Schizophrenia: Epidemiology, Clinical Features, Course and Outcome 453

Schizophrenia: Epidemiology, Clinical Features,

Course and Outcome
W G Frankle, University of Pittsburgh, Pittsburgh,
PA, USA

interviews and agreed-on criteria for case identification, providing improved reliability in the diagnosis.

2009 Elsevier Ltd. All rights reserved.

Prevalence and Incidence

Introduction
Schizophrenia represents a brain disorder (or cluster
of disorders) characterized by hallucinations, delusions, impairments in cognitive functioning, and
blunted emotional relatedness. It ranks among the
top diseases as a cause of disability in industrialized
nations. With its onset in adolescence or early adulthood and the lack of fully effective treatments, it
contributes greatly to the global burden of disease.
In the United States alone, the direct and indirect
costs of schizophrenia were estimated at $32.5 billion
in 1990. In addition, it is associated with increased
rates of general medical illnesses, including heart disease and diabetes, as well as frequent comorbid psychiatric illnesses such as substance abuse. Although
significant advances have been made in the treatment
of this disorder during the past 50 years, much
remains unknown regarding the transmission, clinical
course, and optimum therapy for this illness.

Epidemiology
Studies exploring the epidemiology of schizophrenia
have been performed since the work of Koller in 1895
highlighted the heritability of this disorder. However,
in the intervening century, the determination of epidemiologic factors relating to schizophrenia, such as
incidence, population prevalence, and risk factors,
has been disadvantaged by methodological problems
not encountered in nonpsychiatric complex disease
processes. First and foremost has been the issue of
case identification. To date, as with all psychiatric
illnesses, there are no biological tests to determine
the disease state, and therefore clinical interviews,
clinical observations, and self-reports form the basis
for diagnosis. Moreover, shifting definitions have
been utilized as diagnostic criteria for schizophrenia,
confounding comparisons across studies and over
time. With the development of standardized criteria
for diagnosis in the 1980s, the third edition of
the Diagnostic and Statistical Manual of Mental
Disorders (DSM-III) and the tenth revision of the
International Statistical Classification of Diseases
and Related Health Problems allowed for structured

The prevalence of a disease represents the morbidity

of the disease in the population and is a combination
of the incidence and the length of the illness.
Although certain small populations exist in which
the prevalence of schizophrenia has been found to
be significantly increased or decreased compared
with larger samples, the point prevalence rates across
populations are, in general, similar, in the range of
four per thousand, with lifetime morbidity rates in the
range of seven to eight per thousand.
The incidence rate of a disease represents the risk of
that diseases occurring at a point in time in a particular population. As the onset of schizophrenia is a
relatively rare event, studies examining the incidence
rate of schizophrenia generally use the point of first
contact with mental health workers as the time of
onset of the illness. This potentially represents a confound since the actual onset of symptoms frequently
precedes contact with the mental health system by
several years, a problem which some studies address
by defining the time of onset retrospectively, although
this is not ideal either. Incidence rates of schizophrenia across studies range from 0.07 to 7.1 per thousand per year. The WHO Determinants of Outcome
study, published in 1992, was a ten-country study of
schizophrenia which provided insights into the variability of this disease across cultures. Using a restrictive definition of schizophrenia, the WHO study
found that there were no differences across countries
in the annual rates of schizophrenia, with rates averaging around 0.10 per thousand annually. Given that
the WHO incidence rates were similar across cultures, it would seem that factors such as climate and
economic development of a country play little or no
role in the risk for schizophrenia.
Moreover, there appears to be no difference between
men and women in lifetime risk for schizophrenia. The
lifetime risk for diagnosis of schizophrenia was determined to be approximately 0.13 per thousand in a
study of first-admission cases by Hafner and colleagues. However, gender differences are apparent
when comparing the age of onset of the illness. The
age range of maximum risk for schizophrenia extends
from 15 to 30 years old; for men the onset tends to
occur about 45 years earlier than for women. As
noted previously, first contact with mental health services is frequently delayed from the onset of the illness

454 Schizophrenia: Epidemiology, Clinical Features, Course and Outcome

and occurs between 25 and 35 years of age for both

men and women. In spite of the age difference in onset
between men and women, the core features of the
illness are similar in both genders.
There are several other findings relating to the epidemiology of schizophrenia that remain interesting but
are of uncertain significance. First is the finding of
increased rates of schizophrenia in urban centers. At
times this has been attributed to a drift phenomenon;
in other terms, individuals with schizophrenia may
tend to migrate to urban areas. However, although
Marcelis and colleagues in 1998 found a significant,
positive correlation between the size of urban centers
and the incidence of schizophrenia, they were not able
to detect a difference between urban birth and urban
residence. Another interesting epidemiological factor
that remains unexplained is the highly replicated
finding relating to season of birth. In the northern
hemisphere, there is a 58% increase in schizophrenia
births in the winter and spring compared with the
other seasons. Finally, reports have repeatedly shown
an increased prevalence of schizophrenia in immigrants compared with native-born individuals; however, methodological issues such as access to care,
diagnostic difficulties due to language, and cultural
issues confound the interpretation of these reports.
Risk Factors

Family history of the illness represents the single

greatest risk factor for developing schizophrenia and
was observed in the very first studies of this disease by
individuals such as Koller and Kraepelin in the early
twentieth century. The lifetime risk of developing
schizophrenia for an individual with a first-degree
relative who had the illness is 116%, compared
with less than 1% in the general population. Individuals with a schizophrenic parent have a 15-fold
increased risk of developing the illness; for siblings
of an individual with schizophrenia, the risk of developing the illness is about tenfold greater than the
general population. Second-degree relatives (nephews,
nieces, grandchildren, and half-siblings) have approximate 3 times the rate of schizophrenia in the general
population. The concordance rate for monozygotic
twins ranges from 35% to 69%, depending on the
study, while that for dizygotic twins is similar to that
of siblings (026%). Adoption studies show that the
risk of an adopted childs developing schizophrenia
depends on the presence of schizophrenia in a
biological parent rather than in the adoptive environment. Taken together, these findings indicate that
genetic predisposition to schizophrenia is a risk for,
but is not sufficient for, developing the illness and
that environmental factors clearly play a role.

A variety of environmental factors have been examined as being potentially related to the development
of schizophrenia; however, to date none have been
demonstrated to be definitively causal. Among these
factors are difficulties during pregnancy or birth,
perinatal brain damage, and various early infections.
Several studies have shown that obstetrical complications are associated with increased risk for developing
schizophrenia, on the order of 3 times the risk of
those without obstetrical complications. In one
study, the most significant risk was represented by
perinatal brain damage, which carried a sevenfold
increase in risk of schizophrenia. Intrauterine exposure to influenza or central nervous system infections
has also been associated with increased rates of
schizophrenia, although more-recent work has not
been able to replicate the findings related to maternal
influenza infection.
Additional factors associated with the subsequent
development of schizophrenia include poor premorbid
adjustment, with few friends, isolative behavior, and
lack of significant romantic relationships. However, as
these patterns can be seen frequently in the at-risk age
group of adolescence, their usefulness in predicting the
development of schizophrenia is limited; furthermore,
it is not clear whether these factors represent part of the
illness prodrome or the risk factors.
Recent literature has implicated premorbid cannabis use as a risk factor in the development of
schizophrenia. It has been evident for some time that
the rates of cannabis use among individuals with
schizophrenia are higher than those among the general population, but now, as reviewed by Arseneault
and colleagues in 2004, a relatively strong association
(odds ratio > 2) between premorbid cannabis use and
schizophrenia has been observed, particularly when
cannabis use occurs in adolescence. These data have
led to an increased interest in the link between cannabis use or abuse and the pathophysiology and/or etiology of schizophrenia. Still other risk factors linked to
the development of schizophrenia include low premorbid IQ, increasing paternal age, and epilepsy;
however, no single risk factor has been shown to be
causal in the development of schizophrenia. In conclusion, the transmission of schizophrenia is complex
and likely involves multiple interacting genes which
lead to a predisposition to the illness and that may
combine with as yet incompletely identified contributing environmental factors.

Clinical Features
The current nosology of schizophrenia can be traced
to the German psychiatrist Emil Kraepelin. Relying
on his research, Kraepelin promoted the observation

Schizophrenia: Epidemiology, Clinical Features, Course and Outcome 455

that there was no specific clinical symptom or symptoms unique to the major mental illnesses but rather a
specific pattern of symptoms and course which differentiated these disorders. Using this observation, he
began to develop a classification system for mental
illnesses which not only incorporated the clinical
symptoms but also relied on criteria of age of onset,
course, outcome, and prognosis to separate these disorders. It was with the publication of the sixth edition
of his textbook in 1899 that Kraepelin separated the
entity of dementia praecox from manic depressive
illness. The term dementia praecox (as demence
precoce) was first used by Benedict Augustin Morel
in 1852 to describe the onset of dementia in young
patients. Kraepelin defined dementia praecox as subacute development of a peculiar simple condition of
mental weakness occurring at a youthful age and
separated this entity into three forms hebephrenic,
catatonic, and paranoid (expanding on prior work by
Hecker and Kahlbaum). The true advance by Kraepelin in this area came with his emphasis on etiology and
outcome of the illness. He noted hereditary and premorbid personality as contributing to the appearance
of dementia praecox, as well as suggesting that the
presence of external factors, such as premature birth
and/or obstetrical complications, might increase the
likelihood of developing this illness. Most notably,
he highlighted the underlying biological nature of the
illness and the progressive, relapsing nature of dementia praecox.
The term schizophrenia was introduced by the
Swiss psychiatrist Eugene Bleuler (1908), who defined
it as a group of psychoses characterized by alterations
in thinking, feeling, and relatedness to the outside
world. Bleuler noted four primary or core features
of the illness, (1) looseness of associations, (2) affective flattening, (3) autism, and (4) ambivalence,
which became known as the four As and were widely
utilized as diagnostic criteria for schizophrenia. Bleuler
considered these symptoms essential for the diagnosis,
with the presence of additional, accessory features,
including hallucinations and delusions, being secondary to the diagnosis. The four As continued to be used
in the diagnosis of schizophrenia until the work of
Kurt Schneider, who in 1957 described first-rank
symptoms of schizophrenia. These included audible
thoughts; voices arguing, discussing, or commenting;
somatic passivity experiences; thought withdrawal;
thought broadcasting; and delusional perceptions.
Schneiders criteria shaped the current diagnostic
definition of schizophrenia and have been largely
incorporated into the DSM-IV, which uses a descriptive definition of the illness. The DSM-IV criteria
define what have come to be known as positive
symptoms and negative symptoms of the illness.

Positive symptoms represent the psychotic features

of the illness and include hallucinations, delusions,
disorganized speech, and disorganized behavior. The
negative symptoms of the illness are the absence of
normal behaviors and include affective flattening,
alogia, apathy, and avolition. In addition to clinical
symptoms, the DSM-IV diagnostic criteria for schizophrenia requires impairment in function of one or
more major areas, such as work, interpersonal relations, or self-care, defined as markedly below the
level achieved prior to the onset of the illness. Continuous signs of the disturbance must persist for at
least 6 months in order to meet the DSM-IV level of
schizophrenia.
Although they are not specifically listed as a diagnostic criterion for schizophrenia, it has become evident that this disorder is associated with cognitive
impairments. Of note, recent studies have demonstrated that it is the degree of cognitive impairment
which is the best predictor of long-term outcome in
individuals with schizophrenia. In general, the cognitive impairments seen in schizophrenia are most
marked in the areas of memory and executive function, although mild-to-moderate impairment can be
seen across all neurocognitive domains. The cognitive
impairments tend to persist throughout the course
of the illness, even during periods when the positive
and negative symptoms have waned. The degree of
impairment also appears to be relatively consistent
early on in the illness; however, some individuals
may experience a greater cognitive decline in later
life. The striking lack of treatments available to
address these cognitive deficits, combined with the
association of these symptoms with poorer functional outcomes, has lead to the recent collaboration
between academia, the National Institutes of Health,
and the pharmaceutical industry on the Measurement
and Treatment Research to Improve Cognition in
Schizophrenia initiative to develop treatments for
these symptoms.

Course and Outcome

It is now clear that, as noted by Kraepelin, the onset
of the diagnostic symptoms of schizophrenia is frequently preceded by changes in functioning and
behavior, termed prodromal symptoms. These may
include positive symptoms that do not rise to the
DSM-IV level in severity or in duration, mood symptoms, cognitive impairments, or social withdrawal.
Although useful, these prodromal symptoms exhibit
significant overlap with the range of normal experience in the at-risk age groups, and so they cannot be
used as diagnostic. Typically, the appearance of frank
psychotic symptoms marks the onset of schizophrenia;

456 Schizophrenia: Epidemiology, Clinical Features, Course and Outcome

however, formal diagnosis and subsequent treatment

are frequently delayed, on the average of approximately 1 year from the onset of psychosis. The first
signs of the illness occur before the age of 30 in
approximately 77% of individuals; nearly half the
time, symptoms can be identified as having been
present prior to the age of 20. Notwithstanding
this fact, the majority of individuals diagnosed with
schizophrenia achieve symptomatic recovery, with
estimates as high as 7585% achieving remission
with treatment at 12 years in uncontrolled studies.
Although definitions of remission vary, most studies
have measured significant improvement in positive
symptoms, with less improvement in negative symptoms, with treatment. Several factors have been identified as predicting elevated positive symptoms after
treatment, including a longer duration of untreated
psychosis, a greater degree and longer period of prodromal symptoms, and poor premorbid adjustment.
Similar factors have been noted to predict higher
levels of negative symptoms after 1 year of treatment.
Although most individuals experiencing a first episode of schizophrenia will achieve symptomatic recovery, nearly all will go on to experience at least one, and
likely multiple, subsequent episodes. Relapse rates
after the first episode range from 30% in the first
year to 80% within 5 years. With each subsequent
relapse, a significant proportion of individuals will
not recover to the same degree as after the first episode
of the illness and will experience persistent symptoms
and/or cognitive impairments. This chronic, relapsing
course of schizophrenia results in periods of relative
remissions, rarely reaching the level of premorbid
function, punctuated by acute exacerbation of the
symptoms. This pattern of illness progression was
noted by Kraepelin and appears to differing degrees
across individuals diagnosed with schizophrenia, with
more striking deterioration occurring in the early
years of the illness and a relative stabilization of
functioning in the later years. A number of largescale studies have examined the long-term outcome
in schizophrenia. These include studies such as the
Iowa 500 Follow-Up Study, which, with a retrospective design and an average 35-year follow-up, examined 500 patients admitted to Iowa State Psychiatric
Hospital between 1934 and 1944. Compared with
patients with other diagnoses, those with schizophrenia had poorer long-term outcomes; however, approximately 20% of participants were symptom free at
follow-up. Another example of this type of study is
the prospectively designed Chicago Follow-Up Study,
which has followed participants for up to 20 years.
This study has also found that patients with schizophrenia had poorer outcomes than those with other
psychiatric illnesses but that about 40% of those

with schizophrenia demonstrated periods of recovery

which could last several years. Comparisons between
these and other studies of this nature are hampered by
measurements used to assess outcome as well as the
variability in the diagnostic criteria. Despite these
factors, however, several points are clear. First, in all
studies, a subset of patients with schizophrenia, in
the range of 2057%, demonstrate a good outcome,
depending on the strictness of the criteria used in the
diagnosis of schizophrenia (inclusion of individuals
with some affective symptoms increases favorable
outcome rates) and the definition of good outcome.
Second, a small number, on the order of 68% of
participants, met criteria for recovered at follow-up,
meaning an absence of any symptoms. Finally, approximately 30% of patients with schizophrenia remain
impaired, requiring long-term continuous treatment
and experiencing few symptom-free intervals.
In sum, the clinical course of schizophrenia is highly
variable, with the majority of individuals experiencing a relapsing course, which may include sustained
periods of remission. In a smaller, but significant,
number of individuals, the course of schizophrenia
may be more chronic, with few, if any, symptomfree periods. In any discussion of long-term outcome,
it is important to highlight the fact that schizophrenia
is associated with a significant degree of mortality
due to suicide. Suicide is the leading cause of premature death among individuals with schizophrenia,
whose suicide risk is 8.5-fold that of the general
population. Approximately 2050% of individuals
with schizophrenia will attempt suicide, and 413%
have completed suicide.

Cross-Cultural Outcomes
Studies which have followed up the WHO Determinants of Outcome ten-country study samples have
revealed some interesting differences in outcomes
between developing and developed nations. A 2-year
outcome study of this population found that in developing nations (Colombia, India, and Nigeria), 62.7%
of individuals were remitted or in complete remission,
with 35.7% experiencing continuous or episodic
symptoms. Exactly the reverse was found in developed countries (Czech Republic, Denmark, Ireland,
Japan, Russia, the United Kingdom, and the United
States), with 36.8% remitted or in complete remission and 60.9% experiencing continuous or episodic
symptoms. Several independent studies have also
reported increased percentages of individuals with
better outcomes in developing compared with developed countries. The reason for this difference remains
unknown; possible explanations include differences
in genetic variations, difference in social support

Schizophrenia: Epidemiology, Clinical Features, Course and Outcome 457

and social networks, and other environmental factors.

Pharmacological management of the disease was used
in only a small proportion of individuals in developing
nations and therefore did not contribute to the
improved outcome in this setting.

Treatment
Since the discovery of the antimanic and antipsychotic effects of chlorpromazine in the early 1950s,
the mainstay of treatment for schizophrenia has been
pharmacotherapy with neuroleptic medications
(so termed by early researchers Jean Delay and Pierre
Deniker for the properties of slowing motor activity
and causing affective indifference and emotional neutrality). Earlier, therapies of questionable efficacy
were employed, including application of tuberculin,
insulin coma, and pharmacological agents such as
opium, morphine, cocaine, or bromide. Since the
introduction of chlorpromazine, numerous antipsychotic/neuroleptic medications have been introduced (on the order of 30 distinct compounds). The
introduction of chlorpromazine was followed by
haloperidol. Originally developed as an analgesic by
Paul Janssen in Belgium but quickly found to have
neuroleptic properties, haloperidol became one of
the most widely prescribed medications after its introduction in 1959 (1969 in the United States). The
work with chlorpromazine and haloperidol led to
the development of multiple drugs screened to have
properties in vitro similar to those of chlorpromazine
and haloperidol. These medications have been termed
the first-generation antipsychotics, with about 15
different drugs being introduced in the United States
from 1959 until 1975. Early preclinical research, along
with subsequent brain imaging studies in humans,
revealed a link between blockade of the dopamine D2
receptors and the ability of these medications to treat
psychosis.
In 1975, clozapine, a drug with relatively low affinity for D2 receptors but relatively high affinity to
serotonin 2a receptors (5-HT2a), was introduced in
Europe but withdrawn shortly thereafter due to the
risk of agranulocytosis associated with treatment.
This medication was reintroduced in 1990 with hematological monitoring requirements, allowing for safer
administration of the drug. Clinical studies have
repeatedly demonstrated a superior efficacy for clozapine compared with the first-generation drugs, particularly in treatment of refractory patients. Moreover,
clozapine is associated with fewer extrapyramidal
side effects (EPS), which are prominent with the
first-generation drugs due to blockade of the D2
receptors in the striatal brain regions. These two

facts, increased efficacy with decreased EPS, resulted

in clozapine being termed a second-generation or
atypical antipsychotic and led to the development
of additional medications (risperidone, olanzapine,
quetiapine, and ziprasidone) with high 5-HT2a affinity relative to D2 affinity. At standard clinical doses,
these medications appear to have lower rates of EPS
than the first-generation drugs did, and they have also
been classified as second generation or atypical antipsychotics. Although much work has been done to
examine the efficacy of these second-generation
drugs, with the exception of clozapine they demonstrate no clear superiority when compared with the
first-generation medications. Moreover, despite the
lower rates of EPS, additional side effects, most notably increased rates of impaired glucose metabolism
and diabetes, have been observed with the secondgeneration antipsychotic medications.
While all currently available antipsychotic treatments have been determined superior to placebo in the
treatment of the positive symptoms of schizophrenia,
their effect on negative symptoms and the cognitive
deficits can be described as minimal at best, with
clozapine demonstrating the largest effect. This deficiency in adequate treatments for the negative and
cognitive symptoms seen in this illness is a major
shortcoming of currently available therapeutics for
schizophrenia as the degree of cognitive impairment
has been shown to be a predictor of poor functional
outcome.
Although pharmacotherapy represents the main
first-line treatment for individuals with schizophrenia,
evidence has demonstrated that the best long-term
outcomes are achieved in this illness using a multimodality approach. In support of this is the fact
that many individuals with schizophrenia continue
to have impairments in social, occupational, and cognitive function even after adequate treatment of the
psychotic symptoms. In addition to pharmacotherapy,
treatment systems may include family therapy, individual therapy, cognitive behavioral therapy, social skills
training, employment training, or supported employment (albeit not all at the same time). These psychosocial interventions have been shown to enhance
functional outcomes and the individuals quality of life.

Conclusion
Schizophrenia carries with it a significant morbidity,
in terms of both the individual and the families
affected and the population as a whole. Over the
past half century, significant advances have been
made in standardizing the diagnostic criteria and
characterizing the course of this illness. However, it

458 Schizophrenia: Epidemiology, Clinical Features, Course and Outcome

remains clear that there is a large degree of interindividual heterogeneity in the severity of symptoms,
in the degree of between episode symptom remission,
and in the response to treatment. Three main areas of
focus hold potential for gaining a better understanding of this illness. First, the explosion of molecular
genetic studies in the last 2030 years, both at the
population level and at the individual level, holds
the promise of improving our understanding of the
genes and genetic alterations which place an individual at risk for developing schizophrenia. Second,
ongoing work aimed at further characterizing the
contributory environmental factors linked to increased
risk for schizophrenia may, in combination with
genetic studies, allow better prediction and perhaps
modulation of the risks for developing the disorder.
Finally, the development of treatments, with targets
beyond the standard dopamine D2 receptors, to
address the cognitive deficits and negative symptoms
of the illness could enhance the long-term outcome and
improve the day-to-day quality of life for those with
schizophrenia.
See also: Adolescent Brain Development and the Risk of
Psychiatric Disorders; Antipsychotic Drugs; Cognitive
Deficits in Schizophrenia; Cognitive Dysfunction in
Psychiatric Disorders; Schizophrenia: Genetics.

Further Reading
Adityanjee Y, Aderibigbe A, Theodoridis D, and Vieweg VR (1999)
Dementia praecox to schizophrenia: The first 100 years. Psychiatry and Clinical Neurosciences 53(4): 437448.

an der Heiden W and Hafner H (2000) The epidemiology of onset

and course of schizophrenia. European Archives of Psychiatry
and Clinical Neuroscience 250(6): 292303.
Ban TA (2004) Neuropsychopharmacology and the genetics of
schizophrenia: A history of the diagnosis of schizophrenia.
Progress in Neuro-Psychopharmacology & Biological Psychiatry 28(5): 753762.
Hafner H and an der Heiden W (1997) Epidemiology of schizophrenia.
Canadian Journal of Psychiatry 42(2): 139151.
Jablensky A (2000) Epidemiology of schizophrenia: The global
burden of disease and disability. European Archives of Psychiatry and Clinical Neuroscience 250(6): 274285.
Jobe TH and Harrow M (2005) Long-term outcome of patients
with schizophrenia: A review. Canadian Journal of Psychiatry
50(14): 892900.
Lichtermann D, Karbe E, and Maier W (2000) The genetic epidemiology of schizophrenia and of schizophrenia spectrum disorders. European Archives of Psychiatry and Clinical
Neuroscience 250(6): 304310.
Lieberman JA, Perkins D, Belger A, et al. (2001) The early stages of
schizophrenia: Speculations on pathogenesis, pathophysiology,
and therapeutic approaches. Biological Psychiatry 50(11):
884897.
Lopez-Munoz F, Alamo C, Cuenca E, et al. (2005) History of the
discovery and clinical introduction of chlorpromazine. Annals
of Clinical Psychiatry 17(3): 113135.
McGrath J, Saha S, Welham J, et al. (2004) A systematic review of
the incidence of schizophrenia: The distribution of rates and the
influence of sex, urbanicity, migrant status and methodology.
BMC Medicine 2: 13.
Saha S, Chant D, Welham J, and McGrath J (2005) A systematic
review of the prevalence of schizophrenia. PLoS Medicine 2(5):
e141.
Schultz SK and Andreasen NC (1999) Schizophrenia. Lancet 353
(9162): 14251430.