According to the dopamine hypothesis of schizophrenia, higher amphetamine-provoked dopamine release predicts worsening of psychotic symptoms. The dopamine hypothesis of schizophrenia posits that overactivity of dopamine neurotransmission in the subcortical basal ganglia contributes to positive (not negative) symptoms, and the hypoactivity of prefrontal cortical dopamine neurotransmission contributes to negative symptoms and cognitive abnormalities in patients with schizophrenia. This theory evolved from two observations: (1) the efficacy and the potency of many antipsychotic drugs (i.e., the dopamine receptor antagonists [DRAs]) are correlated with their ability to act as antagonists of the dopamine 2 (D₂) receptor; and (2) drugs that increase dopaminergic activity, notably cocaine and amphetamine, are psychotomimetic. It has been suggested that the dysregulation of dopaminergic neurotransmission in schizophrenia is caused by presynaptic reactivity, not postsynaptic sensitivity. Dopamine release provoked by amphetamine challenge is higher in schizophrenic patients at the onset of illness (drug-naïve patients) and during a relapse and is normal (not higher) during remission. Depletion of endogenous presynaptic dopamine vesicles has demonstrated that there is a higher (not lower) occupancy of D_2/3 receptors by dopamine treatment-naïve patients and in relapsed schizophrenic patients.

The essential neurobiological features of schizophrenia may place some constraints on plausible pathophysiological processes. First, there is a major genetic contribution. Many genes are likely to be involved, and these may function in part by increasing vulnerability to the deleterious effects of environmental factors. Several environmental factors have been hypothesized to increase the risk of schizophrenia, perhaps by producing subtle brain damage. Structural abnormalities have played an important role in placing theoretical constraints on mechanisms. Because they are present from early in the illness and do not appear to progress, they may predate the onset of illness. Neuropathological data and studies of obstetric and perinatal complications support the idea that an early lesion may account for structural changes. The apparent lack of gliosis in postmortem studies is particularly critical and implicates in utero factors. Structural and functional neuroimaging, as well as neuropsychological data and animal studies, present converging evidence for the importance of frontal and temporal regions. Finally, altered dopamine and glutamate neurotransmission is likely to play a part in the expression of psychotic symptoms.

The neurodevelopmental model can account for many of these findings. In short, some process (genetic or environmental) produces damage to selected brain areas early in life. Temporal lobe regions such as the hippocampus may be particularly vulnerable. Secondary functional abnormalities develop later. As the prefrontal cortex matures in late adolescence, the behavioral and cognitive sequelae of subtle structural deficits become manifest. One result is hypofrontality and cognitive impairment. Alterations in limbic and prefrontal function then produce downstream, secondary alterations in subcortical dopamine, glutamate, and other neurotransmitter systems. Dopamine dysfunction, in particular, may lead to positive psychotic symptoms. The feasibility of this model has received substantial validation from animal studies showing the delayed behavioral and neurobiological effects of minor damage to the hippocampus in neonatal rats. Observations that children at risk for schizophrenia have a number of subtle neuropsychiatric abnormalities, such as deficits in attention, motor control, and social interactions, also support the neurodevelopmental model.

Magnetic resonance imaging (MRI) studies have consistently shown that the brains of many schizophrenic patients have lateral and third ventricular enlargement and some degree of reduction in cortical volume. These findings can be interpreted as consistent with the presence of less than usual brain tissue in affected patients; whether that decrease is attributable to abnormal development or to degeneration remains undetermined.

However, the abnormalities reported in MRI studies of schizophrenic patients have also been reported in other neuropsychiatric conditions, including mood disorders, alcohol-related disorders, and dementias. Thus, these changes are not likely to be pathognomonic for the pathological processes underlying schizophrenia. Although the enlarged ventricles in schizophrenic patients can be shown when groups of patients and control subjects are used, the difference between affected and unaffected persons is variable and usually small.

One of the most important MRI studies examined monozygotic twins who were discordant with schizophrenia. The study found that virtually all of the affected twins had larger cerebral ventricles than did the nonaffected twins, although most of the affected twins had cerebral ventricles within a normal range.

Having previously attempted suicide does not increase the risk for developing schizophrenia, although at least 50 percent of patients with schizophrenia attempt suicide once in their lifetimes. Having a schizophrenic family member, especially having one or two schizophrenic parents or a monozygotic twin who is schizophrenic, increases the risk for schizophrenia. Other risk factors include (1) having lived through a difficult obstetrical delivery, presumably with trauma to the brain; (2) having, for unknown reasons, a deviant course of personality maturation and development that has produced an excessively shy, daydreaming, withdrawn, friendless child; an excessively compliant, good, or dependent child; a child with idiosyncratic thought processes; a child who is particularly sensitive to separation; a child who is destructive, violent, incorrigible, and prone to truancy; or an anhedonic child; (3) having a parent who has paranoid attitudes and formal disturbances of thinking; (4) having low levels of monoamine oxidase, type B, in the blood platelets; (5) having abnormal pursuit eye movements; (6) having taken a variety of drugs, particularly lysergic acid diethylamide (LSD), amphetamines, cannabis, cocaine, and phencyclidine; and (7) having a history of temporal lobe epilepsy, Huntington’s disease, homocystinuria, folic acid deficiency, or the adult form of metachromatic leukodystrophy.

None of those risk factors invariably occurs in schizophrenic patients; they may occur in various combinations. The vast majority of people who ingest psychotomimetic drugs do not become schizophrenic. Not every schizophrenic patient has abnormal pursuit eye movements, and some well relatives of schizophrenic patients may also have abnormal pursuit eye movements.

Patients with schizophrenia are more violent as a group than the general population. This is particularly a problem for patients with the paranoid type, who may act quite suddenly and impulsively on a delusional idea. Patients with paranoia tend to be intelligent and capable of forming plans; therefore, they represent a much greater risk than individuals who are disorganized and cannot plan an effective attack. Despite earlier beliefs, command hallucinations do not appear to play a particularly important role in violence. Violence between patients in hospitals frequently results from the attacking patient’s mistaken belief that another patient is behaving in a threatening way or getting physically too close. Studies have revealed that violence in a hospital setting can result from undiagnosed neuroleptic-induced acute akathisia. Persistently violent inpatients often do well in special treatment units that provide a more structured program and a less crowded environment. Patients who fail to respond to this kind of care usually show neurological signs in addition to their diagnosis.

Unfortunately, it is exceedingly difficult to prevent most schizophrenic homicides because there is usually no clear warning. Most of the homicides come as a horrifying surprise. Patients who are known to be paranoid with homicidal tendencies should not, as a rule, be allowed to move about freely as long as they retain their delusions and their aggressive tension.

An important epidemiological factor in schizophrenia is that some regions of the world have an unusually high prevalence of the disorder. Certain researchers have interpreted this geographic inequity as supporting an infectious cause for schizophrenia; others emphasize genetic or social factors.

Schizophrenic patients occupy 50 percent of mental hospital beds, not of all hospital beds.

Female patients with schizophrenia are no more likely to commit suicide than are male patients; the risk factors are equal.

There is a difference in prevalence of schizophrenia according to season, but in the northern hemisphere, schizophrenia occurs more often among people born from January to April, not from July to September. The latter time range refers to a seasonal preference for the disorder in the southern hemisphere. Reproduction rates among people with schizophrenia have been increasing in recent years because of newly introduced medications and changes in laws and policies about hospitalization and community-based care. The fertility rate among people with schizophrenia, however, is only approaching the rate for the general population and does not exceed it.

The inability to follow a moving visual target accurately is the defining basis for the disorders of smooth visual pursuit and disinhibition of saccadic eye movements seen in patients with schizophrenia. Eye movement dysfunction may be a trait marker for schizophrenia; it is independent of drug treatment and clinical state and is also seen in first-degree relatives of probands with schizophrenia. Various studies have reported abnormal eye movements in 50 to 85 percent of patients with schizophrenia compared with about 25 percent in psychiatric patients without schizophrenia and fewer than 10 percent in nonpsychiatrically ill control subjects. Because eye movement is partly controlled by centers in the frontal lobes, a disorder in eye movement is consistent with theories that implicate a frontal lobe pathological process in schizophrenia.

In general, pooled studies show concordance rates of about 50 percent in monozygotic twins. This is the most robust finding pointing to a genetic etiologic component to the disorder.

A person with schizophrenia often experiences a cenesthetic hallucination, a sensation of an altered state in body organs without any special receptor apparatus to explain the sensation—for example, a burning sensation in the brain, a pushing sensation in the abdominal blood vessels, or a cutting sensation in the bone marrow.

A delusional feeling is a feeling of false belief based on an incorrect inference about external reality. A gustatory hallucination involves primarily taste. A tactile or haptic hallucination involves the sense of touch (e.g., formication—the feeling of bugs crawling under the skin). A hypnopompic hallucination is a hallucination that occurs as one awakes. Neither hallucinations nor delusions are pathognomonic of schizophrenia; they may occur in other disorders.

Recent studies have established that the diagnosis of childhood schizophrenia may be based on the same symptoms used for adult schizophrenia. What characterizes childhood schizophrenia is not the nature but the dramatic intensity of its symptoms. Its onset is usually insidious, its course tends to be chronic, and the prognosis is mostly unfavorable. Briefly, it resembles the typical Kraepelinian case of dementia precox. What gives childhood schizophrenia unique importance for research is the observation that anatomical features of the brain that are often associated with adult-onset schizophrenia (e.g., enlarged ventricles) are also present in this early-onset form of the disease. Neurobiological studies of children with schizophrenia may therefore provide significant clues to the developmental pathogenesis of adult-onset schizophrenia.

Late-onset schizophrenia is clinically indistinguishable from early-onset schizophrenia but has an onset after age 45 years. This condition tends to appear more frequently in women and tends to be characterized by a predominance of paranoid symptoms. The prognosis is favorable, and these patients usually do well on antipsychotic medication.

Magnetic resonance imaging (MRI) studies demonstrate that in monozygotic twins who are discordant for schizophrenia, virtually all the affected twins have larger cerebral ventricles than their nonaffected twins. MRI is used in schizophrenia research because its resolution is superior to that with computed tomography (CT). The abnormalities reported in CT studies of patients with schizophrenia have also been reported in other neuropsychiatric conditions and are unlikely to be specific for the pathophysiological processes underlying schizophrenia. Positron emission tomography studies have shown evidence of impaired activation of certain brain areas after psychological test stimulation in schizophrenics. Functional MRI has shown differences in sensorimotor cortex activation and a decreased blood flow to the occipital lobes in patients with schizophrenia.

The majority of CT studies of patients with schizophrenia have reported enlarged lateral and third ventricles in 10 to 50 percent of patients and cortical atrophy in 10 to 35 percent of patients. Controlled studies have also revealed atrophy of the cerebellar vermis, decreased radiodensity of brain parenchyma, and reversals of the normal brain asymmetries. Those findings are not artifacts of treatment and are not progressive or reversible. The enlargement of the ventricles seems to be present at the time of diagnosis before the use of medication. Some studies have correlated the presence of CT scan findings with the presence of negative or deficit symptoms (e.g., social isolation), neuropsychological impairment, frequent motor side effects from antipsychotics, and a poor premorbid adjustment.