Tuesday, January 01, 2002

Genes, Evolution, and the Mysterious Power of Mood

By: J. Raymond DePaulo, Jr. M.D.

Progress in treating depression has been hailed as a triumph of psycho-pharmacology, but neither depression nor manic-depressive illness can be cured, only treated—and at best in only four-out-of-five sufferers. In this final chapter of Understanding Depression, the authors ask: What comes next? A solution to the complex gene puzzle may be within reach, as are better treatments. But deeper understanding will come only when we fathom the still-mysterious nature of mood and why human evolution has kept both depression and mania in play.

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J. Raymond DePaulo, Jr., M.D., professor of psychiatry and behavioral science at Johns Hopkins University, is a master clinician who has treated some 8,000 patients for depression. Understanding Depression, written with freelancer Leslie Alan Horvitz, is a relentlessly honest exploration of what today’s depressed patient and his family face: the unprecedented hope for effective treatment, the limits and dangers, the impact on loved ones, and the long roster of practical decisions required—from when to seek help to how to integrate back into a job. At the end of this journey, the authors turn to the future, asking what research may tell us about the origins, nature, and treatment of depression— and the still mysterious role and power of mood in our lives.

Excerpted from Understanding Depression: What We Know and What You Can Do About It by J. Raymond DePaulo, Jr., and Leslie Alan Horvitz
Co-published by The Dana Press & John Wiley and Sons, Inc. ©2002, by J. Raymond DePaulo, Jr.  Reprinted with permission.

I hope that I have succeeded in conveying what we know about depression and what we don’t know. As a community of professionals, patients, families, and friends concerned about depression, we know so much more now than we did twenty to thirty years ago. We have many more demonstrably effective treatments, both medical and psychological, and we have far more confidence that we will find the important genes that contribute to the predisposition to depressive disorders. In addition, we know more about the limits of knowledge in genetics, brain structure, and neurochemistry. We have made the great leap from simplistic ideas to good questions. It will take time and more bright careers dedicated to this work to get the answers. In my judgment, this is the great biomedical challenge of our age. The age of discovery of insulin, penicillin, and cancer treatment are past or just upon us now. Strides against brain diseases like depression, manic-depressive illness, schizophrenia, Alzheimer’s, and others are on the horizon. I know that knowledge of this research and the hope for better treatments can serve to some extent as an antidote against the feelings of aloneness and hopelessness that depression creates.

We have made the great leap from simplistic ideas to good questions. It will take time and more bright careers dedicated to this work to get the answers.

I also hope that what I’ve elaborated about the impact of depressive illness conveys why I feel it’s so urgent to accelerate our educational efforts to spread the word about these disorders. At the same time I also hope that I’ve made clear how excited I am about the opportunities to define the physiological pathways to these diseases and the promise of rational treatments in the future. In other words, we are closing in on what happens in our brains to cause depressive and bipolar disorders. The sequencing of the human genome, achieved in 2000 and 2001, is certain to provide us with new approaches to finding the genes responsible for depression. These genes will lead to more accurate diagnosis and to more accurate predictions of which treatments will be most effective and which will be safest. Eventually this can be done individually for each patient. Throughout this book I’ve tried to emphasize the most important lessons that I’ve learned from eight thousand patients (and thousands of families) affected with depression and manic depression. Based on what I’ve seen and what we’ve learned from recent research, a strong case can be made that none of us— whether we have depression or not—can afford to remain indifferent to these often devastating but highly treatable conditions. As a leading cause of disability worldwide and one of the most burdensome diseases for millions of people throughout the world, in both economic and human terms, clinical depression affects all of us, directly or indirectly.

No one, as I’ve said many times, really understands what goes wrong in the brain during clinical depression. But what we do know too well is that it is the leading cause of suicide, that it increases the risk of developing heart disease and suffering fatal heart attacks, and that it contributes to increased fatality after strokes. Even though we cannot yet comprehend the mechanism of these diseases, all trained clinicians can diagnose them with a substantial degree of accuracy. Psychiatrists are as consistent in diagnosing clinical depression as other physicians are in diagnosing pneumonia, heart attacks, or enlarged prostate glands, once they’ve taken a direct history and examined the patient. Moreover, even in spite of gaps in our knowledge, we are able to provide effective treatments for most patients with depression and bipolar disorder. We can also make reasonable predictions about the outcome of our patients’ cases; depending on how well they take care of themselves and how faithfully they work together with their caretakers to limit the impact of the illness.

WHAT WE WILL LEARN

What I would like to do in this last chapter is give you some idea about what we might learn beyond the important practical matters when we are able to chart the basic elements of the genetic and brain pathways in depression and manic depression. In practical terms, our increased understanding will allow us to make the diagnosis earlier in the illness, and we will make fewer diagnostic errors. I suspect that we will probably learn that there are six, twelve, or eighteen different genetic types and six non-genetic types of depressive illness.

When we do finally find the genes and environmental factors that cause depressive illness, we will obviously be in a far better position to determine how they promote these disorders. We will have a much clearer picture of how today’s common treatments work and for which patients they will be most effective.

You can’t spend half your life trying to outwit an adversary like depression without gaining both respect and fascination for moods and our affective functions. 

I expect that some of these discoveries will satisfy our intellectual curiosity, too, by providing us with insights about how moods influence all of our everyday activities. You may remember that, at the beginning of this book, I talked about the confusion that often resulted when people mistook a clinical illness (depression) for a normal state (feeling distressed or down for a short period of time). What is illness and what is “moodiness” is not always an easy question to answer. You can’t spend half your life trying to outwit an adversary like depression without gaining both respect and fascination for moods and our affective functions. Thanks to the dramatic experiences of my manic patients, I long ago became fascinated by the mysterious power of mood. Among the traits that our genes contribute to, in addition to intelligence, physical characteristics, and athletic or musical ability, are the affective temperaments.

Many of you may feel the way I do, that it is somehow counterintuitive to think of genes as holding any influence over our moods, whether those moods occur in periods of depression or are the kinds of moods that we experience normally in our daily lives. (Probably at least some of you are wondering, with all the attention I’m giving to genetic influence, whether I think there’s anything genes don’t do! Answer: make the coffee or find my car keys each morning.) As it turns out, though, genes do play an important role in moods. A lot of impressive research is shedding more light on the link. For example, some researchers studying the role of mood in cognition believe that moods make a key contribution to the tone and quality of an individual’s thinking. Other researchers tend to believe the reverse, that “thinking” is how we set the tone and quality of our moods. If the former mood researchers are correct then we’d have to say that, if it weren’t for mood, we’d be indistinguishable from computers. (If moods were generated by intellect alone, then, in theory, a computer could generate moods, too.)

Thus, moods seem to be real things in themselves, present in all of us, not just in people with depressive illness. And moods or affective responsiveness are part of what we call temperament, which by our best calculations is about 50 percent genetic. (Remember what Galen said about how personalities could be categorized by the four “humors”—phlegmatic, melancholic, sanguine, and choleric? He was actually talking about temperament.) Yet moods, it turns out, might play a role in distributing genes in a population. So what I’m suggesting is a kind of evolutionary (selection) dynamic: genes influence moods, moods influence our behavior and relationships that are part of the dynamics of sexual behavior, which is how our genes are distributed as they help define the next generation.

This idea may sound a bit wacky. Try to recall what you heard in high school biology about the theory of evolution: nature tends to preserve those genes that help us adapt, thrive, and survive. And, for better or worse, moods probably play a significant role in sexual attraction (or lack thereof). Yes, we certainly notice other attributes as well, such as looks, IQ, and values, but we also tend to be influenced by the mood of the persons we are. Is it conceivable that nature would want to pair up “mood partners” in some way? There are specific ideas about how mania or depression or both might help humans adapt in some fashion. For example, depression might warn us that there is trouble ahead when no one else sees it. There are about fifty theoretical reasons to claim that mania has survival value, at least for the species, if not for the individual—more energy, more fierceness, more confidence, more sex . . . oh, yes, did I mention more sex? Some or all of these might have merit, but it is also possible that the genes involved in mood disorders are also involved in other processes, such as the immune system, or that it is their effect on normal moods, not in depression or mania, that has survival value. And of course, I haven’t seen any good evidence yet that they have any survival value but I do wonder about it a lot.

Earlier in this book, I wrote about how depressive illness disrupts and often destroys relationships. Yet, ironically, it turns out that moods (and genes) involved in these illnesses appear capable of actually enhancing relationships, too!

BEYOND THE PRACTICAL: THE LESSONS OF ASSORTATIVE MATING

Earlier in this book, I wrote about how depressive illness disrupts and often destroys relationships. Yet, ironically, it turns out that moods (and genes) involved in these illnesses appear capable of actually enhancing relationships, too! How these genes bring couples together is a phenomenon that clinicians and researchers call assortative mating. For years psychiatrists and researchers observed that patients with depression and manic depression are two or three times more likely to marry someone else with the disorder than would be expected by chance. But how to account for this phenomenon? Consider my patients Valerie and John.

When she first came to me, Valerie was fifty years old and had suffered from bouts of intermittent and prolonged depression. As a teenager she’d experienced an episode of psychological or hysterical paralysis, which is thought to be rare in depression today. In her twenties and thirties she began to drink heavily, which is common in those with her illness. Valerie’s condition was also fairly typical in that other members of her family had affective disorders as well. In fact, her family was riddled with them. All three of her sisters, her three brothers, her daughter, and her father have the same condition. In spite of her problems, however, Valerie was a bright, extroverted, and sensible woman of considerable achievement.

I later met John, who was about five years her senior, when he came at Valerie’s urging for an evaluation. His history revealed that he had suffered exclusively from depressions: a unipolar disorder as opposed to his wife’s Bipolar II illness. When he first became ill, the episodes of depression would last up to one to two years each time. It was all that he could do to get up in the morning and go to work. When he came home he would often crawl into bed. There was depression in his family, too: one of his sisters had manic depression and both his grandfather and an uncle had committed suicide. When I did a mental status examination I saw that John appeared to be depressed and withdrawn. He had no energy, he couldn’t concentrate, and even a good night’s sleep failed to refresh him. He also had an unrealistically low opinion of himself and viewed his future bleakly. So as it turned out, while Valerie and John had very different forms of mood disorders (or, as I prefer to call them, affective disorders), they shared lots of depression.

John and Valerie were good observers of their own conditions once they understood their symptoms for what they represented. John, they both agreed, tended to have a more chronic low-grade depressive disorder. Valerie, on the other hand, had distinct periods during which she felt extremely well, even better than normal, for three to six months, followed by periods of equal time when she felt down. For John, Valerie embodied optimism. Her cheerful demeanor balanced out his tendency to look darkly at the world. For Valerie, John represented stability, an anchor that she could hold fast to against the emotional waves that buffeted her.

John didn’t feel like a bastion of stability at all, far from it. Without Valerie’s understanding and affection, he felt, he would be completely lost. But the need and commitment didn’t work in only one direction. Valerie realized that John was committed to her as well, whatever the state of his mood, and in that way he was an anchor for her. I marveled at how their unusual but effective mutual support system worked. This isn’t always the case in marriages between two affected persons. According to several studies, when both husband and wife are depressed at the same time, the rate of divorce is very high.

Psychiatrists have been puzzling over why this apparent assortative mating occurs. A psychiatrist I know who comes from Hungary reported that he’d seen such couples in Budapest in the 1930s. His professor had asked him, “Do they meet in da vaiting room?” This would give us a simple and logical explanation, but, no, it turns out, it’s not the case for the patients in the studies and it was certainly not true for Valerie and John. Neither of them, for instance, knew when they got married that the other was ill. For that matter, they didn’t even realize that they were ill themselves!

Well, let’s take a few steps back. What brings couples together to begin with? Perhaps it’s stating the obvious to say that people are drawn to potential mates who come from similar backgrounds. And we know that people are more likely to marry someone who is of nearly equal intelligence. People seldom marry individuals more than fifteen points from their own IQ. Physical appearance, too, especially height, affects marriage choices. We also know that similar values and religious views tend to be powerful influences in picking mates.

On the other hand, we know that people are sometimes attracted to their opposites as well. Some women who are not themselves rebellious but are at heart sensation seekers tend to marry exciting, risk-taking men who get into a lot of trouble. These marriages tend not to last very long, as the women discover to their dismay that these men are just too exciting.

As important as is what a doctor can do for you with diagnosis and treatments for depression, nothing can substitute for a family member or a friend to hang in there with a depressed person at their lowest point.

Valerie had no problem coming up with an answer about why she chose John from the several suitors she’d dated. “John saw me through a couple of bad periods,” she said. “He didn’t run away.” Her response echoes that of many other patients I’ve known. One of the reasons that John didn’t run away is because he’d seen members of his own family through similar emotional crises. Having supported parents or siblings when they were coping with depression, he might have been more motivated to stick by Valerie. It’s also a tribute to John that he saw Valerie even then as his soul mate whom he would stand by through a dark night. (That’s a point to bear in mind: as important as is what a doctor can do for you with diagnosis and treatments for depression, nothing can substitute for a family member or a friend to hang in there with a depressed person at their lowest point.)

Another observation that persuades me that the pattern of assortative mating is based on some attractive force is that so many patients who have married several times have married an ill person on each occasion. It’s only after they’ve been married for a while that they express surprise that the same thing has “happened again.” I can’t tell you how many times my patients found someone new who seems perfect to them and, whether they were right or wrong about the perfection, they were certainly surprised to find depression or bipolar disorder just as they had in their previous spouse. And when things go wrong they go through the same arguments with them and endure the same crises. “Why do I always find the same man (or woman)?” One of my younger patients is on his third marriage at age thirty-seven. His first two wives had a so-called milder form of manic depression (Bipolar II) and the third had depression, which occasionally required treatment prior to their divorce. Thankfully, the relationships can be very positive even with two ill persons, as Valerie and John’s has been for more than thirty years now.

One of my psychiatrist friends argues that assortative mating behavior has nothing to do with my romantic view of sympathy and support. He reminded me of what the satiric journalist H. L. Mencken once said: “When they say it’s not about sex, it’s always about sex.”

All right, for argument’s sake, let’s say it’s just about sex. What could make you sexually attracted to a person with a depressive illness rather than to a person who didn’t have a serious mood problem? The answer is that we don’t really know. We haven’t studied the differences, if any, in the sexual lives of couples when both are depressed compared to couples where only one mate is depressed. I do know that while most people lose interest in sex when they are depressed, this is not a universal rule. Some patients want more reassurance of their partner’s love, passion, or commitment when they are depressed compared to when they’re feeling healthy and relatively secure. Still other patients say sex is what they need to take the “edge off” of their tension so they can fall asleep at night when they are depressed. But in the pit of depression most patients have no interest in “carnal fun,” to quote William Styron.

Now you might ask, as many of my patients do, whether it is a bad thing to have two depressed people becoming parents, both on genetic grounds and based on the problems they will have if there are any children because of their clinical symptoms. For now my answer (though it might change as I learn more) is that decisions about children should hinge less on the statistical chance of developing the illness at some point in life and much more on the level of commitment by the parents to each other and their commitment to have, raise, and care for children. A medical student conducted a survey of couples in which one spouse had the illness. She asked them whether, if one member of the couple had a gene (or genes) that carried depression or bipolar disorder, would they still have children? Their answer was a unanimous yes. Then she asked them whether, if a test performed during pregnancy showed that their child had the genes for depression, they would have an abortion. Again the answer was unanimous—no.

TEMPERAMENT, DEPRESSION, AND GENES

Now we come to a question that has perplexed scholars, scientists and doctors alike. Given the fact that the abnormal genes that cause depression and manic depression do so much harm—especially in relationships, work, and daily function—why on earth would they have survived for the thousands of years that it seems that they have been around? Do they somehow confer some advantage for survival to offset their clear disadvantage for survival? This question doesn’t apply only to depressive disorders. Actually several other genetic conditions have a similarly double-edged effect on mankind. The best known example involves individuals with one gene for the blood disease known as sickle-cell anemia, which is especially prevalent among northern African populations living along the Mediterranean. (A similar pattern is seen with two other blood disorders, Thallasemia and G6PD deficiency, in populations living around the Mediterranean.) A child has to be born with two copies of the sickle-cell gene to develop sickle-cell anemia, and when that happens he or she is destined to suffer from a terrible illness. However, in families with the mutation, a child is far more likely to inherit only one copy of the sickle-cell gene and one normal hemoglobin gene. When that happens the single sickle-cell gene has a decided advantage for the individual: it offers a natural immunity to malaria. So it’s not surprising that people living in an environment where malaria is endemic—especially in coastal regions of Africa and Mediterranean countries—have maintained a higher rate of sickle-cell genes than populations that have developed elsewhere.

Without knowing what the genes for mood disorders are and what they do, we can’t answer the question of what survival value they might have. But many people have at least speculated about what the answers might look like. Since the genes for depression presumably will influence mood and emotional mechanisms in the brain, perhaps they will contribute to normal personality traits or temperament. In other words, if it takes variations in one or any of three to five genes to cause a mood disorder, the variations in the genes themselves might contribute something positive to normal temperament in humans. How might that happen? 

From an evolutionary standpoint, to insure that there is sufficient variety, it might be critical to have ten to twenty genes affecting mood and optimism levels.

Well, some people never fantasize; they always see things as they really are. We call them realists, pessimists or skeptical types. They are all like Sergeant Friday from the old TV serial, Dragnet, asking for “Just the facts, ma’am. Nothing but the facts.” We certainly need realists and pessimists, among whose number we find a lot of police officers, businesspeople, and scientists. But we don’t want everyone on the team to be the same type. Imagine what sort of world it would be like if everyone were a confirmed realist. If each time we faced a particularly knotty problem and there was someone leaning over your shoulder saying, “You can’t do this, better forget it,” then where would we be? People sometimes overcome seemingly impossible odds, after all, defying the advice of realists. Possibly one or two genes for today’s bipolar disorder might have helped produce extroverted, optimistic leaders who are as needed now as they were in the past. (We would have to hope, however, that any of these optimists today who get elected to higher office are wise enough to appoint a couple of realistic skeptics as their advisers.) In other words, if I were to select people on the basis of temperament—whether it was for a position in government, business, or even on my amateur basketball team—I would want to have a variety of types. So, from an evolutionary standpoint, to insure that there is sufficient variety, it might be critical to have ten to twenty genes affecting mood and optimism levels. However, the urgent task for us is to help the 5 to 10 percent of the population who have too many of the genes that cause clinical depression or bipolar disorder. After all, if this part of the theory is right, we could say that they have paid the evolutionary toll, so that we could have sufficient diversity in moods.

DOES DEPRESSION OR MANIC-DEPRESSION PROVIDE ANY SURVIVAL BENEFIT?

Beyond the genes, could there be some value for elements of the disease itself? So far we have lots of speculation and very little knowledge. However, with the strides we’ve made in our research, we’re almost at the point where we’ll be able to test some of our ideas. In time, we’ll be better able to unravel some of these intriguing mysteries. One of the best-articulated theories, advanced by Dr. Kay Jamison and others, takes note of the fact that a significant number of highly creative artists, poets, and novelists have bouts of depression and manic-depressive illness. Jamison freely acknowledges that most poets and artists are not manic-depressive and that many manic-depressives have no demonstrable artistic talent. All the same, she has found in her studies that four to five times as many poets and novelists have manic-depressive illness than is seen in the general population. This suggests at least some truth to the observations linking genius with madness.

There are other theories, too, some of which suggest that depression evolved because it might have helped our ancestors survive in a world with predators and calamities. In this view, the genes are there to communicate an urgent warning. Depression genes might say: Don’t put up a fight! Stop! Preserve your resources! Hunker down and wait for the storm (or the wooly mammoth) to pass. Maybe clinical depression is a result of that mechanism going awry like a red light that never changes to green, causing a rush-hour mess. This might be the stress-response system failing. It might even be possible to link this frozen stoplight theory with the theory linking depression to creativity. Perhaps people in the artistic professions, driven to inspired heights in their manic states, may not know when to stop trying to tap their creative juices even if they’re running dry. That’s where depression enters the picture. Depression may be the great editor that tempers the flight of artistic exuberance by revealing the mistakes and misjudgments previously hidden by his or her intoxicated state. But great editors can get carried away, too, and start wielding their pencils too freely, leaving little or nothing behind. Maybe such editors’ pencils should be colored depression blue instead of mania red.

The answers to these and other equally tantalizing questions are more likely to be found once we understand the basic genetic mechanisms, brain pathways, and hormonal systems that cause periods of severe depression or manias when they are not working well. We hope that these discoveries will lead to powerful diagnostic, therapeutic, and preventative advances. That doesn’t suggest to me that we will eradicate clinical depression or manic depression, any time soon. (We have not eradicated cancer either, though we certainly can understand it and treat it much better than we did in the past.) What these discoveries do mean in practical terms is that we will be in a position to reduce the delay in diagnosing depression and manic depression and we will be able to make treatments more effective and less toxic. In addition we will begin to develop better ideas about how to answer the questions patients ask themselves after they have recovered from an episode of disease: Where is it that my disease ends and I (my normal self ) begin? What is it about my brain that means I could lose control again?

It is through their patients that doctors come to understand that courage, patience, and grace, far from being exceptional qualities, are the norm, even among patients who are suffering the most.

Even when we can answer these questions, we will still need wisdom that derives from experiences and not just from experiments. People are always going to need their doctors to help them deal with the ambiguous nature of these illnesses. To do that, doctors have to educate themselves. One thing I can assure you is that doctors learn most of what they know not in kindergarten or even in the labs of medical school. They learn from their patients. It is through their patients that doctors (experienced or new) come to understand that courage, patience, and grace, far from being exceptional qualities, are the norm, even among patients who are suffering the most. Depression is in many ways the worst of diseases because it hits patients where they are the most vulnerable, by robbing them of their sense of self-worth and calling into question their very reason for being. That’s why it’s the more remarkable that they manage to demonstrate such courage and act with such grace, and still maintain their patience even when they feel that their illness will last for all eternity. But depression does lift eventually even when treatments fail. Obstetricians have their moments, certainly surgeons do, too, but for me the best place in the world isn’t in a maternity ward or an operating room. I can imagine no better place than to be close to my patients when their depression finally relinquishes its grip and gives them back their lives



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Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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