straight look at schizophrenia
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.
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
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.
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.
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.
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
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.
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.
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.
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
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.
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.
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
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.
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
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
Keefe, R.S.E., and Harvey, P.D. Understanding Schizophrenia: A
Guide to the New Research on Causes and Treatment. New York: Free
Keefe, R.S.E., and Harvey, P.D. Schizophrenia. McGrawHill
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 &
Richard Keefe is an associate professor of psychiatry and behavioral
sciences at Duke University. He can be reached at firstname.lastname@example.org