6. Generating depression
creative depression It is amazing how many world leaders and entertainers have suffered from the disease.
an epidemic of mood swings Depression is on the rise, afflicting well more than 1 in 10 people at some point in their life.
bipolar and monopolar disorders Each, with differing degrees of severity, are much more than prolonged sadness.
the pharmacology of despair Serotonin and cortisol are a neurotransmitter and a hormone that jointly regulate mood.
misbehaving serotonin Genetic variation in the serotonin transporter is associated with some measures of depression and suicide, particularly if life is stressful.
faint genetic signals It seems likely that hundreds if not thousands of genetic variants contribute to mood disorders.
schizophrenia and other mental disturbances Many other types of mental problems are equally as genetically complicated.
the genetic tightrope of the mind Cultural and genetic change have affected the brain perhaps more than any other organ.
a kindling theory in the modern world Depression gets worse with time as mood becomes less stable and more sensitive.
Creative Depression
When the “Piano Man” sings about men at the bar sharing a drink they call loneliness being better than drinking alone, the melancholy is somehow erased by something uplifting in the melody. Few people are aware that the lyrics of another of Billy Joel’s anguished songs, “Tomorrow Is Today,” were penned as a suicide note. For most of us, complete loss of the will to live is incomprehensible, yet more and more people experience the profound and debilitating sadness of clinical depression. What’s going on and what might our genes have to do with it?
It is astonishing to consider how many creative artists have fought or fight the demons of sadness. When Saturday Night Live’s Chris Farley committed suicide, it came as a complete shock to the American public, but he is just one of a half dozen well-known comedians who have at least attempted to take their own lives. Contemporary funnymen Drew Carey and Jim Carrey express their infectious senses of humor in different ways, but for each, the public persona belies private swings of darkness. The bullet in Kurt Cobain’s temple left little doubt that he was unable to find his personal Nirvana here on earth. Even a whole genre is named after the blues. And can it really be true that Harrison Ford, the actor behind the swashbuckling heroes Han Solo and Indiana Jones, got his start in acting in part because his inability to overcome depression-induced sleeplessness had him thrown out of high school?
Nor are intellectual and world leaders immune to the debilitating shadow of sorrow. Two of the towering figures of the nineteenth and twentieth centuries, Abraham Lincoln and Winston Churchill, both suffered from melancholy and depression. Some have argued that Churchill drew inspiration to overcome adversity and the forces of evil from his battles with what he called his “black dog.” Few can argue that the illness can be a well of tremendous creativity: Witness the talents of such profound writers as Tolstoy, Goethe, and Kafka; consider the lives of Tennessee Williams and Ernest Hemingway.
This male-biased menagerie misses a crucial point, which is that women are in fact far more prone than men to mood disorders. If you read accounts on the Web, you quickly notice that depression in women is often attributed to situational cues. Lady Diana, Princess of Wales, battled bulimia in the glare of the enormous pressure of popularity while trapped in a loveless marriage. Brooke Shields and Marie Osmond are the poster women for postpartum depression. Amy Tan and Anne Rice are said to project the tragedy in their lives.
The reality though is that the disability has organic roots and casts a shadow that must be managed and confronted on a lifelong basis for tens of millions of typical adults, the majority of them women. As Sheryl Crow puts it in “Soak Up the Sun,” she’s “gonna tell everyone to lighten up (because she’s) got no one to blame for every time I’m feelin’ lame.” There is no point in blaming the genes either, but as we shall see, these are part of the equation, once more because we’re still finding our way as an evolving species.
An Epidemic of Mood Swings
At any given time, somewhere in the vicinity of four percent of women between the ages of 25 and 45, and two percent of men, are clinically depressed. These are conservative estimates. They mean that without a doubt someone in your neighborhood or workplace is struggling mightily to face each day with characteristic cheer. Multiply them by five to obtain the number of people experiencing the blues, and double again to arrive at a lifetime estimate of the fraction of the population that experiences at least one somewhat debilitating episode of depression.
As far as we know, this disease recognizes no ethnic or socioeconomic boundaries, though of course it is almost impossible to know. Many countries refuse to recognize the existence of mental illness, let alone assemble accessible mental health records. One thing we do know is that in the developed world, it is the leading source of lost life potential. It is expected to become the second leading source of disability worldwide, behind heart disease, in the next decade.
For this reason, depression is sometimes said to be epidemic, implying that it is more prevalent now than ever before, and maybe that it is spreading in an infectious manner. If there is an infectious agent, it is almost certainly cultural, not microbial or viral. Whether depression is truly on the increase is difficult to know. Some authors maintain that the prevalence is underestimated by as much as fifty percent, due to the stigma attached to mental health and the ends that people will go to in order to hide their socially unacceptable anguish. Others maintain that it is overdiagnosed to at least the same degree, because people who are just dealing normally with growing up or with trials in their lives are being incorrectly tagged as depressive.
Those who have never battled the disease often suppose that it is just an extreme form of sadness, but anyone who has so much as brushed against a prolonged episode of depression is more likely to recognize the deeply organic nature of the disease. Every person’s experience is unique, but in the midst of the inability to sleep or to care or to just perform daily routines is the awareness that it is all so very wrong. You know that your behavior is self-destructive, that it is hurting friends and family, and that there is no rationally defensible reason for you to be so self-obsessed and sad. Yet you are absolutely powerless to purge the negative feelings. You can almost feel the bad chemicals swimming around your mind, imposing their will on your mood as surely as alcohol swamps your conscious well-being in a very different way.
For a chilling description of what a mental breakdown due to depression is really like, try Andrew Solomon’s The Noonday Demon. Subtitled An Atlas of Depression, this is a superb account of the disease from the perspective of dozens of different patients, full of sanity and realism. It opens with a telling description of the author’s own battle with the demons, from childhood anxiety attacks to the incapacitating depths of despair in the months after publishing his first novel. What a frail thing is the human mind, what a wonderful thing its capacity for compassion and understanding.
Bipolar and Monopolar Disorders
Psychologists commonly recognize four subclasses of the illness. A basic distinction is made between unipolar and bipolar affective disorders, and within each of these there are at least two categories of severity. Since polarity by definition refers to orientation with respect to two opposites, the term unipolar makes about as much sense as a magnet without North or South, or the sound of one hand clapping. It is used to distinguish patients who experience only the lows of depression from those who alternate low with high episodes, the term bipolar supposedly carrying fewer stigmas than manic depression.
The least disruptive form of depression is a pattern of constant lack of interest in activities and inability to enjoy life that lasts for at least two years. The technical term is dysthymia, which is surely preferable to minor depression, because there is very little minor about it. Dysthymic individuals have problems sleeping, have persistently low energy levels, often either lose their appetite or have troubles with overeating, and may constantly fight feelings of helplessness and of poor self-image. The fatigue keeps them in bed for hours and hours into the day, yet it can also keep them awake long into the night. Doing things that come ever so naturally, such as making a cup of coffee, getting dressed, making a phone call, going for a walk, or even tucking the kids into bed become monstrous chores.
The way to navigate each day is to make each minute or hour a succession of mileage posts that are passed successfully, finding pleasure in the mundane and routine. At times the pressure may become so great that a person is effectively paralyzed, if not physically for minutes or hours, then socially for days or weeks at a time. It is a heavy burden to place on a career in this fast-paced world. It is a ghastly strain to impose on a marriage or relationship that started with such joy and promise. It is a debilitating tension on the psyche that sits constantly poised on the edge of complete breakdown. It is no way to lead a happy life, but it is the reality for 1 in 20 people today.
Major depressive disorder is worse. It is characterized by recurring episodes of pronounced inability to function in anything approaching what might be called a normal manner. It is worse than melancholy, deeper than grief, more than an exacerbation of the symptoms just described. Atypical episodes, which are actually more common, may include overeating and oversleeping, but can give way to leaden paralysis and heightened sensitivity. Normally calm people find themselves reacting with irrational irritability to slights such as being bumped into in the street or jumped in front of in a queue. These episodes of inability to react with positive feelings to anything last from two weeks to a month or two. Now days, chemical intervention is almost always prescribed.
Typical melancholic major depression involves loss of pleasure and a state of depression unlike anything most of us ever experience, a tendency toward anorexia, and such a slowing of thought processes that people are simply incapable of much more than lying around. Solomon describes being so low that he could not even contemplate suicide, the danger period for that and self-mutilation being during the recovery phase. In severe states, patients require nursing help with eating and essential bodily function.
Yet it can get worse, with the descent into psychotic depression. Symptoms include hallucination, aggression, feelings of intense hopelessness and frustration, loss of the sense of self, and possibly delusional or extreme paranoid behavior. I cannot imagine what it is like to live with the constant awareness that such a state may be just around the corner awaiting some trigger, tragic or prosaic, but always unpredictable, knowing too that the drugs that are effective in stabilizing the condition may not be able to hold back the tide of a psychotic episode.
Speaking of triggers, two of the more prevalent forms of disease are postnatal depression and seasonal affective disorder (SAD). The baby blues, consisting of sleeplessness, irritability, headaches, and impaired concentration, apparently affect more than three-quarters of new parents and last a day or two (actually, for different reasons, a decade or two). But some combination of an anxious and naturally melancholy personality, the stress of parenthood, perhaps exacerbated by an unsupportive marriage, stressful job, substance abuse, hormonal swings, and flat out chance, leads to at least five percent of mothers (and some fathers) entering an episode of clinical depression. Untreated, postnatal psychosis can result in infanticide, a generally unthinkable crime that challenges our sense of personal responsibility, and which society is patently unsure how to approach.
SAD by contrast is perhaps the best-named disease on the planet, although if the Icelandic term skammdegisthunglyndi rolled off the tongue a little better it could catch on as well. It means short-day-heavy-mood, and communities with a high prevalence know exactly what to do about it: bathe in the light of a sunlamp for half an hour every morning. My Seattle colleagues swear by it. Given a choice it seems simpler to live by a sunny beach. Citizens of the cloudy people’s republic of Ann Arbor regularly prefer to imbibe the target of sunlight, melatonin, and fittingly wander around battling jet lag symptoms half the year.
Bipolar disease is also conveniently categorized in two types, I and II, which are differentiated by the severity of the manic phase. Mania refers to a period of elevated mood lasting for at least two weeks. The full-blown type I form is often associated with a racing mind as if the brain is working too fast. Sleep is disrupted, the person may be irritable or may be unable to pay attention, and delusions of grandeur are frequent, giving way to psychosis, namely a loss of contact with reality. Less than one percent of people suffer in this way, but an equivalent number if not more may experience the lesser form, hypomania.
Hypomania on the face of it does not sound so bad. Many of us would gladly experience the creative surges that accompany the state, allowing people to write poetry, compose music, have unusually original ideas, and overcome social inhibitions for a time. It sounds a lot like staying at a Holiday Inn Express overnight. I wonder whether that experience also blunts a person’s emotions and makes a person laugh uncontrollably.
Typically, manic and depressive phases last a month or two and alternate every other year, but there is enormous variability. Some cycle much more rapidly, several times a year, and some experience both conditions simultaneously, which you can imagine makes for a volatile state of mind. Some have much stronger manic phases, while some have more prevalent depression. Particularly in children, diagnosis is complicated by coincidence with other psychological conditions including attention deficit hyperactivity disorder and schizophrenia.
One final feature that all modes of depression seem to have in common is that left untreated, the episodes tend to get more intense and more frequent as life proceeds. A first episode of major depression almost always indicates a lifetime of battles, with control, rather than cure, the therapeutic objective. A depressive’s mind wanders along the edge of the cliff, prone to missteps that leave it clinging to sanity until rescued by a helping hand that can never quite drag it to the plane of normality.
The Pharmacology of Despair
Serotonin is e-mail for the brain. This one little chemical seems to be the key to the lousy mental state of a billion people whose neurons just can’t communicate efficiently. One way or another it is the target of just about every antidepressant drug on the market, and quite likely of psychotherapy as well. Google “serotonin” with “depression,” and you will find hundreds of thousands of hits. Search with the same two words on the academic search engine PubMed, and you will be led to more than 12,000 scholarly articles. This is a pretty good indication that the two are linked, but also that we really don’t understand how.
It is all so very complicated. Serotonin does many different things with many different partners, and many different things do some of the things that serotonin does. Among those 12,000 articles you will find references to inducement of vomiting, the age at which we first have sex, sudden infant death syndrome, and aggressive lobsters. They will tell you that humans have seven different types of receptors encoded by 14 genes, and impart more exquisite detail concerning the biochemistry and pharmacology than even an expert can possibly assimilate. Look more deeply and you will discover that at some level most mood-altering drugs converge on serotonin: ecstasy and crystal meth, LSD and all manner of psychedelic snuffs, Ritalin and Fen-Phen, pituri and betel nuts, and indirectly even caffeine and nicotine.
So while low levels of serotonin activity are certainly causal in depression, simply bathing the brain in the chemical is not necessarily a particularly good idea. Actually, it is not that simple, either, since ingested serotonin cannot find its way into the brain. You can try eating foods rich in its precursor, tryptophan, which is said to help, but in my experience those who have diets rich in cottage cheese, wheat germ, and soy aren’t necessarily happier than the rest of us. (Actually, poultry, fish, eggs, avocados, and other beans are also good sources.) The preferred method of serotonin enhancement is via a host of drugs.
To see how these work, let’s return to the e-mail for the brain analogy. We’re not talking about the content of the e-mail here, just the fact that it is a major means of communication. It facilitates talk between neurons, while the content of the messages is a function of which neurons are being connected when and how. Serotonin is not an information-carrying molecule, it is just a chemical that connects one neuron to another, encouraging the electrical signals to continue along their way. Many other chemicals have a similar role, and we can think of them as regular mail, telephones, and text messaging, but why interference of serotonin in particular leads to depression is simply not clear.
In any case, if you are using dial-up or have an unreliable Internet service provider, then your e-mail is slow, and these days most of us can’t function properly without it. This is basically like not making enough serotonin, so drugs such as SAMe and 5HTP have been introduced because they fiddle with the enzymes that convert tryptophan into serotonin. For some reason, they are not yet particularly popular, even though clinically they can be effective and seem to have limited side effects.
Then, perhaps you are still using one of the old e-mail servers such as Pine or Eudora, in which case you can function but probably are not utilizing e-mail as effectively as you might. This would be the situation if one or more of the receptors for serotonin were not functioning properly, but unfortunately the pharmacology is too complex, and fixing this has not proven to be a fruitful approach to treatment.
The most fixable problem with depression seems to be that our natural servers delete e-mails at a rapid rate, sometimes so quickly that the message doesn’t get through. This can be alleviated by preventing the decay of serotonin, or by preventing it from being reabsorbed by the neuron that was using it to send a message in the first place. Monoamine oxidase inhibitors (MAOIs) were the original antidepressants. They work by inhibiting the enzyme that degrades serotonin in the gaps between neurons. However, they also act on several other essential chemicals, so have a variety of nasty side effects, and can cause potentially fatal interactions with other drugs and foods.
They have generally been replaced by tricyclic antidepressants or by selective serotonin reuptake inhibitors (SSRIs). Prozac is the best known, but Zoloft and Paxil are heavily advertised, and there are at least a dozen others. Wellbutrin, preferred by many in part because it has less of an effect on weight gain and libido, inhibits reuptake of another signaling chemical, dopamine, but may act by indirectly stimulating serotonin release.
Each of these drugs has advantages and disadvantages, and it turns out that there is enormous variation in how people respond. Consequently, it can take months to years for clinical psychologists to find the combination and dosage that is right for any particular patient. Most settle on a cocktail that balances the improvement of mood with acceptable side effects, and once they have done so are advised to stick with the drugs for the rest of their life.
Of course, the major problem that plagues e-mail is spam. It is thus surprising that there is precious little written about the possibility that too much messaging can clog up the serotonin system. Manic phases are largely attributable to an excess of serotonin, as are hallucinogenic highs, but that is not the same thing as too much junk signal getting in the way of normal communications. The idea that depression arises not so much from a deficit of serotonin, but rather from the buildup of resistance to it (much as diabetes arises from resistance to insulin), is just starting to gain traction. It is a controversial hypothesis, but an attractive one with respect to understanding the evolution of sadness, as we shall see at the end of the chapter.
Something that is not at all controversial is the role of stress in promoting depression. Psychological stressors such as losing a family member, experiencing prolonged financial hardship, or coping with mental abuse are regarded by many as kindling for depression. They are the sparks that light the fire.
One of the major responses to stress is the activation of cortisol. Cortisol is also the hormone that gets us out of bed in the morning and does many other things such as suppressing the immune system (making us susceptible to infection in the days after a prolonged period of tension) and contributing to obesity by mobilizing blood glucose. Conventional wisdom is that cortisol levels shoot up in depressed patients and contribute to the mood change, either directly or by feeding back to serotonin. Not surprisingly, the pharmaceutical industry is hot on the trail of cortisol inhibitors.
In the meantime, we have Relacore, America’s number 1 belly fat pill. According to the manufacturer’s Web site, excess tummy fat is not a woman’s fault, but rather arises from the harmful combination of everyday stress, overeating, and excess cortisol. The recommended solution is to take this natural mood enhancer and antistress pill that makes you feel better and lose the belly fat by inhibiting serotonin’s natural antagonist. Like so many of the advertisements for antidepressants that show melancholy people taking the drug and soon thereafter hiking with the family through mountain meadows, playing fetch with the dog, and generally enjoying life, you have to wonder whether there aren’t more effective ways of combating the hormones that keep us down—such as going for a hike or playing with the dog.
Or attending psychotherapy sessions. Data suggests that just taking antidepressants works only for about half the population. Similarly, talking with an expert is effective for no more than half of us. But combining the two seems to work well, helping probably at least three-quarters of the clinically depressed population to manage their disease.
Misbehaving Serotonin
Depression is one of the most genetic illnesses there is; yet paradoxically no one has yet found a gene for depression. Certainly not in the sense of “if you have this mutation, you will be bipolar,” but also not even conclusively in the sense of “if you have this variant, you’re strongly predisposed.” There are some suggestions, as we’re about to see, but they’re at best of the “maybe, sometimes, depends on the circumstances” type—which actually makes them interesting.
Even though bipolar disorder afflicts only a few percent of the population, identical twins have about a 70 percent concordance rate. That’s maybe a fiftyfold increase in susceptibility by sharing all your genes (and the womb and upbringing) with your twin. Even nonidentical twins have a 1 in 4 chance of bipolar disorder if their twin is afflicted, also heavily implicating the genome. It is similar for major unipolar depression, though perhaps with a slightly reduced genetic component.
If you’re thinking that the genes that mediate serotonin signaling might be good places to look for an involvement in depression, you’re not alone. The serotonin transporter gene, variously known as 5HTT, hSerT, or SLC6A4, has been a particularly popular object of genetic studies for three reasons. First, SerT is the protein that Prozac, Zoloft, and company act on. Second, many of the studies do actually detect some tantalizing link between variation and mood. Third, a couple of unusual features of the gene affect how much it is used.
Basically, humans have a short and a long form at the front of the gene, and another section of variable length in the middle of it. The one that has been linked to depression is the first one, known, for good reasons that need not concern us, as the 5HTTLPR. About half of us have one copy of each allele, while one-quarter of us have two copies of the long form, and similarly one-quarter have two short forms. It turns out that people with the short form make less of the protein, which almost certainly affects the amount of serotonin that lingers in the little gaps between neurons.
SSRI antidepressants function by preventing 5HTT from transporting serotonin out of these gaps, so it stands to reason that the 5HTTLPR should affect the onset of depression. Well, sometimes it does, and sometimes it doesn’t, and after pooling the results of dozens of studies together, maybe the short form increases your chances of having depression somewhat, but no more than 20 percent. It is a surprisingly small risk factor, and also surprising in that the less active form provides the risk—unless continued elevation of the chemical over time leads to serotonin resistance.
The story does not end there, though. There are a couple of interesting subplots. Because major depression so often leads to suicide, people have asked whether this polymorphism might be involved in the tendency to commit suicide. Believe it or not, suicide also has a large genetic component to it. Several studies have suggested that the short form has a highly significant impact on the incidence of violent suicide, but not of nonviolent suicide. It came as a surprise to me to learn that there is a difference, and the authors of the papers assume this is self-evident. Presumably gunshots, hanging, and jumping off a cliff are violent methods. The speculation is that 5HTTLPR is having an independent effect on the tendency to aggression and self-mutilation, which combined with depression, pushes someone toward violent attempts on their own life.
Dunedin is a city of just more than 100,000 people situated close to the tip of the south island of the beautiful country of New Zealand. It faces out into the great Southern Ocean, next stop Antarctica, and bears the brunt of its cool, damp winds that bring clouds, drizzle, and the sort of conditions that make a person sad. It seems an unlikely place to carry out a groundbreaking study of the genetics of depression, but nevertheless that was the case back in July 2003.
The research team followed almost 1,000 Dunediners from birth through young adulthood. They recorded the number of stressful life events each person had to cope with between the ages of 21 and 26: One-third of them were charmed; one half had one or two episodes of financial, health, relationship, or similar stressors; and the remainder were not so lucky. Around 17 percent experienced some measure of depression in their 26th year, and 3 percent reported either attempting suicide or thinking about it a lot. The startling finding in this study was that neither stress nor genotype alone had much of an effect on measures of depression, but the combination mattered a lot. Experiencing three or more stressors and having at least one copy of the short 5HTTLPR more than doubled the probability of depression symptoms, of clinical major depression, and of suicide thoughts. Additionally, adults with the short form were found to be far more likely to suffer episodes of major depression if they had been maltreated as children.
This was a landmark study because it confirmed with hard data the long-held suspicion that the interaction between a person’s genetic makeup and their environment is what really matters. A dozen groups around the world have since had some success in replicating the finding, though it must be said that not all of them succeed. That is not really surprising, given the complexity of both the biology and of study design. Interestingly, the same group a little earlier had found a similar interaction between a gene that encodes the enzyme that degrades serotonin, monoamine oxidase, and the experience of parental abuse as children. Again, the type of allele or upbringing alone had little effect, but the combination of genetic and environmental risk factors increased the incidence of acts of violence and other antisocial tendencies committed by the teenagers and young adult men. These types of studies are notoriously controversial and the specific conclusions should be taken with a grain of salt, but they point in a direction that many believe must be true, namely that what genes do is very much a function of everything else going on with the person they find themselves in.
Faint Genetic Signals
All this searching for the key to depression underneath the lamplight of serotonin is fine, but we need to remember that it takes a genome. When the book on the genetics of sadness is finally written, it will surely also include entries on the enzymes that synthesize the chemical and on the receptors that take up the signal. It is increasingly apparent, though, that it must include dozens if not hundreds of other chapters that can barely be sketched in outline yet.
The search continues using more traditional approaches. Linkage mapping in pairs of affected twins has turned up a dozen possibilities. This is where researchers look for parts of the genome shared by non-identical twins who both have the disease. As a matter of logic, siblings always share about a half of their genes, but if the same region of a chromosome is shared in a sizeable fraction of hundreds of twins, it suggests that there is a gene thereabouts. One strong possibility is a gene called PREP, not because depression is a preppie disease, but rather because it encodes prolyl endopeptidase, an enzyme that processes a class of mood-altering hormones in the brain.
The contemporary genetic approach is to scan the entire genomes of thousands of unrelated patients for variant SNPs that associate with disease. This has worked quite well for the other diseases we’ve considered, but when the British Wellcome Trust spent a few million dollars on the venture last year, they came up with...nothing. Not even the Serotonin transporter gave more than a hint of a signal. It is a striking result.
Taken at face value, it means that there just aren’t common genetic variants that consistently lead to chronic despair. There’s a chance that they missed one or two, and maybe if they’d studied some group other than Englishmen they’d have had better luck. But more likely, the underlying assumption that common diseases are due to common variants is just wrong in this case—at least, not common variants that increase the risk by more than 20 percent.
There are a couple of alternatives. One is that thousands of sites in the genome contribute, but each one has a barely measurable impact—depression by 1,000 genetic pinpricks. Since morose, moody, or just plain contemplative people tend to end up marrying one another—just as tall people tend to hook up, and scientists pair with scientists, and alas white folk with white folk—these small effect variants would concentrate in families. So would the disease susceptibility, though it would be difficult to find the specific alleles involved.
The other possibility is that hundreds of genes have rare mutations that make a big contribution, but only in occasional cases. On this model, major depression would have a different genetic basis in different people, but whatever the issue is, it would lead to similar problems as far as signaling in the brain is concerned. These mutations would not have to affect everyone who carries them. They could individually increase the risk of depression twofold, or twentyfold for that matter, but would go undetected because only every ten thousandth person has any one of them.
Schizophrenia and Other Mental Disturbances
Iceland would seem to be another unlikely place to find genetic studies of mental health being carried out. Nestled up there in the middle of the North Atlantic Ocean, next stop the Arctic Circle, it is famous for icebergs, glaciers, and winter days that are about as long as a soccer game and doubtless just as dull. Nights are another matter since Reykjavik is also renowned for the beauty of its women, and quite the party culture has grown up there. For the past decade, Iceland has been home to the most ambitious, controversial, and in many respects productive, human genetics study on the planet.
The reason for this is that a prodigal son named Kari Stefansson returned from Harvard in 1996 to set up a pharmaceutical discovery company registered as deCODE Genetics. With the blessing of the government, and financial backing from Hoffmann-La Roche, the company gained sole access to the intensive medical records of most of the 270,000 citizens of Iceland, along with family pedigrees going back centuries to the Viking times. If you’ve ever read Njal’s Saga, you will know that ancient Icelandic society was very much based on brutal retribution that makes an eye-for-an-eye justice look timid. Good family records were thus a must.
Although this right of access has since been overturned in court, the majority of the citizens have in fact granted not just medical records but also blood and hence DNA samples to deCODE. The combination is a rich treasure chest that human geneticists salivate over (while bioethicists make a living worrying about the consequences). It will really get interesting if and when the company starts churning out complete genome sequences for all of these people: Iceland may well be the first country to have the complete genome of its population determined. Out of this mix has emerged the discovery of novel genes for a bundle of common diseases, including prostate cancer, type 2 diabetes, glaucoma, psoriasis, asthma, osteoarthritis, stroke, cardiovascular disease, and even restless leg syndrome.
The reason I mention it here, though, is because deCODE is also honing in on several strong candidates for schizophrenia. Many of the things we’ve discussed about depression are equally true of this delusional psychosis. These include an incidence around one percent of the population, typical early adult onset, and presumed origins in complex genetics and environmental risk factors. Replace serotonin with dopamine, which is another neuronal signaling chemical, and the stories show distinct parallels.
The tale of the genetics of schizophrenia is also sprinkled with hopeful leads and heartbreaking dead-ends. Time and again a result that appears to explain some proportion of the inheritance of the disease has simply turned out to be a nonfactor in another population. This failure makes the experts wonder whether it is a factor in the initial study as well. Either the genes identified are terribly unreliable indicators, or they are specific for different ethnicities or cultures.
Nor does it stop there. Autism has also failed to yield to genetic dissection even though we know it has a heritable component. Mental retardation afflicts a few percent of all children, but with the exception of Fragile X syndrome where a particular gene is well implicated, it looks unlikely that common variants explain the disease. As a class, then, mental illness seems to be even more complicated than other diseases.
One reason for this may be because so much of the genome is used in the brain, well more than half of it. So there are thousands of genes that can go wrong, in each case predisposing to some sort of psychological disturbance. In fact, a couple weeks before this book goes to the printer, papers have started to appear that strongly implicate new mutations known as copy number variations in both autism and schizophrenia. It is beginning to look as though as many as ten percent of sporadic cases of these psychological diseases occur because children a born either with an extra copy, or missing a copy, of one of a handful of genes—so far—and that this disturbance alone deeply upsets the brain. That there aren’t more of these psycho-CNV surprise us. It either is a minor miracle or can be thought of as a sign that evolution has found ways to suppress the effects of potentially harmful mutations.
The Genetic Tightrope of the Mind
What possible good can come of genes that would plunge a person into such depths of darkness that he would want to take his own life? How can we understand why millions of housewives, having chosen to devote their best years to the hopeful raising of wonderful children, nevertheless begin each day with sheer dread at the thought of making breakfast and feel the terrible burden of sadness take over from there? Why do our genes let that happen? And why must genes be responsible for all the children who are so full of anxiety that they cannot converse with their parents, let alone the world at large? How is it that an evolutionary process that has given us Michelangelo and Beethoven, Einstein and Shakespeare, nevertheless endows so many of our most creative artists with the capacity for such debilitating depression?
Many would have you believe that there is some benefit to despair, that it is necessary for us to be able to appreciate great joy, or to be more prosaic that it is the price we pay for possessing a contemplative consciousness. In fact, it is by now almost obligatory for anyone who offers commentary on mental health, whether in a book, on Wikipedia, in a blog, or through a 2-minute television sound bite, to pass judgment on the adaptive value of melancholy. Yet we don’t go out of our way to make such arguments to justify cancer, heart disease, asthma, and arthritis, so there is no reason to go that way for diseases of the mind. You should know that for every evolutionary theorist who promulgates these ideas, there are at least as many practicing evolutionary geneticists who daily get their hands dirty digging around the genome, who reject them as at best unnecessary, at worst just silliness.
For a different perspective, contemplate a tightrope walker. Maybe you have seen a funambulist at a weekend fair, just a couple of feet off the ground, hands held out for balance, or if they are really good perhaps even juggling some balls. There is not much risk, but a lot of joy, and a gentle metaphor for the capacity of the mind to assimilate all kinds of tendencies that would push us into a fall. Now picture one of those maniacs traversing a high wire strung between two tall buildings, supported by little more than a long balancing pole that shifts her center of gravity to a manageable place. This is higher consciousness, a tightrope act if ever there was one, capable yet manageable given the devices at hand, but always at risk of falling into an abyss. Now give her a pole from which you’ve docked a few feet from one end, without telling her, and ask her to cross the Niagara Falls on a windy day, ferocious cascades churning away underneath for dramatic effect. This is the human mind, a delicate balancing act weakened by genetic defects we know little about, trying to cope in a hostile new environment of our own making.
Talk about genetic imbalance and the origin of disease. The argument in a nutshell is that mood is such a complex trait that over millions of years mechanisms have evolved to buffer it from all sorts of stresses. Organisms must cope with a frightful environment, and mutations can hit thousands of genes that tend to disrupt the way the mind works. The human brain evolved in the genetic wink of an eye, fundamentally changing our mental capacities but leaving us more exposed, less buffered, than ever. On top of this, in the last few generations we have created a totally novel environment in which it is expected to act. We should be wondering why any of us are able to cope at all—but what’s that old adage, all the world’s a little strange, except for you and me, and even thee I have my doubts?
Consider first the environmental and cultural changes. No doubt that bangle of colored balls strung across a baby’s crib, or that annoying toy piano that delivers an electronic mimic of some animal when she puts her finger on its picture, is stimulating enough. But it is not a real substitute for the visceral contact with a real world that every infant mammal has grown up with for the past hundred million years. Not that we should go back to hunter-gathering, growing up in tents, and moving our home every few weeks in search of food, but I am saying modern humanity is different from day one.
Growing older, we increasingly inhabit a virtual world. A friend of mine told me the other day that he found his precocious two-year old not just on the computer, but playing a flight simulator game online. We all lament that our kids are more adept at hitting a baseball out of the park on a PlayStation (or, more recently, a Wii station) than they are at running the bases around the cul-de-sac at the end of the street, or that they prefer piling up thousands of hours of cell phone bills to reading 100 pages of a good book, but do little about it. Then there is the violence, sexual innuendo, and nonstop banality of television, and the in your face propaganda of talk radio, and we wonder why adolescents have a hard time adjusting to the modern world.
On the other hand, it never ceases to amaze me how engaged and energetic college students are. The party-versity that Charlotte Simmons finds in Tom Wolfe’s novel is real, but so too are the many twenty-somethings who are putting themselves through school, studying a full 40 hours a week, putting in another 20 hours of community service, and somehow finding time to play a sport and lead a full and healthy social life. Those who aren’t in college are as often as not working two or three jobs just to pay the rent and car loan while keeping the credit card debt somewhat manageable. It is the pace of life and the enormity of the pressures this all places on us that is so different. Humans have always dealt with adversity in their daily lives, but the grind today is nothing like anything ever before. Only in the past century has every single one of us been expected to be active from dawn to midnight with so little downtime and so much peer pressure to keep up, lest we be socially outcast or thrown on the junk heap of a failed career.
Then there is the stress on relationships. Take a walk through the airport terminals in Chicago, Los Angeles, or New York and take in the faces of the travelers. Billy Joel’s scene at the bar has become the scene at the Chili’sToo as waistlines grow ever larger and mascara runs into the stress lines of harried faces. Pursuit of the golden buck that will keep our loved ones close and happy drives businessmen to the place they call loneliness, and young people’s pursuit of a more exciting and meaningful life drives a wedge into the heart of family. Facebook and MySpace might keep acquaintances in touch, and surely we’ve just scratched the surface of virtual friendship, but the mere fact of their popularity says something about how drastically human interactions have changed. It has to be affecting the way the mind develops and carries on.
Finally for now, but certainly not exhaustively, there is the stress of modernity. Martha Stout speaks of “limbic wars” in her book, The Paranoia Switch, arguing that Americans are so fearful in the wake of the 9/11 terrorist attacks that an almost contagious rewiring of the neural circuitry has occurred that has reshaped the way we perceive one another. By undermining our sense of tolerance and compassion, the terrorists have hurt far more people than they ever could place in direct danger. She further points out that there are maybe 1,000 times as many women suffering today in physically abusive relationships than were killed in the attacks. Marital warfare takes a far stronger psychological toll, yet the nature of it is similar to the imprint of three generations of almost constant exposure to military warfare. World War II, the Vietnam War, the Cold War, and now the War on Terror have surely placed a stress on our collective mental health.
So much for environmental imbalance. What of genetic imbalance? Homo sapiens is by any measure one of the younger species on the planet, having been around for fewer than 10,000 generations. By comparison with the average species, we can expect to be around for at least a 100 times that long before we evolve into something else or become extinct. This is also about the length of time since we shared a common ancestor with our closest relatives, the chimpanzees.
A lot has happened in our short time on the planet. Using new statistical methods focusing on those parts of genes that regulate when and where they are used, we can see that genes involved in brain development seem to have been particularly subject to change. Maybe as many as a quarter of our brain genes are used ever-so-slightly differently in humans, though the liver and testes are at least as divergent. It is hard to know which or how many specific changes have been key to the emergence of intelligence, and which have gone along for the ride.
Actually, we don’t need to look at the genes to conclude that there is something different about the human brain. Our reasoning abilities are unparalleled, at least on this planet. We communicate with symbolic language that has just bare rudiments in other primates, and we use signs and tools to build cultural practices that have as profound an impact on humanity as any of our unique genetic attributes. We try to engage in monogamous relationships, for the most part, and live in extended family relationships that are definitively human, typically extending the trust we share with family to friends as well. We have a spirituality that is undetectable in other creatures but seems to be at the very core of what it is to be human, though it is often allied with a sense of wonder that can create a sense of emptiness that is at the heart of depression.
A Kindling Theory in the Modern World
The final piece of the puzzle is to realize that the mechanisms that regulate mood have been exquisitely fine-tuned and genetically buffered, or canalized, ever since the dawn of animals. All the major brain signaling mechanisms, including serotonin, dopamine, and a half dozen others, are in place and working pretty much the same way in flies, pythons, and piranhas. I’m not sure what a depressed python or a manic piranha looks like, but just like us, their mood is regulated within strict bounds that enable the animal to function, and it would not surprise me if some of these animals also have mental health problems.
The buffering is the key here. Just like blood glucose levels that rise and fall with the day and with the stages of your life, serotonin levels adjust to a person’s circumstances. Whether you are fighting or fleeing, sleeping or waking, angry or amorous, comes down at some level to this chemical. Despite the wide daily variation in activity, it is crucial that the basal levels remain within certain bounds, lest your whole mood system gets out of whack.
This is why addictive drugs are so dangerous over the long haul. Cocaine inhibits the reuptake of dopamine, nicotine prevents another signal called acetylcholine from finding its receptors, and hallucinogens mess with your serotonin function. The brain responds to all these drugs by modulating the levels of the receptors: Constantly firing in a bath of elevated serotonin, the logical response of a neuron would be to desensitize itself by turning down the number of receptors. This is what it does, but it means that without the drug an addict is left desperate for more of the signal to overcome the lack of reception. Over time levels can return to normal, but often, heavy drug users are left with a state of chronic low-level depression.
Another sign that the brain modulates itself is seen in the phenomena of sensitization. A fly that is fed volatile cocaine will go a little crazy, buzzing all over the place. As the procedure is repeated, it becomes progressively wilder, crashing about its home like a pinball. Stimulate a rat’s brain with electric shocks at low intensity, and after a couple of weeks it starts convulsing, having become more sensitive to the shocks. In humans, over time, the frequency and intensity of epileptic seizures generally increases, and lately many physicians have begun to wonder whether the same is true of bipolar disorder.
The hypothesis is called the kindling theory. Kindling is the dried small sticks and twigs that we used to use in the days before MatchLight inflammable fluid-soaked charcoal meant that fires could be guaranteed at the strike of a match. So perhaps we should rename this the Match-Light theory, reflecting the idea that we’re all primed for mental disturbance in today’s fast-paced world. In any case, the idea is that once one episode of depression occurs, the changes in the circuitry between the neurons that ensue leave a person prone to another episode.
It is also why the notion of serotonin resistance is so appealing as a causal factor in mood disorders. Over hundreds of millions of years, regulatory systems evolved to ensure that highly reactive signaling mechanisms in the brain stay operational within safe bounds. They include ways to fine-tune the volume controls in the limbic system, but the extraordinary changes in human history have pushed these buffering mechanisms to the limit. The ancient limbic system that regulates mood now has to integrate high-level brain functions that have been around for just hundreds of thousands of years, not to mention cultural practices that have been around for just tens of thousands of days.
As a result, we’re hypersensitive to new mutations that naturally appear in all those mood-related genes every generation. A person who happens to inherit several of these, no matter how rare they are, is at risk. It may take a few thousand generations to recalibrate. Or it may be that selection in modern humans is so weak that there never will be an opportunity to recalibrate and those little mutations will gradually accumulate in the gene pool. There’s a depressing note to end this chapter on: Maybe the ultimate fate of the human species is never-ending deterioration of our mental stability.