NARSAD's Fourteenth Annual Symposium
October 11 - 12, 2002

Session 2: Affective Disorders Research

Melissa DelBello, M.D., of the University of Cincinnati , is using functional magnetic resonance imaging (fMRI) to compare the function of several brain regions between adolescents with bipolar disorder and healthy volunteers. Several brain regions that have been implicated in bipolar disorder, including the prefrontal cortex, thalamus, striatum, and cerebellum, are being investigated. The patients include subjects at the first episode of bipolar mania, and subjects who have experienced previous episodes. Subjects receive an attentional task during the fMRI procedure, which is aimed to activate the above brain regions. Thus far, the results indicate decreased activation in some of these brain regions in the first episode bipolar patients as compared to controls. Bipolar patients with previous episodes had diminished brain activation compared to first episode bipolar patients. Although these results are preliminary, the findings suggest progression of the illness over time.

Comments by Dr. Lewis Judd: "A team is necessary to do this--physicists, a statistician, bioinfomatics people--all of them working to get the right signal in the right place and analyzed in the right way. It's enormously complex. This study is being used as a dependent measure, there is a cross-change. The creativity, which is really being demonstrated by Dr. DelBello's work, is in the design of the study. Her interests were the abnormalities of the brains of bi-polar adolescents as they evolved over time. She has a group of people in their first episode of bipolar disorder. This is the purest and cleanest sample you can have. They have not had any prior onset of illness. The brain hasn't been changed by the illness, other than the acute episode. She is comparing this group with people who have had multiple episodes. By doing so, and by having a mentally healthy control group, she is able to compare any changes to the brain in such a way that she can draw conclusions. When she looked at the bipolar patients in their first lifetime episode, they were underactivated--hypoactive in comparison to controls. When she compared the first-episode patients with the multiple-episode patients she found hyper-, over-activation.

I think this is a beautifully designed clinical study using state-of-the-art methods which are highly technical in nature, and it is getting data for us which we could not get in another way."

Kristin Haga, Ph.D., of the University of Edinburgh , is using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to study brain anatomy and chemistry in subjects who develop depression after having had a stroke. Between 20-60% of patients who have a stroke become depressed, and the mortality rate is increased three times in depressed, post-stroke subjects. Brain chemicals are markedly altered by stroke: levels of glutamate increase and levels of GABA decrease. Previous work suggests that GABA levels are diminished in patients who are depressed and who have not had a stroke. Thus, this work may shed light on the chemical abnormalities found in depression, with special relevance to understanding depression that results from strokes.

Dr. Judd: "There is a high degree of prevalence for the onset of major and minor depressive episodes following a stroke. In a post-stroke period of time, if you follow those people for a year or two, the degree of mortality in those individuals is three times what it is with people who have not had depression. This is a very important phenomenon. We saw the startling figures regarding the disability of depression worldwide. Another characteristic of mood disorder and depressive disorders is that they co-occur with other illnesses very frequently. So it is not uncommon for us to see co-morbidity or co-occurrence between depression and anxiety or depression and posttraumatic stress disorder, etc. We are now finding that when depression co-occurs with a medical illness it makes that medical illness much more severe and the course of that illness has a lot more morbidity and indeed even mortality. Dr. Haga is using state-of-the-art techniques to look at the brain. She is not just using activation or structural imaging, she's looking at the chemical changes in the brain. Fortunately, we are able to image one or two neurotransmitters now. This is a superb study, using state-of-the-art methodology, in addressing a problem that has been with us for a while and has not moved forward. With studies like this we'll see who is vulnerable to stroke or depression. We can even learn to prevent depression in post-stroke individuals as we do with heart attack patients. People are being pre-treated with antidepressants so they will not develop a depression post-heart attack."

Lisa Monteggia, Ph.D., of the University of Texas Southwestern Medical Center at Dallas , has developed a genetically modified mouse in order to examine factors that influence a chemical called brain derived neurotrophic factor (BDNF). A deficiency of BDNF has been proposed to contribute to depression, and antidepressant medications increase the levels of BDNF. Dr. Monteggia and her group implemented a groundbreaking method to create a "conditional knockout" mouse. This means that the function of a gene that codes for a chemical can be increased or decreased at any point in an animal's lifespan, and the changes can be made for as long or as short a period of time as the investigator wishes. This technique involves the use of a gene that drives the expression of BDNF; this gene can be turned on or off with the addition of a drug. This has advantages to more conventional "knockout" approaches, in which a gene is permanently deleted, often early in life, making it difficult to determine the age-specific effects of that gene. Dr. Monteggia has shown that mice in which the gene for BDNF is suppressed have abnormalities in learning and fear conditioning, as well as decreased amplitude of particular brain waves that test for a phenomenon known as long-term potentiation. This method may have very important implications for understanding the role of BDNF and other neurochemicals in mood and other psychiatric disorders.

Dr. Judd: This is a very important study. Dr. Monteggia is describing a mouse model, a conditional knockout model--very few currently exist in the field. She talks about it as if it just fell out of the sky and here it is. But hundreds of hours, more than that, have gone into this. I can't tell you the number of times people have tried this, hundreds and hundreds, and they have failed. This is really a stupendous, technical piece of work. It has very interesting history--the neurotrophic growth factor. A great pioneering Italian neuroscientist, Rita Levi-Montalcini, shared the Nobel Prize with Stanley Cohen, in 1986, for describing, and partially characterizing, new proteins in the brain that had a specific effect. No one knew they were there before, but there were neurotrophic factors. They are very important for the health of neurons to keep them surviving. Dr. Monteggia is building on this by looking at deficiencies of neurotrophic factors. It is logical to pick the most common one, which is brain-derived-neuro-trophic factor (BDNF). It's all over the brain, it's practically in all the neurons. Could it be related to schizophrenia? Or depression? Or to bipolar disorder? etc.? The problem is how do you get rid of BDNF in the brain? That's what Dr. Monteggia has solved. How do you do it in a way that mimics the onset of mental disorder in human beings? She has developed a genetically modified conditional knockout mouse. It's elegantly controlled. She had to work with three different strains of mice to get the one she wanted. She is now going to be taking in a model for antidepressant mechanisms at work. So this research is built on real history--the history of neuroscience. We have to raise our glass both to Rita Levi-Montalcini and to Lisa Monteggia."

Roy Perlis, M.D., of Harvard University , is investigating the genes that may be responsible for anger attacks. These attacks are characterized by in-appropriate anger accompanied by symptoms such as racing heart, shortness of breath, sweating, and a feeling of being out of control. Approximately 1/3 of patients with depression have problems with anger and irritability. There is evidence that anger and aggression may run in families, and some genes, including those related to serotonin, may play a role. Dr. Perlis will examine candidate genes that may underlie anger episodes in 300 patients with major depression and controls. If genes can be identified for anger attacks, this may lead to new medication treatments that target the brain chemicals that are responsible for this behavioral syndrome.

Dr. Judd: "Dr. Perlis is working on finding the gene code for major depressive disorder. There are many around the world who have been trying to do this. So far no certain gene locus has been found, although many have been reported. Almost none of them have been replicated. So people are now looking for different strategies. First of all we are accepting the fact that these diseases are very complex behavioral diseases. The inheritance patterns for them are not simple. More and more we are moving to other strategies to load the dice in favor of finding its locus by dissecting the syndrome or the illness and looking for target symptoms within that, or target characteristics in that, for which you might be able to find a gene locus, rather than looking for the totality, looking for major depression in general. What Dr. Perlis has done is very clever. He is culling out a third or so of patients with major depressive disorder who have a specific clinical characteristic. He is looking at an endophenotype, and cutting out a portion of the phenotype at which they will now be looking for genes. By choosing this endophenotype he already has a list of genes that might likely be abnormal. A list of genes that are subserving as well as coding from the serotonin system. He has listed a series of genes and is looking for abnormalities in them. This is a very current, up-to-date molecular genetic study and I think the likelihood of a pay-off is there."

Steven Thomas, M.D., Ph.D., of the University of Pennsylvania , is examining the role of the neurotransmitter norepinephrine (NE) in depression. Previous studies indicate that NE may be involved in the regulation of mood and affect, and that certain antidepressants may act by altering levels of NE. Dr. Thomas has generated a mouse in which the gene responsible for forming NE was removed, resulting in the total elimination of this neurotransmitter. His work has shown that most antidepressants, even those that are believed to work specifically on serotonin (selective serotonin reuptake inhibitors, or SSRI's, such as fluoxetine (Prozac), do not alter behavior in the absence of NE. This indicates that interactions between the serotonin and NE systems may be important in the regulation of mood. This work may have promise toward the development of more effective treatments for mood disorders.

Dr. Judd: "Right now, even to this day, we don't know precisely how antidepressant drugs work. We know they do. Dozens and dozens of labs across the world were trying, and are trying to find out how these drugs work. Because if we find how they work, reciprocally, we will know more precisely what the pathogenesis is and what the abnormality is in the brains of people who develop depression when they're exposed to certain kinds of stress.

We can use models like these to precisely determine what the role of norepinephrine is. Here, Dr. Thomas has developed a very precise way to remove norepinephrine from the brain by working through the genome, by working with this cell nucleus, by knocking out a gene that codes for an enzyme that makes norepinephrine.

These two presentations really are the coming of age of basic molecular science to show you how we can begin to answer questions that have plagued us for decades and come up with more and more precise answers. The conclusions that Dr. Thomas has made are based upon ability to manipulate through the genomic presence or absence of a very important monoamine neurotransmitter."

• Session 1: Affective Disorders Research

• Session 3: Schizophrenia Research

• Return to the symposia index