DEPRESSION AND THE BRAIN

An edited transcript of a talk by Dr. J Raymond DePaulo Jr., M.D., professor of psychiatry at Johns Hopkins University School of Medicine at a conference on March 17, 1999, sponsored by the Dana Alliance for Brain Initiatives.

As you know, I am a psychiatrist, or to put it more simply, I am a depression doctor. Because I work at Johns Hopkins, I have been able to focus on one illness, depression.

I am here to talk to you about four topics: the impact of clinical depression on patients and families, the current state of clinical care of patients with depression and manic depression (bipolar disorder), the contributions that three brain sciences (genetics, brain imaging, and pharmacology) already have made to the field, and what is needed to assure a brighter future for those afflicted by this illness.

First, I want to clarify what I mean by the term depression. When I talk about depression, I am not talking about discouragement. I remember a patient I evaluated several years ago. When I told him at the end of the evaluation he had clinical depression, he looked at me, shaking his head, as if I was from Mars, and he said 'Look, DePaulo, I know what depression is. That is when your dog dies and you feel sad. I don’t own a dog. I don't feel sad. Start over again." He had clinical depression, but the word depression was confusing to him as it confuses many others. By clinical depression I mean a set of signs and symptoms affecting not only mood, but mental and physical vitality, self esteem, self confidence, and several bodily functions.

Depression's Impact on People and Dollars
What is the impact or importance of clinical depression as compared to other diseases? The first important fact is that 15 million Americans have it. It comes in episodes, often beginning late in adolescence and reoccurring throughout the life span, if untreated. The number of people affected and the long-term course are only the beginning. In 1990, when a series of studies was done to calculate the costs of several diseases, the cost of depression in the U.S. economy was estimated at $44 billion per year.

For comparison, the estimates of the cost of coronary artery disease and of cancer were estimated at the same time. Using the same methods for calculation, the estimated cost of all coronary artery disease was almost identical to depression: $43 billion. The estimated cost to our economy from all cancers taken together was $101 billion. So, depression is enormously disruptive to the lives of our patients and their families, but it is also of economic importance for us as a society.

The World Health Organization has recently published a very extensive study on the causes of disability and the economic and social burden caused by various diseases on a worldwide basis. They found that the leading cause of disability in world today is unipolar depression (i.e., episodes of clinical depression without manic episodes). Bipolar disorder or manic depression is number six on the list. In fact, five psychiatric disorders are among the top ten causes of disability worldwide. Unipolar depression alone makes up 10 percent of all cases. In terms of their impact, these have been the most neglected diseases in medicine.

What is the current state of clinical care? It is quite different than for diseases like Huntington's disease (HD), which Dr. Gusella described. Through the genetics studies he and his colleagues have carried out, we now know much about its cause (the gene, the protein it makes, and even some aspects of the protein's function), but we still don't have a treatment for it.

In depression, just the opposite is true. We have some fairly effective antidepressant medications. Each one works in about 65 percent of patients with major depression. These breakthroughs came from pharmacology. However, we know almost nothing about the mechanism of the disease in the brain, so that when antidepressants are helpful, we don’t know why they work. Nor do we know why they fail when they fail.

SSRIs Make a Difference
The biggest watershed that pharmacology has crossed for us has been the development of the first rationally designed family of antidepressants, the selective serotonin reuptake inhibitors (SSRIs). About 20 years ago pharmacologic studies suggested that some depressions came from depletion of brain catecholamine neurotransmitters. Drugs like Serpasil deplete them and are associated with severe depressions, as Dr. Bloom noted. It was thought that other depressions were caused by a depletion of serotonin. Some pharmaceutical companies wisely set out to develop drugs which would specifically enhance the brain concentrations of those chemicals. In this country, Prozac is the drug that we know as the primary SSRI. Others were developed at the same time in Europe. We still don’t know why they work, but we have better ideas to test now.

It is a strange twist, but that is our situation today. We need to understand the brain mechanism of the disease and the mechanism of action of these drugs to advance beyond this state. Despite the availability of many new antidepressants, only 15 to 30 percent of patients with major depression and bipolar disorder are getting diagnosed and treated for it. That is a scandal.

Why does this happen? First, most depressed patients are not diagnosed. These patients often come to their doctor, but they don't know what they are coming for, and, unfortunately, many clinicians don't recognize the disorder in their patients. There are no laboratory tests to help the clinician resolve or confirm any suspicion.

Once you have diagnosed it, you can at least apply these treatments. Where are these laboratory tests going to come from? Probably genetics, but genetics, imaging, pharmacology, as I said, all work together.

The third thing is what have the contributions been from these research areas? From brain imaging studies, we have learned what brain regions are crucial for depression that comes following stroke.

Searching for the Genes
We know now that Huntington's disease involves the same brain regions, about 40 percent of patients with Huntington's disease have depression in the early stages of their illness, interestingly not so in the later stages. We now know that those brain regions that are important in post-stroke depression and in Huntington's disease are important in families with the familial forms of depression.

Genetic studies have demonstrated in twin and adoption studies that genes are important causes of many forms of depression. Finding the genes has been difficult probably because it is so common. Since depression affects 15 million Americans at any one time, the disease can't be caused by a single gene, but is more likely to be the result of an interaction of several common genes with co-occur in some individuals in some families. We know that for most people a single gene will not be sufficient as it is in Huntington's disease, where having the gene almost guarantees that you will get the disease. Depression and bipolar disorder will occur in an individual when a number of specific genes react in the absence of protective genes. To put it simply, most people with any one of these genes will not have any illness at all.

It is not a needle in a haystack, it's a haystack full of needles that we have got to sort out. We can do it and we must. An early report has recently been presented demonstrating that specific genes can predict which patient will have terrible side effects from one group of psychoactive medicines and which patients will not.

What is needed from the three big brain sciences? We need laboratory tests to help all clinicians improve in diagnosing depression and bipolar disorder. From brain imaging we need more precise localization of the brain areas and brain cells which malfunction in depression. As Dr. Phelps noted, new and more powerful ways of using brain imaging methods can monitor brain function as well as structure. Further development of these methods that will link imaging and pharmacologic experiments in the same patients is crucial.

We also need more rational drug development. That will come from not only basic pharmacology, but also from genetics where we will get blueprints of the molecules which contribute to depression.

What do we need from genetics (and this is the area where I am trying to do my best to be of help)? Fundamentally, we need the genes that predispose people to this illness. We also would be very happy to know of the genes — and we think they are there — that protect people from this illness.

The three major brain sciences, brain imaging, pharmacology, and genetics, can work together hand and glove, and when needed hand and glove and foot, to illuminate a mysterious disorder like depression.

We have come a long way. We have got a much further way to go. How would I conclude? We need much more support for the brain sciences and the clinical sciences that relate to brain diseases such as depression. That support certainly is financial, but it is also in the form of more public education about these illnesses and more scientific careers devoted to studying them.

Reprinted from "Advances in Brain Research 1999", The Charles A. Dana Foundation.

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