Researchers and clinicians are always searching for novel uses of currently available drug therapies. This strategy has the advantage of being able to bring medications to market much quicker, as detailed information on the compound is already known, allowing scientists to focus their attention on studying the effect of the drug in the new paradigm. Now, investigators at University College London (UCL) and the University of Zurich have recently published data detailing the effects of the common antibiotic doxycycline on disrupting the formation of negative associations in the brain—underscoring its potential use in the treatment of post-traumatic stress disorder (PTSD).
The findings from this placebo-controlled, double-blind, randomized controlled study in 76 healthy volunteers were published recently in Molecular Psychiatry through an article entitled “Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline.”
“When we talk about reducing fear memory, we are not talking about deleting the memory of what actually happened,” explained lead study investigator Dominik Bach, M.D., Ph.D., assistant professor at the University of Zurich division of clinical psychiatry research.
For the study, participants were given either doxycycline or a placebo and put in front of a computer. The screen would flash either blue or red, and one of the colors was associated with a 50% chance of receiving a painful electric shock. The process repeated 160 times, with the colors appearing in random order, so that participants learned to associate the “bad” color with the shock.
A week later, under no medication, participants returned to repeat the experiment. This time there were no electric shocks, but a loud sound played after either color was shown. Participants' fear responses were measured by tracking their eye blinks, as this is an instinctive response to sudden threats. The fear memory response was calculated by subtracting the baseline startle response—the response to the sound on the “good” color—from the response to the sound when the “bad” color was showing.
“The participants may not forget that they received a shock when the screen was red, but they 'forget' to be instinctively scared when they next see a red screen,” Dr. Bach noted. “Learning to fear threats is an important ability for any organism, helping us to avoid dangers such as predators. Over-prediction of threat, however, can cause tremendous suffering and distress in anxiety disorders such as PTSD.”
Interestingly, the fear response was 60% lower in participants who had doxycycline in the first session compared to those who had the placebo, suggesting that the fear memory was significantly suppressed by the drug. Other cognitive measures including sensory memory and attention were not affected.
“We have demonstrated a proof-of-principle for an entirely new treatment strategy for PTSD,” Dr. Bach remarked. “The theory is based on the recent discovery that our brains need proteins outside nerve cells, called matrix enzymes, to form memories. Matrix enzymes are found throughout the body, and their over-activity is involved in certain immune diseases and cancers. To treat such diseases, we already have clinically approved drugs that block these enzymes, including the antibiotic doxycycline, so we wanted to see if they could help to prevent fear memories from forming in the brain. Our results support this theory, opening up an exciting avenue of research that might help us to find treatments for PTSD.”
PTSD refers to a broad range of psychological symptoms that can develop after someone experiences or witnesses a traumatic event. PTSD is caused by an overactive fear memory, and this new research shows that doxycycline can reduce the fear memory response in healthy volunteers.
“Using drugs to prevent PTSD would be challenging since in the real world we don't know when a traumatic event is about to occur,” Dr. Bach concluded. “However, there is growing evidence that people's memories and associations can be changed after the event when they experience or imagine similar situations. This is called reconsolidation, and we now plan to test the effect of doxycycline on reconsolidation of fear memories. If this is successful, we would hope to apply the technique to more clinically realistic models of PTSD within a few years.”