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Schizophrenia, bipolar disorder linked
By William Hathaway / Hartford Courant
Wednesday, December 22, 2004

For nearly a century, scientists made a clear distinction between schizophrenics, who have delusions, and patients with bipolar disorder, who are tossed between episodes of mania and depression.

But researchers in the past few years have found a number of genetic and molecular common denominators. Those insights may one day help scientists track down underlying causes of two of the most devastating forms of mental illness and give drug companies new targets for therapies.

"If we understand the common biology behind two disparate illnesses, then it will help explain why some people get one form and not the other," says Dr. Godfrey Pearlson, professor of psychiatry at Yale University and director of the Olin Neuropsychiatry Research Center at the Institute of Living in Hartford, Conn. "New treatments will be based on a sound knowledge of the diseases."

In the early 20th century, Emil Kraepelin, described as the father of modern psychiatry, categorized schizophrenia and bipolar disorder as separate diseases. That view has survived in academic textbooks to this day.

Psychiatrists, however, have long noted an overlap of symptoms. Some schizophrenics exhibit symptoms of mood disorders, and some people with manic depression experience psychotic episodes. Today, some patients with bipolar disorder are given anti-psychotic drugs, and some with schizophrenia get drugs designed to treat manic depression.

But until the last decade, few scientific studies showed a biological link between the diseases.

Stress may be trigger

One of those links is being explored by Amy Arnsten, a neurobiologist at Yale University Medical School, who says she has found a molecular trigger for both diseases, a trigger that seems to be activated by stress.

Bipolar patients and schizophrenics both have elevated activity of an enzyme called protein kinase C, or PKC, in the prefrontal cortex, a highly developed area of the brain that helps govern behavior and emotions. High PKC activity leads to dysfunction of the prefrontal cortex, which in turn leads to symptoms such as distractibility, impulsivity, poor judgment and possibly even hallucinations -- symptoms found in varying degrees among those suffering from schizophrenia and bipolar disease. Drugs used to treat bipolar disease and schizophrenia both lower PKC activity, another sign of PKC's importance, Arnsten says.

Arnsten found that high levels of stress tend to elevate PKC levels, which may explain why stressful events tend to trigger the onset of both diseases. She speculates that because lead increases PKC activity, the elevated levels of PKC may account for the distractibility and poor impulse control often seen in cases of lead poisoning.

Blocking PKC may protect the prefrontal cortex from damage caused by stress and could be useful in treating both schizophrenia and bipolar disease, she says. "We are beginning to get a rational understanding of irrational disorders," Arnsten says.

Common genetic roots

Most scientists believe severe mental illness is the result of a complex interaction between environment and many genes, but finding genetic causes of mental illness has been a slow process. But the evidence is growing that schizophrenia and bipolar disease share a few genetic roots, says Dr. James Potash, assistant professor of psychiatry at Johns Hopkins University Medical School.

"There seems to really be a lot of momentum in that direction in the last five years," Potash says. For instance, genes suspected of playing a role in both ailments have been traced to the same region of chromosome 13, he adds.

Imaging studies also have shown clear differences in brain activity between patients with bipolar disease who experience psychotic episodes and bipolar patients who do not, Pearlson says.

One of the most famous experts on schizophrenia, Dr. E. Fuller Torrey, is investigating whether infectious agents may play a role in triggering schizophrenia and bipolar disorder. The level of anti-bodies to some infectious agents are not only elevated in schizophrenics, but in bipolar patients as well, says Torrey, associate director for laboratory research at the Stanley Medical Research Institute in Bethesda, Md., which supports research on schizophrenia and manic-depressive illnesses.

The evidence of the biological links is strong enough that experts are debating whether psychotic forms of bipolar disease should be grouped with schizophrenia rather than with depressive illnesses, Torrey says.

The research has significance besides finding links and pointing to new treatments, Arnsten says. It helps the public understand that diseases of the mind are as rooted in biology as cancer and heart disease. "What we are demonstrating here is that a part is broken," Arnsten says. "It tells people that we are really talking about a medical illness, not a moral weakness."

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