Everyone occasionally feels blue or sad. However, these feelings are usually short-lived and pass within a couple of days. When a person has depression, it interferes with daily life. Depression is a common and serious illness.  Many people with a depressive illness never seek treatment.  The majority, even those with the most severe depression, can get better with treatment. Medications, psychotherapies, and other methods can effectively treat people with depression.

Most likely, depression is caused by a combination of genetic, biological, environmental, and psychological factors.  Depressive illnesses are disorders of the brain. Neuroimaging has shown that the brains of people who have depression look different than those of people without depression. The parts of the brain involved in mood, thinking, sleep, appetite, and behaviour appear different. However, these images do not reveal why the depression has occurred and cannot be used to diagnose depression despite research around the world concentrating greatly on this area.

Now, a study from researchers at the University of Michigan, University of California, Irvine and the Pritzker Consortium shows that that people with major depression had 32 percent more of a protein called fibroblast growth factor 9 or FGF9 in a key part of their brain than people without the condition, going against previous findings that depressed brains often have less of key components than non-depressed brains. The new study also found that in rats that raising FGF9 levels artificially led to depression-like behaviour and repeated social stress caused brain FGF9 levels to rise.  The team state that if FGF9 or its effects prove to be a good target for drugs, the finding could eventually help lead to better medications for the mental health condition that affects millions of Americans.   The study is published in the journal Proceedings of the National Academy of Sciences.

Previous studies show that once diagnosed, a person with depression can be treated in several ways. The most common treatments are medication and psychotherapy.  Curing depression is not always easy as it’s a disorder at the level of the circuits that connect brain cells, and many regions of the brain are involved.  This means that although modern antidepressants, older tricyclics and MAOIs are definately shown to work, they may cause deficits in other parts of the brain, such as loss of sex drive, nausea, agitation or insomnia. The researchers state that their findings could hold promise for the development of a new class of antidepressants because drugs that block excess production of something in the body generally cause fewer side effects than drugs aimed at increasing something.

Earlier studies from the team focused on fibroblast growth factors, molecules involved in cell growth and maintenance in the brain, and in other areas of the body. They also studied another FGF molecule, called FGF2, in the brain for years, trying to figure out why it’s lower in people and animals with depression and other mental health disorders. Results showed that giving FGF2 injections can calm anxious rats.

The current study found that FGF9 levels were higher in the brains of people who had had depression compared to those who had not. The increased levels held up even after they accounted for differences in the ways the individuals lived, and died, before their brain tissue was preserved for research.  The lab made the finding using post-mortem brain samples from the Pritzker collection, 36 depressed and 56 non-depressed brains in all.

Three different kinds of microarray gene expression studies and a confirming test called quantitative PCR were also used in the current study to look at all the genetic activity that was going on when these brain donors died, specifically in the area of the brain called the hippocampus. The group explain that the hippocampus is a crucial area of the brain for memory, learning and stress control. They go on to add that it has been found to be smaller in people with depression, and this is thought to be the result of chronic stress that affects the health of brain cells in that region.  Results showed higher FGF9 levels in the depressed brains and the levels of several other fibroblast growth factors were down when FGF9 was up.

The group then explored FGF9’s role further in an animal model.  Rats were exposed to repeated social stress over a week and a half, and the levels of FGF9 checked in various regions of the brain’s hippocampus. Results show that not only did the levels rise, the rats also became more socially withdrawn and less likely to maintain a healthy weight.  The lab then decided to develop a treatment for depression.  To accomplish this they first injected FGF9 into the brains of the rats; with other rats receiving a placebo. The rats that received the FGF9 acted more anxious, and moved around less with these depressive-like changes persisting with repeated injections.

The group then developed a virus which interfered with FGF9 production through a process called RNA interference. They injected it, or a comparison virus that didn’t block FGF9 production, into rats’ brains in a specific area of the hippocampus called the dentate gyrus. Data findings show that the active virus caused levels of FGF9 to drop about 30 percent, while other FGF molecule levels stayed the same.  Most importantly, it was observed by the team that the rats showed less anxiety.  The team note that FGF9 is important in the lungs and blood vessels too with more studies needed to find an optimal balance between these organs and the disorder.

The researchers are already performing more experiments to determine why FGF9 production rises, as well as studies in other brain regions to see how it affects communication among brain cells. For the future a patent application has been filed and is being managed by the Pritzker Consortium.

Source:  University of Michigan