Beyond Serotonin: Depression at the microRNA Level

by Kayt Sukel

August 11, 2014

For many people with depression, finding the right treatment isn't easy. While most patients respond well to typical selective serotonin reuptake inhibitor (SSRI) medications like Citalopram (Celexa) or Fluoxetine (Prozac), roughly one-third do not find relief. That adds up to millions of people each year who must suffer through what amounts to a trial-and-error process to find a drug that works for them.

"There's a certain fatigue in trying to find the right medication or combination of medications to treat resistant depression," says James Murrough, a psychiatrist at the Mount Sinai School of Medicine who specializes in mood and anxiety disorders. "There's a lot of frustration, both among doctors and patients, in trying to figure out the right treatment for depression, especially considering there aren't any clear diagnostic tests for the disorder itself or to determine whether a patient is responding to a particular treatment. You just have to wait it out." That wait, for all too many, is agonizing.

For decades, clinicians have focused on the neurotransmitter serotonin for the treatment of depression. But as we learn more about the neurobiological underpinnings of depression, researchers are finding that the future of depression treatment, especially for people with treatment-resistant mood and anxiety disorders, may require a deeper look.

Beyond serotonin

Most people associate depression with serotonin-and that, Murrough says, is due to the relatively large success of serotonin-based drugs used to treat the disorder. But while SSRIs work for many people, it's important to remember that depression is not a serotonin disease, says Michael Thase, a psychiatrist at the University of Pennsylvania's Perelman School of Medicine.

"You don't have a sudden drop in your serotonin when your mood crashes. That's not what is happening," he says. "What's happening, essentially, is a whole system is going offline and we don't know exactly why."

In the past few years, researchers have started to focus more on a different neurotransmitter:  glutamate. This neurotransmitter is essential to learning and memory. "More and more, we're learning that glutamate plays a key role in neuroplasticity and the stress response-and problems with glutamate transmission in the brain may be a bit closer to the fundamental, pathological problem in depression," says Murrough.

Ketamine, better known as an animal tranquilizer, works on a particular receptor in the glutamate system, and studies have suggested it can rapidly reverse depressive symptoms in treatment-resistant patients [See "Ketamine May Help Extinguish Fearful Memories"]. Murrough and colleagues published very positive results on a small clinical trial of ketamine in Biological Psychiatry last year. He says while the work in ketamine is promising, better understanding of abnormalities in the glutamate system may result in even better depression treatments.

"If we can develop drugs that target different components of the glutamate system, we may find whole new avenues of discovery for mood disorder treatments," he says. "Especially for those who don't respond to serotonin-based drugs."

Potential biomarker?

But while Murrough is optimistic about work on the glutamate system, he acknowledges the underlying pathology of treatment-resistant depression still is not fully understood. Gustavo Turecki, the head of the Depressive Disorders Program at McGill University, wanted to better understand that pathology-in particular, the differences between those who respond to traditional depression treatments and those who do not. To start, Turecki and colleagues compared the post-mortem brain samples of people who had died in the context of an episode of depression and those who died without a history of mental illness. They decided to look at microRNAs, small molecules that help regulate the production of proteins. The group found that one particular microRNA, miR-1202, a microRNA only found in humans and primates, was different between depressed and healthy patients. Upon further examination, they discovered that miR-1202 helps regulate an important glutamate receptor. And in a series of follow-up studies, the researchers learned that miR-1202 levels increased when depressed individuals were successfully treated with Citalopram. The results were published in Nature Medicine on June 8, 2014.

"It seems like this microRNA is related to depression. And antidepressant medication, at least with those who respond to it, show more normalized levels of this microRNA as they get better," says Turecki. "So if this finding is confirmed, miR-1202 could be used as a biomarker for treatment response. It could also open the doors to new agents that may be able to target the glutamate receptor this microRNA regulates and treat depression."

Next steps

Murrough says that Turecki's study fits well with other studies looking at the sources of depression. "It showed a really interesting link between this microRNA and the glutamate receptor. It offers a new way to think about proteins, receptors and the molecules that regulate them-and new places to look so we can better understand what is abnormal in the system that results in depression," he says. "It gives us a lot of new leads."

But while Thase agrees the story is consistent with emerging research on depression, he thinks more research is necessary. "Unfortunately, depression is a complex disorder. We see a lot of false leads and this could be another one of those," he cautions. "But the story is consistent with other research and the findings are quite intriguing. And we should be looking at new targets like these that may help us better understand how the brain systems involved in depression are regulated and may go awry."