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Posted March 27, 2002:
Beautiful opinions about Mind:

A straight look at schizophrenia
Physician Richard Keefe '80 takes the cinematic out of this mental disease

The recent film A Beautiful Mind and book by the same title, written by Sylvia Nasar, depict the life of John Nash Jr. *50, who was diagnosed with schizophrenia. The film, directed by Ron Howard, is perhaps the most accurate and moving portrayal of the internal world of someone with schizophrenia ever brought to the general public's attention. It has led many people, particularly Princeton alumni, to ask questions about what schizophrenia is, what causes it, and how it is treated. The following synopsis was developed from work previously published by my colleague Philip Harvey and me.

Schizophrenia is believed by the majority of people to refer to a disorder characterized by multiple personalities. This misconception has been enforced repeatedly by even prestigious institutions such as the New York Times and the Supreme Court of the U.S. In reality, schizophrenia is a brain disorder that is characterized by bizarre mental experiences such as hallucinations and severe decrements in social, cognitive and occupational functioning.


Diagnosis and Clinical Characteristics

Patients with schizophrenia demonstrate a series of biological differences when compared as a group to controls without schizophrenia. At present, however, there is no biological marker available to indicate the presence of schizophrenia. A diagnosis is made on the basis of a cluster of symptoms reported by the patient and signs identified by the clinician. The most recent version of the Diagnostic and Statistical Manual for psychiatric disorders, referred to as DSM-IV, includes the criteria listed in Table 1 to help distinguish schizophrenia from other psychiatric disorders.


People with schizophrenia may report perceptual experiences in the absence of a perceptual stimulus. The most common of these is auditory hallucinations, most often reported in the form of words spoken to the person with schizophrenia. The language is often derogatory in nature, and can be tremendously frightening, especially in people experiencing hallucinations for the first time. Visual hallucinations, such as of human faces, are also possible. Tactile hallucinations, such as the experience of something moving on the skin, are less likely. Hallucinations through the senses of smell (olfactory) and taste (gustatory) are rare. While the film A Beautiful Mind depicted John Nash as having visual hallucinations, most of his hallucinatory experiences were auditory.


People with schizophrenia often maintain beliefs that are not held by the overwhelming majority of the general population. To be considered delusions, the beliefs must be unshakable. In many cases, these beliefs may be bizarre. Many of these bizarre beliefs stem from odd experiences. For instance, a person may report that new thoughts are placed inside his or her head via an outside force (thought insertion), or that his or her movements are being controlled by an outside agency, such as a satellite (passivity experiences). In some instances, the delusions have an element of suspiciousness to them, such as the incorrect belief that others are planning to cause the person with schizophrenia harm. The delusions may or may not be related to hallucinatory experiences.

The portrayal of John Nash's delusions were that they derived from visual hallucinations. While this is not the norm, it is also not unusual. The book and film of Nash's life portrayed a fascinating aspect of schizophrenia that is often overlooked: Nash had great ambivalence about leaving his delusional world behind. He once stated in a letter to me that leaving his delusions behind was "analogous to the role of willpower in dieting; if one makes an effort to ërationalize' one's thinking then one can simply recognize and reject the irrational hypotheses of delusional thinking." While having the genius of John Nash may help this process of rationalizing, it is not limited to Nobel Laureates. I have talked to other people with schizophrenia who have described that the appeal of the "inner world" of psychosis can be very strong, and that one of the sources of their ambivalence about receiving treatment is that this inner delusional world, comforting at times, begins to fade.

Negative Symptoms

While delusions and hallucinations are often referred to as "positive" symptoms, since they represent features of experience that are present in people with schizophrenia and absent in the general population, the phrase "negative" symptoms refers to human behavior that is found in most people, yet absent in people with schizophrenia. Included among these "negative symptoms" are social isolation, lack of motivation, lack of energy, slow or delayed speech, and diminished emotional expression, often referred to as "blunted affect."


People with schizophrenia may manifest an odd outward appearance due to the severity of their disorganization. This presentation may include speech that does not follow logically or sensibly, at times to the point of being incoherent. Facial expression may be odd or inappropriate, such as laughing for no reason. In some cases, people with schizophrenia may move in a strange and awkward manner. The extreme of this behavior, referred to as catatonia, has become very rare since pharmacological treatments have become available.

Cognitive Deficits

Although less striking than delusions and hallucinations, perhaps the most devastating feature of schizophrenia is the cognitive impairment found in most people with the disorder. On average, people with schizophrenia perform in the lowest 2-10 percent of the general population on tests of attention, memory, abstraction, motor skills, and language abilities. These cognitive deficits are perhaps the most important explanation for the difficulties that people with schizophrenia have functioning in everyday society. In addition, people with schizophrenia often have reduced insight regarding their illness. In fact, some may deny all symptoms of their disorder to the point that they will refuse treatment.

Mood Symptoms

Schizophrenia is associated with depression or bipolar disorder (manic-depressive illness) in about 10-15 percent of people with the disorder. The presence of both of these illnesses is referred to as schizoaffective disorder, and is generally associated with a more favorable outcome.

Functional Impairment

People with schizophrenia are far less likely than the general population to work, marry, have offspring, and live independently. About 10-15 percent are able to sustain full-time employment while 25-40 percent marry and have children. The film A Beautiful Mind depicted this type of functional impairment quite well. When his psychosis became full-blown, John Nash was not able to function adequately in his career or in his marriage. While the deinstitutionalization movements of the 1950s and the 1980s drastically reduced the number of people in long-term inpatient facilities, only a small minority of people diagnosed with schizophrenia in the U.S. are able to live without some form of public assistance.


The onset of schizophrenia is generally in the late-teens to early 20's, however onset is possible throughout the life-span, including childhood, which is referred to as childhood schizophrenia, and in the later stages of life (after age 40), which is referred to as late-onset schizophrenia. Little is known about early predictors of schizophrenia, however in some people, social isolation and cognitive deficits appear to be present years prior to the onset of delusions and hallucinations. While the onset of symptoms is abrupt in some people, others experience a more insidious process, including extreme social withdrawal, reduced motivation, mood changes, and cognitive and functional decline prior to the onset of full-blown schizophrenia symptoms. Following the onset of illness, the course of schizophrenia is normally characterized by episodes of relative remission in which only subtle residual and negative symptoms remain, and episodes of exacerbation of symptoms, which are often caused by failure to continue with treatment. While the scientific evidence on the issue of remission at the end-stages of life has been contradictory, John Nash's story provides some anecdotal evidence that some people with schizophrenia can recover substantially, including a return of occupational and interpersonal functioning. Some long-term studies have suggested that some patients may show a reduced tendency to have exacerbations as age increases beyond the sixth decade.

The Costs of Schizophrenia.

In addition to the high emotional cost brought on people with the illness and their families, schizophrenia is the most financially costly of all psychiatric conditions. Patients with schizophrenia use a disproportionately high percentage of mental-health services. The prevalence of schizophrenia in the U.S. is approximately 1 percent, but annual U.S. mental-health care expenditures for the treatment of schizophrenia have been estimated to be higher than 2.5 percent of the total cost of all healthcare in the country. Although schizophrenia affects fewer persons than other mental illnesses including depression and anxiety, estimates for total costs for the treatment of schizophrenia for the year 1994 were approximately $44.9 billion, or 25.8 percent of the total estimated costs of treatment of all mental illnesses. Direct costs (medication, hospitalization, and other mental health interventions) for schizophrenia were $23.7 billion, or about 52.8 percent of total costs for this disorder. Annual morbidity (loss of productivity and wages) and mortality (lifetime wages lost due to premature death of the patient) costs were estimated to be $15 billion and $1.8 billion, respectively. Schizophrenia is one of the top three most costly illnesses in the U.S. (following vascular illnesses and cancer). This high cost is underscored by the fact that many more Americans are affected annually by heart disease and cancer than schizophrenia.

Causes of schizophrenia.

The cause of schizophrenia has been a matter of concern and controversy for the last century. In a sense, the argument of "nature vs. nurture" has been acted out repeatedly in this domain. It is likely that there are various forms of schizophrenia, perhaps all with different causes. Although schizophrenia appears to be inherited, at least in some cases, the influence of genes is far from complete. Many arguments have been put forth regarding environmental factors that could cause schizophrenia. Very few of these theories are consistently supported.


Schizophrenia runs in families. The children of a parent with schizophrenia have a risk of developing the illness of about 10 percent, which is greater than 10 times the risk of developing schizophrenia with no relatives with the illness. This risk appears to be similar regardless of whether the children are raised by their parents with schizophrenia or are adopted away. At the same time, identical twins, who share 100 percent of their genes, are only about 50 percent likely to both develop schizophrenia if one twin is affected. These data argue that a strictly genetic explanation is not adequate to describe the causes of the illness.

Other illnesses, such as Huntington's Disease, which follow a pattern of inheritance associated with a strictly genetic transmission (50 percent of the children of any affected parent will develop the condition), have been found to have specific genetic markers. Unfortunately, no markers have been conclusively found to be associated with schizophrenia, but different studies have found potential chromosomal locations for at least one type of schizophrenia. At this time, the most reasonable conclusion is that schizophrenia has a genetic component, albeit one that is not a classic pattern of single gene inheritance, either recessive or dominant in nature. Research is continuing the search for better indicators of the genetic predisposition for schizophrenia. At present, too little is known for the use of genetic counseling or other interventions.

Obstetrical complications.

Several studies have found that the birth and intrauterine development of someone who eventually develops schizophrenia is more likely than normal to be associated with complications, such as forceps delivery or second-trimester maternal influenza. In addition, children of parents with schizophrenia who experience these complications are more likely than their siblings to manifest schizophrenia when they grow up. However, the number of documented cases of schizophrenia associated with pregnancy and birth complications in individuals without a schizophrenic relative is quite low. Thus, the simple experience of complicated pregnancy and delivery does not mean that any individual child has any meaningful risk for developing schizophrenia.

Family Interaction.

In years past, there were many theories that tried to explain schizophrenia in terms of patterns of family interaction. There is no credible evidence that interaction patterns cause schizophrenia in someone who would not have developed it anyway.

Expressed Emotion.

In contrast to the idea that interaction patterns can cause schizophrenia, it is clear that social interaction patterns in the environment of individuals who already have schizophrenia can have an effect on their course of illness. High levels of criticism directed at newly discharged people with schizophrenia, like other stressors, is associated with increased frequency of re-emergence of symptoms and re-hospitalization.

Regional Brain Dysfunction.

Magnetic resonance imaging (MRI) allows for the visualization of the brain at high levels of resolution. People with schizophrenia often have changes in the structure of their brain such as enlargement of the cerebral ventricles (the spaces in the brain close to the midline that are filled with fluid). Various brain regions have been found to be smaller in patients with schizophrenia, including the frontal cortex, temporal lobes, and the hippocampi.

An additional development in the study of schizophrenia is the ability of scientists to study brain functions. Using MRI machines that take a rapid series of images of the brain, it is possible to capture patterns of blood flow in the brain. Since blood flow correlates with brain activity, it is possible to examine brain activity while people perform mental tasks. Studies of patients with schizophrenia have found patterns of abnormal activation of the brain while performing tests of memory and problem solving. While healthy individuals' brains use the frontal cortex to perform these tasks, patients with schizophrenia tend to have a less organized and coherent pattern of activation. Consistent with their generally less organized approach to learning new information and solving problems, brain activity itself in schizophrenia appears to be organized in a less efficient manner.

Neurotransmitter changes.

Individual cells in the brain (i.e., neurons) communicate with each other using electrical-chemical means. These communications occur when different chemicals (called neurotransmitters) produced by the brain are released in proximity to other neurons. For years it has been suspected that neurotransmitter activity in schizophrenia is abnormal, because many of the medications used to treat schizophrenia act on dopamine receptors in the brain. Also, psychotic conditions can be caused by overdoses of medications that stimulate dopamine, such as amphetamine

Although dopamine is clearly implicated in schizophrenia, it is not simple over-activity of this neurotransmitter that causes schizophrenia. Measures of dopamine functions often do not suggest increased activity in patients with schizophrenia and in some patients there is evidence of decreased activity. In addition, dopamine interacts with several other neurotransmitters, meaning that the effects of dopamine might be indirect. Recent models of neurochemical dysfunction in the brains of people with schizophrenia suggest that other neurotransmitter systems may also be impaired. These include glutamatergic, serotonergic, and GABAergic systems.



Pharmacological Treatment

In the early 1950s, Chlorpromazine became the first pharmacological intervention to substantially reduce delusions and hallucinations in patients with schizophrenia. Several other similar medications were developed in the following decades. This class of medications, referred to as typical neuroleptics or conventional antipsychotics act primarily to block dopamine receptors in the brain. These medications were able to have an impact on delusions and hallucinations in some patients, but treatment was accompanied by a variety of side effects, including sedation, muscular rigidity, and restlessness. Adjunctive medications such as benztropine are used to reduce these side effects, but such anticholinergic medications have side effects of their own, such as dry mouth, dizziness, and further cognitive impairment. Perhaps the worst side effect of typical antipsychotics is tardive dyskinesia, an irreversible movement disorder. The most effective dosage of these medications was initially believed to be very high. Recent studies have suggested that lower doses (e.g. 2-4 milligrams per day of haloperidol) may be as effective with fewer side effects. The disadvantage of these medications is that they have minimal impact on negative symptoms such as social isolation, and they do not improve the severe cognitive impairments associated with schizophrenia.

Since the approval of clozapine in the U.S. in 1988, clinicians have referred to a new group of medications as atypical neuroleptics or novel antipsychotics. The side effects associated with these medications are far different than the conventional antipsychotic medications, and in many cases are believed to be minimized. While clozapine had been available in Europe for years, it was banned in the U.S. due to the presence of a severe side effect, agranulocytosis, which can be fatal. However, clozapine was the first medication that improved negative symptoms and cognitive deficits as well as delusions and hallucinations. Its approval in the U.S. was dependent upon a strict monitoring procedure that required patients to receive frequent blood tests if they were to continue on the medication. In the 1990s, the FDA approved several newer, atypical antipsychotic medications for use in the U.S., including risperidone, olanzapine, quetiapine, and ziprasidone. The advantage of these medications is that they appear to have few of the side effects of the conventional antipsychotic medications, and they improve negative symptoms and cognitive function. One of the disadvantages of these medications is that other than clozapine, all are still patented, thus they are more expensive than the conventional medications, whose patents have expired. The novel antipsychotic medications are not without side effects. At higher doses, some of them have some of the side effects of the older medications, and many of them cause significant weight gain. The efficacy and side effect profiles have not been fully determined for the newest of these medications, quetiapine and ziprasidone.

One must wonder what the impact of these newer medications may have been on the course of John Nash's life. If his first experiences with pharmacological treatment were more palatable, perhaps he may have been able to continue with treatment, and may have emerged from the darkness of his delusions decades earlier. Would he have been able to develop mathematical theories to rival and perhaps even surpass those he came upon in his early 20's? It is difficult not to imagine that we all would have benefited somehow from a more successful treatment of this, then, young brilliant man. It is almost certain that he would have lived a more satisfying life.

Behavioral treatment.

There are several different targets for behavioral treatments in schizophrenia. Patients with schizophrenia have difficulty acquiring skills in social, occupational, and independent living domains. Structured training programs have attempted to teach patients with schizophrenia how to function more effectively in these areas. Family interventions have also been designed to provide a supportive environment for patients with schizophrenia. These interventions have been demonstrated to reduce risk of relapse. A final current behavioral-treatment area is teaching patients how to cope with their hallucinations and delusions. Most patients with schizophrenia do not spontaneously recognize their symptoms as unusual and not truly real. Cognitive-behavioral treatments have been employed to help patients realize that these symptoms are actually not real and to help them develop plans for coping with the symptoms. Finally, given the numerous difficulties confronted by people with schizophrenia, they often benefit greatly from the opportunity to discuss the exigencies of their daily life with someone who does not shirk away from the unusual nature of their disorder.

In many ways, John Nash was able to come upon these behavioral treatments by finding them in his immediate environment and in his personal fortitude. Most other people with schizophrenia are not as fortunate. Yet, hopefully, the interest in schizophrenia that has been generated by the story of John Nash will stimulate the public and the institutions that support us to invest resources into pursuing an understanding of the mechanisms of the causes of schizophrenia and the treatments that may reduce suffering in this devastating illness.



Keefe, R.S.E., and Harvey, P.D. Understanding Schizophrenia: A Guide to the New Research on Causes and Treatment. New York: Free Press, 1994.

Keefe, R.S.E., and Harvey, P.D. Schizophrenia. McGraw—Hill Encyclopedia of Science & Technology, 9th edition, Volume 16, pp 108-111. McGraw-Hill 2002.

Gottesman, I.I. Schizophrenia Genesis: The Origins of Madness. New York: Freeman, 1991.

Torrey, E.F. Surviving Schizophrenia: A Manual for Families, Consumers, and Providers. Third Edition. New York: Harper & Row, 1995.

Weiden, P.J. Breakthroughs in Antipsychotic Medications: A Guide for Consumers, Families, and Clinicians. New York: W.W. Norton & Co., 1999


Richard Keefe is an associate professor of psychiatry and behavioral sciences at Duke University. He can be reached at richard.keefe@duke.edu