Complex PTSD, STAIR, Social Ecology and lessons learned from 9/11- a conversation with Dr. Marylene Cloitre

Dr. Marylene Cloitre is the Associate Director of Research of the National Center for PTSD Dissemination and Training Division and a research Professor of Psychiatry and Child and Adolescent Psychiatry at the New York University, Langone Medical Center in New York City. She is a recipient of several honors related to her service in New York City following 9-11 and was an advisory committee member for the National September 11 Memorial Museum. She has specific expertise in complex PTSD and for the development and dissemination of STAIR (Skills Training in Affective and Interpersonal Regulation), a psychological therapy designed to help survivors of trauma.

Dr. Jain: What exactly is complex PTSD?

Dr. Cloitre:
Complex PTSD has a very long history, really pushed primarily by clinicians who looked at their patients and thought there’s something more going on here than PTSD.
In DSM-4, complex PTSD was recognized in the additional features where there is a mix of problems related to emotion regulation, self-concept and interpersonal relationships. After that, there was really no funding around investigating this further and the research for it has been spotty and it was sort of dying on the vine.

But with the development of a new version of ICD-11, there was an opportunity really to refresh consideration about complex PTSD. I was part of a work group that started in 2012, we looked at the literature and thought there seems to be enough data to support two different forms of PTSD , the classic fear circuitry disturbance and then this more general kind of disturbance in these three core areas of emotion regulation, self-concept and interpersonal relationships.

We proposed that there should be two distinct disorders: PTSD and complex PTSD and it looks like it’s been accepted and it will part of the ICD-11 coming out in the 2018.

Since the initial proposal, I’ve been working with many people, mostly Europeans, where ICD is more prominent than in the United States and there are now about nine published papers providing supporting evidence that these two distinct disorders.

Dr. Jain:
Can you summarize in which ways they’re distinct? So on a clinical level what would you see in complex PTSD?

Dr. Cloitre: Mostly we’ve been looking at latent class analysis which is a newish kind of data analytic technique which looks at how people cluster together and you look at their symptom profile. There are a group of people who very distinctly have PTSD in terms of re-experiencing, avoidance and hyperarousal and then they’re fine on everything else. Then you have another group of people who have these problems as well as problems in these three other areas.And then there are another group of people who, despite exposure to trauma, do fairly well.

What we’ve been seeing are these three groups in clinical populations as well as in community populations and adults as well as in children.

Overall, these latent class analyses are really showing that people cluster together in very distinctly different ways. I think the important thing about this distinction is, what’s next? Perhaps there are different clinical interventions that we want to look at to maximize good outcome. Some people may do very well with exposure therapy. I would say the PTSD clustered folks will do very well and have optimal outcome because that’s all that bothers them. For the other folks, they have a lot of other problems that really contribute to their functional impairment.

For me as a clinician as well as a researcher, I’ve always been worried not so much about the diagnosis of the person in front of me but about how well they’re functioning in the world. What I have noticed is you can get rid of the PTSD symptoms, for people with complex PTSD, but they’re still very impaired.
My motivation for thinking about a different diagnosis and different treatment is to identify these other problems and then to provide interventions, that target these other problems, for the goal of improving our day to day life functioning. If you don’t have ability to relate well to people because you mistrust them or are highly avoidant or if you think poorly about yourself these are huge issues then we need to target these issues in treatment.

Dr. Jain
Have you noticed that different types of trauma contribute to PTSD v complex PTSD?

Dr. Cloitre Yes, it does and it kind of makes sense that people who have had sustained and repeated trauma (e.g. multiple and sustained trauma doing childhood) are the ones who have complex PTSD.

Dr. Jain: Can you tell us a little bit about the fundamental philosophy that drove you to come up with STAIR and what evidence is there for it’s effectiveness?

Dr. Cloitre I came to develop STAIR as a result of paying attention to what my patients were telling me they wanted help with, that was the driving force. It wasn’t a theoretical model, it was that patients came and said,” I’m really having problems with my relationships and that’s what I need help with” or “I really have problems with my moods and I need help with that”.

So, I thought, why don’t we start there? That is why I developed STAIR and developed it as a sequence therapy while respecting the importance of getting into the trauma and doing exposure based work, I also wanted to engage the patient and respect their presented needs. That what it’s all about for me.
Overtime I saw a secondary benefit, that an improved sense of self and improved emotion regulation could actually impact the value of exposure therapy in a positive way.

In my mind, the real question is: What kind of treatments work best for whom? That is the question. There will be some people for whom going straight to exposure therapy is the most effective and efficient way to get them functioning and they’ll be happy with three or four sessions, just like some 9/11 survivors I saw. They only needed three or four sessions.

Other people might do better with combination therapies .

Dr. Jain The studies that you’ve done with STAIR can you summarize the populations you have used it for?

Dr. Cloitre: I began using STAIR + exposure with the population I thought would most need it which is people with histories of childhood abuse. In fact, our data show that the combination of skills training, plus exposure was significantly better than skills alone or exposure alone. So that’s very important. It also reduced dropout very significantly as compared to exposure, which is a continuing problem with exposure therapy especially for this population

Dr. Jain Can you speak to the social ecology/social bonds and PTSD, what the research world can tell us about the social dimensions of PTSD and how we can apply this to returning military members and veterans?

Dr. Cloitre: I think that social support is critical to the recovery of people who have been exposed to trauma and who are vulnerable to symptoms .We have enough studies showing that it’s the critical determinant of return to health.

I think we have done a very poor job of translating this observation into something meaningful for returning veterans. There is general attention that families are part of the solution and communities are part of the solution but it is vague –there isn’t really a sense of what are we going to do about it.

I think these wars (Afghanistan and Iraq) are very different than Vietnam, that’s where soldiers came back and they were called baby killers and had tomatoes and garbage thrown at them. You can really understand why a vulnerable person would spiral downwards into pretty significant PTSD and substance abuse.

I think we need to be more thoughtful and engage veterans in discussions about what’s most helpful in the reintegration progress, because there are probably really explicit things like, being welcomed home, but also very subtle things that we haven’t figured out about the experience.
I think on a community or family level, there’s a general awareness but we haven’t really gotten clear thinking or effective about what to do. I think that’s our next step. The parade and the welcome home signs are not enough.

I’ll give an example of what I witnessed after 9/11. The community around survivors feels awkward and doesn’t know what to do, so they start moving away. Combine this with the survivor who is sad or being irritable and so not the most attractive person to engage with. I say to patients sometimes, it’s a really unfair and unfortunate circumstance, that in a way, not only are you suffering but you’re also kind of responsible for making people around you comfortable with you.

I used to do STAIR because patients ask for it and also I thought,” oh well some people never had these social skills in the first place, which is why they are vulnerable with PTSD” but then I noticed that STAIR was useful for everybody with PTSD because I think the traumatized patient has an unfair burden to actually reach out to people in a process of re-engagement because the community and the family is confused. Others, strangers or say employers are scared. So they have to kind of compensate for the discomfort of others, which is asking a lot.

I think in our therapies we can say look, it’s not fair, but people feel uncomfortable around the veteran. They don’t know how to act and in a way you not only have to educate yourself about your circumstance but, in the end, educate others.

Dr. Jain Survivor perception of social support really matters. If you take a group of disaster survivors, we may feel well we’re doing this for them and we’re doing that for them but if the survivors, for whatever reason, don’t perceive it as being helpful it doesn’t matter. When I think about marginalized populations in our society, I don’t think to communicate to others about how to help you or how to support you is that simple.

Dr. Cloitre It’s very complicated because it is a dynamic. I think we need to talk to trauma survivors and understand what their needs are so that the community can respond effectively and be a match. Not everybody wants the same thing. That’s the real challenge. I think if survivors can be a little bit more compassionate, not only towards themselves for what they have been through but to others who are trying to communicate with them and failing.

Dr. Jain That can be hard to do when you’re hurting. The social ecology of PTSD is really important but it’s really complicated and we are not there, in terms of harnessing social ecology to improve lives.

Dr. Cloitre No. I think we’re just groping around in the dark, in a room that says the social ecology of PTSD is important. We don’t know how to translate that observation into actionable plans either in our individual therapies or in our family therapies and then in our community actions or policies.
But I do think that, in the individual therapy, recognizing the importance of trying to enhance perception of support where they’re real. Secondly, recognizing the burden that they have that’s unfair and try to enhance skills for communicating with people. Thirdly, having compassion for people who are out there who are trying to communicate but failing.
I have had a lot of patients who come, into therapy, and say,
” This is so ridiculous. They’re saying stupid things to me”.
And, I say,
“well at least they’re trying”
I think it’s important for the affected community to have the voice and take leadership, instead of people kind of smothering them with social support that they may or may not need.

Dr. Jain
I know you’re a native New Yorker and you provided a lot of service to New York City following 9/11. Can you speak about that work? And in particular what I’m really interested in is that body of research that emerged after 9/11 because I feel like that has helped us understand so much about disaster related PTSD.

Dr. Cloitre We found out was most people are very resilient. We were able to get prevalence rates of PTSD following 9/11, that in of itself was very important. I think that’s the strongest research that came out.

I think on a social level it broke open awareness, in this country and maybe globally, about the impact of trauma and about PTSD because it came with very little shame or guilt.
Some people say what was so different about 9/11? Well, because it happened to the most powerful country and the most powerful city then if it could happen to them it could happen anywhere. That was the response, there was not this marginalization, ”Well this is a victim circumstance and it couldn’t happen to me and they must have done something to bring it on themselves”.
There was a hugely different response and that was so key to the shift in recognition of the diagnosis of PTSD which then led to more general research about it. I think that that was huge.
Before 9/11, I would say I do research in PTSD and people would say, what is that? Now I say I do research in PTSD, not a single person ever asks me what that is. I mean I’m sure they don’t really know what it is but they never looked confused. It’s a term that is now part and parcel of American society.
9/11 revolutionized the awareness of PTSD and also the acceptability of adverse effects, as a result of trauma. There was new knowledge gained and also just a transformation in awareness that was national and probably global because the impact it had and the ripple effects on another countries.
I think those are the two main things.
I don’t think it’s really done very much for our thinking about treatment. I think we continue to do some of our central treatments and we didn’t get too far in really advancing or diversifying.
For me personally, I learned a lot about the diversity of kinds of trauma survivors. Very different people, very different reactions.
I think probably the other important academic or scholarly advance, was in the recognition of this blend of loss and trauma and how they come together. That people’s responses to death ,under circumstances of unexpected and violent death, has also advanced. In fact now ICD-11 there will be a traumatic grief diagnosis, which I think has moved forward because of 9/11. That’s pretty big.

The Golden Years: Traumatic Stress and Aging – An Interview with Joan Cook

Dr. Joan Cook is a clinical psychologist and Associate Professor in the Yale School of Medicine, Department of Psychiatry. She has specific expertise in the areas of traumatic stress and geriatric mental health. Dr. Cook has served as the principal investigator on four grants from the National Institute of Mental Health, as well as grants from the Agency for Healthcare Research and Quality and Patient-Centered Outcomes Research Institute. She is a member of the American Psychological Association (APA) Guideline Development Panel for PTSD and is the 2016 President of APA’s Division of Trauma Psychology.

 

Recently, I spoke with Dr. Cook about PTSD in older adults.

 

source: pexels
source: pexels

Dr. Jain: Can you comment on the unique methodological considerations for researchers doing PTSD research in the elderly?

 

Dr. Cook: There are a number of methodological considerations that researchers who want to study older traumatized individuals might want to think about beforehand. One issue in working with this current cohort of older (65 and above) adults is their potential denial or minimization of reporting of trauma and related symptoms. For some individuals in this current cohort, their traumas may have preceded the 1980 introduction of posttraumatic stress disorder (PTSD) into the official diagnostic classification. Thus they may associate more stigma or blame themselves for having experienced such event and/or having subsequent symptoms.

 

I think events such as the September 11th terrorist attacks, the wars in Iraq and Afghanistan, and Hurricane Katrina, have helped raise the national consciousness about trauma. But I still clinically come across older adults who lack an understanding of the potential effects of traumatic experiences or don’t accurately label such events as “traumatic.” In addition, there are also cognitive, sensory, and functional impairments that may affect the experience, impact, or reporting of trauma-related symptoms.

 

Dr. Steven Thorp, Heather Sonas and I (2011) provided some recommendations for conducting trauma and PTSD-related assessment and treatment with older survivors. This includes practical issues like the need for large, bold fonts in written assessment or therapy materials to increase readability and minimize frustration, using specific behaviorally anchored questions to assess for traumatic events, and the benefits of using more than one method of assessment (e.g., self-report, observation, caregiver report, and structured interviews).

 

source: pexels
source: pexels

Dr. Jain: Can you discuss the findings of Intimate Partner Violence (IPV) rates (and related PTSD) in older women versus younger women? How might these findings be explained (e.g. reporting bias, less public awareness, lack of resources to help older women)?

 

Dr. Cook: I’m so glad you asked this question! This is a topic that is near and dear to my heart. I’ve done a little research in this area but wish I had time and resources (grant support, interested collaborators) to do more.

 

In general, rates of IPV and related PTSD are lower in older as opposed to younger women. This may be due to more recent violent times in our society, for sure. But it also may be due to an interaction between reporting bias and cohort effects. The current cohort of older women may be less likely both to label IPV as such and to disclose such histories to health care providers. There also appears to be limited public awareness and fewer available services specifically designed for older IPV survivors compared to younger and middle-aged women.

 

A fairly recent systematic review that my colleagues and I conducted found that older women with IPV histories have greater psychological difficulties than older women who do not have these experiences. More specifically we also looked at data from a large nationally representative sample and found that one out of seven older women reported a history of physical or sexual assault, or both. And those who reported this type of traumatic history were generally more likely to meet criteria for past-year and lifetime PTSD, depression, or anxiety than those without such a history. Although IPV does not appear to be a widespread phenomenon in older women, it should not remain a “hidden variable” in their lives. I’d love to see more public attention, research, and clinical endeavors with older traumatized women.

 

Dr. Jain: Much of the studies of PTSD in older populations have been done in Veterans—do you think these findings are applicable to other populations of trauma exposed adults?

 

Dr. Cook: You’re right. The vast bulk of the empirical literature on older adult trauma survivors has been conducted on combat veterans and former prisoners of war. But there is a relatively decent sized research base on older adults who experienced Holocaust-related trauma earlier in their life and individuals who experienced natural or man-made disasters later in life. There is very little research on trauma in aging ethnic and racial minorities and, as explained above, less on physical and sexual abuse in older men and women.

 

I don’t think this means that the findings from the literature can never generalize. That would feel too extreme, right? But I think we need to sometimes exercise caution in our interpretation and recognize the limits of what we can and should say. I’m a researcher. I’m always looking to widen the representativeness of my samples (e.g., men/women, assessing for all types of trauma and a range of mental health and quality of life type outcomes, looking at people from varying SES, racial/ethnic backgrounds, and disability statuses) and to dive more into the nuances or intersectionality of those variables.

 

Dr. Jain: Can you talk about the correlation between PTSD and dementia? How robust are these findings? What other causal factors may be involved? What about the reverse—how does having dementia impact PTSD symptoms?

 

Dr. Cook: This is a hard one for me to answer. It’s intriguing data for sure, but there’s so much we don’t know. We know that older adults with PTSD perform more poorly across a range of cognitive measures, particularly processing speed, learning, memory, and executive functioning compared to older adults without PTSD.

 

Over the years there have been several case reports indicating that dementia may exacerbate existing PTSD symptoms. However in the past few years data from two recent large veteran datasets relatively indicate some evidence for a link between PTSD and dementia. In a sample of 181,000 veterans age 55 and over, those with PTSD were more than twice as likely to develop dementia over a six-year follow-up. In another study, almost 10,000 veterans age 65 and older were categorized according to PTSD status (yes or no) and having received a Purple Heart medal (yes or no). There was a greater incidence and prevalence of dementia in the older veterans with PTSD.

 

Some, however, believe that PTSD and dementia may share a third variable, intelligence, which may account for the link.

 

Dr. Jain: With regards to PTSD and older adults—what do you think are the top 5 questions/priorities for researchers to address in the coming 10-20 years?

 

Dr. Cook: The older adult population is increasing rapidly, and that changing demographic landscape will likely translate to an increased need for mental health services for older adults. Most randomized controlled trials investigating psychotherapy or pharmacotherapy for adults with PTSD do not typically include older individuals or sufficient numbers of them to examine age comparisons. A recent systematic review on psychotherapy for PTSD with older adults identified 13 case studies and seven treatment outcome studies. But this literature is disappointing in some ways. It has significant methodological limitations, including non-randomized research designs, lack of comparison conditions, and small sample sizes. One conclusion from this review was that select evidence-based interventions validated in younger and middle-aged populations appear efficacious with older adults. But while a number of the studies reported that older adults experienced a reduction of PTSD, depression, and anxiety symptoms, few experienced complete remission. It’s currently unclear if those treatments were not delivered in sufficient dose (i.e., intensity and frequency) to produce full benefit or if chronic, severe PTSD is harder to treat in older as opposed to younger adults.

 

Over the past decade there have been several epidemiological studies both in the United States and in several industrialized countries using representative samples of community dwelling adults and examining the prevalence and impact of traumatic experiences and PTSD with sufficient numbers of older adults to examine late-life age effects. Needless to say, this is very exciting and a significant advancement for both the traumatic stress and geriatric mental health fields. Now that we’ve done that I’d love to see more on the experience of trauma and expression of any related distress in the least healthy and potentially most “vulnerable” older adults—those with, physical, emotional, or cognitive impairment; those who are homebound; and long-term care residents.

 

Although the prevalence of full PTSD appears to be relatively low, there is some evidence to suggest that older adults may have clinically important PTSD symptoms. I think it would be great if we could invite subthreshold PTSD in the older adult population as well as trauma-related depression. There is a very robust literature on depression in older adults and only a handful of articles that look at the connection between depression and trauma.

 

Though older adulthood encompasses at least a 30-year age range, the vast majority of studies on older adult trauma survivors lump all of them into a generic older adult group. Ideally I would like to see more fine-grained analyses (even if they are exploratory) on young-old (65–74 years), middle-old (75–84 years) and old-old (85 years and older). This seems to be fairly low hanging fruit that most investigators could try to do.

 

I’ve also included other things in my wish list above.

Cortisol, the Intergenerational Transmission of Stress, and PTSD: An Interview With Dr. Rachel Yehuda

Source: http://www.dissociative-identity-disorder.net/w/images/PTSD.png
Source: http://www.dissociative-identity-disorder.net/w/images/PTSD.png

Cortisol, a stress hormone, is a key player in the subtle hormonal changes that have come to be associated with PTSD, and Dr. Rachel Yehuda, a neuroscientist and the director of the traumatic stress studies division at Mount Sinai School of Medicine in New York, 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.

 

Dr. Jain: You played a key role in re-conceptualizing the neuro-endocrine basis for PTSD after it became apparent that individuals with PTSD consistently have low cortisol levels. Can you speak a little bit about how robust a finding this is and what this means for clinical settings? How can we use cortisol levels in the diagnosis of PTSD? Can we use it to track if people are getting better?

 

Dr. Yehuda: The first published observation on cortisol in PTSD was in 1986 by John Mason and colleagues at Yale.  The group was interested to see if tracking stress hormone levels in patients admitted to the psych unit would aid in determining when patients might be safely discharged, so they measured cortisol levels in a wide range of psychiatric patients. Generally, cortisol levels were higher for patients at admission and then were much lower at discharge, which is what one would expect if cortisol is a marker of stress. However there were two groups of patients, one being patients with post-traumatic stress disorder, for whom this did not appear to be the case. The authors were surprised to find that in fact PTSD patients showed significantly lower cortisol levels at admission and discharge compared to patients with other diagnoses. I joined Yale a year after that finding appeared in the literature. Like many others, I found it curious that cortisol levels would be low and thought for sure there had be some mistake, because we would expect, if anything, that cortisol levels would be high in a stress disorder, particularly one in which there was comorbidity of depression. So I attempted a replication with Mason and his colleagues, and of course, we were able to replicate the low cortisol findings in several studies in the early 90’s.

 

What was so interesting, however, was how long it took the field to accept that the finding may reflect a reality. At the same time, and in the same patients, Mason and I observed elevated catecholamines. Neither Mason nor I had any trouble with the very first publication that catecholamine levels were higher in PTSD.  No one thought to question the finding because it was something expected—that people who are aroused and under stress have high levels of catecholamines, like norepinephrine. Yet the cortisol data from the samples were difficult for people to believe.   I guess when we hear something that makes sense to us, we do not need a lot of data. But we all questioned the low cortisol finding because it didn’t make sense, and then we questioned the methodology and so on. The reason the finding did not make sense, in the early 90s, was because the field of PTSD was new, and we didn’t really understand PTSD yet. There were really no epidemiological studies until the early 90’s, and even this very well accepted idea that PTSD only occurred in a subset of trauma survivors was not yet known. The prevailing concept was that PTSD always occurred following trauma exposure. But once there was a body of literature that showed that a lot of people are trauma exposed and only a smaller subset of those people get PTSD, the field could start speculating that perhaps low cortisol signals an abnormality that helps explain why recovery has not occurred. And when that happened, we began to ask what is cortisol’s role in stress, anyway? In turns out that one of the things that cortisol does in response to stress is that it helps contain the catecholamine system—it helps bring down the high levels of adrenaline that are released during fight or flight. Since we all know that adrenaline and norepinephrine are responsible for memory formation and arousal, not having enough cortisol to completely bring down the sympathetic nervous system, at the time when it is very important for a person to calm down, may partially explain the formation of traumatic memory or generalized triggers.

 

The second part of your question is what does this mean in a clinical setting and how can we use cortisol levels in the diagnosis of PTSD? At this moment, we cannot use cortisol levels to aid in diagnoses. They are too variable, and although there is a mean difference between PTSD and other groups, in every study that has been performed to date, there are a lot of overlapping data.   Furthermore, even the low cortisol levels in PTSD are well within the normal endocrinological range. The reason the low cortisol finding was important was that it led us down a trail of trying to understand why cortisol levels were low. Then it took us into the dynamics of the way that the hypothalamic–pituitary–adrenal (HPA) axis works and is regulated by the brain. Cortisol levels show natural variation during the day, and are affected by environmental perturbations. It is adaptive that cortisol levels vary , because cortisol helps regulate many bodily functions when we are stressed, and when we are not stressed. What we have been doing for the last 25 years is studying the underlying dynamics of cortisol levels. We have examined circadian rhythm changes that may determine how the brain regulates the release of cortisol over a diurnal cycle. We have looked at cortisol metabolism, to try to understand how cortisol is broken down into its various metabolites in the brain, liver, and kidney. But most of our studies have involved the glucocorticoid receptor and all of the genes and proteins that are involved in regulating the activity and sensitivity of that receptor. These studies have begun to give us an understanding that there is something really different about the stress system in PTSD, or in specific subtypes of people with PTSD,, but it is not going to be cortisol levels per se that are going to be useful to a clinician.

 

Dr. Jain: So the picture is much more complicated than what may have been originally conceptualized?

 

Dr. Yehuda: When we say low cortisol levels, an endocrinologist would cringe. In PTSD, cortisol levels are not lower than normal range. They are significantly lower on average compared to persons without PTSD, but the levels themselves are not abnormal. The cortisol levels in PTSD do not suggest that the adrenal gland is broken in any way or not releasing cortisol, but rather, given the normal range of cortisol, which is large—between 20 to 90 micrograms per 24 hours of urine—the means we would get in PTSD were in the 40s. Whereas, a straight mean would be more like in the 50s and 60s. We are not talking about an endocrine problem. We are talking about a tendency to be at the lower end which is within normal variability. Why this was newsworthy, again, was that we were expecting that it would be higher in a stress disorder, because cortisol is associated with stress. I personally would not use cortisol levels, not even 24-hour urinary cortisol levels, as a diagnostic marker. I would want to know a lot more about how the glucocorticoid receptor works. Is it more sensitive? What is the circadian rhythm like? What about cortisol metabolism? What about the genes that control cortisol and glucocorticoid functioning? So there is a potential to find biomarkers that relate to cortisol that may be clinically applicable—we have not given up on that idea at all. It’s just important to understand what kind of neuroendocrine or molecular neuroendocrine information is most relevant.

 

Dr. Jain: But it is not as simplistic as doing a blood test to diagnose PTSD.

 

Dr. Yehuda: Would that it were!

 

Dr. Jain: I know! But you offer a very important clarification: the pattern in PTSD is of lowER cortisol levels, not low cortisol.

 

Dr. Yehuda: Somehow statistically lower became low, but the devil is in the detail.

 

Dr. Jain: Absolutely, and that is why it is so valuable to talk to people like yourself.

 

Dr. Yehuda: Furthermore, the effect size of cortisol differences is small, too. In the Boscarino study (1995), he reported that cortisol was lower in PTSD, but there was a very small effect size. So it is not a diagnostic test. It is just a clue, and we used it exactly as a clue to unravel a deeper mystery.

 

Dr. Jain: I totally see that. 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.

 

Source: http://www.clker.com/clipart-9803.html
Source: http://www.clker.com/clipart-9803.html

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.

 

Source: By File photo, Canwest News Service - http://article.wn.com/view/2009/03/19/Vitamin_B12_deficiency_linked_to_birth_defects/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6533001
Source: By File photo, Canwest News Service – http://article.wn.com/view/2009/03/19/Vitamin_B12_deficiency_linked_to_birth_defects/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6533001

Dr. Jain: That is great. Related to that and transitioning to this concept of this intergenerational transmission of stress: Your 2005 study with the women who were pregnant in the World Trade Center, it was fascinating to read that study. I thought that it was an elegant demonstration of this concept of intergenerational transmission of stress. It would be great if you could talk a little bit about that study. One question that came to mind was a question about the pre-trauma cortisol level in the women. I wondered if that was measured, and did you gather data on their earlier experiences with trauma? That was just one particular question I had, but if you could just discuss the study in general, because I think it was really a fantastic contribution to the literature.

 

Dr. Yehuda: We did not have a lot of information on the women. In fact, this whole study was post-hoc in a sense that the study was designed for a completely different reason. It was to monitor pregnant women to make sure they gave birth to healthy babies. Everyone was really concerned about the level of environmental toxins after 9/11. Somebody from the environmental medicine group reached out to me because they noticed that a lot of women were really not doing very well emotionally and psychologically.

 

So by the time I was involved, some of the women had already given birth, but there had been a lot of information about what trimester they were in, about any pregnancy complications, exposure to toxins, etc. etc. So we added to that an evaluation of PTSD. Then when they came in for their 7 month to 1 year wellness baby evaluation, we were able to get salivary samples from the mother and the child. By then it did not surprise us to see that mothers with PTSD had lower cortisol levels than mothers without PTSD. But what did fascinate us was that in the mothers that had lower cortisol, the babies also had lower cortisol, but that this was a trimester dependent effect and that it seemed to split out in the second and third trimester in mothers who had been exposed in the middle of the second trimester or exposed in the third trimester.

 

When we had those findings, a lot of possibilities opened up in terms of how cortisol levels might be transmitted from parents to child or from mother to child. We were not the first people to make this observation. There has been a literature that that has demonstrated that mothers who are exposed to under feeding before puberty have children and grandchildren that have metabolic problems. Since we knew that the women exposed to starvation during pregnancy also tend to give birth to children who were more prone to hypertension as adults, we knew that there was the possibility of in utero effects.

 

But what seemed to happen here was an example of glucocorticoid programming. In the middle of the second trimester of pregnancy, there is an enzyme that becomes expressed in the placenta. It is an enzyme that blocks the conversion of cortisol to its inactive metabolite, cortisone. The induction of this enzyme really helps protect the fetus from detrimental effects of maternal glucocorticoids, because the cortisol is broken down into its inactive metabolite, cortisone. The enzyme is called 11β-Hydroxysteroid dehydrogenase type 2. We had already been interested in studying this enzyme just because we were interested in cortisol metabolism. But it turns out that in mothers who are under stress, it is very possible that their enzyme levels and the amount of glucocorticoids they have could overwhelm the body’s ability to metabolize cortisol into cortisone and affect the fetus. That was one idea that we had, that there might be a transmission based on offspring response in utero to maternal levels of stress hormones.

 

The message is straightforward: mothers who are stressed during pregnancy can program the stress response of their offspring, in utero, and the offspring accommodates somehow to the level of stress hormone. That has become a very important issue also in our intergenerational studies. It has become one viable mechanism through which mothers may “transmit” different vulnerabilities (or resilience) to their offspring. One does not need to have actual trauma experiences post-natally in order to have some of the neuroendocrine features associated with PTSD and PTSD risk. And this means that pregnancy is an important time with great social implications for our society. I do not think that we think about pregnancy as the very important developmental event that it really is. Otherwise, we would be really taking much better care of traumatized pregnant women than we do.

 

Dr. Jain: Obstetrics care involves screening for gestational diabetes, congenital defects in the baby, and even screening for postpartum depression……

 

Dr. Yehuda: Yes, and we should screen for trauma, too.

 

Dr. Jain: Given how high the rates of trauma exposure are in the population, it is worthwhile screening for trauma in pregnant women.

 

Dr. Yehuda: Exactly.

 

Dr Jain: The other thing I wanted to ask about was early data indicating that exposure to trauma can impact the psychosocial functioning of second, maybe third generation offspring. I think there were some studies done with holocaust survivors. If you could speak a little bit to that, because obviously that has very widespread societal implications, too.

 

Dr. Yehuda: Yes, we have found that in the adult children of holocaust survivors, they are more vulnerable to psychopathology and this is true of offspring who have parents with psychiatric symptoms. In one study we were able to measure biological and epigenetic markers showing that there are effects on holocaust offspring, based on either maternal and in utero developmental factors, maternal exposure, or maternal and paternal PTSD.

 

Dr. Jain: In general, what would you feel are the important questions for trauma scientists to answer in the next one to two decades? What would be top on your list to prioritize?

 

Dr. Yehuda: Many decades ago when the field first conceptualized the diagnosis of PTSD, our response was to emphasize the commonalities in trauma survivors regardless of what their exposures were. But I think it is important now to go back and see in a more clear way whether combat veterans are or are not different than other trauma survivors, or if interpersonal violence leaves a unique biological scar compared to a natural disaster, or whether age at traumatization matters or duration of trauma matters.

 

We basically have a threshold phenomenon where if you are over the threshold of what constitutes a trauma, you could be in the category depending on if you have the symptoms that are the symptoms of PTSD, but that is not very nuanced. In my experience, although there are similarities between trauma survivors in their mental health profile, there are also really important differences.

 

Some of the treatments that we have developed may really work better for some groups rather than others. For example, it seems like prolonged exposure is a fantastic treatment for interpersonal violence in women, and then the question becomes, is it as good for combat veterans? Have we studied this carefully enough? Should we be tailoring treatments based on trauma type and not just whether or not a threshold for trauma and symptoms has been met? We have to start customizing this.

 

The other thing that I think is really important is this idea that the designation of PTSD is a static one, or that it is binary or not dynamic. We have to rethink that. Now that I have the perspective of having years in the field and seeing the same trauma survivors over a period of many years, even decades, I understand that the same person can at sometimes meet diagnostic criteria for PTSD while at other times, that person may not. Do we view the person as always at risk after s/he has recovered? Especially when you have recovered from something and you are asked about having had it in the past, your memory is not so good for how much you have suffered in the past when you are feeling good right now.

 

Sometimes, I have had the ability to actually do a diagnostic interview of someone, meet them 10 years later, ask them about their worst episode of PTSD, and if they are feeling fine today they won’t remember how bad it was. What does that mean for biological studies, for biomarkers, and for risk? Just the idea of whether the categories are binary or not, I think is something that we really want to look at.

 

Finally, I think we have been paying a lot of attention to the psychological aspect of trauma and not enough to the physical illness part—the fact that people who are exposed to combat may die at an earlier age, make poor behavioral health choices, and are more prone to hypertension, metabolic syndrome, inflammatory illness, cardiovascular disease, and cancer.  These cannot be coincidences, but may either be part of the trauma effects, or part of the PTSD effects. Why are we not more focused on the biomarkers that might help explain and reverse some of these illnesses? When will we start seeing PTSD and trauma exposure as the multisystem condition that it is and really try to integrate care plans that not only assess for nightmares, hyper vigilance, and concentration, but diet and exercise and hemoglobin A1c? These are markers for trauma survivors because they are at greater risk for all these issues, not to mention cognitive decline. What I would like to see is us incorporating a much more holistic approach to understanding the effect of trauma that does not divide the mind and the body into different spheres and really focuses on wellness in a much more broad way.

 

Dr. Jain: So that integration between the physical and the mental, even in the way we treat them. Right now, it is separated out into mental health and physical health.

 

Dr. Yehuda: It does not make sense. Many veterans that come for care do not take such good care of themselves. It is not a priority for them. They do not maybe eat as well as they could or they have really disrupted sleep. I would like us to think about trauma as something that really does affect the whole body and our behavioral health choices. We should think broad, because those are the things that are really very important to ward off long-term diseases.

 

Dr. Jain: Yes, and enhance overall quality of life, too.

 

Dr. Yehuda: I think patients talk about what we (as healthcare professionals) want to talk about, and we lead the conversation in a symptom focused way. The symptoms of PTSD are impairing, don’t get me wrong, I am just saying there is a greater range of problems than are contained in the PTSD diagnosis.

 

Dr. Jain: I could not agree with you more. I feel like it is in the air. We are on the verge of embracing it that way. We are just not quite there yet.

 

Dr. Yehuda: I completely agree with you, and I think that the reason for that is that as we do our research on a genome wide level, we identify that so many of the biomarker pathways that seem to be altered relate to inflammatory immune functions. The pathways that are being identified in people with PTSD are not just those that associate with psychiatric symptoms, but really affect much more bodily functioning. I think that is also a lesson, just to close the loop on this that has been learned from the glucocorticoid story in PTSD. Cortisol is not just about mental health. There are glucocorticoid receptors in almost every cell in the body. Cortisol has a myriad of different functions in different target tissues, mostly in the metabolic systems promoting fuel and energy. It is silly to just think about cortisol’s role in traumatic memory when cortisol is a ubiquitous hormone that has so many different roles.

Developments in the Treatment of PTSD Nightmares

What Dreams May Come: Treating the Nightmares of PTSD” was a blog post I published in November 2013. It remains a very popular post, which continues to receive many views and comments. Since publishing that post, I have received multiple questions from readers about treatments for nightmares. These queries reinforce, for me, just how distressing this symptom of nightmares is for individuals who live with PTSD.

In light of this, on 5/22/2015 I interviewed Dr. Murray Raskind about his pioneering work in the field of PTSD and the treatment of nightmares.

Murray A. Raskind, MD, is Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC). He is also Professor and Vice-Chairman in the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine and Director of the University of Washington Alzheimer’s Disease Research Center.

In the late 1990’s, Dr. Raskind pioneered the use of prazosin for nightmares, by giving it to some of his veteran patients with PTSD. What started as clinical innovation eventually morphed into an important research question, and in 2013 Dr. Raskind and his group reported on an encouraging scientific development. They conducted a fifteen week randomized controlled trial of prazosin that involved sixty-seven active duty soldiers with PTSD. The medicine was titrated up based on the participant nightmare response over a period of six weeks. Prazosin was found to be effective in improving PTSD nightmares and sleep quality in two thirds of the sample. It was also associated with the study participants reporting a reduction in PTSD symptoms and an improvement in their overall global functioning.

 

I started my interview by asking Dr. Raskind about any other scientific findings that have emerged from that trial since his 2013 publication.

 

Image: Coalitionforveterans.org
Image: Coalitionforveterans.org

Dr. Raskind: We did an interesting secondary analysis, which we are writing up for publication now, of that sample of 60 or so active duty Iraq/Afghanistan soldiers with PTSD. When we analyze the response to prazosin, prazosin worked a lot better than placebo, but not in everybody. Approximately 2/3 of the soldiers were moderately improved globally, but there were 1/3 who just did not respond even though there were no differences in their symptom severity as measured by the CAPS (The Clinician-Administered PTSD Scale). With just looking at the psychiatric symptomatology, we really could not differentiate why one person would respond and another would not. We started thinking about it and we thought it would be nice to know something about the level of activation in the brain of the alpha 1 receptor for norepinephrine, which is the target of . (Prazosin is an alpha 1 norepinephrine receptor blocker or antagonist.)

We were thinking maybe you had to have a lot of alpha 1 receptor stimulation by norepinephrine to be a responder and maybe there are different underlying biologies to the PTSD symptoms. Unfortunately, there is no way, using imaging technology or anything else, to directly measure the alpha 1 receptor for norepinephrine. But it occurred to me, having been interested in effects on blood pressure of norepinephrine, that the central norepinephrine system and the peripheral sympathetic nervous system, which uses norepinephrine as its neurotransmitter, are often co-regulated. Blood pressure particularly is affected strongly by stimulation of the alpha 1 receptor on the arterial blood vessels that regulate blood pressure.

We hypothesized that soldiers with PTSD who have higher standing systolic blood pressure would have a better response to prazosin than the ones with lower baseline standing systolic blood pressure. We did this before we started them on prazosin, because we were looking for a biomarker of response to prazosin or a predictor of response to prazosin. We just did a straight forward statistical analysis and, lo and behold, the prediction was strongly supported by the data. These are young men and their mean age is 29 and they were in good shape, because they were still in the army, so they have to keep physically fit. We did not have people with a systolic of 180, but if you just compare it, in the statistical model, a person who had a slightly elevated systolic blood pressure of 130, those folks have a big prazosin response. A big improvement. Whereas if you have a baseline standing systolic of 110, your response to prazosin did not differ at all from placebo.

 

Dr. Jain: So you are starting to paint a profile of what kind of patient would respond well to prazosin?

 

Dr. Raskind: Right, which goes to our clinical experience….I often get referred the most agitated, aggravated, and upset combat veterans with PTSD who are having sleep disruption. When they wake up from a nightmare, or even without a nightmare, the bed is wet from sweat and their heart is racing and they cannot get back to sleep. During the day they are hyper vigilant and irritable. The ones I see, the ones who are good prazosin responders, almost always have some degree of elevated blood pressure. When someone comes in to my office with the same clinical picture but their blood pressure is below normal, I say, “I do not think that prazosin is going to work particularly well for this veteran.” I made that observation clinically, but I did not know whether it was valid until we did the study. It is actually sort of exciting. We have to do it prospectively, but I think it will hold up. Even without measuring blood pressures, other indications of increased sympathetic arousal such as sweating when you wake up at night or during sleep is another factor that I think would be a good biomarker, but it is not so easy to quantify.

 

Dr. Jain: That is pretty exciting, because, as far as I know, when we look at medications for PTSD, I do not think we have other biological predictors of response.

 

Dr. Raskind: Right. We do not. That is correct. We presented the data at two places so far. At this year’s Biological Psychiatry meeting and also at ACNP (American College of Neuropsychopharmacology) last December.

 

Dr. Jain: How do you see prazosin being used in the clinical setting 5-10 years from now?

 

Dr. Raskind: Well, I think that I would like to see it being used for people in whom there is a good chance that it would work. It’s not for everybody. Fortunately, it is a pretty easy medication to tolerate and the side effects are relatively uncommon, provided that you start at a low dose and titrate it upwards. The titration should be based both on the target symptoms going away and if there are any adverse effects on blood pressure. Usually, adverse effects are relatively uncommon. The major problem with prazosin is that providers don’t titrate to a high enough dose. If you look nationally, there are about 100,000 veterans with a PTSD diagnosis in the VA who, last year, were prescribed prazosin. About, one out of six. But the downside is that the mean dose is about 4 milligrams.

 

Dr. Jain: Is that sub-therapeutic in your mind?

 

Dr. Raskind: It works for some people, but some people need more. They also often need smaller daytime doses. Either one in the mid-morning and another one at around mid-afternoon somewhere, in addition to the night time dose, because prazosin only has a duration of action of about 6-8 hours. There is no magic number of milligrams. In the 2013 study, we titrated it up to a maximum dose of 20 milligrams at night and 5 milligrams mid-morning. You could go that high. Rules were you titrate it up until all nightmares were gone in the previous week. It took a lot of prazosin. We got up to about a little over 15 milligrams at night and about 4 milligrams mid-morning until we reach that criterion. That suggests that 4 milligrams is too low. On the other hand, some people get better with 2 milligrams. Sleeping great and nightmares are gone. That is the dose for them.

 

Dr. Jain: It sounds like you would like to see prazosin used in a more tailored fashion in people who have a profile which suggests it is more likely to work for them.

 

Dr. Raskind: Exactly. There are other disorders for which it appears that prazosin will also play a therapeutic role.

 

Dr. Jain: Like what?

 

Dr. Raskind: Well, there are three. The first is alcohol use disorder. Second is post mild traumatic brain injury or post-concussion migraine headache. The third is agitation aggression in Alzheimer’s disease and probably dementia in general.

 

Dr. Jain: Alright. Other than prazosin, what else do you like to use for nightmares? Are there any other things you have come across that you are particularly impressed by, non-pharmacological as well as pharmacological?

 

Dr. Raskind: The literature on nightmare psychotherapy is mostly from civilian trauma populations. I don’t know how well it translates over to (veterans)… There are specific nightmare psychotherapies, that I am frankly not terribly familiar with, e.g. imagery rehearsal. Changing the nature of the dream while you are awake and then seeing if that helps. Again, it helps in civilian trauma populations. The nice thing about psychotherapy, in my opinion, is if it is done well with a compassionate and interested person, they all work to some degree and their side effects are pretty low. In general, the psychotherapy along with rational pharmacotherapies is probably the way to go.

 

Dr. Jain: Please offer your perspectives re: clinical innovation in the 21st century? Is it harder for today’s physicians to innovate at the bedside? (too much regulation, oversight, paperwork, legal implications)

 

Dr. Raskind: And these guidelines, which are really, mostly, guesses.

 

Dr. Jain: You mean the clinical practice guidelines?

 

Dr. Raskind: Right. If you do not follow them, people worry that they are going to be called on it and I have seen it happen. The prazosin thing—what happened there was I was working with this Vietnam veterans group in 1995. From their descriptions of their symptoms it was clear that they were having an adrenaline storm at night. So I said, “What do people use to calm excess norepinephrine in the brain?” Block the beta receptor with propranolol! (It has been used for social anxiety, public speaking anxiety, or for performers who get nervous about a performance.) So I gave my first veteran propranolol—I was pretty safe in doing that because he had some hypertension too. He came in and said, “I am getting worse. My nightmares are even more intense.” I looked at the PDR and saw that Beta blockers do intensify dreams!

I did know, from some of the neuroendocrine work that I have been doing in Alzheimer’s, that the beta receptor for norepinephrine and the alpha 1 receptor sometimes had opposite effects, when stimulated or blocked, on various neuroendocrine systems. So I said, “Well if he is getting worse by blocking the beta receptor, maybe he will get better if I block the alpha 1 receptors.” I looked at the available alpha 1 receptor antagonists. Prazosin was the only one that had reasonable penetrance into the brain by its lipid solubility. So I said, “Let’s try prazosin.” The veteran gets better. He got better and dramatically improved. The second one dramatically improved too.

 

Dr. Jain: That’s a great story. That happened in 1995, do you see that happening nowadays?

 

Dr. Raskind: I think it can, if people have open minds. We are not going to change the bureaucratic system, but we need to be observing things rather than saying, “This expert says this and this one says that.” I mean, though it is all well and good and we have studies which demonstrate this and that, it is very important for us to remember our experience with the individual patient. What we thought, a guess of what might help and if we have some rational for doing it. People are so afraid to deviate from what someone says is the right thing to do that it (clinical innovation) may be happening less and less.

 

Dr. Jain: Yes. Keeping an open mind and, like you said, focusing on the individual patient experience.

 

Dr. Raskind: And talking to your colleagues. Anyway, I agree with you that we are tending to under appreciate the ability of clinical observation to give us productive leads in drug development.

The Top Eleven Ways to Tell that a Journal is Fake

I am delighted to offer Mind the Brain readers a guest blog written by my colleague, Eve Carlson, Ph.D.  Eve Carlson is a clinical psychologist and researcher with the National Center for PTSD and the U.S. Department of Veterans Affairs, VA Palo Alto Health Care System.  Her research focuses on assessment of trauma exposure and responses, and she has developed measures of PTSD, dissociation, trauma exposure, self-destructive behavior, affective lability, and risk for posttraumatic psychological disorder.  Her research has been funded by National Institute for Mental Health (U.S.) and the Dept. of Veterans Affairs (U.S.) and recognized by awards from the International Society for Traumatic Stress Studies and the International Society for the Study of Trauma and Dissociation.  Her publications include books on trauma assessment and trauma research methodology and numerous theoretical and research articles.  She has served as President and a member of the Board of Directors for the International Society for Traumatic Stress Studies and on the editorial boards of several journals.

 

The Top  Eleven Ways to Tell that a Journal is Fake

Eve Carlson, Ph.D.

Past President, International Society for Traumatic Stress Studies

If you have ever published a scholarly paper, your email inbox is probably peppered with invitations to submit papers to new journals with plausible-sounding names.  Many people dismiss these emails as spam, but with all one hears about the impending death of paper journals, who knows what is next in the wild, wild West of open source publishing?  And if you venture to click on a link to the journal, you may well see a web page boasting about a journal editor who is a prominent name in your field, an editorial board that includes several luminaries, instructions for authors, and legitimate-looking articles.  With the “publish or perish!” pressure still going strong, what’s an academic to do?

I recently stumbled into an “investigation” of a new, online, open source journal in the course of service as a leader of a professional society.  When I was president of an international professional society, a new journal began soliciting submissions that had a name that was very similar to our Society’s journal -“Journal of XXX”.  The Society feared that the new journal, called “Journal of XXX Disorders and Treatment”, would be mistaken for an offshoot of the original.  I saw the names of colleagues I knew on the editorial board and skimmed some of the opinion piece articles posted online and assumed it was a new experiment in open source publishing. But when I contacted the colleagues and began asking questions, it quickly became apparent that this journal had no editor, editorial board members were acquired via spam emails to authors of published articles, the journal appeared to follow no standard publishing practices, and most editorial board members had observed irregularities that made them suspicious that the journal was not legitimate.  Once informed of the problems observed and put in communication with one another, 16 of the 19 editorial members resigned en masse.

 

Based on actual experiences looking into three questionable open source journals, you can tell a journal is fake when…

 

1)  Searching in the box marked “Search this journal” on the journal web page for the name of an author of an article in a recent issue of the journal does not return any hits.

 

2)  Clicking on a link like this medline on the journal web site leads to the spoof site www.Medline.com.

 

3)  No specific person is identified as the editor of the journal or the person who appears to be identified as the journal’s Editor on the web site says he is not the editor.

 

4)  Google Maps searches for the address of journal shows its headquarters is in a suburban bungalow.

googlemaps

 

5)  You cannot find articles from a bio-medical journal when you search PubMed.  [You can check by searching for the journal title here]

 

6)  The journal’s mission on its home page is described in vague, generic terms such as “To publish the most exciting research with respect to the subjects of XXXXXX.”

 

7)  When you call the local phone number for the journal office listed on the web page, any of these happen:  1. No one answers. 2. Someone answers “hello?” on what sounds like a cell phone and hangs up as soon as they hear you speaking.  3. The call is forwarded to the 800 phone bank for the publisher, and the person on the other end cannot tell you the name of the editor of the journal.

 

8)  PubMed Central refuses to accept content from a publisher’s bio-medical journals and DHHS sends a “cease and desist” letter to the publisher.

 

9)  The journal publisher’s posts online a legal notice warning a blogger who writes about the publisher that he is on a “perilous journey” and is exposing himself to “serious legal implications including criminal cases lunched (sic) again you in INDIA and USA” and directs him to pay the publisher $1 billion in damages.  Check out the legal notice here.

 

10)  The journal issues and posts online certificates with hearts around the border that certifies you as “the prestigious editorial board member of [name of journal here].”

certificate

 

11)  The journal posts “interviews” with members of its editorial board that appear to be electronic questionnaires with comical responses to interviewer questions such as:

interview1

interview3

CORRECTION: The site www.medline.com is real, not a spoof site.

 

 

Repost: The Latest and Greatest in Treatment for PTSD: Magic Bullets and Cutting Edge Innovation

June is PTSD awareness month.  In light of this, I am reposting a blog I wrote about “The Latest and Greatest in Treatment for PTSD.”  If you are interested in knowing more about PTSD please check out the NCPTSD website.

Also, below are links to other blog posts I have written about PTSD and related topics:

 

The Latest and Greatest in Treatment for PTSD: Magic Bullets and Cutting Edge Innovation

I am frequently asked to talk about PTSD to professional audiences and, without 2012-04-05-ptsd1exception, always get a post talk question asking about my experience with some experimental intervention that someone read about somewhere in a newsmagazine or heard about from the T.V.

Internally, I always groan.

Having just spent 60-90 minutes pouring over carefully crafted PowerPoint slides that contain information about the evidence base for the treatments of PTSD and what best practices consist of, why I am always confronted with a zealous audience member who is obsessed with the new, the innovative, or the magic bullet?

In the interest of full disclosure, I have to share my viewpoint as being that of a health services researcher.  I approach PTSD treatment with a basic belief that we already have pretty good treatments, and the issues with getting better outcomes for PTSD lie more in how we implement those treatments, the limitations of the systems that provide care, massive issues of access to care (i.e. those who need care the most simply can’t access it for a myriad of reasons), and healthcare disparities (that an individual’s outcomes for PTSD are more likely linked to their zip code as opposed to their genes/neurotransmitters).

In short, I usually have a healthy skepticism toward the experimental or magic bullets type of treatments for PTSD, which often get a lot of media attention and can be very seductive to the brain of a researcher or clinician who spends their days trying to help individuals who live with PTSD.

 

Still, today I am curbing my skepticism and with much enthusiasm am writing about some of the hottest ideas for innovation in the treatment of PTSD.

 

Please note: MANY of these approaches are still considered EXPERIMENTAL, and I am listing them in no particular order of importance.

1. Mind – Body Practices for PTSD

Image Credit: Cornelius383

Mind Body practices are increasingly used to offer symptom reduction for PTSD.  Approaches such as Yoga, Tai Chi, Mindfulness Based Stress Reduction, Meditation, and Deep breathing are some examples.  There are about 16 rigorous studies that have been done to date, most of which have small sample sizes.  Whilst early findings suggest such practices can have a beneficial impact on symptoms like intrusive memories, avoidance, and increased emotional arousal, there is insufficient evidence to support their use as standalone treatments, though they can be recommended as an adjunctive treatment.

 

2. Cervical Sympathetic Blockade and Stellate Ganglion Block for PTSD 

In 2008, reports started to emerge about a minimally invasive manipulation of sympathetic nerve tissue in patients with PTSD that relieved their anxiety.  The procedure consisted of injecting a local anesthetic into sympathetic cervical nerve tissue at the C6 level and was apparently accompanied by immediate relief by the patient.  In 2012, a case series was reported where treatment resistant veterans with PTSD were given a stellate ganglion block and also a pre and post intervention CAPS. After the intervention, 5/9 of the patients experienced significant improvement; these benefits diminished over time and the benefits were not universal.  Controlled trials are currently underway to investigate this intervention further.

 

3. Virtual Reality Exposure Therapy

Virtual Reality exposure therapy utilizes real time computer graphics, body tracking devices, visual displays, and other sensory input devices to give the patient the experience that they are immersed in a virtual environment. It is an enhanced version of the imaginal exposure typically utilized as a part of trauma-focused psychotherapies. In 2001 an open clinical trial of Virtual Reality exposure therapy yielded promising results. It is currently being studied under controlled conditions.

 

4. D-Cycloserinemanypills

D-Cycloserine is a partial agonist of the NMDA receptor (a brain receptor that plays an essential role in learning and memory). It has been used to treat social phobia and panic disorder and to enhance the effects of psychological therapies for those disorders.  Preliminary data suggests it can be a useful adjunct in addition to evidence-based psychotherapies for patients living with severe PTSD.

 

5. Ketamine

Ketamine is a non-barbiturate anesthetic and antagonist at the NMDA receptor that is typically administered intravenously.  It has been used for years for patients with severe burns and it was, in this use, that its dissociative properties became apparent.  Retrospective studies show that those who received Ketamine after a traumatic event were less likely to develop PTSD.  It has been postulated that Ketamine may disrupt the process via which traumatic memories are laid down. A 2014 JAMA study reported on a RCT which demonstrated a rapid reduction in symptom severity following Ketamine infusion in patients with chronic PTSD.

 

6. Increasing the Intensity of Treatments

In an experimentation with packaging, British researchers compressed versions of trauma-focused psychotherapies for PTSD into a seven day intensive treatment.  This was found to work as well as treatment as usual, which is the same treatment delivered once a week, over 12 weeks.  Such an approach was postulated to be more efficient and convenient and was associated with faster improvement in symptoms and lower dropout rates.

 

7. Memantine colorful-pills

Memantine is a non competitive NMDA antagonist that is thought to protect the glutamergic destruction of neurons and hence prevent the hypothesized neurodegeneration in the hypothalamus, which contributes to the memory issues related to PTSD.  In a 2007 open label small trial, Memantine was found to be associated with some encouraging outcomes.  Double blind placebo controlled trials are pending.

Salvaging psychotherapy research: a manifesto

"Everybody has won, and all must have prizes." Chapter 3 of Lewis Carroll's Alice's Adventures in Wonderland
“Everybody has won, and all must have prizes.” Chapter 3 of Lewis Carroll’s Alice’s Adventures in Wonderland

NOTE: Additional documentation and supplementary links and commentary are available at What We Need to Do to Redeem Psychotherapy Research.

Fueling Change in Psychotherapy Research with Greater Scrutiny and Public Accountability

John Ioannidis’s declarations that most positive findings are false and that most breakthrough discoveries are exaggerated or fail to replicate apply have as much to with psychotherapy as they do with biomedicine.

BadPharma-Dec2012alltrials_basic_logo2We should take a few tips from Ben Goldacre’s Bad Pharma and clean up the psychotherapy literature, paralleling what is being accomplished with pharmaceutical trials. Sure, much remains to be done to ensure the quality and transparency of drug studies and to get all of the data into public view. But the psychotherapy literature lags far behind and is far less reliable than the pharmaceutical literature.

As it now stands, the psychotherapy literature does not provide a dependable guide to policy makers, clinicians, and consumers attempting to assess the relative costs and benefits of choosing a particular therapy over others. If such stakeholders uncritically depend upon the psychotherapy literature to evaluate the evidence-supported status of treatments, they will be confused or misled.

Psychotherapy research is scandalously bad.

Many RCTs are underpowered, yet consistently obtain positive results by redefining the primary outcomes after results are known. The typical RCT is a small, methodologically flawed study conducted by investigators with strong allegiances to one of the treatments being evaluated. Which treatment is preferred by investigators is a better predictor of the outcome of the trial than the specific treatment being evaluated.

Many positive findings are created by spinning a combination of confirmatory bias, flexible rules of design, data analysis and reporting and significance chasing.

Many studies considered positive, including those that become highly cited, are basicallycherrypicking null trials for which results for the primary outcome are ignored, and post-hoc analysis of secondary outcomes and subgroup analyses are emphasized. Spin starts in abstracts and results that are reported there are almost always positive.

noceboThe bulk of psychotherapy RCTs involve comparisons between a single active treatment and an inactive or neutral control group such as wait list, no treatment, or “routine care” which is typically left undefined but in which exposure to treatment of adequate quality and intensity is not assured. At best these studies can tell us whether a treatment is better than doing nothing at all or than patients expecting treatment because they have enrolled in a trial and not getting it (nocebo).

Meta-silliness?

Meta-analyses of psychotherapy often do not qualify conclusions by grade of evidence, ignore clinical and statistical heterogeneity, inadequately address investigator allegiance, downplay the domination by small trials with statistically improbable rates of positive findings, and ignore the extent to which positive effect sizes occur mainly in comparisons between active and inactive treatments.

Meta-analyses of psychotherapies are strongly biased toward concluding that treatments work, especially when conducted by those who have undeclared conflicts of interest, including developers and promoters of treatments that stand to gain financially from their branding as “evidence-supported.”

Overall, meta-analyses too heavily depend on underpowered, flawed studies conducted by investigators with strong allegiances to a particular treatment or to finding that psychotherapy is in general efficacious. When controls are introduced for risk of bias or investigator allegiance, affects greatly diminish or even disappear.

Conflicts of interest associated with authors having substantial financial benefits at stake are rarely disclosed in the studies that are reviewed or the meta-analyses themselves.

Designations of Treatments as Evidence-Supported

There are low thresholds for professional groups such as the American Psychological Association Division 12 or governmental organizations such as the US Substance Abuse and Mental Health Services Administration (SAMHSA) declaring treatments to be “evidence-supported.” Seldom are any treatments deemed ineffective or harmful by these groups.

Professional groups have conflicts of interest in wanting their members to be able to claim the treatments they practice are evidence-supported, while not wanting to restrict practitioner choice with labels of treatment as ineffective. Other sources of evaluation like SAMHSA depend heavily and uncritically on what promoters of particular psychotherapies submit in applications for “evidence supported status.”

"Everybody has won, and all must have prizes." Chapter 3 of Lewis Carroll's Alice's Adventures in Wonderland
“Everybody has won, and all must have prizes.” Chapter 3 of Lewis Carroll’s Alice’s Adventures in Wonderland

The possibility that there are no consistent differences among standardized, credible treatments across clinical problems is routinely ridiculed as the “dodo bird verdict” and rejected without systematic consideration of the literature for particular clinical problems. Yes, some studies find differences between two active, credible treatments in the absence of clear investigator allegiance, but these are unusual.

The Scam of Continuing Education Credit

thought field therapyRequirements that therapists obtain continuing education credit are intended to protect consumers from outdated, ineffective treatments. There is inadequate oversight of the scientific quality of what is offered. Bogus treatments are promoted with pseudoscientific claims. Organizations like the American Psychological Association (APA) prohibit groups of their members making statements protesting the quality of what is being offered and APA continues to allow CE for bogus and unproven treatments like thought field therapy and somatic experiencing.

Providing opportunities for continuing education credit is a lucrative business for both accrediting agencies and sponsors. In the competitive world of workshops and trainings, entertainment value trumps evidence. Training in delivery of manualized evidence-supported treatments has little appeal when alternative trainings emphasize patient testimonials and dramatic displays of sudden therapeutic gain in carefully edited videotapes, often with actors rather than actual patients.

Branding treatments as evidence supported is used to advertise workshops and trainings in which the particular crowd-pleasing interventions that are presented are not evidence supported.

Those who attend Acceptance and Commitment (ACT) workshops may see videotapes where the presenter cries with patients, recalling his own childhood.  They should ask themselves: “Entertaining, moving perhaps, but is this an evidence supported technique?

Psychotherapies with some support from evidence are advocated for conditions for which there is no evidence for their efficacy. What would be disallowed as “off label applications” for pharmaceuticals is routinely accepted in psychotherapy workshops.

We Know We Can Do Better

Psychotherapy research has achieved considerable sophistication in design, analyses, and strategies to compensate for missing data and elucidate mechanisms of change.

Psychotherapy research lags behind pharmaceutical research, but nonetheless hasCONSORT recommendations and requirements for trial preregistration, including specification of primary outcomes; completion of CONSORT checklists to ensure basic details of trials are reported; preregistration of meta-analyses and systematic reviews at sites like PROSPERO, as well as completion of the PRISMA checklist for adequacy of reporting of meta-analyses and systematic reviews.

nothing_to_declare1Declarations of conflicts of interest are rare and exposure of authors who routinely failed to disclose conflicts of interest is even rarer.

Departures from preregistered protocols in published reports of RCTs are common, and there is little checking of discrepancies in abstracts from results that were actually obtained or promised in preregistration by authors.  There is  inconsistent and incomplete adherence to these requirements. There is little likelihood that noncompliant authors will held accountable and  high incentive to report positive findings in order for a study is to be published in a prestigious journal such as the APA’s Journal of Consulting and Clinical Psychology (JCCP). Examining the abstracts of papers published in JCCP gives the impression that trials are almost always positive, even when seriously underpowered.

Psychotherapy research is conducted and evaluated within a club, a mutual admiration society in which members are careful not to disparage others’ results or enforce standards that they themselves might want relaxed when it comes to publishing their own research. There are rivalries between tribes like psychodynamic therapy and cognitive behavior therapy, but suppression of criticism within the tribes and in strenuous efforts to create the appearance that members of the tribes only do what works.

Reform from Without

Journals and their editors have often resisted changes such as adoption of CONSORT, structured abstracts, and preregistration of trials. The Communications and Publications Baord of the American Psychological Association made APA one of the last major holdout publishers to endorse CONSORT and initially provided an escape clause that CONSORT only applied to articles explicitly labeled as a randomized trial. The board also blocked a push by the Editor of Health Psychology for structured abstracts that reliably reported details needed to evaluate what had actually been done in trials and the results were obtained. In both instances, the committee was most concerned about the implications for the major outlet for clinical trials among its journals, Journal of Consulting and Clinical Psychology.

Although generally not an outlet for psychotherapy trials, the journals of the Associationvagal tone for Psychological Science (APS) show signs of even being worse offenders in terms of ignoring standards and commitment to confirmatory bias. For instance, it takes a reader a great deal of probing to discover that a high-profile paper of Barbara Fredrickson in Psychological Science was actually a randomized trial and further detective work to discover that it was a null trial. There is no sign that a CONSORT checklist was ever filed the study. And despite Frederickson using the spun Psychological Science trial report to promote her workshops, there is no conflict of interest declared.

The new APS Clinical Psychological Science show signs of even more selective publication and confirmatory bias than APA journals, producing newsworthy articles, to the exclusion of null and modest findings. There will undoubtedly be a struggle between APS and APA clinical journals for top position in the hierarchy publishing only papers that that are attention grabbing, even if flawed, while leaving to other journals that are considered less prestigious, the  publishing of negative trials and failed replications.

If there is to be reform, pressures must come from outside the field of psychotherapy, from those without vested interest in promoting particular treatments or the treatments offered by members of professional organizations. Pressures must come from skeptical external review by consumers and policymakers equipped to understand the games that psychotherapy researchers play in creating the appearance that all treatments work, but the dodo bird is dead.

Specific journals are reluctant to publish criticism of their publishing practices.  If we at first cannot gain publication in the offending journals of our concerns, we can rely on blogs and Twitter to call out editors and demand explanations of lapses in peer review and upholding of quality.

We need to raise stakeholders’ levels of skepticism, disseminate critical appraisal skills widely and provide for their application in evaluating exaggerated claim and methodological flaws in articles published in prestigious, high impact journals. Bad science in the evaluation of psychotherapy must be recognized as the current norm, not an anomaly.

We could get far by enforcing rules that we already have.

We need to continually expose journals’ failures to enforce rules about preregistration, disclosure of conflicts of interest, and discrepancies between published clinical trials and their preregistration.

There are too many blatant examples of investigators failing to deliver what they promised in the preregistration, registering after trials have started to accrue patients, and reviewers apparently not ever checking if the primary outcomes and analyses promised in trial registration are actually delivered.

Editors should

  • Require an explicit statement of whether the trial has been registered and where.
  • Insist that reviewers consult trial registration, including modifications, and comment on any deviation.
  • Explicitly label registration dated after patient accrual has started.

spin noCONSORT for abstracts should be disseminated and enforced. A lot of hype and misrepresentation in the media starts with authors’ own spin in the abstract . Editors should insist that main analyses for the preregistered primary outcome be presented in the abstract and highlighted in any interpretation of results.

No more should underpowered in exploratory pilot feasibility studies be passed off as RCTs when they achieve positive results. An orderly sequence of treatment development should occur before conducting what are essentially Phase 3 randomized trials.

Here as elsewhere in reforming psychotherapy research, there is something to be learned from drug trials. A process of intervention development ought to include establishing the feasibility and basic parameters of clinical trials needs to proceed phase 3 randomized trials, but cannot be expected to become phase 3 or to provide effect sizes for the purposes of demonstrating efficacy or comparison to other treatments.

Use of wait list, no treatment, and ill-defined routine care should be discouraged as control groups. For clinical conditions for which there are well-established treatments, head-to-head comparisons should be conducted, as well as including control groups that might elucidate mechanism. A key example of the latter would be structured, supportive therapy that controls for attention and positive expectation. There is little to be gained by further accumulation of studies in which the efficacy of the preferred treatment is assured by comparison to a lamed control group that lacks any conceivable element of affective care.

Evaluations of treatment effects should take into account prior probabilities suggested by the larger literature concerning comparisons between two active, credible treatments. The well-studied treatment of depression literature suggests some parameters: effect size is associated with a treatment are greatly reduced when comparisons are restricted to credible, active treatments; better quality studies; and controls are introduced for investigator allegiance. It is unlikely that initial claims about a breakthrough treatment exceeding the efficacy of existing treatments will be sustained in larger studies conducted by investigators independent of developers and promoters.

Disclosure of conflict of interest should be enforced and nondisclosure identified in correction statements and further penalized. Investigator allegiance should be considered in assessing risk of bias.

Developers of treatments and persons with significant financial gain from a treatment being declared “evidence-supported” should be discouraged from conducting meta-analyses of their own treatments.

Trials should be conducted with sample sizes adequate to detect at least moderate effects. When positive findings from underpowered studies are published,  readers scrutinize the literature for similarly underpowered trials that achieve similarly positive effects.

Meta-analyses of psychotherapy should incorporate p-hacking techniques to evaluate the likelihood that pattern of significant findings exceeds likely probability.

Adverse events and harms should routinely be reported, including lost opportunity costs such as failure to obtain more effective treatment.

We need to shift the culture of doing and reporting psychotherapy research. We need to shift from praising exaggerated claims about treatment and faux evidence generated to  promote opportunities for therapists and their professional organizations.  Instead, it is much more praiseworthy to provide  robust, sustainable, even if more modest claims and to call out hype and hokum in ways that preserve the credibility of psychotherapy.

criticism
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The alternative is to continue protecting psychotherapy research from stringent criticism and enforcement of standards for conducting and reporting research. We can simply allow the branding of psychotherapies as “evidence supported” to fall into appropriate disrepute.