For some of the millions of people worldwide who take selective serotonin re-uptake inhibitors (SSRIs) to treat depression, the drug may actually increase the patient’s fear and anxiety. This family of widely prescribed drugs includes Prozac (fluoxetine) and Zoloft (sertraline).
New research by a team from the University of North Carolina’s School of Medicine shows that these widely prescribed drugs have an unfortunate side effect for some users. The SSRIs can worsen anxiety in the first few weeks of use, Science Daily reports. Because of this troubling side effect, many patients stop taking the SSRI.
The UNC scientists have mapped out a serotonin-driven anxiety circuit that may explain the anxiety side effect. They hope this work will lead to treatments to counteract the side effect.
The UNC study, published in the journal Nature, counters the common view that serotonin promotes only good feelings. Studies have linked depression to abnormally low levels of serotonin and serotonin does seem to improve mood through certain brain circuits. But 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 examine the problem of the SSRI side effect, UNC researchers looked at a serotonin-activated pathway in mice brains that drives anxious behavior. The team provoked anxiety behavior 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. The researchers noted that the anxiety behaviors triggered by fluoxetine were greatly reduced, according to Science Daily.
The researchers now need to confirm that this serotonin-sensitive DRN-to-BNST anxiety circuit exists in humans as well. Senior investigator 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” therefore it is logical that the circuit would exist also exist in humans.
According to Kash, 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.” Researchers will need to test drugs for their ability to alter this anxiety circuit and thereby block the anxiety-inducing effect of SSRIs. In principle, a CRF-blocker might work, according to Science Daily.
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.