Depression: Discovery of new brain pathway could yield new treatments

October 5, 2016

Scientists have discovered a new brain pathway that could be targeted to ease depression, paving the way for new treatments for patients who do not benefit from current antidepressant medications.

Researchers say their brain pathway discovery could lead to new treatments for depression.

The research team, from the Northwestern University Feinberg School of Medicine in Evanston, IL, found blocking the BMP signaling pathway in the hippocampus - the brain region associated with emotion and memory - alleviated symptoms of depression and anxiety in mice.

The study is the first to show the BMP pathway is involved in depression, and the researchers believe their discovery could advance the development of new, effective therapies for the condition.

First author Sarah Brooker, an M.D/Ph.D. student at Feinberg, and colleagues publish their findings in the journal Molecular Psychiatry.

According to the National Institute of Mental Health (NIMH), in 2014, around 15.7 million American adults aged 18 and older had at least one major episode of depression in the past year, representing 6.7 percent of all adults in the United States.

Antidepressants are considered a primary treatment for patients with depression, but studies have shown that around 10-30 percent of patients fail to improve with the drugs or only show a partial response.

As a result, researchers are on the hunt for new therapeutic strategies for depression, and one way to achieve this feat is to get a better understanding of how current antidepressants work in the brain. This was the aim of the new study by Brooker and team.

Uncovering the role in BMP signaling in depression

To reach their findings, the researchers assessed how the antidepressant fluoxetine (Prozac) - a selective-serotonin reuptake inhibitor (SSRI) - and tricyclic antidepressants affected the brains of mice with depression.

They found that, as well as targeting numerous other brain pathways, these drugs also target the BMP signaling pathway in the hippocampus - an activity that had never before been identified with antidepressants.

Further investigation revealed that the antidepressants block the BMP signaling pathway, which causes stem cells in the brain to increase production of nerve cells that play a role in mood and memory.

However, because these antidepressants target a variety of brain signaling pathways, the researchers were unsure whether inhibiting the BMP pathway alone played a direct role in reducing depression.

To find out, the team increased BMP signaling in the hippocampus of depressed mice treated with fluoxetine. This blocked the drug's effects, and no reduction in depressive symptoms was seen.

BMP signaling 'a new and powerful target for the treatment of depression'

Next, the researchers gave the depressed rodents a brain protein called noggin, which is known to block BMP signaling and increase the production of new nerve cells - a process called neurogenesis.

"We hypothesized it would have an antidepressant effect, but we weren't sure," notes Brooker.

It turned out that their hypothesis was correct; not only did noggin inhibit the BMP signaling pathway more effectively and accurately than fluoxetine and tricyclics, but it led to a significant reduction in depressive and anxious behavior among the rodents.

"These observations indicate that BMP signaling in the hippocampus regulates depressive behavior and that decreasing BMP signaling may be required for the effects of some antidepressants," the authors write. "Thus, BMP signaling is a new and powerful potential target for the treatment of depression."

Senior author Dr. Jack Kessler, a professor of neurology at Feinberg, believes the team's results may bring us closer to new treatment options for depression, especially for patients who do not benefit from current therapies.

"The biochemical changes in the brain that lead to depression are not well understood, and many patients fail to respond to currently available drugs.

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."

Dr. Jack Kessler

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