Big picture -- there must be some
evolutionary advantage?
story.  Over time, this story about bipolar disorder
will likely become longer as well.  I will try to keep
this page updated with new findings.
As of 2008, treatment of bipolar disorder is roughly
equivalent to when diabetes was treated without
insulin.  We do not know the fundamental cause and
cannot therefore target our treatments accordingly.
However, our understanding is growing very
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.

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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 up-
to-date picture. 

Gene Name Variant Effects

SERT Serotonin Gene length Depression, anxiety, alcohol
Transporter polymorphism
COMT Catechol-O- Val-158-met Intelligence, BP, schizophrenia
methyltransferase
 DRD4 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):

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

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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 decision-
making 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:

 
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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

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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

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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 Gene Effect Just a little Too much

A Connect unrelated ideas Creativity Tangential, disorganized
Jumping from project to
B Seek novelty Fascinated by change, curious
project
Bad judgment about
C Take risks Courageous
harm
Anxious, suspicious,
D Be aware of others' opinions Socially polished
paranoid
Can't stop, slow down
Racing thoughts
E High energy level Very productive
Unable to focus
Scattered activity

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.