Schizophrenia is a brain disorder that effects how people think, feel, and perceive the world.

Essential update: Uninherited genetic mutations pose risk for schizophrenia

In a pair of recent exome sequencing studies, researchers identified uninherited (de novo)
genetic mutations in patients with schizophrenia that cluster in specific proteins involved in
brain function and overlap with mutations that have been identified in patients with autism,
mental retardation, and intellectual disability. Both studies found mutations in genes involved
in synaptic pathways, which play a role in modulating connections between nerve cells, and
mutations in genes involved in the control of the fragile X mental retardation protein, which
is also seen in individuals with autism.
[1, 2]

Signs and symptoms
The symptoms of schizophrenia may be divided into the following 4 domains:
Positive symptoms - Psychotic symptoms, such as hallucinations, which are usually
auditory; delusions; and disorganized speech and behavior
Negative symptoms - Decrease in emotional range, poverty of speech, and loss of
interests and drive; the person with schizophrenia has tremendous inertia
Cognitive symptoms - Neurocognitive deficits (eg, deficits in working memory and
attention and in executive functions, such as the ability to organize and abstract);
patients also find it difficult to understand nuances and subtleties of interpersonal cues
and relationships
Mood symptoms - Patients often seem cheerful or sad in a way that is difficult to
understand; they often are depressed
See Clinical Presentation for more detail.
Diagnosis
Schizophrenia is not associated with any characteristic laboratory results.
Diagnostic criteria
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,
(DSM-5), to meet the criteria for diagnosis of schizophrenia, the patient must have
experienced at least 2 of the following symptoms
[3]
:
Delusions
Hallucinations
Disorganized speech
Disorganized or catatonic behavior
Negative symptoms
At least 1 of the symptoms must be the presence of delusions, hallucinations, or disorganized
speech.
Continuous signs of the disturbance must persist for at least 6 months, during which the
patient must experience at least 1 month of active symptoms (or less if successfully treated),
with social or occupational deterioration problems occurring over a significant amount of
time. These problems must not be attributable to another condition.
The American Psychiatric Association (APA) removed schizophrenia subtypes from the
DSM-5 because they did not appear to be helpful for providing better-targeted treatment or
predicting treatment response.
See Workup for more detail.
Management
Antipsychotic medications diminish the positive symptoms of schizophrenia and prevent
relapses.
There is no clear antipsychotic drug of choice for schizophrenia. Clozapine is the most
effective medication but is not recommended as first-line therapy.
Psychosocial treatment is essential. The best-studied psychosocial treatments are social skills
training, cognitive-behavioral therapy, cognitive remediation, and social cognition training.
Psychosocial treatments are currently oriented according to the recovery model. According to
this model, the goals of treatment for a person with schizophrenia are as follows:
To have few or stable symptoms
Not to be hospitalized
To manage his or her own funds and medications
To be either working or in school at least half-time
See Treatment and Medication for more detail.
Background
Schizophrenia is a brain disorder that probably comprises several separate illnesses. The
hallmark symptom of schizophrenia is psychosis, such as experiencing auditory
hallucinations (voices) and delusions (fixed false beliefs). Impaired cognition or a disturbance
in information processing is a less vivid symptom that interferes with day-to-day life. People
with schizophrenia have lower rates of employment, marriage, and independent living
compared with other people.
Schizophrenia is a clinical diagnosis. It must be differentiated from other psychiatric and
medical illnesses, as well as from disorders such as heavy metal toxicity, adverse effects of
drugs, and vitamin deficiencies. (See DDx and Workup.)
Treatment of schizophrenia requires an integration of medical, psychological, and
psychosocial inputs. The bulk of care occurs in an outpatient setting and is best carried out by
a multidisciplinary team. Psychosocial rehabilitation is an essential part of treatment.
Antipsychotic medications, also known as neuroleptic medications or major tranquilizers,
diminish the positive symptoms of schizophrenia and prevent relapses. Unfortunately, they
are also associated with a number of adverse effects. (See Treatment and Medication.)
Diagnostic criteria (DSM-5)
The specific DSM-5 criteria for schizophrenia are as follows
[3]
:
The presence of 2 (or more) of the following, each present for a significant portion of
time during a 1-month period (or less if successfully treated), with at least 1 of them
being (1), (2), or (3): (1) delusions, (2) hallucinations, (3) disorganized speech, (4)
grossly disorganized or catatonic behavior, and (5) negative symptoms
For a significant portion of the time since the onset of the disturbance, level of
functioning in 1 or more major areas (eg, work, interpersonal relations, or self-care) is
markedly below the level achieved before onset; when the onset is in childhood or
adolescence, the expected level of interpersonal, academic or occupational
functioning is not achieved
Continuous signs of the disturbance persist for a period of at least 6 months, which
must include at least 1 month of symptoms (or less if successfully treated); prodromal
symptoms often precede the active phase, and residual symptoms may follow it,
characterized by mild or subthreshold forms of hallucinations or delusions
Schizoaffective disorder and depressive or bipolar 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) any mood episodes
that have occurred during active-phase symptoms have been present for a minority of
the total duration of the active and residual periods of the illness
The disturbance is not attributable to the physiologic effects of a substance (eg, a drug
of abuse or a medication) or another medical condition
If there is a history of autism spectrum disorder or a communication disorder of
childhood onset, the additional diagnosis of schizophrenia is made only if prominent
delusions or hallucinations, in addition to the other required symptoms or
schizophrenia are also present for at least 1 month (or less if successfully treated)
In addition to the 5 symptom domain areas identified in the first diagnostic criterion,
assessment of cognition, depression, and mania symptom domains is vital for distinguishing
between schizophrenia and other psychotic disorders.
Various course specifiers are used, though only if the disorder has been present for at least 1
year and if they do not contradict diagnostic course criteria. These specifiers include the
following
[3]
:
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
The presence or absence of catatonia is specified. Individuals meeting the criteria for
catatonia receive an additional diagnosis of catatonia associated with schizophrenia to
indicate the presence of the comorbidity.
Finally, the current severity of the disorder is specified by evaluating the primary symptoms
of psychosis and rating their severity on a 5-point scale ranging from 0 (not present) to 4
(present and severe).
Schizophrenia subtypes were removed from DSM-5 because they did not appear to help with
providing better-targeted treatment or predicting treatment response.
Pathophysiology
Anatomic, neurotransmitter, and immune system abnormalities have been implicated in the
pathophysiology of schizophrenia.
Anatomic abnormalities
Neuroimaging studies show differences between the brains of those with schizophrenia and
those without this disorder. For example, the ventricles are somewhat larger, there is
decreased brain volume in medial temporal areas, and changes are seen in the hippocampus.
[4,
5, 6]

Interest has also focused on the various connections within the brain rather than on
localization in a single part of the brain. Magnetic resonance imaging (MRI) studies show
anatomic abnormalities in a network of neocortical and limbic regions and interconnecting
white-matter tracts.
[7]
A meta-analysis of studies using diffusion tensor imaging (DTI) to
examine white matter found that 2 networks of white-matter tracts are reduced in
schizophrenia.
[8]

In the Edinburgh High-Risk Study, brain imaging showed reductions in whole-brain volume
and in left and right prefrontal and temporal lobe volumes in 17 of 146 people who were at
high genetic risk for schizophrenia. The changes in prefrontal lobes were associated with
increasing severity of psychotic symptoms.
[9]

In a meta-analysis of 27 longitudinal MRI studies comparing schizophrenic patients with
control subjects, schizophrenia was associated with structural brain abnormalities that
progressed over time. The abnormalities identified included loss of whole-brain volume in
both gray and white matter and increases in lateral ventricular volume.
[10]

These findings are of interest more for research purposes than for clinical application.
Neurotransmitter system abnormalities
Abnormalities of the dopaminergic system are thought to exist in schizophrenia. The first
clearly effective antipsychotic drugs, chlorpromazine and reserpine, were structurally
different from each other, but they shared antidopaminergic properties. Drugs that diminish
the firing rates of mesolimbic dopamine D2 neurons are antipsychotic, and drugs that
stimulate these neurons (eg, amphetamines) exacerbate psychotic symptoms.
Hypodopaminergic activity in the mesocortical system, leading to negative symptoms, and
hyperdopaminergic activity in the mesolimbic system, leading to positive symptoms, may
coexist. (Negative and positive symptoms are defined elsewhere; see Presentation.)
Moreover, the newer antipsychotic drugs block both dopamine D2 and serotonin (5-
hydroxytryptamine [5-HT]) receptors.
Clozapine, perhaps the most effective antipsychotic agent, is a particularly weak dopamine
D2 antagonist. Thus, other neurotransmitter systems, such as norepinephrine, serotonin, and
gamma-aminobutyric acid (GABA), are undoubtedly involved.
Much research focuses on the N -methyl-D-aspartate (NMDA) subclass of glutamate
receptors because NMDA antagonists, such as phencyclidine and ketamine, can lead to
psychotic symptoms in healthy subjects.
[11, 12]
Some researchers consider schizophrenia, in
large part, a hypoglutamatergic disorder.
Inflammation and immune function
Immune function is disturbed in schizophrenia.
[13]
Overactivation of the immune system (eg,
from prenatal infection or postnatal stress) may result in overexpression of inflammatory
cytokines and subsequent alteration of brain structure and function. For example,
schizophrenic patients have elevated levels of proinflammatory cytokines that activate the
kynurenine pathway, by which tryptophan is metabolized into kynurenic and quinolinic acids;
these acids regulate NMDA receptor activity and may also be involved in dopamine
regulation.
Insulin resistance and metabolic disturbances, which are common in the schizophrenic
population, have also been linked to inflammation. Thus, inflammation might be related both
to the psychopathology of schizophrenia and to metabolic disturbances seen in patients with
schizophrenia.
[14]

Etiology
The causes of schizophrenia are not known. Most likely, there are at least 2 sets of risk
factors, genetic and perinatal. In addition, undefined socioenvironmental factors may increase
the risk of schizophrenia in international migrants or urban populations of ethnic
minorities.
[15, 16, 17]
Increased paternal age is associated with a greater risk of schizophrenia.
Genetic factors
The risk of schizophrenia is elevated in biologic relatives of persons with schizophrenia but
not in adopted relatives.
[18]
The risk of schizophrenia in first-degree relatives of persons with
schizophrenia is 10%. If both parents have schizophrenia, the risk of schizophrenia in their
child is 40%. Concordance for schizophrenia is about 10% for dizygotic twins and 40-50%
for monozygotic twins.
Genome-wide association studies have identified many candidate genes, but the individual
gene variants that have been implicated so far account for only a small fraction of
schizophrenia cases, and these findings have not always been replicated in different studies.
The genes that have been found mostly change a genes expression or a proteins function in
a small way.
Some loci of particular interest include the following:
Catechol-O-methyltransferase (COMT) gene
RELN gene
Nitric oxide synthase 1 adaptor protein (NOS1AP) gene
The COMT gene codes for the postsynaptic intracellular enzyme COMT, which is involved in
the methylation and degradation of the catecholamine neurotransmitters dopamine,
epinephrine, and norepinephrine. The several allelic variants of COMT affect its activity. The
valine-valine variant degrades dopamine faster than the valine-methionine variant does;
subjects with 2 copies of the methionine allele were less likely to develop psychotic
symptoms with cannabis use than were other cannabis-using subjects without that variant.
[19]

The RELN gene codes for the protein reelin, which plays a role in brain development and
GABAergic activity. In an international study, a common variant in this gene increased the
risk of schizophrenia, but only in women.
[20]

The NOS1AP gene codes for the enzyme nitric oxide synthase, which is found in high
concentration in inhibitory neurons in the brain. Nitric oxide acts as an intracellular
messenger. Using a newly developed statistical technique, the posterior probability of linkage
disequilibrium, researchers have identified a single-nucleotide polymorphism associated with
higher levels of expression of this gene in postmortem brain samples from individuals with
schizophrenia.
[21]

Other genetic changes involve the structure of the gene. For example, copy number variants
are deletions and duplications of segments of DNA; they can involve genes or regulatory
regions. These variants are usually inherited, but can arise spontaneously. Copy number
variants such as the deletions found at 1q21.1, 15q13.3, and 22q11.2 increase the risk of
developing schizophrenia.
[22, 23]
At most, however, these findings probably account for only a
small part of the heritability of schizophrenia.
In addition, the effects of some of these copy number variants are not restricted to
schizophrenia. Other copy number variant disorders include autism, intellectual disability,
attention-deficit hyperactivity disorder, and epilepsy.
[24]

In a study of 39,000 people referred to a diagnostic laboratory, about 1000 had a copy
number variant at 1 of the following loci: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and
22q11.2. Clinically, these people had various neurologic or psychiatric disorders, including
developmental delay, intellectual disability, and autism-related disorders. Subjects also had
congenital anomalies.
[25]

Many studies have also looked for abnormalities in neurodevelopmental genes. Disruptions in
the DISC1, NRG1, DTNBP1, KCNH2, AKT1, and RGS4 genes have been associated with
schizophrenia, albeit with significant variability between studies.
[26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,
37, 38]
These findings also lend support to the hypothesis that schizophrenia is a disease in
which multiple rare genetic variants lead to a common clinical outcome.
Some people with schizophrenia have no family history of the disorder. These cases may be
the result of new mutations. De novo mutations in the exome (the part of the chromosome
that codes for proteins) seem to be more common in patients with schizophrenia than would
otherwise be expected.
[39, 40]
In a pair of exome sequencing studies, researchers identified de
novo genetic mutations in patients with schizophrenia that cluster in specific proteins
involved in brain function and overlap with mutations that have been identified in patients
with autism, mental retardation and intellectual disability.
[1, 2]

A recent genome-wide association study beginning with a Swedish sample of 5,000 cases and
6,000 controls compared the results with a previous genome-wide association study and
findings of single-nucleotide polymorphisms (SNP) in independent examples. It found a
clustering at 22 loci, 14 of which were new. Most of the SNPs were common and,
collectively, could account for perhaps as much as one third of the variance in liability for
schizophrenia. In other words, common genetic variation may be involved in schizophrenia.
This is somewhat similar to the understanding of other complex trait diseases such as
coronary artery disease.
[41]

Schizophrenia and bipolar disorder are likely to have a large overlap in genetic risk factors,
but only a small portion of this genetic risk has been identified.
[42]

As can be seen, working out the details of these genetic factors is difficult. Interactions with
the rest of the genome and with the environment will doubtless prove to be important.
Nonetheless, a meta-analysis of twin studies estimated that genetic factors account for about
four fifths of liability to schizophrenia.
[43]

Perinatal factors
Women who are malnourished or who have certain viral illnesses during their pregnancy may
be at greater risk of giving birth to children who later develop schizophrenia.
[44]
For example,
children born to Dutch mothers who were malnourished during World War II have a high rate
of schizophrenia.
After the 1957 influenza A2 epidemics in Japan, England, and Scandinavia, rates of
schizophrenia were higher among offspring of women who contracted influenza during their
second trimester. Women in California who were pregnant between 1959 and 1966 were
more likely to have a child who developed schizophrenia if they had influenza in the first
trimester of their pregnancy.
[45]

Obstetric complications may be associated with a higher incidence of schizophrenia. Children
born in the winter months may be at greater risk for developing schizophrenia.
[46]

A study of Finnish women supported an interaction between genetic and environmental
influences on causation of schizophrenia.
[47]
In this study, a review of 9596 women in
Helsinki who received hospital treatment during pregnancy for an upper urinary tract
infection between 1947 and 1990 found no overall significant increase in the risk of
schizophrenia among their offspring but a 5-fold higher risk among the offspring of women
who also had a family history of psychosis. The authors estimated that among offspring of
women with both prenatal pyelonephritis and a positive family history of psychotic disorders,
38-46% of schizophrenia cases resulted from the synergistic action of the 2 risk factors.
[47]

Epidemiology
United States and international statistics
The lifetime prevalence of schizophrenia has generally been estimated to be approximately
1% worldwide.
[48]
However, a systematic review by Saha et al of 188 studies drawn from 46
countries found a lifetime risk of 4.0 per 1000 population; prevalence estimates from
countries considered least developed were significantly lower than those from countries
classed as emerging or developed.
[49]
Immigrants to developed countries show increased rates
of schizophrenia, with the risk extending to the second generation.
[15, 16, 17]

Age-related demographics
The onset of schizophrenia usually occurs between the late teens and the mid 30s.
[3]
For
males, the peak age of onset for the first psychotic episode is in the early to middle 20s; for
females, it is in the late 20s. The first 5-10 years of the illness can be stormy, but this initial
period is usually followed by decades of relative stability (though a return to baseline is
unusual). Positive symptoms are more likely to remit than are cognitive and negative
symptoms (see Presentation).
Sex-related demographics
The prevalence of schizophrenia is about the same in men and women. The onset of
schizophrenia is later in women than in men, and the clinical manifestations are less severe.
This may be because of the antidopaminergic influence of estrogen.
Race-related demographics
Although some variation by race or ethnicity has been reported, no racial differences in the
prevalence of schizophrenia have been positively identified. Some research indicates that
schizophrenia is diagnosed more frequently in black people than in white people; this finding
has been attributed to cultural bias of practitioners.
Prognosis
The prognosis is guarded. Full recovery is unusual. Early onset of illness, family history of
schizophrenia, structural brain abnormalities, and prominent cognitive symptoms are
associated with a poor prognosis. The prognosis is better for people living in low-income and
middle-income countries.
[50]

Symptoms usually follow a waxing-and-waning course and their nature may change over
time. Positive symptoms respond fairly well to antipsychotic medication, but the other
symptoms are quite persistent.
Because of vocational difficulties, many patients with schizophrenia also have to cope with
the burdens of poverty. These include limited access to medical care, which may lead to poor
control of the disease; homelessness; and incarceration, typically for minor offenses.
People with schizophrenia have a 5% lifetime risk of suicide.
[51]
Other factors that contribute
to increased mortality include lifestyle issues such as cigarette smoking, poor nutrition, and
lack of exercise, and perhaps poorer medical care and complications of medications. A study
from Britain shows that this mortality gap is increasing.
[52]

Patient Education
The nature of schizophrenia makes it a potentially difficult illness for patients to understand.
Nevertheless, teaching the patient to understand the importance of medication compliance
and of abstinence from alcohol and other drugs of abuse is important.
It is helpful to work with the patient so that both patient and family can learn to recognize
early signs of a decompensation (eg, insomnia or increased irritability). A review of 44
studies showed that education of patients about the nature of their illness and treatment, when
added to standard care, led to reductions in rehospitalization and symptoms.
[53]
Education
may improve adherence to medication and may help the patient cope with the illness better in
other ways.
Family members can be referred to the National Alliance on Mental Illness (NAMI) (or
another appropriate support group, if one is available). These groups can provide education
and support.
People with schizophrenia have also championed self-help recovery-based approaches to
care, with an emphasis on developing the personal strengths and resilience needed to combat
this illness.
Much psychosocial treatment that is discussed below has an educational component.
Because other illnesses are common in schizophrenia, education about the importance of a
healthy lifestyle and regular health care is helpful. Counseling with respect to sexuality,
pregnancy, and sexually transmitted diseases is important for these patients.
The following resources may also be helpful:
Mayo Clinic -Schizophrenia
National Institute of Mental Health -Schizophrenia
Medline Plus -Schizophrenia
For patient education resources, see the Schizophrenia Health Center, as well as
Schizophrenia.
Proceed to Clinical Presentation