Fall 1996 Volume 5, Number 4

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Schizophrenia

Schizophrenia is a major psychotic disorder. By psychosis, we mean a gross impairment of reality testing. In other words, a person is out of touch with reality. The three ways in which this can happen are hallucinations, delusions, and formal thought disorder.

Hallucinations are false perceptions in the absence of any external source --hearing voices or seeing visions. Delusions are firmly held false beliefs. An example would be, the young man who believes that people are breaking into his room at night, stealing his internal organs, and replacing them with the internal organs of another person. Typically, in schizophrenia, delusions tend to be very bizarre and even in the face of overwhelming evidence to the contrary, a person will not give up these beliefs.

Then finally, a formal thought disorder is a disorder in the form or the organization of thinking. Patients can either be entirely incoherent to the point that we can't understand them or, more typically, patients may have subtle idiosyncratic logic which makes their speech seem peculiar and illogical.

In schizophrenia, there are also negative symptoms. Negative symptoms refer to human qualities that seem to be missing in patients with schizophrenia. They include apathy, social isolation, and a loss of emotional expressiveness.

Typically, the first symptoms of schizophrenia occur in about the late teens or early twenties in men and somewhat later in women. The illness often begins with a "prodrome:" The young adult may begin to withdraw, become apathetic; they may begin to neglect their hygiene and personal grooming. At this point, parents often assume that their child has become involved with drugs. It is not until the psychotic symptoms --the hallucinations and the delusions --appear, sometimes years later, that it becomes obvious that this is a major psychiatric disease.

Schizophrenia typically lasts for a lifetime and follows a chronic deteriorating course --at least, for the first ten years of the illness. The degree of disability, which can be quite severe, is primarily determined by the degree to which patients respond to medication. This can be quite variable.

Schizophrenia has a very strong genetic or hereditary component. A landmark study more than 20 years ago, the Danish Adoption Study, examined adoptive children and demonstrated that the adopted child's risk of developing schizophrenia was not related to the parents who raised the child. Rather, the risk was determined by the biological parents, the parents from whom the child inherited its genes. This was a critically important study, because prior to this it was believed that schizophrenia was the result of inadequate parenting. And that is absolutely not the case.

When we look at identical twins, if one twin develops schizophrenia, the other twin develops it about 50 percent of the time --50 percent concordance. Non-identical twins have about 18 percent concordance, while the risk in the general population is about one percent.

The fact that concordance is not closer to 100 percent suggests that there are other important factors. This is an area of intense research. Some evidence suggests that exposure to viral illness in utero may be a candidate for such a factor. People who are exposed to influenza epidemics during gestation seem to have a higher risk for developing this illness as adults.

Finally, I would like to mention some recent neuroimaging results. It has been known for over fifty years that the cerebral ventricles, hollow spaces in the brain filled with cerebrospinal fluid, are enlarged in patients with schizophrenia. It seems to be the result of a loss of brain tissue in the areas of the temporal lobes, though this is not specific enough to serve as a diagnostic test.

More recently, technology such as positron emission tomography, or PET scanning, has allowed us to look at the metabolic activity of individual regions in the brain. This has shown that people with schizophrenia seem unable to activate or to turn on the prefrontal cortex, the front portion of the brain, when asked to perform certain cognitive tests that light up that region of the brain in normal individuals. So, we are now beginning to identify functional abnormalities in the brain as well as structural.

Now, Dr. Benes will explain some of these findings for us.

DR. BENES: Our work has been primarily at the microscopic level, because we've been trying to understand what exactly could cause this deterioration, the disturbances in thinking and perception that we see every day in patients with schizophrenia. In our studies we look at post mortem schizophrenic brains, donated to research after death, and we also do studies with rats.

We've looked for evidence of a degenerative process, perhaps something similar to what occurs in Alzheimer's disease, because patients with schizophrenia --during the first five years of their illness, particularly --do show pronounced deterioration. We looked very carefully, with a reasonable number of cases, and we did not find evidence for a degenerative process.

Many patients show a loss of volume in certain parts of their brain --shrinkage --and also a loss of neurons, although not all patients show these. Because of the absence of one other finding, called gliosis, it was very clear that a typical degenerative pattern in no way could explain the deterioration of functioning in these patients.

So, we were left with the problem of trying to understand how the wiring of the brain in schizophrenia perhaps might be abnormal in such a way to produce the characteristic disturbances in this disorder.

In the human brain --the prefrontal cortex, specifically --we made certain nerve fibers visible, using a chemical tracer for glutamate, a very important neurotransmitter in all mammalian brains. We were testing a specific hypothesis: that schizophrenics might have excess numbers of these fibers. We counted hundreds of thousands of fibers and found evidence for an increase.

This was very interesting, because clinically it has been observed for decades that, when a schizophrenic walks into a room in which a lot of people are talking or there is a lot of noise, light, or activity, they very typically become overwhelmed with the amount of sensory stimulation that they are receiving.

The part of the brain in which we made this finding is involved in attentional mechanisms --the ability to focus on specific objects of interest in a room. It was therefore relevant that the schizophrenics had too many of these fibers; this finding could potentially help us to understand why these patients were becoming overwhelmed by sensory stimulation.

Now, two different types of neurons are important: "Projection cells" are the principal cells of the brain, sending fibers to many different sites throughout the central nervous system; and small neurons, known as "local circuit" cells, help to modulate the activity of the larger neurons and are of fundamental importance to how well the cortex works.

We tried to determine if, in schizophrenia, the distribution or functioning of either of these cell types might also be disturbed. And we found evidence to suggest that one type of small cells --so-called inhibitory cells, which damp down activity and help filter out excessive stimulation --seemed to be reduced in number in the schizophrenic subjects. These inhibitory cells use a neurotransmitter called GABA to dampen excessive stimulation.

Putting all this together, we had a working model for the idea that two principle defects might be present in schizophrenia: First, an increase of the fibers using the transmitter glutamate, making for an increase of excitatory inputs. And at the same time, a decrease of inhibitory modulation, the small cells that damp down this stimulation. So, it is no surprise that a schizophrenic could be overwhelmed in a crowded, noisy room and would only have one recourse to control this input --running out of the room, which is a typical response of these patients.

Recently, we have been attempting to understand what role the dopamine system might play in schizophrenia. Dopamine is another transmitter that is extremely important in this disorder; the drugs we use to treat schizophrenia specifically block dopamine receptors. So, we felt that any good model of schizophrenia had to take into account the dopamine system.

We thought: If our drugs block dopamine's effects, maybe there is excess dopamine input to an impaired population of inhibitory cells. I obviously can't go into all our data, but we now do have evidence suggesting that this aspect of the model may also be correct.

After Dr. Goff talks about the treatment of schizophrenia, I will return to this point and tell you about some neural circuitry models that we are working with to understand new treatment strategies.

DR. GOFF: Prior to any of the discoveries that Dr. Benes described, it was discovered, just through serendipity, that chlorpromazine, or thorazine, was highly effective in the treatment of schizophrenia. Following the introduction of thorazine in 1953, the number of chronically hospitalized psychiatric patients in the United States decreased by over 60 percent.

Thorazine and related drugs, known collectively as "conventional anti-psychotic agents," had an enormous impact on this illness. But, although they are effective at suppressing psychotic symptoms to the point that most patients can leave the hospital, they are by no means a cure. Most patients continue to have some symptoms; the negative symptoms tend not to respond to these drugs. And patients continue to be very vulnerable to relapse from stress and often require re-hospitalization. In addition, thorazine and related drugs are associated with some very disturbing neurological side effects. One is tardive dyskinesia, a potentially irreversible movement disorder.

The next major breakthrough occurred only five years ago --the introduction of clozapine, or clozaril, to the market in the United States. Clozapine was the first drug in 35 years that was more effective than thorazine and similar drugs. Clozapine is not only far more effective for psychotic symptoms; it is also more effective for negative symptoms and doesn't cause the same neurological side effects.

But clozapine is not without problems. Most important is agranulocytosis, a loss of white blood cells that, if not monitored closely, can be fatal. Because of that, when we administer clozapine, we have to draw blood every week and follow the person's white blood count. So, clozapine's use is limited, largely to just extremely treatment-resistant patients.

The hope is that we are going to discover son-of-clozapine, a drug with similar efficacy, but without the same problem of side effects. With the remarkable advantages of clozapine, there have been very concerted efforts to examine the profile of this drug to identify the receptors that this drug is active upon.

One of the first clues was the observation that clozapine has an "affinity" to a serotonin receptor as well as to dopamine D2 receptors that seemed to set this drug apart. That has spawned a whole host of new agents, known as "the serotonin-dopamine antagonists." The first of these is risperidone, which has been available for about a year. Two more drugs in this class will be available this year, sertindole and olanzapine. The preliminary evidence suggests that these drugs offer quite an advantage, and there is still hope that one will turn out to be as effective as clozapine, without the same side effects.

Finally, Dr. Benes mentioned glutamate. A new model is emerging that suggests that glutamate may also play a very important role in this illness. Our group has been working with a nearly forgotten drug, used about 30 years ago for tuberculosis, D-cycloserine, that acts through glutamate systems. When we add this drug to other anti-psychotic agents, we find remarkable improvement in negative symptoms. This finding is quite exciting, because it suggests a new therapeutic option for patients with resistant negative symptoms. It also holds promise of opening up an entirely new avenue for drug development.

DR. BENES: Our strategies are to try to work out the neural circuitry that might give rise to the abnormalities we see clinically in schizophrenia. We are also identifying the circuitry that anti-psychotic medications may act on, in the hope that this will give us clues to improved therapy.

When we study brain tissue under a microscope, we can see dopamine fibers forming very close connections with the inhibitory GABA cells that I was telling you about. So, such interactions exist. However, there is another transmitter called serotonin. What we have observed is that, not only are dopamine fibers sweeping in and converging on the inhibitory GABA cells, but also serotinergic fibers are converging on the very same cells.

Now we have learned that the serotonin receptor involved in the action of clozapine is localized, preferentially, on these inhibitory GABA cells and that two different dopamine receptors are localized on this very same cell.

Clozapine has really revolutionized the treatment of schizophrenia. I have patients who could not leave the McLean grounds for 15 to 20 years; they're now living in condominiums, driving cars, and holding part time jobs because of clozapine.

Why is this drug so effective? One of the things that is absolutely striking is that it's what we call a "dirty drug;" it's non-selective in its mechanism of action. It blocks the 5HT2A (serotonin) receptor, the D1(dopamine) receptor, the D2 receptor. And the question that we're asking is, is it possible that its unique efficacy is because all three of these receptors are localized on the population of cells that we believe to be impaired in schizophrenia?

In other words, is it possible that clozapine is blocking three different receptors simultaneously, instead of only one receptor, or only two receptors? And could it be that the simultaneous blockade of all three is having a profound impact on the ability of this cell to fire more effectively and modulate the activity of the larger excitatory cell?

Finally, an important issue is that schizophrenia has been known for over a hundred years to characteristically begin between 16 and 25 years of age. We have brilliant young scholars, athletes, artists and so forth, who suddenly at age 16 to 18 begin to withdraw, become odd, and undergo an inexorable deterioration. Why is this?

We are exploring the idea that normal maturational changes in the brain may take place during late adolescence and trigger the appearance of schizophrenia in individuals who carry the vulnerability for this disorder. Now, you might be saying, "Brain development during adolescence, that's absurd; the brain develops in-utero, the brain develops during the first one or two years of life, but it doesn't continue to develop in meaningful ways after that." Well, it does continue to develop, and one of the neurotransmitter systems that show extremely extensive changes is the dopamine system.

We've been able to show in studies of rats that, around the time equivalent to adolescence, dopamine fibers show a pronounced increase in number. And a pronounced increase by the start of adulthood in the extent to which dopamine fibers are interacting with any given GABA cell.

So, if there are defective GABA cells, it's possible that the growing-in of dopamine fibers and formation of interactions with GABA cells may be what triggers the start of this disorder during late adolescence. If this is the case, it may suggest novel treatment strategies that could be applied early in the illness, directed at the interaction between dopamine fibers and GABA cells. In such a way it may be possible to prevent not only the onset of the illness, but certainly the deterioration in functioning, which characteristically takes place in the first five years of illness.

Questions from the floor

DR. BENES: Actually there has been quite a bit of research on that. Several studies in different parts of the world have demonstrated that, as a group, schizophrenics have a much higher than expected incidence of obstetrical complications in their birthing records.

Viral infections in utero during the second trimester are only one of the prenatal complications that have been identified. Another is exposure to prolonged labor that is associated with low oxygen levels at the time of birth. The current thinking is that physiological stress may be the common denominator, both pre- and peri-natally. The brain is a very sensitive organ during that period, and the steroid hormones that are released in abundance under conditions of stress do have the potential to be neurotoxic to the brain.

It is very important to emphasize that many people have been exposed to complications in utero and at the time of birth and do not become schizophrenic. In fact, people with cerebral palsy who have been exposed to profound anoxia at the time of birth have no higher than expected incidence of schizophrenia. So, it is generally accepted that there must be a vulnerability to schizophrenia, probably determined by a gene, for one of these obstetrical complications to culminate in schizophrenia. The complication by itself cannot cause schizophrenia.

Q: Is there not at least anecdotal information that relates schizophrenia to an increased intellect and aesthetic sense, in some people?

DR. BENES: There have been reports of that over the years. Albert Einstein's son was actually a very gifted young poet before he developed schizophrenia. But if you look at a cross section of individuals in the general population who have schizophrenia, as I understand it, there is no difference in IQ before the illness develops.

In manic depressive illness, there is some tendency toward greater creativity. In fact, many great artists were known to have manic depressive illness.

DR. GOFF: There has been a misconception that genius is a form of insanity and people with schizophrenia are more likely to be very bright. There is one study looking at biographies of 300 historical geniuses; none of them had schizophrenia. The closest was James Joyce, who had auditory hallucinations but primarily while he was drinking. His daughter actually developed schizophrenia so he may have had the vulnerability, but it wasn't fully expressed. When you look at the school records of people who develop schizophrenia, their grades are actually poorer than controls. So, if anything there is probably a slight cognitive impairment in people who go on to develop it.

Q: Do schizophrenics who are treated and discharged from the hospital, and stop taking their medication, relapse --or is there a lasting effect of clozapine?

DR. GOFF: No, relapse is almost the rule when people stop their medication. I also just wanted to comment in reference to Dr. Benes' final remarks about protecting people by treating the illness early enough: There is actually clinical evidence that the longer we delay treating schizophrenia, the worse the outcome. And there is some reason now to think that psychosis itself may be toxic in some way to the brain. So, it appears to be very important to try to treat this illness as early as possible, with as an effective an agent as we can offer.