1996 Interview


Reprinted with permission from THE SATURDAY EVENING POST, March/April '96, pp. 50-95

Genetics and Manic-Depression

To learn more about the genetics of manic-depression, we turned to John Nurnberger, Jr., M.D., Ph.D., director of the Institute of Psychiatric Research at Indiana University and professor of psychiatry and medical neurobiology at the Indiana University School of Medicine.

Post: Could you explain the evidence that manic-depressive illness is hereditary?

Dr. Nurnberger: Well, we know there are inheritable or genetic factors involved with these disorders. For instance, the disorder is very much more likely to happen in one twin if the other twin has the disorder. You also see the same kind of preponderance in families of people who have the condition, and you see it in adoption studies. If a person is adopted from a family and develops the disorder, and you trace back to the biological family, it's more likely you'll see the illness occurring in the biological family of a person with depression than you will in a biological family of somebody else.

The genetic determination of these disorders is about two thirds. In other words, about two thirds of the variance in whether somebody is likely to get the disorder or not is probably related to genetic factors. This another one third of the variation is probably environmental. We don't understand very well yet what the specific genetic factors are, nor do we understand what the specific environmental factors are that may cause this in some people.

Post: What studies are you working on now in this area?

Dr. Nurnberger: The studies at the Institute relate to primarily genetic factors that may be involved in predisposing people to develop bipolar or unipolar disorder. The current evidence in the field suggests there may be a mixture of genes causing these disorders. There is evidence for genes on chromosome 18, X, 11, and 21 as well as some evidence for other areas, but those areas are the ones most likely implicated at present. It seems to be a complex pattern of inheritance. The other thing we are looking at is the effect of stress in causing depression. We have been studying animal models to look at the effects of stress.

Post: Are some populations more prone to bipolar disease than others?

Dr. Nurnberger: That's a difficult question to answer, because it's not clear that the same methods of diagnosing these disorders have been used in different populations. There is some evidence that some populations have relatively higher rates of mania. The Amish have been studied quite intensively, and it does appear, in the Amish in Pennsylvania, that the rate of bipolar disorder is about equal to the rate of unipolar disorder, which would mean that mania may be relatively more common in that population. Also in the Mediterranean populations that have been studied, it appears as though the relative incidence of mania is higher. In Scandinavian populations, it appears that the relative incidence of depression is higher. But again, it's somewhat hard to compare different populations unless you're really clear that you're using exactly the same methods of diagnosing.

Post: What is the prevalence of depression?

Dr. Nurnberger: It depends on how you define depression as to how many people are affected. In its milder forms, you may be talking about 40 percent of the population who, at one time or another in their lives, have symptoms of depression. In its severe, incapacitating forms, it's more like seven percent of the population. In manic-depressive illness, which has highs as well as lows, it's more like one percent.

Post: Can you describe these severe, incapacitating cases?

Dr. Nurnberger: An incapacitating depression is a state that lasts for weeks or months and involves sadness, inability to enjoy anything, and changes in sleep and appetite. There may be increased sleep and appetite or decreased sleep and appetite. There may also be increased speed of thought and movement together with agitation, or a person may be slowed down and not able to move or think very quickly. Either of those things can go along with depression. Usually, there is an impairment in memory and concentration, difficulty making decisions, thoughts of guilt or pessimism, a sense of hopelessness, and often thoughts of death and suicide.

Post: This is one end of the bipolar spectrum?

Dr. Nurnberger: Yes. The other end of the spectrum would be increased activity and talkativeness, racing thoughts, decreased need for sleep, and grandiosity, in which people think they have special powers or abilities. There is also impulsiveness; people might spend money or they might have sexual behavior that they wouldn't ordinarily have. There is also distractibility; they aren't able to concentrate on things going on around them. Sometimes there are hallucinations or delusions where they become truly out of touch with reality. Usually when people have severe mania, they are effectively incapacitated, and they may need to be hospitalized. In any case, they are unable to do things that they would usually do. Sometimes people have milder high moods known as hypomanias, which have some of the same symptoms but are not quite so severe.

Post: What are the different forms the disorder can take?

Dr. Nurnberger: Usually depressions go along with the hypomanias, so that most people who have recurrent hypomanias will also have low periods. It's often the low periods that bring them in to treatment. Sometimes the high periods in people who have hypomania are not really impairing or incapacitating. A person may even function better than normal during those periods. Those by themselves may not be a problem, or they may become a problem to people around the affected person. The condition of having hypomania together with depression is called bipolar II. The condition of having mania together with depression we call bipolar I. There's also a designation we use for recurrent episodes of depression without mania, which we call unipolar disorder. You would have recurrent depressions, but without highs.

Post: At what age does bipolar disorder usually become evident?

Dr. Nurnberger: Typically the onset would be in the 20s, but increasingly we see evidence of onset of severe disorder in adolescence. I think we're becoming more aware that a lot of times these mood swings do start in adolescence and they may be misdiagnosed at first because it may look like a behavioral problem or a parent-child problem. It may first manifest as drug or alcohol abuse, and only later does it become clear that it's really manic-depressive illness. On the other hand, you ran also have onset of depressions or manias later in life, even into your 70s.

Post: What different types of treatments are available for people who have this disorder?

Dr. Nurnberger: A variety of treatments are available these days for people with depression and mania. We think in terms of two types of medications for these conditions: one is the mood stabilizers, which are most useful for people with bipolar illness; the other is the antidepressants, which are useful for both bipolar illness and unipolar disorder. Among the mood stabilizers are lithium, which is the classic medication for bipolar illness, but also, more recently, carbamazepin (Tegretol) and valproate (Depakene) have been used. These medicines were developed as anticonvulsants but now are used for mood disorder as well.

Among the antidepressants, there are different classes. The tricyclics were first developed in the 1950s, and they include a lot of medications that are familiar to people who used antidepressants during the 1970s and '80 such as Tofranil, Elavil, Aventyl, Pamelor, Sinequan, Vivactil, an Norpramin. These are very effective medications, but they have certain side effects—people would complain of dry mouth, blurred vision, difficulty urinating, dizziness—so other medications were sought. The medications that were developed include the serotonin-specific, re-uptake inhibitor [SSRIs] such as Prozac, Zoloft, and Paxil; Serzone and Luvox are the most recent ones in this category. These medications are an improvement over the tricyclics in that they don't cause the side effects that I mentioned. The serotonin-specific, re-uptake inhibitors do sometimes cause side effects, such as nervousness initially or sexual dysfunction in some people, but generally they are much more easily tolerated. There are some medications that don't fall into either of those categories. One of them is Effexor, or venlafaxine, and another is Wellbutrin. Each has its role in the treatment of depression now. There are also the MAO inhibitors, which have been available since the 1950s. They aren't used as much as they used to be because one has to follow a special diet and avoid interactions with other medications when they are used. But they still do have their place in the treatment of certain, specific kinds of depression.

Post: What is serotonin?

Dr. Nurnberger: It's a neurotransmitter, or messenger chemical, in the brain.

Post: Is serotonin the chemical responsible for causing the mood swings?

Dr. Nurnberger: We don't know that for sure. But there is a lot of suggestive evidence that it's involved, yes.

Post: So these medications affect that particular messenger, whereas the tricyclics affect something else.

Dr. Nurnberger: Actually, almost all the effective antidepressants affect the serotonin system, but some affect other neurochemical systems as well. The tricyclics also affect norepinephrine, the histamine systems, and the cholinergic systems. Part of the reason for the side effects of tricyclics was the fact that they affect these other systems. So the thoughts of people developing new medications in the past ten years have been to try to get more specific medications that affect only serotonin, or only specific serotonin receptors, or only norepinephrine.

Post: How can you determine which drugs will work best in specific individuals?

Dr. Nurnberger: It can be difficult to know where to start sometimes. In terms of efficacy, there's little evidence that one medication is better than another medication. What you try to look at is the side-effect profile. You look at the history of that particular patient, as to whether they've responded to something in the past. Sometimes you look at family history, whether people in their family have responded to anything in particular. A lot of times you try one or more to see which is best tolerated.

Post: It has been said that many famous people in history have had bipolar disease. These are some of the most creative people. Is it true some people don't want to address this problem because they like those highs that come with mania?

Dr. Nurnberger: Absolutely, although not so much with the mania, but with the hypomania.

Post: Is treatment always called for in people with hypomania?

Dr. Nurnberger: No. And there are people who may not wish to be treated who really do have these mood swings. But when it starts to interfere with the person's functioning, then we tend to look at it as something that really deserves to be treated. Usually people come to us because they are having trouble, or other people are having trouble with how they are acting. Sometimes the manias become evident because somebody brings the person to the hospital, because the person himself may not realize what's happening at that point.

Post: If you were to take a medication that affects serotonin, such as Prozac, would that take away that person's creativity?

Dr. Nurnberger: I've never heard that Prozac does that. Now, lithium perhaps might in some cases, because lithium does tend to reduce the highs and to stabilize the mood. What people are often looking for is to reduce the lows but not the highs, which is rather difficult to achieve actually in a stable way. So sometimes people on lithium may find that their thoughts may not come as quickly at various times as they may have previously. But if you look at productivity, even among creative people who are writing or painting or composing, they typically do better with treatment than without.

Post: Like Vincent Van Gogh?

Dr. Nurnberger: It's very difficult to make diagnoses, and you wouldn't want to really make diagnoses on the basis of secondhand descriptions or books, but, from what we know about Van Gogh's life, it wouldn't be surprising if he did, in fact, have bipolar illness. From what we know about Lincoln, he had recurrent episodes of depression. Hemingway had recurrent episodes of. depression, and perhaps high episodes as well. Winston Churchill probably did. Kay Jamison summarizes a lot of this in her book, Touched With Fire, going into a lot more about very creative people who had these episodes.

Post: In her latest book, An Unquiet Mind, Dr. Jamison comes out of the closet, so to speak, bringing this disorder out into the open. Why has there been such a stigma attached to bipolar disorder? And why is it that people don't want to acknowledge or address this problem?

Dr. Nurnberger: I think it's because it used to be thought that this was a personality weakness of some kind. People who had mood swings just weren't able to exercise control over their own thoughts, feelings, or actions; somehow it's their fault, and because of this, they might have other deficiencies of personality'. They might be people who couldn't be trusted. I think it is a misapprehension we are dealing with. Now we recognize that bipolar disorder is a medical disorder. It's similar to diabetes or hypertension or to thyroid disease: it results from chemical abnormalities. It can be treated with medication. People who have this illness are just like everybody else when the mood disorder is controlled.

Post: The U.S. vice-presidential candidate Thomas Eagleton had to withdraw back in 1972 because he had been treated for depression. Do you think we should be so concerned if a vice-presidential or presidential candidate has this type of disorder?

Dr. Nurnberger: We have had presidents who have had serious illnesses. John Kennedy had Addison's disease, and he took medications for that. Franklin Roosevelt, of course, was disabled for a good part of his presidency. I think you have to look at it in a medical context and consider the illness that's involved, as well as the particular course of the illness in that person. You also have to consider how efficacious the treatment has been. Certainly health is an issue when you consider a presidential candidate or someone else with a very responsible job. But I don't see why it should rule out a person from consideration. There was a candidate in Florida in the past couple of years who had a similar experience, and apparently the information came out from his opponent's camp that he had, in fact, had depression and had been treated with Prozac. This was used as a way of trying to get him out of the race. And, in fact, he came out and described his experience and said, yes, this happened, and the treatment worked, and it's under control. And he went on to win.

Post: Maybe we're seeing a trend now that manic-depression is more understood and that people won't be stigmatized for having the disorder.

Dr. Nurnberger: I'm hoping that's the case.

Post: We have heard that manic-depression becomes more severe or has an earlier onset as it is passed down within a family-say, from grandparents to grandchildren. Has there been research into this phenomenon?

Dr. Nurnberger: Yes, there is research from Johns Hopkins where they found in several family studies that there appears to be what we call "anticipation." That is, the disorder is more severe in younger generations, or comes on earlier in the younger generation. The cause of this is not entirely clear, but in some illnesses with the pattern like this, it has to do with an expansion of the gene, where actual elements in the gene expand from one generation to the next and the increased size causes the gene to function less well. When the size gets large enough, the gene effectively does not function at all. This is true in some forms of mental retardation. It's true of Huntington's disease, and now this is a subject of active research in bipolar affective disorder and also in schizophrenia.

Post: Would this always continue into the next generation as well?

Dr. Nurnberger: Not always. In fact, there is evidence now that this can reverse itself.

Post: Through the generations?

Dr. Nurnberger: Yes.

Post: You said animals have been used in studying mood disorders. Is it possible to know if an animal is depressed?

Dr. Nurnberger: It is not possible to really reproduce the human syndrome in animals in any way that we can be clear about, but we can identify parts of the human experience of depression and the human symptoms of depression and look for those kinds of changes in animals. One way we do this is by looking at the decreased activities in animals after a stressful situation. For instance, we have done studies in which rats or mice are restrained in a plastic tube, and this can produce a state in which the animal does not move around as much afterwards, even though it's perfectly able to move around. It hasn't been harmed in any way, but it is less mobile afterwards. This may last for a few days and is prevented if you give the animal antidepressants beforehand.

We've also studied another model in which we look at the motor activity of animals throughout the day and night. We look at whether light disrupts their pattern of motor activity. Light will disrupt the pattern of motor activity in some strains of mice much more easily than in others, and it's in those strains of mice that we also find the decreased activity after restraint. So we are looking at both of these models. One may be more a model of unipolar illness; the other may be more a model of bipolar illness. It is the second model, where we're looking at the day-and-night rhythm of motor activity, that we find is very subject to treatment with lithium.

Post: In bipolar disorder, we have heard about patients who could get rid of depression by not sleeping for long periods. Can exercise and sleeping habits have an effect on this disorder?

Dr. Nurnberger: Sometimes. We usually recommend that people with mood disorder try to maintain a regular rhythm of daily activity with eight hours of sleep and with regular meals and exercise in the normal way that would be recommended for other health reasons. Some people do seem to be able to come out of a depression by depriving themselves of sleep, although, typically, this is not a long-lasting treatment. It may reverse itself after a day or so, unfortunately. Sleep is an important trigger for these mood states. Very often a mania will be brought on, or will come on, after a person has a night or two or three without any sleep at all. Sometimes, the depression comes on when a patient begins to oversleep. Now, this doesn't necessarily mean that sleeping too much or too little causes the mood shift; it may just be the first symptom that we see.

Post: How about the phenomenon of seasonal affective disorder brought on by lack of sunlight in winter?

Dr. Nurnberger: Some people have seasonal patterns of mood disorder, where they may have increased depression during the winter and they may feel fine or even hypomanic during the summer. Those people do seem to respond, at least in some cases, to increased light during the winter. The light is used to extend the period of daylight. Typically, you would use the light early in the morning or late at night. These kinds of remedies should be done under a doctor's supervision.

Post: But sunlight therapy isn't going to work in extreme cases, is it?

Dr. Nurnberger: Typically not.

Post: You mentioned earlier that onset of manic-depression is usually in the 20s. More and more we are hearing about young children having depression. Do you think this is because we are recognizing these problems earlier on, or are there environmental factors causing this?

Dr. Nurnberger: I think we are recognizing these things more and more. It used to be thought that depression and mania didn't appear until adulthood or young adulthood. Then it became clear that you could see it in adolescents. In recent years, it's become clear that you can see depression in young children down to the age of five or so, and you can probably see mania as well under the age of 12, although it's much less common.

Reprinted with permission from The Saturday Evening Post Society, a division of Benjamin Franklin Literary and Medical Society, Inc. © 1996.

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