Mood Disorders at the Turn of the Century: An Expert Interview With Peter C. Whybrow, MD

May 19, 2005

Editor's Note:
On behalf of Medscape, Randall F. White, MD, interviewed Peter C. Whybrow, MD, Director of the Semel Institute for Neuroscience & Human Behavior and Judson Braun Distinguished Professor and Executive Chair, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles.

Medscape: The prevalence of mood disorders has risen in every generation since the early 20th century. In your opinion, what is behind this?

Peter C. Whybrow, MD: I think that's a very interesting statistic. My own sense is that, especially in recent years, it can be explained by changes in the environment. The demand-driven way in which we live these days is tied to the increasing levels of anxiety and depression. You see that in the latest cohort, the one that was studied with the birth date of 1966, depression has grown quite dramatically compared with those who were born in cohorts before then. So anxiety now starts somewhere in the 20s or 30s, and depression is also rising, so the prevalence now for most people in America is somewhere around 25%.

Medscape: Lifetime prevalence?

Dr. Whybrow: Yes, lifetime prevalence.

I think it's a socially driven phenomenon; obviously there's not a change in the genome. I think we've been diagnosing depression fairly accurately for a fair length of time now, since the 1960s, and the people who were born in the 1960s are now being diagnosed with depression at a higher rate than those who were born earlier and who were diagnosed in the 1960s, 1970s, and 1980s.

Medscape: And is this true of both unipolar and bipolar mood disorders?

Dr. Whybrow: It's particularly true of unipolar disorder. There has been a growth in interest in bipolar disorder, partly I think because of the zeal of certain authors who have seen cyclothymia and other oscillating mood states as part of a larger spectrum of manic-depressive illness, much as Kraepelin did. And I think that has expanded the prevalence of the bipolar spectrum to probably 5% or 6%, but the major increase in prevalence, I think, would be diagnosed as unipolar depression.

Medscape: Do you think that unipolar and bipolar mood disorders are distinct, or do they lie on a continuum that includes all the mood disorders in our nosology?

Dr. Whybrow: The way I see it is they are both phenotypes, but they have considerable overlap. If you think about them from the standpoint of the psychobiology of the illnesses, I think they are distinct.

Medscape: Why are women more vulnerable than men to depression?

Dr. Whybrow: My own take on that is that it is driven by the change in hormones that you see in women. Estrogen and progesterone, plus thyroid and steroids, are the most potent modulators of central nervous system activity. If you tie the onset of symptoms to menarche or the sexual differentiation in boys and girls, you find that prior to that age, which is now around 11 to 13, boys and girls have essentially the same depressive symptoms. As adolescence appears, you find this extraordinary increase in young women who complain of depressive symptoms of one sort or another. Boys tend to have other things, of course, particularly what some consider socially deviant behavior.

The other interesting thing one sees quite starkly in bipolar illness is that, after the age of 50 or so, when menopause occurs, severe bipolar illness can actually improve. I've seen that on many occasions.

Also interesting and relevant to the hormonal thesis is the way in which thyroid hormone and estrogen compete for each other at some of the promoter regions of various genes. In the young woman who has bipolar disease -- this is pertinent to the work I have done over the years with thyroid hormone -- and who becomes hypothyroid, estrogen becomes much more available in the central nervous system, and you then see the malignant forms of bipolar illness. Almost all the individuals who have severe rapid cycling between the ages of about 20 and 40 are women -- high proportions, something like 85% to 90%. So this all suggests that there is an interesting modulation of whatever it is that permits severe affective illnesses in women by the fluxes of estrogen and progesterone.

There is, of course, a whole other component of this, which is a social concern in regard to the way in which women are treated in our society compared with men. It's far different from when I was first a psychiatrist back in the 1960s and 1970s; women are much more independent now, but there is still some element of depression being driven in part by the social context of their lives, both in family and in the workplace, where they still do not enjoy absolute equality.

Medscape: Why would the genotype for mood disorders persist in the human genome? What aspect of the phenotype is adaptive?

Dr. Whybrow: I think you have to divide that question into 2. If we talk about bipolar disease and unipolar disease separately, it makes more sense.

If we take bipolar disease first, I think there is much in the energy and excitement of what one considers hypomania that codes for excellence, or at least engagement, in day-to-day activities. One of the things that I've learned over the years is that if you find an individual who has severe manic depressive disease, and you look at the family, the family is very often of a higher socioeconomic level than one might anticipate. And again, if you look at a family that is socially successful, you very often find within it persons who have bipolar disease.

So I think that there is a group of genes that codes for the way in which we are able to engage emotionally in life. I talk about this in one of my books called A Mood Apart[1] -- how emotion as the vehicle of expression and understanding of other people's expression is what goes wrong in depression and in mania. I think that those particular aspects of our expression are rooted in the same set of genes that codes for what we consider to be pathology in manic-depressive disease. But the interesting part is that if you have, let's say for sake of easy discussion, 5 or 6 genes that code for extra energy (in the dopamine pathway and receptors, and maybe in fundamental cellular activity), you turn out to be a person who sleeps rather little, who has a positive temperament, and so on. If you get another 1 or 2 of them, you end up in the insane asylum.

So I think there is an extraordinary value to those particular genetic pools. So you might say that if you took the bipolar genes out of the human behavioral spectrum, then you would find that probably we would still be -- this is somewhat hyperbolic -- wandering around munching roots and so on.

Medscape: What about unipolar disorder?

Dr. Whybrow: Unipolar is different, I think. This was described in some detail in A Mood Apart .[1] I think that the way in which depression comes about is very much like the way in which vision fails, as an analogy. We can lose vision in all sorts of ways. We can lose it because of distortions of the cornea or the lens; the retina can be damaged; we can have a stroke in the back of our heads; or there can be a pituitary tumor.

I think it's analogous in the way depression strikes: from white tract disease in old age to the difficulties you might have following a bout of influenza, plus the sensitivity we have to social rank and all other social interactions. Those things can precipitate a dysregulation of the emotional apparatus, much as you disturb the visual apparatus, and you end up with a person who has this depressive phenomenon. In some individuals, it repeats itself because of a particular biological predisposition. In 30% or 40% of individuals, it's a one-time event, which is tied to the circumstances under which they find themselves. So I think that's a very distinct phenomenon compared with bipolar illness.

In its early forms, depression is a valuable adaptive mechanism because it does accurately focus on the fact that the world is not progressing positively, so the person is driven to do something about it. Sometimes the person is incapable of doing something about it, or the adaptive mechanisms are not sufficient, and then you get this phenomenon of depression. I know that there have been speculations about the fact that this then leads to the person going to the edge of the herd and dying because he or she doesn't eat, et cetera, and it relieves the others of the burden of caring for him or her. And that might have been true years ago, when we lived in small hunter-gatherer groups. But of course today we profess, not always with much success, to have a humanitarian slant, and we take care of people who have these phenomena, bringing them back into the herd as they get better.

So I think that it's a bit of a stretch to say that this has evolutionary advantage because it allows people to go off and die, but I think that in the bipolar spectrum there are probably genes that code for extra activity, which we consider to have social value.

Medscape: Let's go back to bipolar disorder. The current approach to finding new treatments for bipolar disorder is to try medications that were developed for other conditions, especially epilepsy. Do we know enough yet about this disease to attempt to develop specific treatments de novo?

Dr. Whybrow: Well, we're getting there, but we're not really yet in that position. You're quite right, most of the treatments have come from either empirical observations, such a lithium, or because there is this peculiar association between especially temporal lobe epilepsy and bipolar disease, both in terms of phenomena and also conceptually. But we do know more and more about the inositol cycle, we do know something about some of the genes that code for bipolar illness, so I think we will eventually be able to untangle the pathophysiology of some of the common forms.

I think the problem is that there are multiple genes that contribute to the way in which the cells dysregulate, so it's probably not that we'll find one cause of bipolar illness and therefore be able to find one medication as we've found for diabetes, for example.

Medscape: Let's talk about your new book American Mania: When More Is Not Enough , in which you use mania as a metaphor to describe aspects of American culture.[2]

Dr. Whybrow: The metaphor came because of the work I've done over the years with bipolar illness. In the late 1990s, when I first moved to California, I was struck by the extraordinary stock-market bubble and the excitement that went on. You may remember those days: people were convinced that this would go on forever, that we'd continue to wake up to the sweet smell of money and happiness for the rest of our days. This seemed to me to have much in common with the delusional systems one sees in mania.

So the whole thing in my mind began to be an interesting metaphor for what was happening in the country, as one might see it through the eyes of a psychiatrist watching an individual patient. I began to investigate this, and what particularly appealed to me was that the activity that you see in mania eventually breaks, and of course this is exactly what happened with the bubble. Then all sorts of recriminations begin, and you enter into a whole new phase.

The book takes off from there, but it has also within it a series of discussions about the way in which the economic model that we have adopted, which is, of course, Adam Smith's economic model, is based upon essentially a psychological theory. If you know anything about Adam Smith, you'll know that he was a professor of moral philosophy, which you can now translate into being a psychologist. And his theory was really quite simple. On one hand, he saw self-interest, which these days we might call survival, curiosity, and social ambition as the 3 engines of wealth creation. But at the same time, he recognized that without social constraints, without the wish we have, all of us, to be loved by other people (therefore we're mindful of not doing anything too outrageous), the self-interest would run away to greed. But he convinced himself and a lot of other people that if individuals were free to do what they wished and do it best, then the social context in which they lived would keep them from running away to greed.

If you look at that model, which is what the book American Mania: When More Is Not Enough does, you can see that we now live in a much different environment from Smith's, and the natural forces to which he gave the interesting name "the invisible hand," and which made all this come out for the benefit of society as a whole, have changed dramatically. It's losing its grip, in fact, because we now live in a society that is extremely demand-driven, and we are constantly rewarded for individual endeavor or self-interest through our commercial success, but very little for the social investment that enables us to have strong unions with other people. This is particularly so in the United States.

So you can see that things have shifted dramatically and have gone into, if you go back to the metaphor, what I believe is sort of a chronic frenzy, a manic-like state, in which most people are now working extremely hard. Many of them are driven by debt; other people are driven by social ambition, but to the destruction very often of their own personal lives and certainly to the fabric of the community in which they live.


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