Millions of people worldwide take selective serotonin re-uptake inhibitors (SSRIs) to treat depression. In some patients, however, the drug has the unfortunate side effect of increasing fear and anxiety in the first few weeks of use.
A new study by a research team from the University of North Carolina’s School of Medicine offers an idea of how these widely prescribed drugs produce this troubling side effect in some users. Because SSRIs, including the popular drugs Prozac (fluoxetine) and Zoloft (sertraline), can increase anxiety, some patients stop taking the SSRI.
In an experiment with mice, the UNC scientists found an anxiety circuit driven by serotonin that may explain the anxiety effect. The researchers hope this study, which appears in the journal Nature, is a step toward a treatment that to counteract the SSRI anxiety side effect.
Previous studies have linked depression to abnormally low levels of serotonin in the brain and serotonin does seem to improve mood through certain brain circuits. But the UNC study disputes the common view that serotonin promotes only good feelings. In some patients, often younger ones, serotonin can have negative effects on mood, depending on which brain circuit it acts on, according to Science Daily.
To delve into the SSRI anxiety side effect, UNC researchers looked at a serotonin-activated pathway in mice brains that drives anxiety behaviors. The researchers provoked anxiety behaviors in mice by administering a mild shock to the animals’ paws. The anxiety activated serotonin-producing neurons in a brain region involved in mood and depression. Increasing the activity of these neurons enhanced anxiety behaviors in the mice. The researchers then exposed 2C-receptor BNST neurons to fluoxetine (Prozac), which boosts serotonin levels wherever the neurotransmitter is at work. The fluoxetine worsened fear and anxiety behavior in mice. The team then added a compound to block CRF activity in order to block the serotonin effect. With CRF activity blocked, the anxiety behaviors triggered by fluoxetine were greatly reduced, according to Science Daily.
The next step for the researchers is to confirm that this serotonin-sensitive DRN-to-BNST anxiety circuit exists in humans. The senior investigator on the study, Thomas L. Kash, Ph.D., the John Andrews Distinguished Professor of Alcohol Studies in the UNC medical school’s department of pharmacology said the pathways in these brain regions “tend to be very similar in mice and humans.” Kash says it is logical to expect that the circuit would also exist in humans. The research team hopes “to identify a receptor that is already targeted by established drugs. One of them might be useful for people as they start taking SSRIs,” Kash said. Any drugs identified will have to be tested for their ability to alter the anxiety circuit and thereby block the anxiety-inducing effect of SSRIs.
Pharmaceutical companies have been working to develop CRF blockers to treat depression, anxiety and addiction. No CRF blocker has yet proved successful in clinical trials, and researchers think an effective CRF blocker is still years away, according to Science Daily.