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An in-depth report on the causes, diagnosis, and treatment of schizophrenia


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

Abnormalities in Brain Structure, Circuitry, and Chemicals

Brain scans using magnetic resonance imaging (MRI) have now detected a number of abnormalities in the brain's structure that have been associated with schizophrenia. Such abnormalities can cause nerve damage and disconnections in the pathways that carry brain chemicals.

Abnormalities of Brain Volume 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 and abnormal activity in the prefrontal cortex, which contains the white matter of the brain, and the temporal lobes, which contain the limbic system.

  • Reductions in volume of the prefrontal cortex have been observed in many patients with schizophrenia. Deterioration here can damage nerve cells and impair the connections that are required for verbal memory, attention, decision-making, reasoning, aggression, and meaningful speech. Impairment in the left side of the cortex is also associated with auditory hallucinations (e.g., hearing voices). (Not all patients have this deficit. For example, patients with paranoid schizophrenia tend to have normal left prefrontal volumes.)
  • Loss of volume in the limbic areas (located deep in the brain), which contain the hypothalamus, amygdala, and, importantly, the hippocampus. A number of studies have specifically noted smaller left hippocampi in people with schizophrenia, which is associated with problems in verbal memory. Activity in the limbic area in general is related to emotions and memory, and abnormalities there are also associated with positive symptoms, including delusions and hallucinations, and also with disordered thinking.
  • Because such abnormalities tend to show up on brain scans of people with chronic schizophrenia rather then in newly diagnosed patients, some experts believe they may be a result of the disease and its treatments rather than a cause. (Medications used for schizophrenia can also cause brain volume loss over time.) Nevertheless, there is now strong evidence to suggest that small hippocampi coupled with environmental conditions (notably low oxygen levels at the time of delivery) are important contributory factors in many cases of schizophrenia.

Abnormal Brain Chemicals. Schizophrenia is associated with an unusual imbalance of neurotransmitters (chemical messengers between nerve cells) and other factors.

  • Abnormalities in dopamine receptors. Imbalances in the neurotransmitter dopamine are important research targets in schizophrenia. Dopamine overactivity is now known to be closely linked to reduced prefrontal cortex activity. Overactivity, particularly on the left side, is associated with psychotic symptoms and appears to be due to an increase in specific chemical receptors, particularly those called C1 and D1. (These receptors attract and lock dopamine.)
  • Abnormalities in glutamate receptors. Glutamate, an amino acid known to affect dopamine and excite nerve activity, is also under scrutiny. For example, glutamate binds to N-methyl-D-aspartate (NMDA) receptors, which play a critical role in healthy nerve development and may be abnormal in schizophrenia. Abnormalities in NMDA and other molecules in the glutamate pathway appear to play significant roles in impairment of mental function and development of negative symptoms. Calcineurin, a protein that regulates the NMDA receptor, plays a role in cognition and is now recognized as a marker of risk for schizophrenia.
  • Loss of reelin. A protein called reelin, which is involved in the nerve cell architecture, is also being investigated. Studies have observed abnormally low levels of reelin in the prefrontal cortex region of patients with both schizophrenia and bipolar psychosis, perhaps contributing to psychosis and to impaired information processing.

Abnormal Circuitry. Abnormalities in brain structure are also reflected in the disrupted connections between nerve cells that are observed in schizophrenia. Such miswiring could impair information processing and coordination of mental functions. For example, auditory hallucinations may be due to miswiring in the circuits that govern speech processing. Strong evidence suggests that schizophrenia involves decreased communication between the left and right sides of the brain.

Genetic Factors

Schizophrenia undoubtedly has a genetic component. 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. Family members of patients also appear to have higher risks for the specific symptoms (i.e., negative or positive) of the relative with schizophrenia.

Researchers are seeking the specific genetic factors that may be responsible for schizophrenia in such cases. Current evidence suggests that there are a multitude of genetic abnormalities involved in schizophrenia, possibly originating from one or two changes in genetic expression. Scientists are beginning to discover the ways in which specific genes affect particular brain functions and cause specific symptoms.

An international team has identified the neuregulin-1 gene as a major candidate gene for schizophrenia risk. This gene is involved with growth of the glial cells in the brain, memory, and motor neuron functioning, all of which are abnormal in schizophrenia.

Other research targets are genes that affect brain structure. For example, mutations in the COMT gene may make people susceptible to deficits in the prefrontal cortex of the brain, where schizophrenia develops. In addition to COMT and neuregulin-1, other genes and genetic regions implicated in schizophrenia include dysbindin, G72, RGS4, PPP3CC, and others.

It should be noted that heredity does not explain all cases of the disease. About 60% of people with schizophrenia have no close relatives with the illness.

Infectious Agents

Viruses. The case for viruses as a cause of this disease rests mainly on circumstantial evidence, such as living in crowded conditions. The following are some studies suggesting an association:

  • Winter and Spring Births. The risk for schizophrenia worldwide is 5% to 8% higher for those born during winter and spring, when colds and viruses are more prevalent.
  • The risk is higher for people who are born in cities than in the country. The longer one lives in the city, the higher the risk.
  • Large Families. The risk for schizophrenia 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.
  • Pregnant Mother's Exposure to Viruses. The mother's exposure to viral infections such as rubella, measles, chicken pox, or others while the infant is in the womb has also been associated with a higher risk for schizophrenia in her child.
  • Researchers are trying to identify specific viruses that may be responsible for some cases. Of particular interest is research finding evidence of a virus that belongs to the HERV-W retrovirus family in 30% of people with acute schizophrenia.

Toxoplasmosis. Some researchers have found an association between some cases of schizophrenia and toxoplasmosis (a parasite carried by cats and other domestic animals), which can lie dormant in the nervous system and migrate to the brain over many years. Schizophrenic patients who are exposed to the parasite respond poorly to clozapine treatment. There is no evidence, however, that exposure to toxoplasmosis causes schizophrenia.

Loss of Oxygen around the Time of Birth

Many studies have reported an association between schizophrenia and problems surrounding birth, particularly those that cause oxygen deprivation, which could affect the nerve growth or structure in the developing brain. Specific complications that have been associated with such a higher risk include the following:

  • Prolonged labor.
  • Bleeding during pregnancy.
  • A short gestation period and low birth weight.

Psychologic Factors

Although parental influence is no longer believed to play a 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 deficits in a vulnerable brain 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. In another interesting 2000 study, criticism by family members was significantly correlated with the onset of disorganized thinking in patients with impaired working memory. (This effect of criticism was not observed in patients with functioning working memories.)


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