INTRODUCTION Schizophrenia is among the most disabling and economically

catastrophic medical disorders, ranked by the World Health Organization as one of the top
ten illnesses contributing to the global burden of disease [1].
Characteristics of schizophrenia typically include positive symptoms such as hallucinations
or delusions, disorganized speech, negative symptoms such as a flat affect or poverty of
speech, and impairments in cognition including attention, memory, and executive functions.
The illness is commonly associated with impairments in social and occupational
functioning [2]. Antipsychotic medications are first-line treatment for schizophrenia.
Evidence-based psychosocial interventions in conjunction with pharmacotherapy can help
patients achieve recovery.
This topic discusses the epidemiology and pathogenesis of schizophrenia. Clinical
manifestations, assessment, diagnosis, and course of schizophrenia are discussed separately.
Anxiety and depression in schizophrenia are discussed separately. Pharmacologic and
psychosocial treatments for schizophrenia are discussed separately. Other psychotic
disorders are discussed separately. (See "Schizophrenia: Clinical manifestations, course,
assessment, and diagnosis" and "Pharmacotherapy for schizophrenia: Acute and
maintenance phase treatment" and "Pharmacotherapy for schizophrenia: Side effect
management" and "Pharmacotherapy for schizophrenia: Long-acting injectable
antipsychotic drugs" and "Psychosocial interventions for schizophrenia" and "Depression in
schizophrenia" and "Anxiety in schizophrenia" and "Clinical manifestations, differential
diagnosis, and initial management of psychosis in adults".)
EPIDEMIOLOGY Schizophrenia occurs throughout the world. The prevalence of
schizophrenia (ie, the number of cases in a population at any one time point) approaches 1
percent internationally. The incidence (the number of new cases annually) is about 1.5 per
10,000 people [3]. Slightly more men are diagnosed with schizophrenia than women (on
the order of 1.4:1) [4], and women tend to be diagnosed later in life than men. There is also
some indication that the prognosis is worse in men [5,6].
A number of risk factors have been associated with the development of schizophrenia,
including living in an urban area [7,8], immigration [9,10], obstetrical complications [11],
and a late winter-early spring time of birth (perhaps reflecting exposure to influenza virus
during neural development). Advanced paternal age at conception has been associated with
increased risk of schizophrenia in epidemiologic studies [12], and may be associated with
an increased risk of de novo mutations [13].
Co-occurring conditions People with schizophrenia have higher rates of several
psychiatric disorders than people without schizophrenia, including:

Depressive disorders (See "Depression in schizophrenia".)

Anxiety disorders: social anxiety disorder, posttraumatic stress disorder, and obsessivecompulsive disorder (See "Anxiety in schizophrenia".)
Alcohol and other substance use disorders (See "Co-occurring schizophrenia and
substance use disorder: Epidemiology, pathogenesis, clinical manifestations, and
diagnosis".)
People with schizophrenia are also at greater risk for co-occurring conditions such as
metabolic and neurological problems. (See "Schizophrenia: Clinical manifestations, course,
assessment, and diagnosis", section on 'Associated physical manifestations'.)
The rate of suicide among people with schizophrenia is much higher than in the general
population. Approximately five percent of people with schizophrenia commit suicide over
their lifetime [14]. About 10 percent of all completed suicides are among people with
schizophrenia [15,16].
Cost The cost of schizophrenia is staggering. The overall cost of schizophrenia in the
United States in 2002 was estimated at about $63 billion [17]. This figure includes direct
healthcare costs and indirect costs associated with loss of productivity. A recent study
examining US insurance claims found that the annual health-related expenses of someone
with chronic schizophrenia averaged more than $15,000 [18].
Deficit schizophrenia Deficit schizophrenia, characterized by primary, enduring negative
symptoms, seems to be a specific disease process within the larger syndrome of
schizophrenia. Approximately 15 to 20 percent of the total schizophrenia population has the
deficit form of schizophrenia [19-22]. They are more likely to be male and more likely to
have relatives with schizophrenia than people with nondeficit schizophrenia [23-27]. As
opposed to the excess of late winter-early spring births observed in schizophrenia in
general, there is a disproportionate rate of summer births in the deficit group [19,28].
Examples of negative symptoms include decreased expressiveness, apathy, flat affect, and a
lack of energy. People with deficit schizophrenia are less likely to have addictions,
depression, suicidality, or delusions with high emotional content (such as jealous delusions)
compared to nondeficit schizophrenia [29-31]. (See "Schizophrenia: Clinical
manifestations, course, assessment, and diagnosis", section on 'Deficit schizophrenia'.)
PATHOGENESIS Although the pathogenesis of the disorder is unknown, it is almost
certain that schizophrenia represents a syndrome comprised of multiple diseases that
present with similar signs and symptoms [32]. This heterogeneity complicates the
elucidation of the etiological and pathophysiological factors that underlie the group of

disorders. Schizophrenia appears to be a uniquely human condition, which limits the utility
of animal models [33]. There is little doubt that schizophrenia proceeds from a complex
interaction between genes and the environment, but even the attempt to differentiate genetic
from environment risk factors may be artificial, since environmental factors can influence
gene expression just as a persons genetic make-up can influence response to environmental
stressors.
Research studies have found the following genetic and environmental risk factors in
schizophrenia, which may act through disrupted neurotransmitter system function.
Genetic risk Twin studies have been conducted in monozygotic and dizygotic twins to
examine concordance rates of schizophrenia within the twin pairs. The observed
concordance rate in monozygotic twins, who share 100 percent of their genes, is about 40
to 50 percent, whereas the observed concordance rate in dizygotic twins, who share 50
percent of their genes, is about 10 to 15 percent. [34-36]. The increased concordance rate of
schizophrenia in monozygotic compared to dizygotic twins suggests a strong genetic
component to schizophrenia. The offspring of the unaffected monozygotic twins are at
increased risk of schizophrenia, which further supports the existence of a genetic
predisposition for the illness. The fact that the monozygotic twin concordance rate is less
than 100 percent, however, suggests that non-genetic, environmental factors are also
involved in the development of the illness. [34-36]. Adoption studies have provided further
evidence for the presence of genetic risk factors
Although there is abundant evidence for genetic risk factors, the specific genes involved in
the etiology of schizophrenia have not been identified. Initial studies have used genetic
linkage or candidate gene approaches to identify several specific genes as candidates for a
role in the development of schizophrenia (table 1).
The mapping of the human genome has allowed for the study of associations between gene
variants and risk or occurrence of diseases, ie, genome-wide association studies (GWAS).
The results of GWAS of schizophrenia support a polygenic model, in which multiple genes
with additive small effects lead to the disorder. As many as 500,000 single nucleotide
polymorphisms (SNPs) have been tested in GWAS for association with schizophrenia. As
an example, in one study, 108 SNPs were found to have a significant association with
schizophrenia [37]. The identified genetic loci supported the involvement of the
dopaminergic and glutamatergic neurotransmitter systems in the pathophysiology of
schizophrenia. It replicated previous studies that have shown an association between genes
of the major histocompatibility complex, which support immune functions. (See "Genetic
association studies: Principles and applications".)

Another attempt to delineate the genetics of schizophrenia is the evaluation of copy number
variants (CNVs), which are genes that have been duplicated or deleted. People with
schizophrenia have been found to have higher rates of CNVs. The most frequent CNV
associated with schizophrenia is a deletion on the long arm of chromosome 22 (22q11)
[38]. (See "Genetic association studies: Principles and applications".)
Environmental risk
Obstetrical complications Various perinatal problems, grouped together for analysis as
obstetrical complications, increase the risk of later development of schizophrenia twofold [11]. These perinatal problems include:
Hemorrhage
Pre-term labor
Blood-group incompatibilities
Fetal hypoxia
Maternal infection (See 'Infections' below.)
The accuracy of these data, based on maternal recall many years after childbirth, has been
questioned, but studies suggest that the risk does not appear to be influenced by inaccurate
memories [39,40]. The association between obstetrical complications and the development
of schizophrenia has also been observed in data from medical records, which do not rely on
recall [11].
Pregnancy during famines in the Netherlands (1944 through 1945) [41] and in China (1959
through 1961) [42,43] has been associated with a two-fold risk of schizophrenia in the
offspring, in studies based on subsequent hospital records. This may indicate maternal
nutrition is a factor in the development of schizophrenia. Other, related factors associated
with an increased risk of subsequently developing schizophrenia include being the product
of an unwanted pregnancy [44] and the prenatal death of the father [45].
Increased maternal stress has been proposed as the common pathophysiological mechanism
underlying risk factors, such as famine, bereavement, and antenatal infection. An animal
model provides some support for this theory [46].
Infections Several epidemiologic findings have suggested a possible role of certain
infectious agents as potential risk factors for the development of schizophrenia:

Numerous epidemiological studies have found a rise in schizophrenia prevalence in

cohorts born during influenza epidemics [47].
The increased risk for schizophrenia among those born in the late winter-early spring. This
could possibly reflect increased maternal exposure to influenza virus during prenatal neural
development.
High maternal IgG antibodies to the parasite toxoplasma gondii have been found to
increase the relative risk of developing schizophrenia in offspring by about 60 to 70 percent
[48,49].
Studies have varied on whether herpes simplex virus type 2 maternal infection increases
the risk for schizophrenia; some studies have found increased risks between 60 percent to
more than 400 percent [50,51], while other studies have found no increased risk [52].
Other infectious agents associated with schizophrenia appear to have an influence outside
the model of perinatal exposure of the affected individual. As examples:
Higher maternal levels of IgG to toxoplasma gondii are related to the later development of
schizophrenia in the mother herself [53].
Measles antibodies are higher in people with schizophrenia, especially in those with
recent-onset of psychosis, than controls [54].
The mechanism by which infections increase the risk of schizophrenia is unclear. There is
little evidence to suggest that the risk is associated with direct damage to the CNS by the
infectious agent. A study comparing individuals hospitalized for meningitis as children to a
control group who were hospitalized with gastroenteritis as children found no difference in
the risk of later hospitalization for schizophrenia [55]. A more likely explanation is that
infection by certain agents triggers an immune response in a mother that is passed through
the placenta to the developing fetus, which comprises the blood brain barrier and allows
antibodies, which cross-react with CNS proteins, to enter into the developing nervous
system [56]. Early childhood infections could also initiate an immune response and lead to
a general state of increased inflammation. (See 'Inflammation' below.)
Inflammation Increased immune system activation leads to higher levels of circulating
pro-inflammatory cytokines. Increased pro-inflammatory cytokine levels have been
frequently observed in schizophrenia [57]. Cytokines can alter the blood-brain barrier, or be
produced locally in the CNS by activated microglia, and may be responsible for psychosis,
its exacerbation, or cognitive impairments [58]. The actions of antipsychotic drugs may be
partially mediated by the anti-inflammatory effects of these agents [59].

In addition to associations between schizophrenia and some infections, there is other

evidence for abnormal immune activation in people with schizophrenia. (See 'Infections'
above.)
Autoimmune disorders that have been associated with a higher prevalence of schizophrenia
include [60,61]:
Acquired hemolytic anemia
Bullous pemphigoid
Celiac disease
Interstitial cystitis
Thyrotoxicosis
(A notable exception is rheumatoid arthritis, in which schizophrenia rates are lower than
expected based on rates in the general population [62]. People with schizophrenia are also
more likely to have circulating antibodies to proteins common in most Western diets, such
as gluten [63,64] and casein [65,66].)
Clinical trials are investigating several anti-inflammatory agents in the treatment or
prevention of psychosis, including:
Omega-3 fatty acids [67]
Minocycline
Statins
Non-steroidal anti-inflammatory drugs [68,69]
Inflammation in people with schizophrenia may also be responsible for some of the
disorders associated conditions such as heart disease (through decreased elasticity of
inflamed blood vessels) and diabetes (See "Schizophrenia: Clinical manifestations, course,
assessment, and diagnosis", section on 'Metabolic disturbances'.)
Cannabis use Epidemiological studies suggest that cannabis use is a risk factor for the
development of psychosis [70-72]. Initial findings from retrospective studies were
inconclusive because people with psychotic disorders, even before they were diagnosed,
could be using cannabis. This would indicate that psychosis was a risk factor for using

cannabis rather than the reverse. Well-controlled, prospective studies following hundreds of
people have subsequently supported the hypothesis that cannabis use is the risk factor and
psychosis the result [73,74]. The increased risk posed by cannabis use depends on other risk
factors, such as family history, but is generally reported with odds ratios of 2.2 to 2.8
[71,73,74]. Acute infusions of delta-9-tetrahydrocannabinol have provoked psychotic-like
symptoms in people with and without schizophrenia [75,76], providing further evidence for
cannabis as a risk factor for psychosis. (See "Cannabis use disorder: Epidemiology,
comorbidity, and pathogenesis".)
Immigration Numerous studies in multiple countries have observed a higher prevalence
of schizophrenia in immigrant populations compared to native-born populations [9,10].
This increased relative risk can be as high as four-fold, depending on the study. An
increased risk appears to extend to second-generation immigrants as well [10].
Several possible explanations for the association between immigrants and schizophrenia
have been proposed:
Schizophrenia may be overdiagnosed in immigrant populations; however, further research
suggests that this cannot entirely explain the increase in risk observed [77].
In people with either a genetic or neurodevelopmental biological risk for schizophrenia,
stress can play a role in the ultimate development of the disorder. In this way, the stress of
immigration, becoming part of an outsider group, may contribute to the development of
schizophrenia. Studies have found associations between the amount of social discrimination
experienced by immigrant groups and the rates of schizophrenia in the group; that is,
immigrant groups experiencing more discrimination have higher rates of schizophrenia than
immigrant groups experiencing lower rates of social discrimination. This finding has been
observed in several immigrant groups in several countries:
Ethiopian immigrants to Israel [78]
Moroccan immigrants to Holland [10]
Caribbean immigrants to the United Kingdom [79]
The increased risk of schizophrenia in immigrants may be related to vitamin D deficiency,
especially among individuals who move to more northern latitudes [80].
Neurotransmitters
Dopamine All drugs with antipsychotic properties block the dopaminergic D2 receptor,
a finding that has led to the dopamine hypothesis of schizophrenia, in which excess

dopamine in the mesolimbic tract has been hypothesized to cause positive psychotic
symptoms. However, if dopamine were the sole neurotransmitter disrupted in
schizophrenia, then antipsychotics would be universally and completely effective for these
symptoms. However, despite adequate antipsychotic treatment, many people with
schizophrenia continue to exhibit positive symptoms. Therefore, it is likely that dysfunction
in other neurotransmitter systems is required to explain why many people with the illness
exhibit only a partial reduction in positive symptoms, and why clozapine, the most
efficacious antipsychotic in schizophrenia, is a weak D2 antagonist.
Decreased dopamine in the prefrontal cortex (largely affecting the D1 receptor) may be
responsible for some of the cognitive and negative symptoms observed in schizophrenia
[81,82]. (See "Schizophrenia: Clinical manifestations, course, assessment, and diagnosis",
section on 'Clinical manifestations'.)
Glutamate Glutamate is the major CNS excitatory neurotransmitter. Hypofunction of the
N-methyl-D-aspartate (NMDA) glutamate receptor has been hypothesized to contribute to
the pathology of schizophrenia [83]. Evidence comes from:
Clinical observations of people who have misused phencyclidine (a NMDA receptor
antagonist)
Challenge studies using ketamine (a NMDA receptor antagonist) [84-86]
Genetic findings [83]
Post-mortem studies [87]
Studies measuring the level of endogenous NMDA receptor antagonists in the CNS of
people with schizophrenia [88,89]
Clinical trials with agents that enhance glutamatergic neurotransmission have had varied
results depending on the mechanism of the agent used [90,91]. (See "Pharmacotherapy for
schizophrenia: Acute and maintenance phase treatment".)
Gamma-amino-butyric acid Gamma-amino-butyric acid (GABA) is the major CNS
inhibitory neurotransmitter GABAergic interneurons are important for regulation of
prefrontal cortical function, through their modulation of glutamatergic pyramidal cells.
Several lines of evidence suggest that these interneurons are dysfunctional in people with
schizophrenia [92-97].
Postmortem studies in people with schizophrenia have found decreased levels of glutamic
acid decarboxylase (GAD67) mRNA expression in the prefrontal cortex [98].

In people with schizophrenia with decreased GAD67, there is a decrease in the density of
chandelier cell connections with the pyramidal cell axon initial segment [98] and in the
immunoreactivity of the GABA plasma membrane transporter-1 in chandelier cell axon
terminals [98].
There appears to be a decrease in GABA reuptake transporter mRNA levels [98] and an
increase in GABAA 2 subunit density on the axon initial segment [98], both of which may
be compensatory shifts.
Acetylcholine The increased smoking behaviors observed in people with schizophrenia
[99-102] has led to the hypothesis that nicotine, which stimulates a subset of acetylcholine
receptors, is correcting a fundamental neurochemical problem in schizophrenia. Treatment
with nicotine or a nicotinic cholinergic drug can normalize some eye-tracking and EEG
abnormalities observed in people with schizophrenia [103-107] and may acutely improve
some aspects of cognition [108,109]. However, nicotinic acetylcholine receptors can affect
many other neurotransmitter systems (for example, nicotine can enhance current mediated
by glutamate receptors in dopamine neurons of the rat ventral tegmentum [110,111]), and
so it is not clear whether the cholinergic system is primarily disrupted in schizophrenia or
the disruption is secondary to other pathological characteristics of the illness.
INTRODUCTION Schizophrenia is a psychiatric disorder involving chronic or recurrent
psychosis. It is commonly associated with impairments in social and occupational
functioning [1]. It is among the most disabling and economically catastrophic medical
disorders, ranked by the World Health Organization as one of the top ten illnesses
contributing to the global burden of disease [2].
Characteristics of schizophrenia typically include positive symptoms such as hallucinations
or delusions, disorganized speech, negative symptoms such as a flat affect or poverty of
speech, and impairments in cognition including attention, memory and executive functions.
A diagnosis of schizophrenia is based on the presence of such symptoms, coupled with
social or occupational dysfunction, for at least six months in the absence of another
diagnosis that would better account for the presentation.
This topic discusses clinical manifestations, assessment, diagnosis, and course of
schizophrenia. The epidemiology and pathogenesis of schizophrenia are discussed
separately. Anxiety, depression, and substance abuse in schizophrenia are discussed
separately. The treatments for schizophrenia are discussed separately, as are other psychotic
disorders. (See "Schizophrenia: Epidemiology and pathogenesis" and "Depression in
schizophrenia" and "Anxiety in schizophrenia" and "Pharmacotherapy for schizophrenia:
Acute and maintenance phase treatment" and "Pharmacotherapy for schizophrenia: Side
effect management" and "Co-occurring schizophrenia and substance use disorder:

Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "First-generation

antipsychotic medications: Pharmacology, administration, and comparative side effects"
and "Second-generation antipsychotic medications: Pharmacology, administration, and
comparative side effects" and "Psychosocial interventions for schizophrenia" and
"Psychosocial interventions for severe mental illness" and "Clinical manifestations,
differential diagnosis, and initial management of psychosis in adults".)
CLINICAL MANIFESTATIONS Schizophrenia is a syndrome. People with
schizophrenia generally present with several symptom domains (ie, areas of distinct
psychopathology):
Positive symptoms
Negative symptoms
Cognitive impairment
Mood and anxiety symptoms
Positive symptoms This group of symptoms includes the reality distortion symptoms of
hallucinations and delusions as well as disorganized thoughts and behavior [3-5].
Hallucinations Hallucinations are defined as the perception of a sensory process in the
absence of an external source. They can be auditory, visual, somatic, olfactory, or gustatory.
Auditory hallucinations are the most common form of hallucination, with prevalence
estimates between 40 and 80 percent in people with schizophrenia [6,7]. Although auditory
hallucinations are frequently voices, they can take the form of other sounds such as music,
body noises, or machinery. Some people with schizophrenia describe the sounds as coming
from inside their head, whereas others can point to a specific external location from which
they emanate. Auditory hallucinations are often the manifestation of the illness most
responsive to antipsychotic medication. Many people with schizophrenia report
antipsychotics turn down the volume of these hallucinations such that they can cope with
them better.
Visual hallucinations are often unformed, such as glowing orbs or flashes of color.
However, some people with schizophrenia describe fully formed human figures, faces, or
body parts.
Somatic hallucinations can include feelings of being touched, of sexual intercourse, or of
pain.

Olfactory and gustatory hallucinations have not been systematically studied, but
occasional patients will report a strange taste or smell.
Delusions Delusions, defined as a fixed (ie, resistant to change, even in the face of
overwhelming contradictory evidence), false belief, are present in approximately 80 percent
of people with schizophrenia [7]. Because insight into their illness may be impaired, people
with schizophrenia often have delusional explanations for their hallucinations. Delusions
are broadly categorized as bizarre or non-bizarre although the distinction is less important
in the current diagnostic rubric.
Bizarre delusions are clearly implausible, ie, they have no possibility of being true (eg,
contradict the laws of physics). Their content is not understandable [8]. Basic concepts may
be described in an unusual way, eg, how the person experiences time, space, the self, or
causality [9]. An example of a bizarre delusion is a patients belief that aliens have cloned a
patient a perfect body, but he must find a way to take off his head so that his spirit can flow
into the new body.
A non-bizarre delusion is one that while not true is understandable and has the possibility
of being true. An example is that the IRS is after the patient for not paying taxes.
The content of delusions can often be categorized as ideas of reference, grandiose,
paranoid, nihilistic, and erotomanic.
Ideas/delusions of reference are beliefs that random or neutral events are not random or
neutral, but include the individual in a special way. Common ideas of reference include
believing that occurrences on the television or radio (certain words said or songs played)
are meant to deliver a special message to the individual.
Grandiose delusions form around the belief that the person has some special significance
or power.
Paranoid delusions are clinically important because they may prevent the individual from
cooperating with evaluation or treatment, and because they may increase the likelihood of
problems like homelessness as the person goes off the grid.
Nihilistic delusions are uncommon, bizarre beliefs that one is dead or ones body is
breaking down or that one does not exist.
In erotomanic delusions, the person erroneously believes that he/she has a special
relationship with someone. These delusions can lead to legal problems such as restraining
orders and trespass charges.

Disorganization Schizophrenia is a thought disorder. People with schizophrenia typically

display some disorganization in behavior and/or thinking. Disorganized behaviors are
directly observed while disorganized thoughts must be inferred from the patients speech.
Disjointed, disconnected speech patterns reflect a disruption in the organization of persons
thoughts. The most commonly observed forms of abnormal speech are tangentiality and
circumstantiality, while more severe thought disorder includes derailment, neologisms, and
word salad. The symptoms of disorganization are independent of the severity of
hallucinations or delusions [10].
Tangential speech The person gets increasingly further off the topic without
appropriately answering a question.
Circumstantial speech The person will eventually answer a question, but in a markedly
roundabout manner.
Derailment The person suddenly switches topic without any logic or segue.
Neologisms The creation of new, idiosyncratic words.
Word salad Words are thrown together without any sensible meaning.
Negative symptoms While positive symptoms represent an exaggeration of a normal
processes, negative symptoms are conceptualized as an absence or diminution of normal
processes. Negative symptoms may be primary or secondary.
Primary, enduring negative symptoms represent a core feature of schizophrenia; they are
also referred to as deficit symptoms. Examples of negative symptoms include decreased
expressiveness, apathy, flat affect, and a lack of energy. Independent of the
primary/secondary distinction, negative symptoms appear to cluster into two components: a
diminished expression symptom cluster and an avolition-apathy cluster [11,12]. The
recognition of the existence of these two clusters may facilitate the delineation of the
pathophysiology of this illness component and lead to the development of novel
therapeutics. A table lists negative symptoms (table 1).
Primary negative symptoms are very resistant to treatment [13-15] and closely related to
functional outcome [16,17]. The severity of negative symptoms is independent of the
reality distortion positive symptoms (ie, hallucinations and delusions) [18]. A person may
simultaneously have deficit symptoms and be quite psychotic, or have deficit symptoms in
the absence of positive symptoms.
Alternatively, negative symptoms may be secondary to other manifestations of the illness or
its treatment. As examples, paranoia may lead to social isolation, and depression may lead

to anergy. An unchanging facial expression may be an extrapyramidal side effect of

medication.
Deficit schizophrenia While not a recognized DSM-5 subtype of schizophrenia, people
with schizophrenia who have prominent negative (or deficit) symptoms appear to represent
a distinct subgroup [18]. People with deficit schizophrenia are less likely to have delusions
with high emotional content (such as jealous delusions) compared to nondeficit
schizophrenia [17,19,20]. People categorized as deficit are least likely to show
improvement and recovery over the course of the illness. (See "Schizophrenia:
Epidemiology and pathogenesis", section on 'Deficit schizophrenia'.)
Cognitive impairment Areas of cognition that seem to be the most affected in
schizophrenia are described below [21]. It is not known whether these areas reflect multiple
unique deficits, or a generalized deficit that affects multiple areas of cognition [22,23].
Processing speed
Attention
Working memory
Verbal learning and memory
Visual learning and memory
Reasoning/executive functioning
Verbal comprehension
Social cognition
These impairments are reflected in the performance on neuropsychological tests among
people with schizophrenia. On average, the neuropsychological test performance of
someone with schizophrenia is one to two standard deviations lower than the performance
of healthy controls [22,24]. If an individual tests within the normal range on any given
neuropsychological battery, then his or her pre-morbid performance was very likely to have
been above average. People with schizophrenia who appeared to lack cognitive impairment,
when matched to healthy controls on age, education, and intelligence quotient (IQ), may
actually show a unique pattern of performance deficits in memory and processing speed
[25,26].

Cognitive impairments usually precede the onset of positive symptoms [27]. Impairment in
performance of cognitive tasks in people with first-episode schizophrenia is usually of a
similar magnitude as that seen people with multiple episodes [28]. The same pattern of
cognitive impairment is observed in the family members of people with schizophrenia,
though the magnitude of impairment is less [29]. In a study of monozygotic twins
discordant for the disorder, affected twins performed worse on tests of memory and
vigilance than the unaffected siblings [30].
Although antipsychotic medication and anticholinergic medication can impair cognition
[31,32], reports of memory disturbances in schizophrenia predate the advent of medication
[33]. The same pattern of cognitive dysfunction in people with schizophrenia is seen in
both treated groups and those who have never been exposed to antipsychotics [34].
Mood and anxiety symptoms Mood and anxiety symptoms are common in
schizophrenia; mood and anxiety disorders appear to occur at a higher rate than in the
general population. The epidemiology, clinical manifestations, diagnosis, and treatment of
mood and anxiety symptoms in schizophrenia are discussed separately. (See "Depression in
schizophrenia" and "Anxiety in schizophrenia".)
Associated physical manifestations There are several physical manifestations associated
with schizophrenia, including neurological disturbances, catatonia, and metabolic
disturbances.
Neurological disturbances Neurological soft signs involve subtle impairments of
sensory integration, motor coordination, and sequencing [35]. Examples of neurological
soft signs are right-left confusion, agraphesthesia (the inability to recognize letters or
numbers traced on the skin, usually on the palm of the hand), and astereognosia (the
inability to identify familiar objects by touch alone). These neurological soft signs are
observed in schizophrenia, are relatively stable, and are largely unrelated to medication [3538].
Research findings have linked certain symptom domains to neurological signs, ie, sensory
integration problems have been correlated with deficit symptoms, disorganization, and
cognitive impairment, while impaired sequencing of complex motor behaviors has been
correlated with disorganization [37,38].
Most neurological disturbances readily observed in people with schizophrenia are likely
medication-induced. Antipsychotic dopamine blockade can cause extrapyramidal symptoms
(EPS), such as tremor and bradykinesia, acute dystonias, akathisia (a subjective sense of
restlessness or actual restlessness), or tardive (meaning late) dyskinesia (which includes
abnormal peri-oral and other movements). However, descriptions of movement disorders

including signs of pseudoparkinsonism, choreiform movements, and myoclonic jerking are

common in the descriptions of schizophrenia that predate the development of
antipsychotics [34]. (See "First-generation antipsychotic medications: Pharmacology,
administration, and comparative side effects" and "Second-generation antipsychotic
medications: Pharmacology, administration, and comparative side effects" and "Tardive
dyskinesia: Etiology and epidemiology" and "Pharmacotherapy for schizophrenia: Side
effect management".)
Catatonia Catatonia can present in schizophrenia as either extreme negativism, eg,
motiveless motor resistance to instruction or attempts to move the person or mutism, or
catatonic excitement, eg, excessive, purposeless motor activity. Catatonia is reviewed in
more detail separately (See "Catatonia in adults: Epidemiology, clinical features,
assessment, and diagnosis".)
Metabolic disturbances Schizophrenia is associated with diabetes, hyperlipidemia, and
hypertension. Although many antipsychotics cause metabolic disturbances including weight
gain and diabetes, people with schizophrenia often have other risk factors for these
conditions, including a sedentary lifestyle and smoking. There is also evidence from the
pre-antipsychotic era and insulin coma treatments that schizophrenia itself is associated
with insulin resistance [39]. The life expectancy of people with schizophrenia is reduced by
more than a decade compared to the general population. This excess medical mortality is
largely mediated by heart disease [40]. (See "Pharmacotherapy for schizophrenia: Side
effect management".)
COURSE Although earlier descriptions of schizophrenia suggested that the course was
quite poor, the course actually shows considerable heterogeneity. One of the first and most
influential longitudinal studies of the course of schizophrenia described eight course types,
which differ in several ways [41]:
Onset Abrupt versus insidious
Symptom presentation Continuous versus intermittent
Outcome Poor versus non-poor
Most people with schizophrenia in the study had an acute onset, intermittent symptoms, and
later had no or only mild symptoms. Only about 20 percent had the stereotypical insidious
onset, continuous symptoms, and poor outcome. In a re-examination of these data,
participants were re-diagnosed with more stringent DSM-IV and ICD criteria, and the
results among those retaining a schizophrenia diagnosis were largely unchanged from the
original course observations [42].

Other influential longitudinal studies of schizophrenia demonstrate that the course of

schizophrenia is not uniform and that there are subsets of individuals with fairly good
outcome [43-45]. A 15 to 25 year follow-up of 644 participants with schizophrenia who
participated in World Health Organization studies (including the International Pilot Study
of Schizophrenia and the Determinants of Outcome of Severe Mental Disorders study)
found that about half had favorable outcomes (minimal or no symptoms, employment,
Global Assessment of Functioning (GAF) scores greater than 60) [45,46].
However, earlier in the illness, functional recovery is rarer. In a medication algorithm study,
only about 14 percent of 118 people with a first episode of schizophrenia or schizoaffective
disorder met recovery criteria for 2 or more years during the first 5 years of the illness [47].
Recovery in this study was defined as no more than mild psychotic symptoms, no more
than moderate negative symptoms, adequate role function (student, employment,
homemaker), attention to hygiene, and independence in daily chores. An exception to this
heterogeneity seems to be people with deficit schizophrenia, who seem to have a more
consistently poor prognosis compared to their nondeficit peers [16,17].
The DSM-5 has several specifiers that can be applied to describe the course of illness after
one year following the patients diagnosis [1]. (See 'Specifiers for schizophrenia in DSM-5'
below.)
Remission and recovery Remission of schizophrenia refers to a state in which the
individual has no symptoms, or minimal symptoms that do not interfere with behavior, for a
period of at least six months [48,49].
Over the past decade, consumer advocacy has drawn attention to the concept of recovery
from schizophrenia. The model of recovery that has emerged differs from a strictly clinical
model of recovery (eg, no or mild symptoms, restored functioning). The consumer-driven
model is a blend of function, life-satisfaction, and independence. Despite scientific efforts
to capture this outcome, there are no currently accepted scales to measure recovery [50].
ASSESSMENT The differential diagnosis of psychosis, and the medical workup to
identify/exclude psychoses secondary to medical conditions, are described separately. (See
"Clinical manifestations, differential diagnosis, and initial management of psychosis in
adults".)
The diagnosis of schizophrenia is often one of exclusion. No symptom or group of
symptoms is pathognomonic for schizophrenia; however, there are specific hallucinations
and delusions that are characteristic of the illness, known as first-rank symptoms [51]
(table 2). Although upwards of 85 percent of people with schizophrenia endorse these
symptoms, up to 25 percent of manic bipolar patients endorse first-rank symptoms in cross-

sectional studies [7], and about 45 percent endorse these symptoms in longitudinal studies
[52], which suggests that these symptoms are not specific to schizophrenia [52,53]. There
are no laboratory or physical examination findings or other biomarkers that are useful in
making the diagnosis.
The patient assessment is based on the diagnostic interview supplemented by collateral
information. Family members or caregivers are often a good source of information about a
patients clinical presentation outside the office or hospital. Medical records, especially
from the initial presentation of the illness and most recent hospitalization, can give
additional information.
Working with patients who are uncooperative, whether from paranoia or for other reasons,
can be challenging. Even if a person denies hearing voices, it is sometimes observed that he
or she seems to be responding to internal stimulation (by smiling inappropriately, looking in
the direction from where they hear a voice, or seeming distracted during an interview).
Although there are other reasons a person might act this way, and diagnosis should not be
based solely on these observations, the behaviors of a person may provide useful
information as to their ongoing internal experiences.
The severity of symptoms should be assessed in each domain affected by the illness, ie,
psychosis/thought disorder, negative symptoms, cognitive impairment, mood/anxiety.
Assessment of someone with schizophrenia should include evaluations of health including
cholesterol, blood glucose, weight and BMI, prolactin, evaluation of motor disturbances,
and a urine drug screen.
In the course of assessment and ongoing clinical care, the clinician can be a critical source
of compassion and education for the patient and family. Along with treatment for their
symptoms and medication side effects, the patient may need help coping with disabilities,
associated losses, and the stigma associated with the diagnosis of schizophrenia. This
stigma can be as damaging as the direct effects of the illness.
DIAGNOSIS The diagnosis of schizophrenia requires the presence of characteristic
symptoms of the disorder (delusions, hallucinations, disorganized speech or behavior,
and/or negative symptoms) coupled with social and/or occupational dysfunction for at least
six months in the absence of another diagnosis that would better account for the
presentation.
DSM-5 diagnostic criteria for schizophrenia are described in more detail below [1].
A. Two or more of the characteristic symptoms below are present for a significant portion
of time during a one-month period (or less if successfully treated):

1. Delusions
2. Hallucinations
3. Disorganized speech (eg, frequent derailment or incoherence)
4. Grossly disorganized or catatonic behavior
5. Negative symptoms, ie, affective flattening, alogia, or avolition
B. For a significant portion of the time since the onset of the disturbance, one or more
major areas of functioning such as work, interpersonal relations, or self-care are markedly
below the level achieved prior to the onset. When the onset is in childhood or adolescence:
failure to achieve expected level of interpersonal, academic, or occupational achievement.
C. Continuous signs of the disturbance persist for at least six months. The six-month
period must include at least one month of symptoms (or less if successfully treated) that
meet Criterion A (ie, active-phase symptoms) and may include periods of prodromal or
residual symptoms. During these prodromal or residual periods, the signs of the disturbance
may be manifested by only negative symptoms or two or more symptoms listed in Criterion
A that present in an attenuated form (eg, odd beliefs, unusual perceptual experiences).
D. Schizoaffective disorder and mood disorder with psychotic features have been ruled
out because either: (1) no major depressive, manic, or mixed episodes have occurred
concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during
active-phase symptoms, their total duration has been brief relative to the duration of the
active and residual periods.
E. The disturbance is not due to the direct physiological effects of a substance (eg, a drug
of abuse or medication) or a general medical condition.
F. If the patient has a history of autistic disorder or another pervasive developmental
disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or
hallucinations are also present for at least a month (or less if successfully treated).
Specifiers for schizophrenia in DSM-5 The following course specifiers can be applied
only after at least 1 year has elapsed since the initial onset of the disorder. Specify if:
First episode, currently in acute episode
First episode, currently in partial remission

First episode, currently in full remission

Multiple episodes, currently in acute episode
Multiple episodes, currently in partial remission
Multiple episodes, currently in full remission
Continuous
Unspecified
Specify if: with catatonia
Specify current severity: Each of the following symptoms may be rated for its highest
severity in the last seven days. A five-point scale is used: from 0 (not present) to 4 (present
and severe).
Delusions
Hallucinations
Disorganized speech
Abnormal psychomotor behavior
Negative symptoms
Changes to the diagnostic criteria for schizophrenia from DSM-IV to DSM-5 included [1]:
At least two of the five A-criteria symptoms must be present, and at least one must be
delusions, hallucinations, or disorganized speech in DSM-5. One symptom was sufficient in
certain circumstances inDSM-IV.
A specifier to document the presence of catatonia was added in DSM-5; the DSM-IV
specifier, with prominent negative symptoms, was omitted from DSM-5. (See "Catatonia in
adults: Epidemiology, clinical features, assessment, and diagnosis".)
DSM-5 included new specifiers for rating the severity of A-criteria symptoms and for
describing the patients course of illness.
DSM-5 excluded the five subtypes of schizophrenia that were included in previous
versions of the manual. There was little evidence that these subtypes were stable [54],

clustered in families [55], or provided clinical utility beyond a description of the patients
presentation at the time of diagnosis.
Differential diagnosis The most common psychiatric disorders in the differential
diagnosis of schizophrenia include schizophreniform disorder, schizoaffective disorder,
bipolar disorder, and major depression with psychotic features, and substance-induced
psychotic disorders
In schizophreniform disorder all the criteria for schizophrenia are met, but the total
duration of the disorder is less than six months.
Schizoaffective disorder, bipolar disorder, and major depression with psychotic features
all differ from schizophrenia in that there is a prominent mood component to the patients
presentation. (See "Unipolar major depression with psychotic features: Epidemiology,
clinical features, assessment, and diagnosis" and "Bipolar disorder in adults: Clinical
features".)
Schizoaffective disorder is essentially schizophrenia with manic episodes or a significant
depressive component. The validity and reliability of schizoaffective disorder remains
unresolved [56].
The difference between mood disorders with psychosis and schizoaffective disorder is the
timing of symptoms. In schizoaffective disorder, psychosis can and does occur in the
absence of a mood episode; in psychotic mood disorders the psychosis is only observed in
the presence of a mood episode. (See "Unipolar major depression with psychotic features:
Epidemiology, clinical features, assessment, and diagnosis".)
In substance-induced psychotic disorders the symptoms are a manifestation of
intoxication or acute withdrawal and do not persist after the individual is sober.
Psychosis due to a general medical condition should be ruled out. Conditions such as
previous CVA or TBI, Wilsons disease, porphyria, syphilis infection, and others can
present with psychotic symptoms.
Delusional disorder is present if the individual has a delusion, but criteria from
schizophrenia have never been met. An exception to this is that the person may have
olfactory or tactile hallucinations consistent with the delusion, but not auditory
hallucinations.
Schizotypal personality disorder is a long-standing pattern of odd or eccentric beliefs
and/or perceptual disturbances that do not rise to the level of delusions or hallucinations.

People with this presentation may eventually transition to a psychotic disorder, but many do
not [57].
Schizoid personality disorder is a long-standing pattern of little interest in social
relationships or intimacy. There is overlap with the negative symptoms seen in schizoid
personality disorder and schizophrenia, but schizoid personality disorder does not present
with psychosis.
Pervasive developmental disorders may present with psychosis or negative symptoms. An
additional diagnosis of schizophrenia should only be made in a patient with autism if
psychotic symptoms last more than one month.
The diagnoses of schizophreniform disorder, schizophrenia, schizoaffective disorder,
schizotypal personality disorder, and schizoid personality disorder are described
collectively as schizophrenia spectrum disorders. Although most researchers believe
schizophrenia is likely a syndrome of distinct disease entities, the concept of schizophrenia
spectrum disorders is useful for epidemiological research.
In many cases, repeated assessment longitudinally is necessary to definitive diagnose a
patient presenting with a schizophrenia spectrum disorder.
ICD-10 Diagnosis The World Health Organizations International Statistical
Classification of Disease and Related Health Problems, 10th Revision (ICD-10) is primarily
a coding source text and not a diagnostic manual, i.e. there is minimal guidance on making
a diagnosis [58]. Psychiatric diseases are listed with a short, prototypical description. The
schizophrenia section describes first-rank and negative symptoms as characteristic and
includes information on the variable course that can be seen in the illness .
ICD-10 includes the following subtypes of schizophrenia, many of which are similar to the
subtypes found in DSM-IV, but no longer present in DSM 5:
Paranoid Prominent delusions and hallucinations with little disturbance in affect or
speech.
Hebephrenic Similar to the DSM-IV disorganized schizophrenia, affective changes are
prominent mood is shallow and inappropriate should normally only be diagnosed in
adolescents and young adults.
Catatonic (See "Catatonia in adults: Epidemiology, clinical features, assessment, and
diagnosis".)

Post-schizophrenic depression Although listed with the subtypes of the illness, this
diagnosis refers to a period of depressed mood occurring after the resolution of an acute
psychotic exacerbation in someone with schizophrenia.
Residual Described as a chronic stage in which there has been a clear progression
from an early stage to a later stage characterized by long-term negative symptoms
Simple The picture of residual schizophrenia without having previously experienced any
explicit psychosis.
Undifferentiated Schizophrenia that does not fit a subtype.