Schizophrenia: Summary of Presentations

Steven E. Hyman, M.D.
Director, National Institute of Mental Health

This briefing, in part, is a response to requests by Members of Congress following the tragic shootings in the U.S. Capitol building not long ago. It is a very positive response to desire more education rather than to engage in the kind of mythmaking and unnecessary fear that people often associate with mental illness.

Schizophrenia, in many ways, is the most severe of the mental illnesses. One in every one hundred Americans has schizophrenia. This disease, once thought to be psychological, is clearly a brain disease. Throughout the world, whether in Washington or New York City or in rural Kenya, the rate of schizophrenia is still the same: one percent of the population. Schizophrenia is not a cultural artifact but a brain disease in which vulnerability is caused by genes; something happens during brain development that converts this genetic vulnerability into disease. Exactly what happens is the subject of neuroscientific research.

In some ways, schizophrenia is like other diseases. People who develop diabetes or heart disease have a genetic vulnerability, and then external circumstances convert this vulnerability into disease. Rather than being unusual and mysterious entities, mental illnesses are real diseases of an organ - in this case, the brain.

Schizophrenia is particularly tragic because its onset usually occurs in the late teens or early 20s, just when families, society, and educational institutions have already put their full effort into launching a person into the world. Tragically, then, we lose them, often to chronic and persistent hallucinations and delusions, fixed false beliefs about the world, and an inability to live up to their potential; often they withdraw from society and lose their ability to cope with everyday life.

Our current medications do a better job of controlling symptoms with fewer of the terrible side effects that characterized older drugs. They are far from perfect, however; they palliate, but they do not cure, and their side effects are still far from benign. More research is desperately needed.

Medication, furthermore, is not the only component of optimal treatment. People with schizophrenia need medication, yet to treat someone this ill a doctor cannot just write a prescription and send the person away. The medical treatment of mental illness has to be embedded in thoughtful and comprehensive psychosocial and rehabilitative treatments. For the most impaired, such treatment must include assertive outreach or else the most effective pills will stay in the bottle and the most effective crisis interventions will go unused. Too often, the result is needless tragedy.

As good as our current treatments are, they are not cures. We continue our research because we are a long way from cures and a longer way from prevention. This situation mirrors that in many other severe chronic diseases. Insulin controls the symptoms of diabetes but does not cure the disease. The best drugs we now have for schizophrenia and for other severe and persistent mental illnesses control symptoms but do not cure the illnesses. And we have not yet resolved the vital issue of delivering these available treatments to the people who need them.

Jeffrey Lieberman, M.D.
Vice Chair, Department of Psychiatry
and Director, Mental Health Clinical Research Center
University of North Carolina-Chapel Hill

It has been said, perhaps melodramatically, that schizophrenia is to psychiatry what cancer is to medicine. It is in some ways a sentence as well as a diagnosis. The reason why that may be the case is because the illness usually first manifests itself when people are reaching the prime of their life. Normal individuals entering adulthood are struck down by the virulent symptoms of this illness, an illness which in most cases is progressive and produces lasting impairment.

The seeds of this illness begin in gestation, in the earliest stages of development. There is a latency period during which time patients function as normal individuals - grade school, junior high - and it is only in the later stages of adolescence and the early periods of adulthood that the symptoms of the illness begin to manifest themselves.

One does not wake up one day and have schizophrenia, like Gregor Samsa did in Kafka's The Metamorphosis; it is not like suddenly developing the flu. Schizophrenia develops more gradually, often preceded by a period of what are called prodromal, or early warning, signs. These are not the cardinal symptoms of the illness, but in retrospect can be seen to presage the onset. Eventually, these gradual early warning signs give way to the hallmark features:> the delusions, hallucinations, and thought disorganization that are very disruptive mentally. An individual has what is considered his or her first episode: the first persistent, fulminant, acute episode of illness, which usually brings them into treatment.

If they receive prompt and proper treatment, the outcome is quite good. In fact, many can return to the way they were before they got sick. What usually happens, however, is that after this first episode, patients have recurrences because they do not remain in treatment; they do not understand that schizophrenia is a recurrent and potentially lifelong illness, and they do not like the treatments that they receive. The medications historically used to treat schizophrenia have noxious side effects and patients do not want to take them.

There also are problems with the lack of mental health care services. For various reasons, then, patients stop taking medications, thinking they are well; they drift out of treatment; and then they relapse. With each relapse, they do not recover as well as they may have before. Their symptoms persist; their functioning is not as good; they cannot return to the community and live independently, resume their schooling, continue their jobs, or develop social relationships. Gradually, they become functionally incapacitated and persistently symptomatic. Because schizophrenia does not directly kill, as does Alzheimer's disease, they become permanently disabled. If their family does not sustain them, they become wards of the state and live the rest of their lives essentially disabled and dependent on the mental health care profession and society.

One in one hundred people will develop this illness. The proportion really depends on the age of the population. The incidence rises between 15 and 30 years of age, the peak period of onset, and then levels off to an incidence rate of one percent.

The symptoms characterizing this disorder are manifold. Most common and notorious are the so-called delusions, hallucinations, and disorganization of thought: the positive symptoms of schizophrenia. There also is an erosion of the affective and emotional capacity of patients: they lose all the emotional vibrancy in life, they lose the intellectual richness of thought, they lose interest in general, and they become shadows of their former selves. These are the negative symptoms of schizophrenia.

In addition, their ability to mentally attend, remember, and engage in abstract thinking diminishes over time, so they cannot negotiate the problems of daily living and continue to develop in their vocation. They experience disturbances of mood, leading many to attempt and succeed in committing suicide. All of these symptoms have the capacity to disable performance, and the functional disability is perhaps one of the most devastating aspects of the illness.

Treatments do work. As stated earlier, if patients are treated promptly and effectively, the vast majority will respond and even go into remission. Studying remission rates, we have learned that the shorter the time period that patients have been actively symptomatic before receiving the first treatment, the better their outcome, and the higher and faster the rate of remission. If patients have been symptomatic persistently for longer periods of time, however, the rate of remission is lower and slower.

Thus it is as critical as with stroke, for example, that we identify people early after they develop the signs, so we can implement treatment, shut off the underlying pathophysiological process, and prevent the degenerative effects of the illness from occurring. You would think that if someone were affected by a delusion or hallucination or severe thinking disturbance, they would be observed and brought - or bring themselves - to treatment. In fact, if you look at the time that patients have been symptomatic, in a variety of studies, it is over a year - more than 50 weeks - in almost all cases. There are people in the community who are actively symptomatic and either do not know or do not want to receive treatment, or they do not have access to treatment. From a public health standpoint, this is a critical lapse in our ability to control this illness.

Treatments for schizophrenia have existed since 1952, when chlorpromazine (Thorazine? was introduced in the United States, and medications called antipsychotic drugs came into use. For forty years, we used these with some success, but we did not really improve on the pharmacological capacity of these treatments. In 1990, clozapine was introduced and ushered in a group of new, superior, and far safer medications called atypical antipsychotic drugs.

A cruel irony about this long-awaited breakthrough is the fact that it dovetailed with the introduction of managed care. These new medications cost nearly ten times as much as the original antipsychotic drugs, and physicians therefore have not been allowed to use them as first-line treatments; they have to prove the old treatments fail before they can prescribe the new ones.

While schizophrenia primarily affects the individual, their families react in varied but always distressing ways. Family life is disrupted; often the patient leaves the family and lives separately, usually supported by the state. Patients have an increased mortality, not because of the disease but because of their lifestyle: they may not eat properly, may live in poor conditions, and may not attend to their health care. They die earlier than they would if they did not have the illness. Perhaps 10 to 20 percent of all patients who develop the illness will die by suicide. Substance abuse also is a common comorbidity that afflicts patients.

Finally, they are susceptible to criminal behavior, particularly violence. Violence occurs more commonly than we previously understood. It is usually driven by patients' hallucinations and delusions, as they respond to thoughts and voices telling them what to do. The recent shooting in the Capitol is just one tragic example; others include the so-called Unabomber, Theodore Kaczynski; the heir to the DuPont fortune, John DuPont; and the "Long Island gunman," Colin Ferguson.

In North Carolina, we recently had the case of an individual named Wendell Williamson. Mr. Williamson was a law student at the University of North Carolina in Chapel Hill who developed schizophrenia. He was being treated, but because of a lapse in his care, stopped his medication. One day he killed two people with a shotgun before he was subdued. Even though Mr. Williamson did not want to take his medication, he sued his psychiatrist for not ensuring that he took it. It is a very interesting case for the questions it raises in ethics, civil liberties, medicine, and health care reform.

The realities of schizophrenia are sobering, indeed. However, there is reason for optimism. We have the pharmacologic and psychosocial tools to control the symptoms of the illness, if we use them properly, and we also have the capacity to identify schizophrenia's cause and prevent it. Everything is contingent on our ensuring an environment that supports research and adequate funding for treatment and prevention.

Daniel R. Weinberger, M.D.
Chief, Clinical Brain Disorders Branch
Intramural Research Program
National Institute of Mental Health

To me, the great tragedy of schizophrenia is that it affects people before they have had an opportunity to accomplish anything. Schizophrenia disenfranchises its victims from galvanizing the attention of people who would take an interest in this illness and make a difference at the level of public awareness. They are unable to organize people at a corporation where they were never able to get a job, or the university from which they had to drop out, or in a professional society they were unable to join.

As researchers, our Holy Grail has been to understand the basic biology of schizophrenia. It is safe to say that in the past ten years we probably have learned more about the basic biology of this disease and its promise for future treatment and prevention than in all previous years of studying it. In the next ten years, the pace will be even quicker; we are optimistic because we have a better understanding about how genes account for this disorder and more information about the biological changes that occur in the brain.

We have known for a long time that people inherit something that increases their risk of manifesting schizophrenia. We have learned from studying twins that identical twins are much more likely to share schizophrenia than fraternal twins. Identical twins share virtually all of their genetics. Fraternal twins share 50 percent of their genes, just like siblings born years apart. Children of schizophrenic parents, even if the children have been adopted away at birth, are much more likely later in life to manifest schizophrenia than children of normal individuals, even if the children of normal parents have been adopted by schizophrenic parents.

With the new technologies for studying DNA, it is possible to look in families for pieces of the human genome, pieces of DNA that are inherited along with illness in these families.

We are only at the beginning of the search for specific genes, and there probably are a number of different ones that conspire to provide risk for schizophrenia. Unlike the genes for Huntington's disease or muscular dystrophy, these genes in and of themselves do not make one schizophrenic. Rather, they seem to provide genetic vulnerability. Either because they interact with themselves and other genes in ways we do not yet understand or because they interact with environments in ways we do not yet understand, they set the stage for manifesting the illness.

We are at the beginning of the search, but at least we can see the path we must follow to greater knowledge. While we can begin to search for genes that put someone at risk, we also need to understand what happens to the brain that accounts for the signs and symptoms of the disease. Studies of the brains of living patients with schizophrenia clearly show that the brain is involved in this illness.

Schizophrenia affects not only how the brain looks but how it works. To study this, we use another type of scanning technique - positron emission tomography or PET scanning - to look at brain function.

Such approaches give us a broad sense of how the brain looks anatomically and how it functions physiologically. To understand how genes affect the brain in a way that puts it at risk, we need to examine in a much more finely detailed way the actual cells of the brain. We can do this with living brain tissue to some degree, and we can do this with postmortem brain tissue to a much greater degree.

One of the ways we can do this in living brain tissue is by using techniques such as magnetic resonance spectroscopic imaging (MRSI), a chemical technique that allows us to measure the concentrations of certain chemicals to determine the integrity of specific populations of nerve cells. One of the chemicals that we have been very interested in is called N-acetylaspartate (NAA); it is a measure of the health of certain critical populations of nerve cells.

These chemicals are reduced in specific areas of the brains of patients with schizophrenia, suggesting that there are particular populations of suspicious cells that we can identify better from these studies. What is interesting about this NAA measure is that it is also reduced in healthy siblings of patients with schizophrenia. This suggests that the cells identified by this marker are a population of cells that is genetically at risk. Healthy siblings of patients with schizophrenia do not manifest the illness, but to the extent that they share 50 percent of their genes with the ill sibling, they also share 50 percent of those genes that establish risk.

To understand what genes have done to put particular cells at risk requires that we look at these cells in much greater detail, and we do this by looking at brain tissue. The revolution in DNA technology has enabled us to study how cells interact with genes in relation to the stimuli that cells experience. An emerging series of studies suggests that certain cells of patients with schizophrenia have a defect in how they relate to the stimuli in their cellular environment. So we have clues about how genes may put these cells at risk for not developing the appropriate relationships as they mature and as they grow with other cells in the cellular environment of the brain.

We are optimistic about our opportunities for understanding schizophrenia, provided we continue to raise the consciousness of people whose consciousness needs to be in tune with us. We are very confident that genes will be identified and confirmed to be related to clinical risk and to the cellular biology of manifest illness.

It is very clear that genes confer risk but not fate. There has to be some second hit, something else that happens. Every member of the human race has some deleterious genetic risk. If it is not for schizophrenia, it may be for coronary heart disease or for breast or prostate cancer.

One day we will understand what happens to a brain that accounts for this illness, and we will be able to characterize the risk that is genetically predetermined. Such information, as in other areas of medical research, is certain to translate into actual prevention - something we have not seen much of to date - and certainly to improved treatment and rehabilitation.