One of the many dirty little secrets in the fight against clinical depression is that there is a significant number of patients who don’t adequately improve with the currently available lot of antidepressant drugs. In fact, the lifetime prevalence of major depressive disorder is between 10 to 20 percent of the population.
So it is exciting news when scientists discover a wholly new pathway in the brain that can be manipulated to alleviate depression, as researchers from Northwestern Medicine have just done. It opens doors for developing a drug that could be effective in individuals for whom other antidepressants have failed.
“Identifying new pathways that can be targeted for drug design is an important step forward in improving the treatment of depressive disorders,” said Sarah Brooker, the first author and an MD/PhD student at Northwestern University Feinberg School of Medicine.
Brooker and her colleagues discovered that antidepressant drugs such as Prozac and tricyclics target a pathway in the hippocampus called the BMP signaling pathway. This is a collection of molecules in a cell that collaborate to control one or more cell functions. Like a chain of dominoes, after the first molecule in a pathway receives a signal, it activates another molecule and so forth until the cell function is carried out.
The researchers proved that Prozac and tricyclics triggered stem cells in the brain to produce more neurons by inhibiting this pathway. These particular neurons are involved in mood and memory formation. But the scientists didn’t know if blocking the pathway contributed to the drugs’ antidepressant effect because Prozac acts on multiple mechanisms in the brain.
They confirmed their theory by experimenting on depressed mice. (How do you know if your mouse is depressed? Hang him upside down by his tail; if he struggles to right himself, he's normal; if he just sort of hangs there, going with the flow, he is depressed.) The scientists injected a brain protein into the mice that is known to block the BMP pathway. The result was that the mice energetically tried to lift themselves up.
The research has been published in Molecular Psychiatry.
"The biochemical changes in the brain that lead to depression are not well understood, and many patients fail to respond to currently available drugs,” said senior study author Dr. Jack Kessler, a professor of neurology at Feinberg and a Northwestern Medicine neurologist. “Our findings may not only help to understand the causes of depression, but also may provide a new biochemical target for developing more effective therapies."