New research from the Centre for Addiction and Mental Health (CAMH) and the Canadian Institutes of Health Research (CIHR) may lead to the first clinical diagnostic tool for post-traumatic stress disorder (PTSD) and novel, reliable treatments.
Image credits Department of Defense / Katie Lange.
PTSD is a debilitating mental health condition that can be triggered by either experiencing or witnessing extreme trauma. However, there are no clinical diagnostic tools for PTSD today, and treatment options are limited and of limited efficacy.
A new study into the physiological roots of PTSD and preventive measures against it could set that right, however. The authors report identifying a protein complex that’s elevated in the bodies of PTSD patients. The team developed a peptide compound that targets and disrupts this protein, which has proven effective in preventing the formation or recall of traumatic memories in early tests in mice.
Chemical bliss
"The discovery of the Glucocorticoid Receptor-FKBP51 protein complex provides a new understanding of molecular mechanisms underlying PTSD," said Dr. Fang Liu, the study's corresponding author. "We believe this protein complex normally increases after severe stress, but in most cases, levels soon go back to baseline levels."
"However, in those who develop PTSD, the protein complex remains persistently elevated, and so this could be a blood-based biomarker for PTSD as well as being a target for pharmacological treatment."
Back in 1915, English psychologist Charles Myers coined the term "shell shock" to describe the state of soldiers who were involuntarily shivering, crying, fearful, and experienced constant intrusions of distressing memories following their service in the hellscapes of World War One. "Shell shock" isn't in current psychiatric use any longer as it has been rolled into the wider-ranging concept of PTSD. However, it can be seen as its intellectual forerunner.
We now know that such symptoms aren't limited to army personnel. Victims of violent or sexual assault also often develop PTSD, as do survivors of non-assault based trauma (such as natural disasters), albeit less often.
PTSD is characterized by persistent and intrusive memories or nightmares of the traumatic event, heightened levels of anxiety and vigilance, general emotional unresponsiveness, and persistent avoidance of stimuli related to the trauma. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) lists 17 different symptoms of PTSD, and requires at least one (of the five) re-experiencing symptoms, at least three (of seven) avoidance symptoms, and at least two (of five) arousal symptoms to be present for one month for a diagnosis to be made.
Image credits Department of Defense / Katie Lange.
It's still a very current problem. The team examined statistics from 24 countries and found that Canada currently has the highest prevalence of PTSD among the lot. Around 9.2% of Canadians will develop PTSD during their lifetimes, they explain. A 2017 study estimated that around 6.8% of Americans will develop PTSD during their lifetime.
The authors of the new paper report that individuals with PTSD have heightened levels of a complex protein formed from the glucocorticoid receptor (GR) and the FKBP51 binding protein compared to healthy controls, people who were exposed to trauma without developing PTSD, and patients with major depressive disorders. Fear-conditioned mice also showed heightened levels of this protein complex, they add. These findings strongly suggest that the complex is a mediator for the disorder.
In order to validate their findings, the team designed the peptide TAT-GRpep (think of peptides as being chunks of protein) that binds to and disrupts the function of the GR-FKBP51 complex. TAT-GRpep works by binding to the GR, effectively taking up the spot that the protein complex needs to bind to in order to elicit a response in the body. They tested this peptide on lab mice and report that it was "able to decrease GR-FKBP51 complex levels in both blood and brain tissue from mice," suggesting that it could also prove effective in humans.
"Because our interfering peptide can block the consolidation of fear memories, we propose that it or a therapeutic analog could be given to patients exposed to severe trauma, as a prophylaxis against the future emergence of PTSD," the paper reads. "The protein complex could also be a treatment target for established PTSD symptoms and as a biochemical diagnostic marker for PTSD."
"Any of these advances would significantly improve on current clinical approaches to this important brain disorder."
Dr. Liu and her team plan to further test and refine the peptide before conducting human clinical trials.
The paper "The glucocorticoid receptor–FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder" has been published in the Journal of Clinical Investigation.
