The University Record, October 9, 2000

U research team finds signs of brain chemistry abnormalities in bipolar disorder

By Kara Gavin
Health System Public Relations

People with bipolar disorder have an average of 30 percent more of an important class of signal-sending brain cells, according to new evidence being published by U-M researchers.

The finding, published in the American Journal of Psychiatry, solidifies the idea that the disorder has unavoidable biological and genetic roots, and may explain why it runs in families.

The discovery is the first neurochemical difference to be found between asymptomatic bipolar and non-bipolar people. It could help the understanding and treatment of a disease that affects as much as 1.5 percent of the population. Bipolar disorder has in the past been known as manic depression.

“To put it simply, these patients’ brains are wired differently, in a way that we might expect to predispose them to bouts of mania and depression,” says Jon-Kar Zubieta, assistant professor of psychiatry and radiology. “Now, we must expand and apply this knowledge to give them a treatment strategy based on solid science, not on the current method of trial and error. We should also work to find an exact genetic origin and to relate those genetic origins to what is happening in the brain.”

Bipolar disorder is marked by wild, cyclical mood swings, which typically begin in a person’s late teens or 20s and strike men and women with equal frequency. Its milder type II form causes depression alternating with hyperactivity, while the more severe type I disorder produces frenzied, even psychotic episodes that may send the patient to the hospital, followed by deep, crippling depressions. Current treatment uses a mix of mood-stabilizing, anti-psychotic and antidepressant drugs, but patients and physicians often struggle to strike the right combination.

Zubieta and his colleagues made the discovery in 16 patients with type I bipolar disorder using a brain imaging technique called positron emission tomography (PET). The scans let them see the density of cells that release the brain chemicals dopamine, serotonin and norepinephrine.

These monoamines, as the chemicals are called, send signals between brain cells, or neurons. They’re involved in mood regulation, stress responses, pleasure and reward, and cognitive functions like concentration, attention and executive functions. Scientists have hypothesized their role in bipolar disorder for decades, but have never proven it.

By looking at the intensity of the DTBZ signal, a weakly radioactive tracer, in all the subjects’ brains, the U-M team found that bipolar patients averaged 31 percent more binding sites in the region known as the thalamus, and 28 percent more in the ventral brain stem. In the thalamus, bipolar women actually had levels nearing those of healthy comparison subjects, but bipolar men had a 42 percent higher binding rate, suggesting that there may be specific biological causes for the clinical differences in the course of the illness in men and women.

Adding in the results of functional tests, they found that the more monoamine cells patients had, the lower their scores on tests of executive function and verbal learning. This finding confirms earlier results from research at the U-M, and suggests that the altered brain chemistry due to the excess monoamine cells may directly impact the patients’ cognitive and social function.

The study was carefully designed to produce consistent results. It compared brain scans and neuropsychological test results from bipolar disorder I patients who were using medications to control their symptoms, and healthy subjects matched to the bipolar subjects for age, sex, ethnicity, handedness and other factors. Careful physical and psychiatric exams ruled out differences caused by other variables.

Now, Zubieta and his colleagues hope their initial finding will lead to further research on brain chemistry and bipolar disorder. A combination of both genetic research and neuroimaging studies would help define both the genetic components of this illness, and their relationship with the expression of specific brain chemical markers in specific patients.

“The reality is that we still have only sketches of what is going on in these brains, what the basic changes are, and how they are related to the course of illness,” Zubieta says. “We need to look further.”

The study was funded by the General Clinical Research Center, by the National Alliance for Research on Schizophrenia and Depression, and by the Mental Illness Research Association’s Arthur Forrest Tull II Research Fund.