Deborah Brauser

December 10, 2009

December 10, 2009 (Hollywood, Florida) — Alterations in the neurosteroid biosynthetic pathways of veterans of the current conflicts in Iraq and Afghanistan may be associated with multiple symptoms of posttraumatic stress disorder (PTSD), according to an initial biomarker study presented here at the American College of Neuropsychopharmacology (ACNP) 48th Annual Meeting.

In fact, serum levels of the neurosteroid allopregnanolone were found to be inversely associated with depression, anxiety, and pain symptoms.

"In other words, the greater the symptom severity, the lower the allopregnanolone levels, resulting in statistically significant inverse relationships," lead investigator Christine Marx, MD, associate professor in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center and the Durham VA Medical Center in North Carolina, told conference delegates.

"These results are very consistent with preclinical animal models and emerging clinical data suggesting a role for allopregnanolone in identifying these symptoms," Dr. Marx added.

Limited Research

Troops who serve in Iraq and Afghanistan frequently experience high rates of psychiatric and neurologic comorbidities after deployment, said Dr. Marx.

Although research on the neurobiological mechanisms and optimal treatment for these comorbidities remains limited, increasing evidence has linked changes in a number of small molecules, including amino acids and neurosteroids, to the neurobiology of depression and suicidality.

"We investigated a panel of hypothesis-driven candidate biomarkers of depression and suicidality in these veterans, symptoms that frequently co-occur in traumatic brain injury and PTSD."

A total of 90 male veterans from the VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center Registry were enrolled in the study, and blood samples were collected from all participants.

Results showed that "candidate biomarkers were associated with specific symptom domains in the veterans," reported Dr. Marx.

For example, the researchers found that serum levels of allopregnanolone were inversely associated with symptoms of depression, anxiety, and low back pain.

"This is consistent with the analgesic properties of allopregnanolone that have been described in animal models," said Dr. Marx.

In addition, allopregnanolone to progesterone level ratios were also significantly reduced in the veterans with depression and PTSD, as well as in those who reported suicidality compared with the veterans who reported no suicidal ideation (Mann-Whitney P = .028).

Biomarkers May Predict Therapeutic Response

In an additional small randomized controlled trial just completed, the investigators examined the effect of treatment with the neurosteroid pregnenolone in veterans with traumatic brain injury.

Preliminary findings suggest that increases in neurosteroid levels after this intervention can predict PTSD symptoms "showing possible biomarker utility for the prediction of therapeutic response," said Dr. Marx.

"Improvements in resilience were significantly correlated with elevations in the neurosteroid pregnanolone in the group treated with pregnenolone," she added.

Total cholesterol levels were also decreased after treatment in the pregnenolone group compared with the placebo group, but no improvement was found in total PTSD symptoms or cognitive performance.

Finally, improvements in Cluster D PTSD symptoms, including irritability, sleep difficulty, and poor concentration, were significantly correlated with increases in neurosteroids after treatment with pregnenolone.

Promising Biomarker

"Overall, allopregnanolone looks like a particularly promising biomarker that we might use to help assess symptom severity in PTSD and pain disorders, understand their neurobiological underpinnings, develop new treatment options, and predict therapeutic response," Dr. Marx said in a statement.

"In addition, we've now developed a method that can rigorously quantify neurosteroids in blood and may help us identify people at risk at earlier time points, which could enable us to better tailor treatment options to each individual," she added.

Although Dr. Marx cautioned that biomarker research in psychiatric disorders is currently in its earliest stages, she said that these studies are yielding important clues to understanding and eventually treating these illnesses.

New Possibilities

"The idea that these kinds of neurosteroids are changing in stress conditions is really fascinating, and it's something that is gaining more and more attention," said John Neumaier, MD, PhD, professor of psychiatry and head of the Division of Neuroscience at the University of Washington, Seattle, and member of the ACNP Public Information Committee.

"It's almost like a different channel of neurochemical events are going on that we weren't aware of until more recently. So it's very exciting because it opens up the possibility of not only making more accurate diagnoses but also new types of treatments," Dr. Neumaier added.

"It's still early to say how predictive these biomarkers will be, and I don't think that it's a solid conclusion yet, but this study certainly suggests that there are some correlations between the levels of allopregnanolone in the blood and changes that were observed in people who were being treated with PTSD," said Dr. Neumaier, who was not involved with this study.

"I also think it's important to point out there is a difference between finding biomarkers and turning that around into treatment opportunity, such as with pregnenolone," added Dr. Neumaier. "There's still a lot more research that needs to be done."

In the future, he said he would also like to see whether these neurosteroids are state or trait markers. "By this, I mean, are they abnormal or changed only when somebody's having symptoms or are they routinely changed in these individuals? Learning how they behave over time will be very important in helping us to understand their role as biomarkers."

This study was funded by the Veterans Administration, the National Institutes of Health, the Department of Defense, and the National Alliance for Research on Schizophrenia and Depression. Dr. Marx is an unpaid adviser and unpaid board member for NeuroScience Pharmaceuticals, and Duke has filed 2 patents related to this work. However, no licensing or patents are currently in place. Dr. Neumaier has disclosed no relevant financial relationships.

American College of Neuropsychopharmacology (ACNP) 48th Annual Meeting: Abstract P-805. Presented December 8, 2009.

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