Cortisol and PTSD, Part 2

An interview with Dr. Rachel Yehuda

Posted Jun 22, 2016

Last week, I shared part 1 of my interview with Dr. Rachel Yehuda, a neuroscientist and the director of the traumatic stress studies division at Mount Sinai School of Medicine in New York. Dr. Yehuda has played a major role in advancing our scientific understanding of the role of cortisol in PTSD.

More recently, Dr. Yehuda also offered the PTSD scientific community a novel and intriguing idea: that the children of traumatized parents are at risk for similar problems due to changes that occurred in the biology of their parents, as a consequence of their trauma exposure. It is these epigenetic changes that are then transmitted to their children via a process called “intergenerational transmission.”

Recently, I spoke with Dr. Yehuda about cortisol, intergenerational transmission of stress, and the future of PTSD treatment and research. Here is part 2 of our interview.

Dr. Jain: My next question is about the potential role of cortisol in the treatment of PTSD. Maybe if you could speak about that a little bit. From a clinician point of view, that is really intriguing. It feels like immediate clinical applications might be on the horizon.

Dr. Yehuda: I see at least three or four ways that we could think about cortisol-based interventions. The first one might be prevention. That is the Zohar study, which is a study being conducted in Tel Hashomer hospital in Israel, headed by Dr. Joseph Zohar. When I first heard his idea of using cortisol in the ER to prevent PTSD, I have to admit I was skeptical, even though we are the ones that published that cortisol levels are lower in the immediate aftermath in persons who are more likely to develop PTSD. What Dr. Zohar said was, if that is true then we should be able to give cortisol during the “golden hours.” But I was nervous. Why? Because I think that hormonal response is something that you want to be very careful about changing, because the body has a wisdom. That is my general view of the world, but he convinced me that if you give a single really high dose of glucocorticoids within a 4-hour window of a trauma, then the effect that that might have would be to recalibrate the HPA axis in a way that provides enough cortisol to quiet down the sympathetic nervous system in a very organic and permanent way. Also, Dr. Hagit Cohen’s in Ben Gurion Medical School in Beer Sheva work with animal studies had shown that this might actually work to prevent PTSD if given during the “golden hours.”

Dr. Jain: By “golden hours” you refer to that 4-hour window after the trauma?

Dr. Yehuda: We do not know what the window is. In our study we said 4 hours. I do not know if it is 8 hours or 12 hours! We do not know if it is 2 days! Ironically, when people give benzodiazepines in the acute aftermath of a trauma, they are doing the opposite thing, as benzodiazepines lower cortisol levels. So even though in the short run, you may experience some relief, in the long run it just kicks the can down the road. Dr. Zohar’s idea is that by intervening early you can set a pathway towards recovery.

There have been other studies like this. In fact, the first observation of this was by a physician in Germany named Dr. Gustav Schelling. He was treating septic shock and using hydrocortisone as a treatment for septic shock. What he noticed was that those who had received high levels of glucocorticoids, which not everyone did, had fewer complaints of traumatic memories from their traumatic experience of being critically ill. He searched for an explanation and finally did a randomized clinical trial. He concluded that there were beneficial effects of administering high doses of glucocorticoids in the early aftermath of a trauma. So prevention is certainly one potential avenue.

But there are people who have given glucocorticoids not during the “golden hours,” but in a more sustained way over several weeks. They have also found potentially beneficial effects. We have just completed our study with Dr. Zohar and eagerly await the results. In this study we also measured biomarkers to see if treatment could be predicted.

Another way to effect changes in the HPA axis might actually be to block the glucocorticoid receptor. There is a trial that is ongoing now using a drug called mifepristone, which is a glucocorticoid receptor antagonist. You might know this drug by a different name. This study is being run by my colleague Dr. Julia Golier. You might know mifepristone as RU-486, or the abortion pill. RU-486 obviously has effects on the progesterone receptor, which is why it is an effective treatment to prevent pregnancy, but it also has effects on the glucocorticoid receptor. There is a trial that is ongoing now, ending August. The pilot study showed some benefit. What happens with that treatment is that you can block the glucocorticoid receptor and really recalibrate the ratio of peripheral to central cortisol. The beauty of that treatment is again you give it once or you give it for a very short period of time, and you look for recalibration effects. People like to take medications that way as opposed to every single day.

Another way to think about glucocorticoid treatments is to use cortisol as an augmenter of psychotherapy. We have been doing some studies where you give moderate doses of cortisol or hydrocortisone about half an hour before an exposure based treatment. The rationale for that is that glucocorticoids facilitate new learning. They facilitate extinction, and it could be that administration of moderate doses of hydrocortisone could really set the stage for doing better in exposure therapies. We found that in case reports in a small trial we conducted. What we found was that there were fewer drop-outs out of prolonged exposure therapy if they were given hydrocortisone compared to placebo. If that continues, that is a big deal, because we know that a lot of patients drop out of these treatments prematurely. Anything that makes somebody just stay in treatment is probably good.

Dr. Jain: Moving on to the next question then. There is this whole issue regarding lower cortisol levels being a pre-traumatic trait, like, somebody already has this and then they are trauma exposed and have a higher chance of developing PTSD. What are the implications of this for screening and resiliency programs in clinical settings?

Dr. Yehuda: We have an artificial view of what “pre-trauma” means. Pre-trauma of the event that we happen to be thinking about now? Many of us don’t consider enough what kind of early environmental events people have experienced before they present for effects of the trauma that they are coping with now.

We know that many people in the military have had traumatic experiences prior to being in the military, yet we define their pre-trauma cortisol as being pre- combat, as opposed to before they ever experienced any adversity.

I think this is a tough nut to crack. In our studies, we found that lower cortisol levels were present in rape victims who had had a prior assault. They are more likely to develop PTSD, but was their cortisol level already low? Is that why it did not climb up higher than it could have?

I think that these are important issues. Now, there was a fascinating study that was published by Mirjam van Zuiden and her group in the Netherlands that basically took a thousand soldiers, before they went into combat, and looked at cortisol and glucocorticoids receptor measures and markers, as well as genes and epigenetic markers of the glucocorticoid receptor. They found that low cortisol and enhanced glucocorticoid receptor sensitivity were predictors of people that had PTSD a few months later.

Now, of course, we do not know if they also had prior trauma. We do not know that, but that was a very elegant demonstration.

It is exactly as you say, but it is hard to unpack these things. At least we are getting closer to understanding that not all the action occurs at the time of the trauma. That the stage might be set in advance, we are actually an accumulation of our experiences, and we hold biologic changes and then use them to respond differently to traumatic events as they emerge in our lives.

Dr. Jain: That is very true. I like that phrase—it is setting the stage for subsequent trauma reactions. We have not figured out exactly how all those pieces come together.

Dr. Yehuda: There are a lot of people that are studying the effects of child abuse and early trauma even in the absence of PTSD. Their work is also supporting lower cortisol levels. It may be that low cortisol will impacts whether someone gets PTSD to a later trauma. The problem can be that when you study someone at one point in time and they have low cortisol but they don’t have PTSD, that does not mean that they will not develop PTSD if exposed to a trauma in the future. We do not know whether low cortisol measures are markers or predictors of the future, but I would suspect that there is a genetic component as well as an early environmental component that would make these markers predictors. That is one of the difficulties in conducting such studies. The challenge of clinical research is that we are looking at a few points in time and trying to make decisions as if we were looking at stable phenotypes, when we know that there is an awful lot of change that occurs within individuals in terms of their mental state, not to mention the fact that people often have really complex lives with a lot of things going on. So, you might be resilient following the first three events, and then the fourth one occurs and then you develop PTSD. We do not really know how useful these measures are, but there is probably a way that we can do more longitudinal prospective studies to get a flavor of that. I know that those are studies that are ongoing in the VA system, which is really good.

In my next blog post, I'll share part 3 of my interview with Dr. Yehuda.

Copyright: Shaili Jain, MD. For more information, please see PLOS Blogs.