OITZL: Did I miss something about the temporal aspect of PTSD? That is, are there differences between individuals who may have had PTSD for a limited duration like 6 months and those with chronic PTSD who have had PTSD for many years?
BREMNER: We’re starting to study this in people that are coming from Iraq. The argument that we make is that people coming from Iraq in the first 6 months to a year after their return have a different type of PTSD than some of the older PTSD veterans from Vietnam. Until now the subjects we have studied have chronic forms of PTSD, such as the PTSD related to abuse in early childhood or Vietnam combat veterans with PTSD. We are looking at adolescents with abuse-related PTSD in which the PTSD is more acute, but that study is not completed. And then we do have a current study that is looking at returning Iraqi veterans trying to get people in the first 6 months after they were discharged from service. We are doing a brain imaging and intervention that involves mindfulness-based stress reduction.
JOËLS: The number of newborn cells in adult brain is extremely low. It is not well known how many newborn cells there are in children, but from the little that is known it is not a lot. Even if these numbers are doubled and you look over a couple of weeks, the increase in hippocampal volume or 5% you see in your studies after paroxetine treatment cannot easily be explained by these newborn cells. So where do you think this increase of volume comes from? Is it maybe a change in blood flow or something else?
BREMNER: It could be that in addition to new neurons developing with paroxetine treatment, there are other contributions to increased volume such as an increase in dendritic branching. It could also be that treatment results in an increase in water content. However, we have preliminary data showing an increase in N-acetyl aspartate (NAA) measured with magnetic resonance spectroscopy (MRS) in the hippocampus of PTSD patients. NAA is a marker of neuronal integrity, so this suggests that paroxetine has effects on neuronal structure.
SECKL: I would like to ask a slightly different type of question and also about your findings with DHEA, which among us as endocrinologists has been a graveyard for many people’s careers. But it is a pretty unique association: Do you think there is a fundamental underlying diathesis in this condition with this altered 17 hydroxylase? What is your thinking about this finding?
BREMNER: Our study showed that DHEA is elevated in women with abuse-related PTSD, and also that there was an elevation in DHEA to cortisol ratio where there was even more of a difference between the patients and the controls. From the standpoint of PTSD pathology, you can argue that it is a paradoxical finding since DHEA supposedly should have antiglucocorticoid-protective effect on the hippocampus. Here we are getting elevated levels, and smaller hippocampal volume and lower cortisol in the same subjects. In terms of the pathophysiology of why it is elevated, I do not know if I have a good explanation. If you look at the depression literature it is a mixed literature. In PTSD there are two studies that have a single sample, one significantly decreased and one significantly increased. Do you want to comment? I am not an endocrinologist.
YEHUDA: You have a lot of data and it is really impressive that you can get so many measures on the same subjects, and that is really what helps you make progress in the field because we tend to make these observations usually in different subjects; to me that is terrific. However, I am wondering I think there is a point in your presentation where you present like this is the theory and here are the data, the data don’t fit the theory, and then we come back then about the theory, e.g., you have one slide about traumatic stress spectrum and all that, and depression and PTSD should be alike and elevated cortisol and cortisol damages the brain. Ok all that’s fine and we know that is in the literature out there. But now you have collected your data, you are one of the few people on the planet that have multiple measures in the same cohort. So you can say, “Hey wait a minute, I have low cortisol at baseline and small hippocampuses, ha!” So what does that do to those slides in the beginning of the talk that summarize the literature and form the basis of your model? How do you feel about extending that?
BREMNER: There’s some pattern that you know, e.g., that we can see correlations between memory performance measured at the time of the 24 h cortisol measure. In normal subjects there is an inverse correlation, so the higher the cortisol the lower the memory function which makes sense in terms of what is known about how administration of cortisol impairs declarative memory function in normal subjects. Because of time I did not show the trial in which we have given dexamethasone to healthy subjects in a 3-day protocol. After 3 days memory function becomes impaired in healthy subjects but not in the PTSD patients. We can see low cortisol and small hippocampal volume in the same subjects. And then we put them through a trauma-specific task that gives them anxiety and cortisol release is increased. So there could be some pattern cortisol release that causes hippocampal damage and memory impairment. But…
YEHUDA: How can it do that when it is low? How does low basal cortisol cause hippocampal damage?
BREMNER: Well low basal cortisol does not cause hippocampal damage. And we do not find correlations between hippocampal volume and cortisol in our patients with PTSD from traumas 20 years ago.
YEHUDA: You did not show cortisol and hippocampal volume correlation?
BREMNER: No we don’t have this correlation; there is not a correlation in PTSD. So you know whether cortisol at one point in time resulted at the time of trauma in a kind of damage that would be a speculation. I do not know if we could ever really look at that. But what it looks like more is that there is a pattern of findings in subjects at baseline that, maybe, points at some central pathological process that leads to lower cortisol and smaller hippocampal volume that may not even be related in terms of the pathogenesis.
YEHUDA: It is at the heart of the matter of when we decide that maybe cortisol does not damage the hippocampus. I mean how much data do you need to look at the literature and say “Ha, this does not apply here.” But it does not sound that there ever is going to be evidence of such a correlation for some of us.
DE KLOET: There is a literature out there, in which it is stated explicitly that high cortisol concentrations are damaging to the hippocampus, but in my opinion that cannot be generalized because there many situations like exercise that also produce high cortisol, but that are paradoxical not damaging at all. Only if levels of cortisol are chronically elevated for prolonged periods of time under conditions of distress one may see deterioration of the immune system, metabolic changes, and impairment of brain function. The question then is: What is special in the pattern of cortisol secretion that it damages the brain?
YEHUDA: The point is that at some time the data that we get should force us to have new models and abandon models that don’t fit the data. Because then we are just trying to make that data fit models that are no good and you can have low cortisol and small hippocampal volume and somehow it still becomes important to say at some time there was no high cortisol, why, maybe, maybe not, maybe that does not fit, I am just wondering at what point we do that.
DE KLOET: I think the jury is out. There is a need for good controlled studies to measure the pulsatile patterns of cortisol to demonstrate what the actual significance of cortisol is, whether it is a predisposing factor or a consequence of the PTSD condition.