UNC Discovery Could Help Prevent Antidepressant Side Effects

UNC Discovery Could Help Prevent Antidepressant Side Effects
September 27, 2016

In a time when we see more prescription drug ads on TV than ever, antidepressants are getting their fair share of airtime. Each commercial is guaranteed to have 15 seconds of cartoon rocks or happy people riding bikes and boats while a disembodied voice reads out a lengthy list of side effects.

Curiously, the antidepressants—which are meant to treat depression and anxiety—have anxiety and suicidal thoughts or actions as potential side effects.

ZoloftNew research from the UNC School of Medicine has uncovered how the biology of the brain can turn antidepressants on their head, making the anxiety and suicidal thoughts worse.

Catherine Marcinkiewicz and Christopher Mazzone, postdoctoral researcher and graduate student at UNC, respectively and co-authors of the study, followed the effects of antidepressants in mouse brains, and found that the drugs can activate a part of the brain associated with fear and actually suppress the happiness center. They published their findings in the journal Nature.

The technical name for antidepressants like Prozac, Paxil and Lexapro is “selective serotonin reuptake inhibitors” or SSRIs. They act on how cells process the neurotransmitter, serotonin. Nerve cells in the brain and other parts of the body use serotonin to communicate with each other.

Research has shown that too little serotonin outside the nerves where it is meant to act as a communicator is a cause of major depression. SSRIs block those nerve cells from soaking up too much serotonin. That leaves it open to act as a communicator and return the brain’s chemistry to a happy balance. Because of serotonin’s role in treating depression, it has the reputation of being a happiness molecule.

Marcinkiewicz and Mazzone wanted to see if the SSRIs or serotonin itself was having some other effect on the brain that could cause the anxiety and depression side effects.

They started by monitoring what happens in the brain when mice experience fear and anxiety. A mild shock to the paws—a standard method of producing a fear response in mice—activated a part of the brainstem commonly associated with depression. It seems like an obvious connection, but the nerves in that part of the brainstem secreted serotonin to create that fear response.

ProzacThe serotonin from the brainstem activates other neurons called the bed nucleus of the stria terminalis (BNST) through a specific type of receptor molecule called a 2C receptor. When the researchers artificially activated the BNST through the brainstem in the mice, they acted more anxious.

The BNST reaches out and connects to the lateral hypothalamus and ventral tegmental area, reward and motivation centers, respectively, in the brain. The BNST has the ability to suppress the reward centers. When BNST creates that inhibitory signal, mice get more anxious at the foot shocks.

When the researchers introduced Prozac to the 2C receptors in the BNST, the same effect happened. The BNST suppressed the reward centers and the mice became more anxious. Marcinkiewicz and Mazzone found that the BNST receptors were releasing a hormone called corticotropin releasing factor (CRF). CRF is first in a sequence of hormones that lead to the production of cortisol, the so called “stress hormone.”

So because the brain uses the same neurotransmitter keep the happy thoughts running as it does to signal the creation of stress hormones, SSRI antidepressants have the unfortunate side effect of stress and anxiety.

The good news is that there are ways to block many types of hormones. Marcinkiewicz and Mazzone used a CRF blocker on the mice and their anxiety did not spike when they were put on Prozac.

This is also potentially good news for the roughly 10 percent of Americans who take antidepressants, especially for adolescents who are at greatest risk for suicidal thoughts or actions according to the FDA.

The first step, says Thomas Kash, a professor of pharmacology at UNC School of Medicine, is to verify that those connections between the brainstem, BNST and reward centers of the brain work the same way in humans. Mammal brains are relatively similar to each other but there could still be some differences.

After that, Kash says, the key is to find a good CRF blocker that can prevent those side effects. Finding one begins with testing FDA-approved drugs, but there aren’t any specific CRF blockers FDA-approved currently. There might be, however, FDA-approved drugs that can interfere with BNST cells in other ways that could achieve the same result, making antidepressants, which benefit tens of millions of people in the United States, safer and more effective.

—Daniel Lane

Daniel Lane covers science, medicine, engineering and the environment in North Carolina.

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