Myxedema

An Interview with Peter Whybrow, M.D.

The Post continues its series on mood disorders in an interview with Dr. Peter Whybrow, who published his recent findings in the journal Molecular Psychiatry. The Post also spoke with his collaborators, Dr. Michael Bauer, in Berlin, and with Dr. Edythe London, who performed the PET scans included in this article.

Post: Could you discuss your research into the link between thyroid function and bipolar disorder, particularly recent findings published in Molecular Psychiatry?

Dr. Whybrow: The study is the most recent piece of a lot of work that attempts to understand how thyroid hormones modulate brain function and mood disorders. In this report specifically, how thyroid hormone may modify severe unremitting depression.

It has always intrigued me that people with severe hypothyroidism develop a syndrome that is very similar to depression, a finding that is historically well-known.

I first started studying the syndrome about 30 years ago. This recent study clearly shows that the addition of high-dose thyroxine in some individuals actually shifts the physiological activity in the brain, as measured by blood flow with positron emission tomography (PET) scans, to the areas which we know usually become active in recovery from depression. In these resistant depression patients, it mimics the same activity you see in other depressed individuals during recovery usually achieved just with antidepressant drugs.

The findings validate the idea that thyroid hormones have a powerful effect upon brain physiology. When that shift occurs in chronically depressed people, it associates with behavioral changes that we recognize as improvement in the depression.

Post: Were you impressed with the results of the study, or did you anticipate improvements in the patients when you supplemented standard treatment with high-dose thyroid?

Dr. Whybrow: We anticipated the results because we've seen this happen many times before in our research over the past ten years. But the magnitude of the findings was very encouraging.

Post: In the study, you administered supraphysiological doses of levothyroxine. What does "supraphysiological" mean, and what is an ordinary dose?

Dr. Whybrow: The doses that we have been using clinically lie between 0.2 and 0.4 rag, which produce blood levels of the hormone that are higher than the usual, hence the term "supraphysiological." My colleague in Germany, Michael Bauer, M.D., Ph.D., who's the first author on the recent paper in Molecular Psychiatry, has used up to 0.5 rag, but we haven't done that in the U.S. These doses are much higher than ones used simply for thyroid hormone replacement in individuals with hypothyroidism or myxedema, usually following Hashimoto's disease, or secondary to the treatment of Grave's disease. But the doses are not quite as high as one might imagine from an historical viewpoint.

If you look through the scientific literature, you'll see that 25 to 30 years ago it was routine for individuals to be replaced with about double the dose they receive now. Most people today receive somewhere around 0.1 mg and 0.15 mg. Earlier, the doses given were in the 0.2 to 0.25 mg range. Thus, although we're using higher doses in our studies today, the fact is that they're not extraordinary. And certainly we've done extensive studies looking at bone metabolism, which, of course, every endocrinologist, including myself, worries about when administering thyroid hormone. I'm glad to say that we haven't found any significant shifts in bone metabolism, even in longitudinal studies of individuals who receive these doses.

Post: This may be a naive question, but are thyroid problems more common in certain forms of bipolar disorder, such as in mixed states or rapid cycling?

Dr. Whybrow: That's not a naive question at all. In fact, that is where the research into bipolar illness began. As background, I used to work for the Medical Research Council in London when I initially started this program. We treated thyroid carcinoma, and I was interested in the strange way in which people began to behave after we deprived them of thyroxine for about six months. This was in the early days when we didn't have triodothyronine to give them. From that, I began to look at thyroid hormone in relation to the treatment of depression, and I worked with Dr. Arthur Prange at the University of North Carolina to give doses of thyroid hormone--triodothyronine in this particular case--in association with antidepressant drugs. We found that the supplementation with thyroid hormone accelerated the activity of the antidepressant and people got better faster--a finding particularly true in women.

Fast-forward a decade or so and lithium became generally in use, which, of course, is an antithyroid agent as well as an antimanic agent. We along with others reported that thyroid disabilities had begun surfacing in people receiving lithium. In the late '80s, we studied a series of patients who had been given lithium and had an interesting syndrome now called rapid cycling disease, which is the most malignant form of bipolar disorder. As you know, manic-depressive illness, or bipolar disorder, is genetically predisposed, and there are several subtypes. Those individuals cycling extremely rapidly frequently had high levels of thyroid disability. Some studies show up to 50 percent with thyroid problems, but in our studies done at the University of Pennsylvania, we found about 20 to 25 percent had thyroid disease. Another fascinating observation was that almost all of those individuals who suffered this malignant form were women, usually premenopausal women.

Initially, we studied people only with abnormal thyroid indices in their peripheral blood. We discovered that actually we could manipulate mood in these severely ill people and that sometimes we could stop the cycling by administering high doses of thyroxine. Then later we found the same effect even in those patients who didn't have peripheral thyroid disease. So we began to develop the hypothesis, which eventually led to these brain imaging studies, that there might be some central brain-thyroid disability at work in rapid cycling disorder rather than a general thyroid problem. The brain controls its thyroid hormone rather precisely by deiodinazing--with a special deiodinase enzyme--the [T.sub.4] to [T.sub.3] on site. So we began to postulate that there might be some abnormality of the deiodinase or some other mechanism, such as thyroid receptor insensitivity in the brain. We have studied many of these possibilities over the years in various venues, and we found that, indeed, lithium does diminish deiodinase activity in the brain. We have also found that lithium changes the activity of some nuclear thyroid receptors in the brain.

If you put all that together, it suggests that there may be some people who are more vulnerable than others to the antithyroid effects of lithium. Even though they don't develop peripheral thyroid disease, they may be having some disability centrally, which would explain why it is that you can change the nature of their mood. Thus, in the case of rapid cycling, one can change the expression of the illness by giving high doses of thyroxine, even when peripheral thyroid metabolism appears to be normal.

Post: Do you recommend that psychiatrists check thyroid function in bipolar patients?

Dr. Whybrow: One of the most important tests that I recommend to psychiatrists treating someone with manic-depressive illness who becomes resistant to lithium or other anticycling drugs, and develops a more malignant form of the illness, is a check of thyroid function.

Another thing that should be done because of this association between women and the cycling problem is to look at thyroid function in any young woman who has the rapid cycling illness. One possible explanation of why this occurs may lie in the competitive relationship between thyroid hormones and estrogens in the brain. Genetically, they share the same family of receptors, and these hormones tend to compete with each other. So if you are a premenopausal woman who has flushes of estrogen and progesterone driven by the monthly cycle, then if thyroid function diminishes for any reason, the competition tends to be won by the estrogens. This might be one of the destabilizing factors for young women with bipolar illness. Thus, the doctor should definitely check thyroid function in any female who has rapid cycling, measuring thyroid stimulating hormone (TSH) to see whether it's elevated at all.

Post: In your seven-week study, you utilized four doses of the level of thyroxine. Did any particular dose appear to be most effective?

Dr. Whybrow: We escalated the doses to give ultimately a high level of circulating thyroxine, so those doses were just the way in which we paced the escalation. For four weeks or so, we maintained patients at the levels that in our experience are therapeutic for individuals with severe resistant depression.

Post: Did participants in the study remain on mood-stabilizing drugs?

Dr. Whybrow: Yes. We've learned over the years that because these people are so sick, very often taking them off their medications is unethical. Their illness gets worse. Thus, we stabilize their medications, then we add in the thyroxine as an independent variable.

Post: Why did your study include only menopausal or premenopausal women between 18 and 55 and not include, for example, senior patients?

Dr. Whybrow: The reason we constrained it 18 to 55 is because we were looking particularly in this group of patients who had vulnerability. The answer to your other question is that you have to be careful when using these medications. Obviously, we always review very carefully cardiovascular disease or any other disorder that we would be concerned about in regard to the use of thyroid hormone. As age increases, you have to worry about bone metabolism and cardiovascular function when using high doses of thyroid medication.

One interesting thing we have discovered is that when we give individuals with severe depression or rapid cycling high-dose thyroxine, they do not respond in the same way as would, let's say, "normal" people respond to thyroid hormone. If you give somebody without illness increasing amounts of thyroid hormone, then after a certain dose they begin to feel very anxious and distressed. For reasons we don't yet understand, this doesn't occur in rapid cycling or resistant depression patients. Very often they tolerate high doses without any side effects whatsoever. They don't experience changes in blood pressure, sweating, or anxiety. The pulse rate goes up a little bit, but not much, which also suggests that they have some sort of physiological difference.

Up to age 55, we feel fairly confident that high-dose thyroxine therapy is not going to harm anybody, but above that age level, we are much more cautious.

And there are other caveats. First, those who come to us usually do so after they've tried many, many other things. Most are suffering badly, either with chronic malignant depression or rapid cycling--both of which are very miserable illnesses to live with, believe me.

One must think of the issue in terms of physiological costs versus benefits. Most patients have come to the end of a long list of treatments before they receive high-dose thyroxine. And the good news is that some patients do extraordinarily well--with almost magical improvement.

Post: Your report mentioned a decrease in systolic blood pressure. Wouldn't that be a plus for geriatric patients with bipolar and hypertension?

Dr. Whybrow: It would be, yes. But again one has to be cautious, because if patients do have cardiovascular problems, one doesn't want to jump in too enthusiastically without appropriate assessment.

Post: In your study, you used levothyroxine, which consists of synthetic [T.sub.4]--the generic form of thyroxine. How does this compare with Armour Thyroid tablets, which include [T.sub.3] and [T.sub.4]?

Dr. Whybrow: In our studies, we've always used thyroxine because it's physiologically much more easily tracked. We want to be able to find out what is happening to the levels of T4 and also to the thyroid stimulating hormone (TSH). If you give [T.sub.3], which has a much shorter half-life, it confuses the situation, because it switches off [T.sub.4] production in the indigenous gland. In general, it's not as clean as a physiological experiment. Armour Thyroid tends to have both [T.sub.3] and [T.sub.4] in there. Although it's pretty well stabilized, there is some variation between the [T.sub.3] and [T.sub.4] percentages.

Post: Therapeutically, do they have the same benefit?

Dr. Whybrow: Yes. Whether it's synthetically produced or from a sheep's gland, thyroxine is exactly the same molecule.

Post: Are you familiar with psychiatrists in the United States who are using thyroid medications to treat bipolar depression?

Dr. Whybrow: There are many individuals. I can't give you a list. But many psychiatrists who care for a large number of severely ill bipolar people eventually explore the use of thyroid hormone as one possible solution to their patients' difficulties.

Post: How can Post readers throughout the United States work with their local medical center to perhaps reap the benefits of your research?

Dr. Whybrow: If people are suffering from severe depression or rapid cycling disease without relief, you can certainly suggest that they contact me and I will do my best to help them.

Post: Could you potentially coordinate this therapy using your guidelines with their caregiver?

Dr. Whybrow: Yes. I can send the doctor the appropriate literature.

Post: You mentioned earlier your collaboration with researchers in Germany. Is the therapy utilized more commonly in Europe or elsewhere?

Dr. Whybrow: Yes. In fact, Dr. Bauer has done an enormous amount of work in Berlin. We have collaborated for probably about eight years now. He was actually here at UCLA's Neuropsychiatric Institute for a couple of years and he was the leader on the study recently published in Molecular Psychiatry. Dr. Bauer also has ongoing studies in Germany, and two or three different universities in Europe.

Post: Would you envision this research expanding in the United States?

Dr. Whybrow: Many universities use this. There aren't too many that have formal programs in thyroid and depression. For some reason, it has not been of as much interest in the United States as has the study of steroids and depression. But as I mentioned, there are many individual practitioners who are familiar with these ideas and use them around the country. But there aren't as many organized research programs as you might imagine.

Post: In your recent paper, why did you mention right-handedness?

Dr. Whybrow: When you're doing a brain study, the handedness makes a difference in terms of the way blood flow distributes itself, so the dominant hemisphere needs to be the same in each patient. We chose handedness as a simple way of measuring dominance.

Post: In your imaging scans, the positron emission tomography scans were simply to follow brain metabolism?

Dr. Whybrow: Exactly.

Post: In the study published in Molecular Psychiatry, could you discuss the imaging studies that demonstrated the altered brain activity?

Dr. Whybrow: We were measuring the shifts in blood flow as reflected by the glucose utilization in the brain.

In these severely depressed patients, we found that the distribution of blood flow was very similar to that of other reports in the literature, when scanned by the same technique. Crudely put, the limbic structures tend to be active and the frontal lobes tend to be inactive, a finding that reverses when the depression is treated. We witnessed that shift in our patients as well. The only difference is that our patients had already been treated very energetically with antidepressants and had not responded in the typical way. It was as if the abnormal distribution of blood flow persisted, even though they received what is considered adequate intervention for depression.

Post: What role do you think that your research will play in the future treatment with bipolar and rapid cycling? Do you think it will integrate into the therapy?

Dr. Whybrow: Yes, eventually. In some ways, what we're seeing is similar to the use of steroids as a pharmacologic agent (as opposed to an endocrine agent) in the treatment of conditions like acute asthma or chronic inflammatory disease and so forth.

The goal of future studies is to become more sophisticated in understanding the central mechanisms that are impaired in these individuals who don't get better when given the usual therapeutic agents but who nonetheless are triggered into improvement through the use of thyroid hormone. We must now investigate potential genetic differences within the receptors and the neurochemical pathways that are influenced by thyroid hormones.

Dr. Bauer has been talking with some scientists in Scandinavia about looking at potential genetic variance and possible syndromes of thyroid receptor resistance in these patients. It may well be that in the long run, we'll discover something that will circumvent the need for the use of thyroid hormone, because the thyroid hormone may be just the mechanism that "un-sticks" the system, in the same way as eventually we might find something that will turn off the inflammatory action in the person with severe asthma.

Post: Do you have any suspicions about other potential causative agents, such as viral agents, in rapid cycling and bipolar disorder?

Dr. Whybrow: My own sense is that bipolar disorder is one of the diseases predisposed by genetics. The fascinating thing about bipolar disease in general--not just about the link between bipolar disease and thyroid disease--is that bipolar illness is heavily influenced by familial and therefore genetic inheritance. Four or five different areas in the genome now seem to be shaping up for possible sites where abnormalities or aberrations of genetic accounting occur in bipolar disorder. These sites vary from study to study, suggesting that bipolar illness is a complex trait. Not all the genes may be aberrant genes, but rather, they are aberrant in combination. There is no unique gene as, for example, the Huntington's gene. In bipolar illness, we may discover just variations of genes that are very important and useful in what they usually do. It may well be that's why you find in families with bipolar disorder: a disturbance of emotional and social behavior, others who seem to be very emotionally and socially adept. You get this interesting matrix of people, some of whom are extremely talented and rewarded in our social structure while other family members with just a slight genetic variation have too much energy until they surge over the top and collapse into the asylum. Probably these variants of genetic composition are not driven by viral illness, although that may be so in schizophrenia and other illnesses where structural abnormalities early in life express themselves later during maturation and adolescence.

Post: Could you share new treatments for rapid-cycling and other forms of bipolar disorder in the pipeline?

Dr. Whybrow: What manic-depressive illness and schizophrenia have in common is that both respond in the acute phases to dopamine-blocking drugs. The new dopamine-blocking drugs, introduced mainly for schizophrenia, also work in severely ill bipolar patients. Another area for long-term control, which shows mixed promise, is the use of agents used in the treatment of epilepsy. One way of conceptualizing manic-depressive disease is as a disorder with a radically different time course but nonetheless sharing some similarities with epilepsy, where focal firing oscillates with quiescence.

Post: Would those agents include neurontin (gabapentin) and lamictal (lamotrigine)?

Dr. Whybrow: Yes, that's right.

Post: We have written about Dr. Andrew Stoll's research at Harvard on the use of omega-3s. What do you think about the potential of omega-3s?

Dr. Whybrow: It is empirical evidence in the same way that the thyroid research is empirical, but Dr. Stoll seems to get positive results that make a clinical difference. We know that omega-3 fatty acids are particularly important in the central nervous system, so the theory has logic behind it. Omega-3 supplementation is a treatment, like thyroid, which we need to explore and follow carefully. I would not throw out without research any potential agents for these individuals because they suffer so badly.

RELATED ARTICLE: Thyroid therapy.

In the recent study led by Dr. Whybrow, researchers used positron emission tomography (PET) scans to compare the brain activity of bipolar patients--before and after treatment with elevated doses of thyroid medication--with those of non-bipolar individuals.

Before treatment, the red and yellow "hot" areas in PET scans indicate pronounced differences in metabolic activity in several regions of the brain of bipolar patients, particularly in the amygdala and hippocampus (Before Treatment)--areas characteristically active during bipolar depression.

After receiving thyroid hormone treatment, researchers discovered reduced activity, denoted by the blue "cool" areas, in the amygdala and hippocampus regions (After Treatment), indicating that previously "hot" areas of activity were turned down following thyroid treatment, according to UCLA brain imaging expert Dr. Edythe London.

According to Dr. Whybrow, the study clearly shows that the addition of high-dose thyroid hormone in bipolar individuals actually shifts the physiological activity in the brain, as demonstrated in PET scans, to the areas long known to become active during recovery from depression--a promising development for patients who suffer rapid cycling and treatment-resistant bipolar disorders.

"The findings validate the idea that thyroid hormones have a powerful effect upon brain physiology," notes Dr. Whybrow. "When that shift occurs in chronically depressed people, it associates with behavioral changes that we recognize as improvement in the depression."

Marauding Vikings and Mood Swings

"What makes a great Viking? Radical mood swings!" Dr. Peter Whybrow was reading to us from the "Hagar the Horrible" cartoon on his wall. Dr. Whybrow is probably the world authority on the treatment of rapid-cycling mood swings. Because he is world-renowned in this area, it is small wonder that one of his colleagues sent him the vintage comic strip about the Vikings and their mood swings.

With apologies to Dr. Whybrow and serious researchers, we suggest that perhaps there is more here than meets the eye. In fierce attacks, the Vikings marauded the British Isles, the Low countries, and most of what is now called France and Germany. Did their mood-swinging genes set us up for our goodly supply of cyclothymics and manic-depressives?

We're told that bipolar gene defects don't "burn out" or weaken through the decades, and of course there is ample evidence that bipolar disease is hereditary.

There is good treatment for most depression and most bipolar highs and lows, but psychiatrists agree that rapid-cycling bipolar disease is extremely difficult to treat. Dr. Whybrow has compassion for those who struggle with rapid cycling and get no relief from the traditional antidepressants. When all else fails, he has championed the use of thyroxine. His studies have shown an amazing success rate of help for 50 percent of these individuals where the thyroxine provided "almost magical improvement."

He has limited his trials to persons 55 years of age or younger. Might he be persuaded to expand his trials to otherwise healthy elderly patients who suffer from rapid cycling? This might give hope to long-suffering patients. Participants would be limited to those who were not suffering from any cardiovascular problems that could possibly be exacerbated by thyroid supplementation. The Saturday Evening Post Society's research department would like to hear from any afflicted rapid cycling patients who might be interested in volunteering for treatment should trials be developed which might include the otherwise healthy elderly. Please send confidential letters stating your interest to Cory SerVaas, M.D., 1100 Waterway Blvd., Indianapolis, IN 46202. Your letters will be held in confidence but shared with Dr. Whybrow and other physicians who search for treatments.

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