BETHESDA, MD—The science into the biological mechanisms behind the psychological symptoms of PTSD is still in its infancy, but studies have linked PTSD to other serious health problems, including cardiovascular disease, chronic pain, fatigue, and metabolic disorders. Research funded by NIH is suggesting that the cause of this link might have its roots in endocrine and immune function differences in patients with PTSD and most significantly in those with co-morbid major depressive disorder.

Inflammation and PTSD

“PTSD and major depressive disorder (MDD) share a common vulnerability along the experience of a trauma, such that they are highly comorbid. Depression is a significant risk factor for the onset of PTSD following a trauma,” explained Jessica Gill, PhD, RN, an assistant clinical investigator at the National Institute of Nursing Research, during an NIH clinical center lecture last month. “When the two diseases are comorbid, additional medical conditions present, including conditions that have an inflammatory pathology.”

Gill’s research over the last few years has led her to describe the endocrine and immune function differences in patients with PTSD and MDD, and to link inflammatory risks in those patients with subsequent physical health decline. “We need to understand why PTSD is often related to low levels of cortisol, especially when MDD is comorbid,” Gill said. “It’s counterintuitive to what we would think since stress such as trauma is associated with high levels of cortisol and over-activation of that system.”

It is also counterintuitive to find lower levels of cortisol—a glucocorticoid produced by the adrenal gland in times of stress—in patients with PTSD and MDD, since depression alone is associated with higher levels of plasma cortisol, Gill added. And yet in individuals who experience early life trauma and have MDD without PTSD, studies show lower levels of cortisol in their systems.

Studies have also found that patients with PTSD and comorbid MDD have greater levels of the inflammatory marker interleukin-6 (IL-6). “Studies of Katrina survivors and survivors of myocardial infarctions show higher levels of IL-6 in those patients with PTSD and MDD. But when depression is controlled for, these findings are no longer significant,” Gill explained.

In a study published in 2008, Gill looked at baseline endocrine and immune function in women with PTSD, women with PTSD and comorbid MDD, and controls. She and her colleagues found that cortisol was significantly lower in those women with PTSD and inflammatory markers were significantly higher. There was also a trend of elevation in the PTSD and MDD group compared to PTSD alone. There were similar findings in a previous study of male and female refugees.

However, in studies of male combat veterans with PTSD and no MDD, there were higher immune cell counts in relation to cortisol levels.

A 2009 study by Gill looked at overnight levels of endocrine and immune markers in PTSD and MDD patient populations, and added the injection of hydrocortisone upon waking. The study confirmed that individuals with PTSD and MDD had significantly reduced levels of cortisol, especially in the morning hours. The researchers focused on nocturnal levels because patients with PTSD frequently suffer from sleep/wake cycle disturbances that significantly impact health. Also, high levels of IL-6 prior to waking have been shown to be a significant risk factor for myocardial infarction.

The study found IL-6 to be significantly elevated in the PTSD and MDD group. But it was the PTSD without MDD group that was hyper-responsive to the administration of hydrocortisone. For those patients with PTSD and MDD, even after administration of hydrocortisone, their IL-6 levels remained significantly higher. This could have significant impact on patient health, since inflammatory markers have been linked to significant risk for mortality and morbidity.

Predicting and Preventing PTSD

These results suggest not only that there is a differential function in the immune and endocrine systems in individuals with PTSD and MDD, but also that there might be insufficient regulation of the inflammatory actions of the immune system by the low levels of circulating cortisol. “These low levels may not be able to restrain the mechanisms of the immune system,” Gill declared. And an unrestrained immune system could lead to inflammation that could later lead to other health problems, such as CV disease and metabolic diseases.

But questions remain concerning whether treating cortisol levels can have a direct effect on the symptoms of PTSD. “We need more prospective studies to identify when biological changes occur following the advent of trauma, so that we can understand how they are linked to long-term consequences to physical and psychiatric health,” Gill explained. “This could inform the development of interventions to screen and prevent the onset of PTSD as well as the medical consequences associated with it.”

For example, could anti-inflammatories have a preventative effect on PTSD and its subsequent physical symptoms? “NSAIDs have not yet been used to prevent the onset of PTSD. But that’s something we’d like to look at,” Gill said. “There hasn’t been a lot of research to look at pharmaceutical agents to prevent the onset of PTSD. Hopefully future studies will be prospectives so we can look at the trends that may predict the onset of PTSD psychologically and biologically, as well as social factors. Right now we just don’t have enough prospective studies to understand that risk factor profile.”

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