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 obsessive-compulsive 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 person’s 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 two-fold [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 disorder’s 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 α2 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 patient’s 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 one’s 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 patient’s speech. Disjointed, disconnected speech patterns reflect a disruption in the organization of

person’s 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 [35-38].

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 patient’s 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 patient’s 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 patient’s 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 patient’s 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 patient’s 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, Wilson’s 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 Organization’s 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.