The Neurobiology of Schizophrenia: An Expert Interview With Joshua L. Roffman, MD

Pippa Wysong


August 11, 2009

Editor's Note:

In recent years, neurobiology has become an ever-increasing presence in psychiatry research. The study of cells in the nervous system, their interactions and organization, and more are revealing new and exciting details about the underlying causes and mechanics of schizophrenia. Joshua Roffman, MD, is actively doing research in this field. He is a faculty member in the Massachusetts General Hospital Schizophrenia and Psychiatric Neuroimaging Programs and an assistant professor of Psychiatry at Harvard Medical School. He also serves on the editorial board of the Harvard Review of Psychiatry. Medscape's Pippa Wysong spoke with Dr. Roffman about what neurobiology is and what it can offer to the field and practice of psychiatry.

Medscape: Can you start with defining neurobiology?

Dr. Roffman: Neurobiologists study the structure and function of the nervous system, including the brain. In psychiatry, we use MRI [magnetic resonance imaging] and other neuroimaging techniques to look at the ways the brain is put together anatomically and the way it works when performing certain tasks. Clinical neurobiology researchers may also look at electrical activity of neurons using technologies such as electroencephalography and magneto-encephalography [MEG]. Some neurobiologists use probes to look at how neurons and other supporting cells work on the level of proteins and even down to the level of DNA. Researchers also use animal models and study donated postmortem brain tissue. In sum, neurobiology is the study of how all these things work in concert to influence the way the brain works in both healthy people and in [patients with] neurological and psychiatric disorders.

Medscape: What are key challenges in schizophrenia?

Dr. Roffman: Schizophrenia is complex. Even though the clinical manifestations of schizophrenia are quite dramatic, changes in the brain itself are actually fairly subtle. A challenge is to understand what those subtle changes are and how they translate into symptoms.

Medscape: A majority of neurobiology research is focused on genetics. Could you tell Medscape readers about that?

Dr. Roffman: About 80% of someone's risk for developing schizophrenia has to do with their genetic makeup. Still, it's a challenge to find specific genes that are implicated in the disorder because it's not like there's one or two genes that in most cases will cause the illness. If that were the case, we would have already found them.

Medscape: There could be different combinations of genes in different people leading to the disease, right?

Dr. Roffman: Right. Each gene by itself has a very small effect. Recently, rare mutations were found that are less subtle and which, in some cases, may be more directly responsible for the illness. So far, those kinds of mutations (called copy-number variance) appear to cause the disorder in a relatively small number of patients.

For most schizophrenia genes, the reason why the effects are so small is because what you're measuring are clinical problems -- but from a biological standpoint those problems occur far downstream [from] the level of the gene. Many researchers are working on ways to amplify these genetic signals.

Medscape: How do you see what genes are doing?

Dr. Roffman: Genes code for proteins, and proteins organize themselves into cells, and cells into neural networks. There are many processes that happen between the level of the gene and what we see clinically. To really understand what's happening, we bring in brain imaging, which allows us to measure the effects of the gene directly on the level of brain structure and function. This sort of research shows that many genes involved in what has long been suspected to be important biochemical processes in schizophrenia, do affect brain activity.

Medscape: Are there many candidate genes in the field?

Dr. Roffman: Several dozen genes are being studied. New genes are also being discovered using genome-wide association [GWA] studies, which use a high-throughput method that captures most of the genetic variation within an individual. GWA studies help identify specific genes which occur more frequently in schizophrenia patients than in healthy individuals.

Medscape: If 80% of an individual's risk has to do with the genes, does that mean 20% of cases are sporadic?

Dr. Roffman: It probably isn't the case that 20% of schizophrenia patients have sporadic or nongenetic developmental causes of the disorder. It's more like within an individual, 80% of that individual's chance has to do with genetic factors and 20% has to do with nongenetic factors.

Medscape: What about the recent finding that the offspring of older men fathering children have a higher risk for schizophrenia? Is that inherited or environmental?

Dr. Roffman: Good question, and it's a fairly robust finding. We don't know. There could be something related to environmental factors, or maybe how stable the DNA is in sperm cells in older men versus younger men. Studies like that open up new avenues to explore.

Medscape: You mentioned studying electrical activity of neurons. What's new there?

Dr. Roffman: There are several different ways to look at brain electrical activity. One new method is MEG, which provides a precise way of looking at electrical activity across the cortex. It can measure how that activity changes from millisecond to millisecond. Measures such as functional MRI and positron emission tomography, which have good spatial resolution, lack the degree of temporal resolution MEG has.

Medscape: In schizophrenia neurobiology research, what has trickled down into practice?

Dr. Roffman: Some research has trickled down through pharmacology. For instance, the new antipsychotics that came out in the nineties emerged from basic and animal research looking at brain chemistry systems in schizophrenia. This research led to newer drugs with different mechanisms of action.

Medscape: What are possible scenarios about how all this can affect practice?

Dr. Roffman: As genetic research into schizophrenia has really taken off, the cost of genotyping has plummeted. It's easy to imagine that some day patients would come in, and as part of an evaluation for schizophrenia, a simple blood test or saliva test would be performed. We would canvas their entire genome looking for the presence of schizophrenia-related genes. Then we'd use that information to confirm the diagnosis, help subtype the illness, and, more importantly, know ahead of time whether someone is likely to respond to a specific treatment. For example, a few years ago several studies showed that patients with a certain version of the COMT gene were likely to respond to olanzapine. However, genetic tests are not yet routinely used in schizophrenia.

Medscape: While neurobiology sounds so mechanistic, traditional approaches to treatment won't disappear, right?

Dr. Roffman: No. Other forms of treatment such as psychotherapy can be complementary to neurobiologically focused treatments, and can help patients handle the symptoms of schizophrenia. However, unlike with depression or anxiety, psychotherapy cannot take away the symptoms of schizophrenia.

Medscape: Do you have any general messages for physicians about the neurobiology of schizophrenia?

Dr. Roffman: It's an exciting time in schizophrenia research. I think the genetics of schizophrenia, in particular, is an alluring and rapidly moving target. As with other areas of medicine, we expect that over the next several years we'll have a much better idea of how particular genetic variants contribute to the disease. The pace of genetics research has accelerated to the point where it's now possible to look at all the genetic variants in an individual quickly and inexpensively. We all hope this will translate into clinical progress in schizophrenia.