Scientists have discovered a new pathway in the brain which can be manipulated to treat depression, offering a drug target to create more effective antidepressants.
New antidepressant options are important because a significant number of patients do not adequately improve with currently available antidepressant drugs, researchers said.
The lifetime prevalence of major depressive disorder is between 10 and 20 per cent of the population.
“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, researcher at Northwestern University in the US.
In the study, scientists discovered for the first time that antidepressant drugs such as Prozac and tricyclics target a pathway in the hippocampus called the Bone morphogenetic proteins (BMP) signalling pathway.
A signalling 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.
Researchers showed that Prozac and tricyclics inhibit this pathway and trigger stem cells in the brain to produce more neurons.
These particular neurons are involved in mood and memory formation. However, the scientists did not know if blocking the pathway contributed to the drug’s antidepressant effect because Prozac acts on multiple mechanisms in the brain.
After confirming the importance of the BMP pathway in depression, researchers tested a brain protein, Noggin, on depressed mice. Noggin is known block the BMP pathway and stimulate new neurons, called neurogenesis.
“We hypothesised it would have an antidepressant effect, but we were not sure,” Brooker said. They discovered Noggin blocks the pathway more precisely and effectively than Prozac or tricyclics. It had a robust antidepressant effect in mice.
Scientists injected Noggin into the mice and observed the effect on mood by testing for depression and anxiety
behaviour. Depressed mice have a tendency to hang hopelessly when held by the tail, rather than trying to get upright.
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After receiving Noggin, mice energetically tried to lift themselves up, whereas control mice were more likely to
give up and become immobile.
When put in the 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 senior study author Jack Kessler, professor at Northwestern University. The study appears in the journal Molecular Psychiatry.