No single cause can account for all cases of schizophrenia. Rather, it appears to be the result of multiple hits from genetic factors, environmental assaults, and possible hormonal changes that alter the brain's chemistry and trigger this devastating disease.

Brain Structure and Circuitry

Abnormalities of Brain Shape and Activity.Imaging techniques have revealed reduced volume and actual loss of tissue in the brains of people with schizophrenia. Of particular importance are volume losses in the prefrontal cortex and in areas involving the limbic system and the temporal lobes. Prefrontal loss affects memory, attention, reasoning, aggression, and meaningful speech, all functions involved in negative symptoms. Loss of volume in the temporal lobe affects the limbic areas (located deep in the brain), which contain the hypothalamus, amygdala, and hippocampus. Activity in this area is related to emotions and memory, and abnormalities are associated with positive symptoms, including delusions and hallucinations. Researchers, however, have been unable to find signs of specific nerve or tissue damage that might lead them to clues concerning the source of schizophrenia. There is some evidence that suggests that there are fewer than normal connections between nerve cells in those with schizophrenia. In any case, abnormal brain circuitry is under intense study as the basic abnormality in schizophrenia. Such miswiring could impair information processing and coordination of mental functions.

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Abnormal Brain Chemicals.Schizophrenia is associated with an unusual imbalance of neurotransmitters (chemical messengers between nerve cells). Dopamine is the subject of important research in schizophrenia. An abnormal balance of dopamine appears to trigger the schizophrenic syndrome. Imaging studies have detected an over-activity of dopamine in parts of the brain, particularly the left side, where psychotic symptoms occur. This imbalance does not appear to result from overproduction of dopamine in this location, but to an increase in specific chemical receptors, particularly those called C1 and D1, that attract and lock dopamine. On the other hand, there appears to be low activity of dopamine D1 receptors in the prefrontal cortex of the brain where negative symptoms originate. Other neurotransmitters and chemicals in the brain are also being studied, including abnormal levels of glutamate, an amino acid known to affect dopamine and excite nerve activity. Some other studies indicate that patients tend to have abnormalities in proteins that effect the repair, structure, and function of nerve cells.

Genetic Factors

Schizophrenia undoubtedly has a genetic component. Scientists may be close to pinpointing the genetic locations of schizophrenia, with possible suspects being chromosomes 13, 22, and possibly 8. According to some studies, individuals with a family predisposition to schizophrenia have several structural brain abnormalities, including reduced brain size and enlarged ventricles that are similar to those in patients with schizophrenia. Family members and their schizophrenic relatives also have a higher incidence of common traits. In one study, for example, both non- and schizophrenic relatives shared deficits in working (short-term) memory (although not impairments in general attention). Mixed-handedness (the use of different hands for different tasks), particularly in females, may also be an inherited trait linked to schizophrenia. Eye tracking dysfunction is a genetic trait strongly associated with schizophrenia, which may reflect abnormalities in the frontal regions of the brain. Some experts believe that this is such a powerful marker that it can be used to predict individuals who are at high risk for the disease. Heredity does not explain all cases of the disease, however. The risk for inheriting schizophrenia is 10% in those who have one immediate family member with the disease, and about 40% if the disease affects both parents or an identical twin. About 60% of people with schizophrenia have no close relatives with the illness.

Environmental Factors

Viruses. The case for viruses as a cause of this disease rests mainly on circumstantial evidence. The risk for schizophrenia, at least in people living in the Northern Hemisphere, is higher in those born during winter months and in cities. It is also greater in large families in which there are short intervals between siblings (two or fewer years). Such observations suggest that exposure to infectious agents early in infancy may help set the stage for later development of the disease. The mother's exposure to infections while the infant is in the womb, however, does not appear to be a risk factor for her baby.

Oxygen Deprivation in the Fetus or Newborn. Many studies have reported an association between schizophrenia and problems surrounding birth, particularly those that cause oxygen deprivation. Complications that have been associated with increased risk for schizophrenia include prolonged labor, bleeding during pregnancy, a short gestation period and low birth weight, and malnutrition in the mother during the first trimester of pregnancy (less than 1,000 calories a day). One study suggests that the risk for schizophrenia increases if abnormalities occur during the fetal life at critical points in brain development, which are between the 34th and 35th weeks of gestation.

Psychologic Factors

Although parental influence is no longer believed to play any major role in the development of schizophrenia, it would be irresponsible to ignore outside pressures and influences that may exacerbate or trigger symptoms. The prefrontal lobes of the brain, which are the brain areas often thought to lead to this disease, are extremely responsive to environmental stress. Given the fact that schizophrenic symptoms naturally elicit negative responses from the sufferer's circle of family and acquaintances, it is safe to assume that negative feedback can intensify the already vulnerable neurologic state and perhaps even trigger and exacerbate existing symptoms. One study to support this indicated that early parental loss, either from death or separation, increases the risk for psychiatric disorders, including schizophrenia.