The brains of people with severe depression have lower levels of several related molecules that are key to the development, organization, growth and repair of the brain than the brains of people without the disease, or those with the bipolar form of depression, a new study finds.

The discovery, which surprised researchers in the multi-university consortium that made it, suggests a new direction for understanding depression and developing new treatments. It may even help scientists understand how some antidepressant medications work in the brain to ease symptoms, and why there is wide variation in how depressed people respond to different antidepressants.

The finding was made in two specific areas of the brain known to be important to depression. The study relied on microarray analysis of 32 post-mortem brain samples; the microarray method can simultaneously measure the level of activity of tens of thousands of genes that are functional in a given tissue.

The researchers found that levels of molecules called fibroblast growth factors (FGFs), and two of the receptors that bind to them, were significantly lower among people who had been diagnosed with severe clinical depression and had died in a depressed state. There also was some indication that those depressed people who had been taking antidepressants before their deaths had levels of FGF and FGF receptors that were closer to normal.

The results were published online last week in the early edition of the Proceedings of the National Academy of Sciences by researchers from the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Family Philanthropic Fund and by the National Institute of Mental Health. The research team consisted of scientists from U-M’s Mental Health Research Institute and Department of Psychiatry, working in close collaboration with researchers from the University of California’s Davis and Irvine campuses and from Stanford University.

“This finding comes from a completely unbiased search that began with no hypothesis, to find what genes best differentiate major depression brains from normal and bipolar brains,” says senior author Huda Akil, the Gardner C. Quarton Distinguished Professor of Neurosciences in Psychiatry. “A wide set of individual genes came up as different between the depressed and control individuals, but the family of genes that was most different and showed the highest significance as a coherent group was the FGF family. This suggests a more profound change in an entire system of communication and control within the brain.”

No previous studies have directly examined the role of FGFs or their receptors in psychiatric illnesses.

The research group started the study by measuring levels of approximately 20,000 different kinds of messenger RNA in dissected brain samples from people who died from suicide, accidents and sudden medical causes.

The analysis was conducted on samples from two areas of the brain involved in the coordination of thinking and emotion: the dorsolateral prefrontal cortex and the anterior cingulate cortex. In the paper, the researchers report what they found when they zeroed in on a group of six kinds of related mRNA that had the most coordinated differences between the samples from depressed brains, the non-depressed brains and the bipolar brains.

These turned out to be mRNAs for four different FGF molecules and two receptors that bind to FGF and are key to their function. Levels of all of the mRNAs encoding these proteins were lower in the brains of people with major depression. Lower mRNA levels mean the brain may not produce enough protein to carry out normal function.

The team confirmed its finding using another genetic technique called PCR analysis, which revealed that the most significant differences were in levels of mRNA for one of the FGFs and for the two receptors.

The researchers emphasize that they do not know yet whether the depressed people were born with lower levels of these molecules, or whether the lower levels were brought on by the effects of depression on the brain or by external factors such as stressful events.

“The bottom line is, the FGF system is less active in depressed individuals and presumably, correcting that would be part of how you can make them better,” says Akil, who is co-director of the U-M Mental Health Research Institute.

The lead author was research investigator Simon Evans. Other authors from U-M are Stanley J. Watson, Juan F. Lopez, Robert C. Thompson, J. D. Stead, C.R. Neal and F. Meng. Several authors are members of the Depression Center.