This issue excerpts the October 23, 1996 "Dialogues on the Brain." The Dialogues are public forums in which basic and clinical researchers share up-to-date information about important brain and nervous system disorders and answer questions from the audiences. They are presented twice a year by the Harvard Mahoney Neuroscience Institute.
Presenting the research were Steven E. Hyman, M.D., currently on leave of absence from Harvard Medical School to serve as Director of the National Institute of Mental Health, and Edwin H. Cassem, M.D., chief of psychiatry at Massachusetts General Hospital. Gerald Fischbach, president of the Harvard Mahoney Neuroscience Institute, was joined by CBS 60 Minutes co-editor Mike Wallace to moderate the forum.
DR. FISCHBACH: After introductory statements from Steve and Ned, Mike and I will conduct the forum and answer some questions.
DR. HYMAN: The recognition that depression and other mental disorders are brain diseases has been critical in changing public perception, in helping people come forward and seek help, and in helping the medical profession. But we have a long way to go.
When people suffer depression, they often wait many, many years before seeking help. No one with chest pain or any other physical disorder would wait the four or eight years that on average many people wait.
Similarly, many patients find that when they first go to a doctor, they're met with either reassurance -- "Well, you can't really be depressed; everything is fine in your life" -- or complete misunderstanding.
How did we get into this fix? Well, the idea of separation of mind and body is something we have carried forward in western culture and medicine for centuries. And it makes apparent sense: It is very hard to recognize that our thoughts and our feelings are the product of an organ, the brain.
What I do every day -- reach for a cup of water, or a cup of coffee -- is a voluntary act. I have control over it, but I don't recognize that my brain is taking care of an awful lot of work for me. My brain is calculating the trajectory of the movement; it's decided to stabilize my shoulder girdle. It's decided that one set of muscles may fire for so many hundred milliseconds; other muscles will fire for so many hundred milliseconds. All of these things are taken care of, but I'm not aware of it. I'm only aware of the voluntariness.
We could have a disease of the brain, like stroke, that interrupted that circuitry and we would no longer be able to move our arm. No one would say, "Try harder. Pick yourself up by your bootstraps." Yet, we do that when people have disorders of mood, disorders of thought.
But there's no difference. Just as our brain in background is taking care of all kinds of things when we move our arm, our brain is taking care of all kinds of things for us in the background when we process our feeling states, our emotions, our thoughts. We have no more conscious control over this circuitry than we do over background motor circuits.
Of course, one can learn new ways of thinking about the world; one can think pleasant thoughts and so on and certainly influence this circuitry. But one does not have direct control over it, and that's very important to recognize.
The functioning of this circuitry is also unconscious. One of the key structures in the circuit is called the amygdala, a very complex structure. Its job is to paint the world with affective valence, with significance. Problems in this and other structures have very much to do with why we become depressed, why we develop anxiety disorders.
Fortunately, we have wonderful drugs that can be extremely helpful in treating depression. Some of the key drugs used in the treatment of depression interact with the neurotransmitter, serotonin, one of the chemicals that modulate the arousal states of the brain -- we could say, the mood of the nerve cells of the brain.
The serotonin system spreads throughout the brain, so a drug that affects the serotonin system would have a lot to say to all of the nerve cells in the brain -- and we know in practice such drugs alter the function of the serotonin system so that our mood brightens and the depression lifts.
I'm going to end there, but the message is that we're learning that depression is a real brain disease, underlaid by real circuitry that we can understand. And we have effective chemical and psychotherapy treatments that will reverse the symptoms.
DR. CASSEM: Thank you, Steve. As a psychiatrist, of course, I have to confess, depression has been good to me. But this is a chance that I welcome, to gain for depression the respect that it deserves.
How common is this illness? If we look at lifetime incidence for all people, 17 percent will have at least one episode of major depression. Eighteen percent, white; blacks are at less risk, 12 percent. Hispanics, at the same high risk, 17 percent. It's higher in women than in men: lifetime incidence in women, 21 percent; one out of five will have at least one episode of major depression.
Right now, if you walked out on the street and found people and said, "Do you meet any five of the following nine symptoms," you would find that six percent would say yes. This is a common disease. And it's costly.
If you look at all mood disorders and the total costs as they did at MIT recently, you find that the cost is stunning -- $44 billion total. Loss of time from work, $24 billion; medical, psychiatric and rehab services, $12 billion; lifetime loss to suicide, $8 billion. You can see that from suicide alone, the loss is great.
That's my second point. It is a devastating illness -- 15 percent of persons who have major depression die by their own hand. If you have manic-depressive disorder, your chances are closer to 20 percent.
Here is what are we talking about -- the symptoms -- a person needs five of the nine:
Any five of those nine symptoms, and you meet the criteria.
It's common, serious, and tends to recur. That's very important. If you have a first episode, you have a 50-50 chance of having a second. If you have two episodes, there's an 80 to 90 percent chance that a third episode will follow. That's why one needs to know what it is and to watch it very closely.
The final point is that, for reasons still unknown, the rates of depression are increasing in the population and the age of onset has been getting earlier and earlier. In Steve's birth cohort, when he was around twenty-five and in medical school, Steve's classmates had twice as high a chance of getting major depression as I and my birth cohort did at that age. In the Dean's birth cohort, it's much lower.
That's the bad news of depression. The good news is that it's a disease that does respond to treatment.
DR. FISCHBACH: Questions; first, from the podium. Mike?
MR WALLACE: I have a couple, right off the bat. Why more women? Why do more women than men get a clinical depression?
DR. HYMAN: It's not clear. Certain mental disorders affect women more than men. Depression is one. Panic disorder is another and eating disorders. Other mental disorders, like attention deficit disorder and alcoholism, affect more men than women. But many, like manic-depressive illness and obsessive-compulsive disorder, affect them evenly.
Clearly, there are differences in the brains, development and hormonal lives of men and women. There are also differences in the way societies treat men and women. We're a long way from understanding, in real scientific terms, how this comes about.
But there is increasing evidence that estrogens and progesterone can have profound effects on the brain and profound effects on mood. We'll have a better answer in a few years time, when we start to understand what those effects really are.
DR. CASSEM: One thing of great interest is that you see a ratio of about two to one in the United States, two women for every man who would be depressed. If you go to a different culture, like the older order Amish, you find that it's equal. So, there are cultural factors that are there, too.
MR. WALLACE: Why is the number of people who get depressed growing? You've said that twice as many of Steve's birth group than your own birth group?
DR. CASSEM: It's not known. The overall lifetime rates may eventually turn out to be the same, but two things are pretty clear and would affect people early on. One is that the support of the family, a big supportive family, is gone, and that may serve to buffer a lot of the injuries that a person would have. That's gone in our cultures, gone in cultures generally.
The second thing is that drug use is dramatically increased. Alcohol is a major complicating factor of depression, but cocaine, which is a more recent phenomenon, has a marked relationship to mood disorder.
DR. HYMAN: I agree. I think that drugs play an important role -- alcohol, as well as illegal drugs. But something that we have to confess is still the mystery of some of the environmental triggers of depression.
There was just a study looking at the actual prevalence. If you took a cross section in many different countries, it wouldn't surprise you that the rates are among the highest in the world in Beirut, Lebanon. But it is shocking that the rates are equally high in Paris, France. Lower in the United States. Higher in Western Canada. So, there are clearly things, in terms of the usual suspects that we round up as causes of depression, that we really don't understand yet.
MR. WALLACE: What about genetics and depression? Is it passed on?
DR. HYMAN: Run in families? Yes, especially manic-depressive illness: If you took identical twins and one had manic-depressive illness, the other would have about an 80 percent chance of manic-depressive illness. That tells you that genes have a lot to say. It also tells you -- since the rates are not a hundred percent and they have all of their genes in common -- that so does the environment. Again, we need to know what the environmental triggers are.
For people who have only depression and not mania, so-called unipolar depression, genes have a lot to say, but less than for manic-depressive illness, and the genetics is very complicated. Suffice to say that the more densely one's family is affected by depression, the more likely you are to have depression, even in the absence of any identifiable environmental cause.
On the other hand, some people without any family history, in the right circumstances, will also get depressed. What's interesting is that, whether one has familial depression or non-familial depression, the same medications are still effective.
MR. WALLACE: You were talking about chemicals, and I wondered, what triggers it? I know what triggered it in me, and I didn't think it was chemical. I was on trial for my life, so to speak, with the General Westmoreland trial, and it was not easy. But what did chemicals have to do with that, with me?
DR. CASSEM: Well, I'm not the chemical expert, but I think that you can get there four different ways. You could get there by pure genes -- it would come out at some time or another. Second way you could get there is by drugs. Third: by severe physical illness. We know that the more physical illness, the more severe it gets, the more likely a person will get the complication of major depression.
A fourth way would be in the psychosocial stressor area, the learned helplessness model. That is, how much stress can one person take, just as yourself, on trial, day after day after day. Assault, assault on your character, assault on your self-esteem, repeated stressing and you would end up in the same final common pathway as a person both of whose parents have the disease.
DR. FISCHBACH: One aspect of the chemicals involved that may be related to stress is hormonal influences from the adrenal glands -- the fight or flight reaction -- which lead to all sorts of changes in bodily function, redirecting blood flow to your muscles, increased sweating, hair standing on end, increased heart rate.
The same chemical, cortisol, has an effect in the brain. In fact, one recent study pointed out changes in one region of the brain that are very reminiscent of chronic treatment with cortisol. In this case, uncontrolled stressors releasing this hormone into the blood.
DR. HYMAN: The fact is, all life experience, everything we feel, everything we remember is recorded in the brain; learning creates a physical change, a change in synaptic connections in the brain. Under strong emotional stress, under all kinds of powerful cognitive and emotional experiences, these changes can affect all kinds of systems in a brain, including the stress systems, the serotonin system, and the amygdala, whose job it is to learn what's dangerous for us. It's a survival system --
MR. WALLACE: In the brain?
DR. HYMAN: In the brain. Let me give you an example. If a child touches a hot stove, the child will never touch the stove again. It's one-trial learning, and it's very different from studying. There are structures in the brain, like the amygdala, whose job it is to say, "This is important. Learn it well; learn it immediately. This is important for survival." If we didn't learn this way, we would be battered and bruised; we would step in front of moving cars.
The trouble is, these systems can get usurped, subverted by certain stressful emotional responses that they record. These kinds of stresses literally track along, or utilize, the survival circuits, but now in ways that end up malign.
MR. WALLACE: Pain. This person, this youngster who puts his hand on a hot plate, the pain is triggered in the brain?
DR. HYMAN: Absolutely. The interesting thing about pain is that when you have pain, the actual nerve impulses divide in two. One part goes to the feeling part in the brain, so you can say, yes, I felt a burning sensation, right here. But most of the fibers actually go to parts of the brain that are involved in alerting, in emotion, and in emotional memory. Pain is the great interrupter of behavior; it gets our attention and it is a great teacher.
MR. WALLACE: How fast does the brain age -- what takes place as the brain ages?
DR. CASSEM: It's pretty discouraging, if you look at the chart showing brain weight with age; it kind of goes in a straight downhill curve. But not the number of neurons, fortunately.
DR. HYMAN: A small number of some nerve cells, like those in the serotonin system, may actually die. The ones that make another neurotransmitter, dopamine, are kind of quietly dropping out, especially in males, as we age. Most of the other nerve cells don't actually seem to die with aging.
What happens is that their processes tend to get more sparse and retract, and that really reflects the shrinking of the brain when we see brain atrophy. Now, here's the interesting thing: With extreme stress, including the stress of depression, stress hormones called cortisol can circulate back into the brain. We're finding that with protracted and extreme stress, one can actually see this kind of pruning process going on in parts of the brain, like the hippocampus, that are involved in memory.
Hopefully, these things, at least in depression and stress, will prove to be reversible. But it's important to recognize that depression itself can be bad for a person, bad for the brain. And this may actually contribute to the likelihood of relapse.
FROM THE FLOOR: Does it seem as if certain grades of intellects or imagination are more afflicted than others?
DR. CASSEM: Certainly for bipolar, or manic-depressive illness, there are people that it tends to select, and some of the most famous of our literary figures are included. Byron, Keats, Shelley, were devastated by depression and they turned out some of the most beautiful poetry that we have. Hemingway was bipolar -- manic-depressive.
MR. WALLACE: So is Ted Turner.
DR. CASSEM: He is.
FROM THE FLOOR: If depression is accompanied by biochemical changes, do you think everyone with depression should be on antidepressants and for how long? And if you can alter the environmental triggers, will their biochemical balance be restored?
DR. CASSEM: I'd say that everyone who meets five out of the nine criteria should be on medication. That would be my recommendation. But it doesn't mean that you can't alter the depressive state with psychosocial manipulations, as well.
MR. WALLACE: What are psychosocial manipulations?
DR. CASSEM: One, just simple plain talk. You could talk to the person, about what's going on in their life, interpersonal things, having to do with loss, grief, relations with their spouse, with their family, what's going on at work, their self-esteem. And you would talk to them about those practical things.
Or cognitive therapy, which addresses the way in which depression alters thinking. That is, that one's view of the world, the self and the future is completely negative; nobody loves me. And one works to challenge those, in an aggressive cognitive manner.
Talking treatments don't do much in the face of immediate, severe depression. Later on, they're more powerful in keeping you out of depression than the medications are. And if one does not do a good enough job about learning what it is, who I am, and trying to answer the question, am I my old self now -- if you don't work on that and work it through, then, you're more vulnerable.
FROM THE FLOOR: Before the use of these medications, psychoanalysis was the only procedure used on a long-term basis for the treatment of depression. Has any study been made of the effect of psychoanalytical techniques on serotonin, dopamine and other neurotransmitters?
DR. HYMAN: No. There have been interesting studies of psychotherapy and drugs in people with obsessive-compulsive disorder, and cognitive behavioral therapy -- a short, directed psychotherapy -- actually visibly altered brain function on a PET scan, in a direction that was very similar to high-dose Prozac.
The problem with psychoanalytic interventions for depression is that psychoanalysis takes a very, very long time, and the person suffering with depression really doesn't have that kind of time to spend. The other thing is that, at least in traditional psychoanalysis, the analyst might be more distant and neutral. For the depressed person, it would be all too easy to interpret that as rejection and distaste. Psychoanalysis is not recommended in any current practice guideline for the treatment of acute depression.
DR. FISCHBACH: How will a person with a ten to fifteen year history of depression do in today's managed care environment? Who is going to pay for them?
DR. CASSEM: Basically the plan of the managed care is you get them into the hospital and get them out. I think the patients have already begun to do badly. I think that it bodes terrible things for depressed patients.
DR. HYMAN: One thing this new health care environment does is put primary care family physicians on the front lines. And we have distressing news from careful research about the recognition and understanding of depression. In an HMO or primary care, somebody with depression or an anxiety disorder has well under a 50 percent chance of having their symptoms recognized and identified. And even if identified and recognized, they still have a substantial chance of being undertreated. Certainly, for those who would benefit from psychotherapy, there is very little chance.
We have an important educational mission, all of us, in educating not only potential consumers, but also health care providers, that these diseases are real, diagnosable and treatable.
MR. WALLACE: Why are doctors so slow to understand?
DR. CASSEM: The hardest lesson in medicine to learn is that the mind and body are one. It's very difficult. So, as soon as the thing takes a symbolic nature, or the symptoms sound psychological, it's, in a way, relegated to a less serious condition; it's not taken seriously.
DR. HYMAN: It's striking: Depression causes as much or more disability
as commonly recognized and treated medical disorders, such as diabetes, or
hypertension. Yet, people say, well, it's all in your head. Well, they're
right; it's in your brain, but I don't think they've quite made those
connections yet. *
(Photos courtesy of Harvard Mahoney Neuroscience Institute.)