A significant number of patients do not respond to antidepressant drugs, and some even feel worse, a somber fact that emphasizes the urgent need to find other treatment options.
In a new study on mice, scientists at Northwestern Medicine have discovered a pathway in the brain that may be a promising new drug target for people with non-responsive depression.
“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 M.D./Ph.D student at Northwestern University Feinberg School of Medicine.
Brooker conducted the study in the lab of senior study author Dr. Jack Kessler, a professor of neurology at Feinberg and a Northwestern Medicine neurologist.
The aim of their research is to gain a better understanding of how current antidepressants work in the brain, with the ultimate goal of finding new drug targets that are more effective for people who do not respond to current medications.
During the study, scientists discovered for the first time that antidepressant drugs such as Prozac and tricyclics target a pathway in the hippocampus called the BMP signaling pathway. A signaling pathway is a group of molecules in a cell that work together to control one or more cell functions.
Like a cascade, 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 found that Prozac and tricyclics inhibit this pathway and, thereby, trigger stem cells in the brain to produce more neurons responsible for mood and memory formation. However, the researchers didn’t know if blocking the pathway contributed to the drugs’ antidepressant effect because Prozac acts on multiple mechanisms in the brain.
After confirming the importance of the BMP pathway in depression, the scientists investigated a brain protein, called Noggin, on depressed mice. Noggin is known to block the BMP pathway and stimulate new neurons, a process known as neurogenesis.
“We hypothesized it would have an antidepressant effect, but we weren’t sure,” Brooker said.
They discovered Noggin blocks the pathway more precisely and effectively than Prozac or tricyclics, as the mice soon experienced a strong antidepressant effect.
A sign of depression in mice is a tendency to hang lifelessly when held by the tail, rather than struggle to get themselves upright. After receiving Noggin, mice energetically tried to lift themselves up, whereas control mice were more likely to give up and just hang there.
The mice were then placed in a maze with secluded (safe) and open (less safe) spaces. The Noggin mice were less anxious and explored more mazes than the control mice.
“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 Kessler, also the Ken and Ruth Davee Professor of Stem Cell Biology.
“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.”
The study was published in the journal Molecular Psychiatry.
Source: Northwestern University