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.
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).
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.
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.
It is now blatantly clear that a woman’s increased vulnerability to developing PTSD is closely linked to that fact that, when compared to a man, she is much more likely to be the victim of the toxic traumas of childhood sexual abuse, rape, and intimate partner violence. More recently another type of trauma that women are uniquely vulnerable to enduring is garnering increasing attention—the psychological trauma associated with giving birth.
Dr. Rebecca Moore is the lead psychiatrist for the Tower Hamlets Perinatal Mental Health service based in London, U.K. Her clinical interests include PTSD and birth trauma, premenstrual dysphoric disorder (PMDD), the treatment of anxiety and depression in the perinatal period, and supporting the parent infant bond. Dr. Moore is passionate about improving services for women traumatized by birth and hosts an annual forum on Birth Trauma in London in December each year. Her goal is to form networks with those working with families with Birth Trauma around the world to share knowledge and innovative practices.
I recently spoke with her to understand more about Birth Trauma and PTSD.
Dr. Jain: You are a perinatal psychiatrist who specializes in treating psychological aspects of birth trauma. Can you start by talking a little bit about what a perinatal psychiatrist does and why there is a specific need for this type of expertise for pregnant women? Can you comment specifically on your work with immigrant/refugee populations who may have high rates of mental health problems to begin with?
Dr. Moore: Perinatal psychiatrists work with women with new onset or preexisting moderate to severe mental health diagnoses through their pregnancy and up to a year after birth.
We are community based and work with women and their families to support their mental health through this vulnerable time period. This includes regular outpatient review, community nursing support, psychological support, and expertise around prescribing medication during pregnancy and breastfeeding, alongside monitoring the developing parent infant bond.
Perinatal services recognize the fact that for some women, pregnancy is a challenging time period and that certain disorders—Anxiety or Bipolar Disorder, for example—have high rates of relapse.
There is an increased risk of suicide after pregnancy, and suicide remains one of the leading causes of maternal death in the first 42 days after birth in the United Kingdom, as highlighted by the last MBRRACE-UK release “Saving Lives, Improving Mothers’ Care – Surveillance of Maternal Deaths in the UK 2011-13.”
Perinatal disorders often develop rapidly, and our team provides a rapid specialist response to these crises and can facilitate rapid treatment and admission to local Mother and Baby Units if needed. London has three Mother and Baby Units, but many areas of the country still have no provision at all, such as Wales or Northern Ireland.
I work within Tower Hamlets, a very deprived area in East London, with a young population who have higher than average numbers of children. Our population is growing rapidly, it is expected to grow by 26% over the next twenty years, and there is a high birth rate, around 5500 births per year, so the demand on our service grows yearly.
50% of our referrals are Bangladeshi women, which reflects our local population. We have a hugely transient population with people moving in and out of our area, and we have women within our service from all over the world who have often been exposed to war or huge trauma. We often work with interpreters and have to be extremely mindful of the cultural and spiritual aspects of our care.
Dr. Jain: When researching this topic of Birth Trauma, I ran into some issues regarding definitions: there appears to be considerable variability regarding what this term means. Can you offer a definition of Birth Trauma and also comment on how this is different from Postpartum PTSD?
Dr. Moore: You are right, there is not yet any standard diagnostic definition, and this can cause confusion as there is a significant difference between Birth Trauma and Postpartum PTSD regarding symptoms and treatment.
When a woman has a traumatic birth, I mean that there was something subjective about the birth that was traumatic. This does not have to be life threatening or medically traumatic. We are thinking of the psychological impact of that birth experience on the mother.
Birth Trauma definitions include “a negative and disempowering physiological & emotional response to a birth” or “when an individual (mother, father, or other witness) believes the mother’s or her baby’s life was in danger, or that a serious threat to the mother’s or her baby’s physical or emotional integrity existed.” I love Rachel Yehuda’s use of the term trauma as “a watershed event, an event that kind of divides your life into a before and after.”
Common themes include feeling unheard or not listened to, a lack of compassion from medical professionals, and feeling out of control or helpless.
Around 25% of all births in the UK are identified by women as being traumatic. This really strikes me, as it is such a high rate. In fact, if we look at the annual birth rate in the United Kingdom, this means around 173,000 women are traumatized after delivering per year.
Only 1% of births in the UK result in infant death or life threatening near-miss episodes, indicating that subjective understanding of the birth event is crucial.
One third of women present with sub-clinical trauma, and I believe it is essential to perceive trauma responses as being on a continuum.
For many women, these birth experiences will never be discussed or explored. Although women may not develop a diagnosable disorder, they will often experience significant levels of distress and symptoms may persist for many years without treatment. There is often a significant impact on women’s future pregnancies and birth experiences, and I have met women who only have one child because their first birth experience was so negative and they cannot contemplate coping emotionally in another pregnancy.
When we talk about Postpartum PTSD, we are talking about women who had a traumatic birth who then go on to develop all the diagnostic criteria we would expect in PTSD.
Around 1-6% of women who have a traumatic birth will go on to develop a diagnosable clinical episode of PTSD.
It’s also important to mention and think about birth partners who can also be traumatized by birth as well as mothers.
Dr. Jain: In your experience, what are the common pitfalls surrounding diagnosing Postpartum PTSD? How is it distinguished from the more well-known Postpartum Depression? What are the clinical markers for who is more vulnerable to developing Postpartum PTSD, and what are the associated resiliency factors?
Dr. Moore: Unfortunately, this is an issue we see time and time again in clinical practice. Many professionals know little about Birth Trauma or PTSD following birth, and services in the UK are very much focused on identifying Postnatal Depression.
If we think about the criteria needed to make a formal diagnosis of PTSD, there are clear differences in the symptoms needed to make a diagnosis of Postnatal Depression.
With Postpartum Depression we would look for core symptoms of pervasive low mood or anxiety, fatigue, and anhedonia, with possible altered sleep and appetite or suicidality.
In PTSD we would expect to see the key features of avoidance, intrusive memories, labile mood, nightmares, or flashbacks, and taking a history of the birth experience in depth would be key.
Research has been carried out into what makes someone more likely to develop PTSD following childbirth. These risk factors can be thought of as those that exist before the birth; the birth itself; and the type of support and care women get after birth.
Some women will be more vulnerable to a traumatic birth because of pre-existing problems, such as women with a history of psychiatric problems or previous trauma. There is also evidence that women with a history of trauma will be more vulnerable to PTSD following birth if they have inadequate support and care during the birth.
During birth, certain complications or events may be more stressful to women than others. Broadly speaking, women are more likely to get PTSD if they have an emergency cesarean or assisted birth (forceps or ventouse), although PTSD can develop after a vaginal delivery.
Other stressful aspects of birth, such as blood loss, a long labor, a high level of pain, or a large number of interventions, are not conclusively related to getting PTSD.
Women who feel out of control, helpless, or overwhelmed by events during birth, or who have poor care and support from midwives and doctors, are significantly more likely to get PTSD.
Following the birth, support from friends and family, and possibly that from healthcare professionals, may help women resolve their experiences and recover from a traumatic birth.
Studies have also highlighted an increased risk of developing postpartum PTSD with a stillbirth, the birth of a baby with a disability resulting from birth trauma, or a baby requiring a stay in the Neonatal Intensive Care Unit (NICU).
One of the strongest risk factors we know of is when women dissociate during birth. One woman I worked with spoke of dissociating in pregnancy and “losing all track of time” and “feeling like she was in a fog.” She believed her baby “had been born” and “taken out of the room without her consent” and felt overwhelmingly anxious, until suddenly she looked down and saw her pregnant bump and realized she was still pregnant.
The literature regarding resilience is unclear, and we still do not fully understand why some women develop PTSD after birth and some do not. Women come into labor with their own unique genetic make up, personal history, and own expectations of their labor and how it will proceed. To my mind the issue that often makes the most difference regarding the outcome is that psychological expectation and understanding of birth and how it is addressed and handled during labor. I have seen women who had long distressing labors with numerous physical interventions or complications who have not gone on to be traumatized as they have had one amazing healthcare professional with them through the whole process explaining, listening, and comforting them and hearing their fears or wishes voiced.
Dr. Jain: It appears to me there are a couple scenarios of how Postpartum PTSD might occur:
A woman already has PTSD (treated or untreated) and the psychological stressors associated with pregnancy/giving birth trigger a relapse of her PTSD symptoms
The actual experience of giving birth is traumatic—either the mother’s life is threatened or she witnesses a threat to the life of her newborn. This trauma then serves as the stressor, which can, in some cases, lead to PTSD.
Can you speak about other scenarios?
Dr. Moore: These are the most common routes to PTSD after birth that we see; the variance is in the individual stories and responses to trauma that we hear.
I think it’s important to flag up here that the woman’s life might not actually be in danger, it is her response to events that she perceives as traumatic, so she might have a non life threatening bleed but find that traumatic or it may be the after care that is traumatic—care on the postnatal ward, for example. What medical professionals might class as “normal” may be far from normal to the mother involved. Women have repeatedly spoken to me of this issue.
It is important to distinguish between women who feel angry about their birth experience and have irritability and intrusive thoughts about their birth, but who lack the other symptoms of PTSD.
Subclinical symptoms are really important in my opinion and incredibly common, and these women may not have diagnosable PTSD but must still be heard and listened to and supported.
Dr. Jain: If one does a Google search for Birth Trauma or Postpartum PTSD, it is impossible to ignore the number of self-help organizations, patient advocacy groups, and online support forums that pop up. Indeed, prevalence statistics for Postpartum PTSD from Western studies are approximately 1 to 3%. From an epidemiological standpoint, this would make it quite common. Yet Postpartum PTSD is something that receives very little attention in medical schools and psychiatry training programs. Is this a case of medical science needing to catch up with what is happening every day on the frontlines?
Dr. Moore: Absolutely!
I think at present this is a really neglected area of teaching and training whilst being something that affects thousands and thousands of women each year here in England.
My sense is that this is changing. Certainly here we are starting to see Birth Trauma being discussed and talked about, and networks of professionals are coming together to push for more training and better awareness.
It’s something that I feel really passionate about, and locally I run a Birth Reflections Clinic to allow women to debrief after a traumatic birth and an Annual Birth Trauma Conference in London (this year December 9th 2016, which all are welcome to attend free of charge). I lecture medical students, psychiatrists, health visitors, and midwives, and I feel this is an area that should be a key part of the undergraduate and postgraduate curriculum.
Here in the UK we are really fortunate to have some amazing web forums, such as MatExp, which allows members to share best practices and knowledge. There are many excellent blogs by women writing about their own Birth Trauma, such as Unfold Your Wings or Ghostwritermummy, which helps raise awareness. There are also some nice sites sharing good birth experiences, which can be empowering for first time mothers to read and prepare for birth, such as tellmeagoodbirthstory.com.
Dr. Jain: Related to this, there appear to be some very real social and systemic phenomenon that may be exacerbating the issue of Postpartum PTSD: Unrealistic images/perceptions of what birth and motherhood should be driven by popular media/culture (similar to the propagation of unrealistic body images for women); the very high tech and invasive medical environment where many women in high income settings give birth; and advances in neonatal care and NICU care that have changed the way we treat and care for premature babies.
Dr. Moore: A question that is often asked is whether women have too high expectations of achieving a natural or drug-free birth, contributing to them being traumatized when birth does not go as expected. The answer to this is complex, but research studies point towards it not being the case. Firstly, women’s expectations are found, on average, to be similar to their experiences. That is, if a woman has broadly positive expectations, she is more likely to have a positive experience. Secondly, if unrealistic expectations were linked to PTSD, we might expect to find more trauma responses in first time mothers. This has been found, but subsequent analysis suggests it is due to the higher rate of intervention in these women. Finally, one study looked at this question directly and found that a difference between expectations and experience in the level of pain, length of labor, medical interventions, and level of control was not associated with PTSD symptoms. However, a difference between expected support from healthcare professionals and the level of care experienced was predictive of PTSD symptoms. Women don’t seem necessarily to be traumatized by the events of birth not happening as they expected, but are more affected when they do not receive the care they expect.
For many women I meet there is a real lack of honest conversations about the process of birth, and my sense is many women enter their labor emotionally unprepared for what might happen and have high expectations of what they want to happen, which may or may not be realistic.
I think there is a much greater need for midwives and obstetricians to have repeated conversations with women about birth and listen to women’s fears, hopes, and preferred choices.
The issue that comes up time and time again here is a lack of continuity of care and that women often see a different midwife at each visit, which means that these discussions don’t happen.
I personally encourage women to think in depth about their birth and the choices they may or may not like, whilst grounding any discussion in the reality of what might happen.
I personally think if women can afford it and would like it, that using an independent midwife or doula can be really beneficial and help provide a constant support and advocate throughout pregnancy and birth.
There is also no doubt that medical interventions and having a baby in the NICU play a role in trauma. There is a wealth of literature showing that these mothers and fathers are at increased risk of developing PTSD.
In 2013, Youngblut et al looked at parent health and functioning 13 months after infant or child NICU/PICU death. Parents (176 mothers, 73 fathers) of 188 deceased infants/children were recruited from 4 NICUs, 4 PICUs, and state death certificates 2 to 3 weeks after death. Data on parent physical health (hospitalizations, chronic illness), mental health (depression, PTSD, alcohol use), and functioning (partner status, employment) were collected in the home at 1, 3, 6, and 13 months after death. Thirteen months after infant/child death, 72% of parents remained partnered, 2 mothers had newly diagnosed cancer, alcohol consumption was below problem drinking levels, parents had 98 hospitalizations (29% stress related) and 132 newly diagnosed chronic health conditions, 35% of mothers and 24% of fathers had clinical depression, and 35% of mothers and 30% of fathers had clinical PTSD. More Hispanic and black mothers than white mothers had moderate/severe depression at 6 months after infant/child death and PTSD at every time point.
Lefkowitz et al looked at the prevalence of PTSD and depression in parents of infants in the NICU, identifying 86 mothers and 41 fathers who completed measures of acute stress disorder (ASD) and of parent perception of infant medical severity 3-5 days after the infant’s NICU admission (T1), and measures of PTSD and Postpartum Depression (PPD) 30 days later (T2).
35% of mothers and 24% of fathers met ASD diagnostic criteria at T1, and 15% of mothers and 8% of fathers met PTSD diagnostic criteria at T2. PTSD symptom severity was correlated with concurrent stressors and family history of anxiety and depression. Rates of ASD/PTSD in parents of hospitalized infants are consistent with rates in other acute illness and injury populations, suggesting the relevance of traumatic stress in characterizing parent experience during and after the NICU.
There is a wealth of excellent resources online for parents with babies in the NICU/Special Care Baby Unit (SCBU), such as Bliss, Headspace Perspective, and Tommy’s. These all offer a wealth of practical advice, including telephone support and local groups or buddy schemes.
Dr. Jain: What psychological interventions work for Postpartum PTSD? What about preventative measures (e.g. identifying high risk women or screening programs) or debriefing interventions?
Dr. Moore: There isn’t a standardized screening program as of yet in the UK. We screen women in our service but they only represent a minority of women. One also wonders how a woman may feel about being identified as “high risk” for developing perinatal trauma, and care would need to be taken to fully explain this risk in a nonthreatening or frightening way.
Psychological interventions that work in the postnatal period include the usual trauma focused psychotherapies, like cognitive behavioral therapy (CBT) and eye movement desensitization and reprocessing (EMDR), and Compassion Focused therapy approaches are also frequently used.
Debriefing can be used and can help some women but not all—it very much depends on who is doing the debriefing and how it is done. Studies into the efficacy of debriefing have not identified any clear link with it leading to reduced maternal morbidity, and formal debriefing is not recommended. In 2011, Professor Ayers from City University, a leading expert in this area, found that 46 women with PTSD who had formal debriefing had reduced PTSD over time and a greater reduction in symptoms overall than women who had not been debriefed. Debriefing also led to reduction in negative appraisals but did not affect symptoms of depression. Therefore, results suggest that providing debriefing as a treatment to women who request or are referred to it may help to reduce symptoms of PTSD.
In my service we have a specialized pathway of care for women with a prior traumatic birth or those at risk, which includes regular review and having these long detailed discussions about birth. We have a specialist team of midwives who co-work cases with us to give extra support and an obstetric lead who reviews women prior to birth.
We offer informal debriefing postnatally and really take time and care to listen to women’s birth stories, and this is crucial. If needed we can then also add in specialist timely therapeutic interventions—we offer CBT, Compassion Focused Work, Yoga Therapy, Art Therapy, and Music Therapy in my service.
Dr. Jain: Finally, are there any biological or physiological factors associated with the act of giving birth itself (e.g. hormonal shifts, changes in adrenaline, cortisol, serotonin, or dopamine) that may be implicated in increasing vulnerability for developing PTSD during that particular life event?
Dr. Moore: That’s a very complex question that we don’t yet fully understand the answer to. There is as of yet little research on the specific area of perinatal PTSD, and we have to try to piece together what we know about the etiology of PTSD along with the large evidence base for depression after birth related to hormonal shifts.
Of course I am sure your readers will know the existing literature purely relating to PTSD that suggests that lower baseline cortisol at the time of a psychological trauma may facilitate over-activation of the central CRH-NE cascade, resulting in enhanced and prolonged stress responses which could then be accentuated by poor regulation of GABA, serotonin, and NPY. Altered norepinephrine and stress hormone activity may be involved in learning and extinction. This mixture of elevated noradrenergic activity and relative hypocortisolism may lead to the enhanced encoding of traumatic memories and the lack of inhibition of memory retrieval, both of which then trigger the re-experiencing phenomena in PTSD.
My own interest lies more in the role of the HPA axis in pregnancy and after birth. Much of the literature relates to depression, but there are studies now focusing on PTSD. It is likely that prenatal hormones are both markers of risk and causal factors in the development of postpartum depression.
During pregnancy the maternal hypothalamic-pituitary-adrenal axis undergoes dramatic alterations, due in large part to the introduction of the placenta, a transient endocrine organ of fetal origin.
Models are suggested, such as those by Professor Vivette Glover, where the positive feedback loop involving the systems regulating the products of the HPA axis results in higher prenatal levels of cortisol and placental corticotrophin-releasing hormone. Greater elevations in placental corticotrophin-releasing hormone are related to a disturbance in the sensitivity of the anterior pituitary to cortisol and perhaps to decreased central corticotrophin-releasing hormone secretion. Secondary adrenal insufficiencies of a more extreme nature may predict an extended postpartum hypothalamic-pituitary-adrenal refractory period, which in turn would represent a risk factor for the development of postpartum depression
During pregnancy we see a rapid rise in plasma estrogen and progesterone, coupled with a very large increase in plasma corticotrophin-releasing hormone (CRH), and an increase in cortisol. Levels of all these hormones drop rapidly at birth, as do serotonin levels. We can also assume that for most women, adrenaline levels will be raised for some of their birth experience.
We also need to add into this discussion the literature on the role of estrogen, and its role in fear conditioning and fear extinction. Estrogen calms the fear response in healthy women and, as illustrated by the work of Kelimer Lebron-Milad, the same is true for women suffering from PTSD. The higher the estrogen was in their blood when they trained on a fear-extinction task, the less likely women were to startle.
Progesterone is also known to have antiglucocorticoid properties and thus interfere with the HPA axis reactivity to stress. Studies have demonstrated a higher neuroendocrine response to stress (i.e., higher cortisol levels after ACTH administration) in women during the luteal phase of the menstrual cycle, indicating that the negative feedback of the HPA axis may be somewhat affected.
Further research is needed to understand the impact that changes in sex hormone levels may have on subjects’ behavioral and neuroendocrine ability to respond to stress. It could be plausible that abrupt changes in hormone levels (such as that observed in the immediate postpartum period) would alter not only the HPA axis response to a stressful event, but also the negative feedback necessary to avoid potential damages induced by prolonged exposure to “stress hormones.”
How all these strands connect is not yet fully understood, but to my mind women entering labor are subject to momentous physiological and psychological changes over a rapid time frame, which to some can lead to the development of their perinatal PTSD.
Among Americans, rape is the trauma that is most likely to lead to PTSD. The medical profession is becoming increasingly aware that sexual trauma represents a serious medical and mental health concern. Several years ago, in recognition of the downstream consequences of sexual trauma on veteran health, the VA healthcare system developed the position of a Military Sexual Trauma (MST) Coordinator. The MST coordinator is the point person, within any VA healthcare system, who provides education, outreach, and consultation to support MST survivors and the healthcare professionals who take care of them.
Katie Webb, L.C.S.W., is the Military Sexual Trauma Coordinator for the VA Palo Alto Health Care System. Katie received her Master’s Degree in Social Work from New York University. Prior to joining the Palo Alto VA, she served as Assistant Director at a community non-profit agency in New York City, working with survivors of interpersonal violence who have disabilities. Her clinical interests include the treatment of PTSD and comorbid diagnoses, intimate partner violence, military sexual trauma, and the implementation of telehealth technology to expand mental health care access to underserved communities.
I spoke with Katie about MST, PTSD, the risk of suicide, and how the VA experience can inform the national debate about college campus rape.
Katie Webb: MST stands for Military Sexual Trauma, and it’s defined as sexual assault or repeated threatening sexual harassment that occurs at any point during a veteran’s military service.
Shaili Jain: Obviously, this would apply to male veterans and female veterans. Does the definition depend on who the perpetrator of the crime is?
Katie Webb: Perpetrator identity doesn’t matter. It could be anyone from enemy combatant to a civilian, spouse, girlfriend, boyfriend, commanding officer, or fellow service member. Any perpetrator still qualifies as MST.
Shaili Jain: Why do you think VA facilities need somebody in your position, someone who is an MST coordinator? What is the scope of the problem? Why has it become such a salient issue that we need a coordinator? What does your job entail?
Katie Webb: Increasingly, over the years the VA (and I think this parallels the process of society, too) is realizing that sexual trauma is a serious medical and mental health concern. It can lead to so many different physical and mental health diagnoses, and it is more likely to actually result in PTSD than combat trauma. So taking all of that into account, the VA is increasingly pushing it to the forefront of their priority, and they developed the position of MST coordinator several years ago. The MST coordinator is the point person within any VA healthcare system who can provide education, consultation, and support to the healthcare system that they’re in. I primarily work to provide education, outreach materials, training on new initiatives, and to consult with any healthcare provider who’s working with an MST survivor and needs some assistance. I also serve as the point person for anyone calling the VA Palo Alto healthcare system with questions – any survivors that call and are interested in getting engaged in care would contact me.
Shaili Jain: There have been a lot of really great big data studies in the VA recently, and some of them have identified risks associated with MST. I’m referencing the recent publication by Rachel Kimerling and her lab that was published in The American Journal of Preventative Medicine where they actually identified MST as a significant risk factor for suicide. Can you comment on that and how this research maps on to what we’re doing day to day in our clinical work with patients?
Katie Webb: The research was saddening but not surprising. It really just puts a research voice to what people who work with MST survivors already know and see, anecdotally – that there is a very positive relationship between MST and suicide. I think it really highlights the importance of being sure to address and assess for suicidality any time you’re working with someone who’s experienced Military Sexual Trauma, or any sexual trauma, and of keeping that as a very key piece of their care plan.
Shaili Jain: I guess what’s tricky is that MST is an experience and not an actual diagnosis or mental health condition. You can have someone who has an MST history but not necessarily a PTSD diagnosis. Yet there’s this correlation that they’re high risk for suicide. I think that’s where the seriousness of the situation can get diluted.
Katie Webb: It does, and it gets confusing because oftentimes people will come and they’ll ask for the MST treatment. We then have to further sub break it down and say, what symptoms are you experiencing in relation to this experience? Just like combat trauma is not a diagnosis, but that is easier to understand. There has to be education with healthcare professionals, veterans, and survivors so when they hear that (it is not a diagnosis) they’re not thinking it is not important. MST does matter, it is important, but what is most important is how it has impacted the survivor.
It is important to recognize that the dynamics of MST can be a little bit different than civilian trauma. Oftentimes, this is something that happens when someone is living away from their social supports, away from people they know, and their perpetrators are often within their new social support system. Unfortunately, the result of sexual trauma is that the victim is then isolated from their social support system at a time when they most need it. I think it makes a lot of sense that people would experience an increase in intensity of whatever mental health symptoms they’re having and make them more prone to suicide.
There’s a lot of stigma associated with identifying as an MST survivor. I think sometimes people can put their symptoms in silos and not necessarily make the connection to their experience of sexual trauma. This makes sense, as Rachel’s study mentioned something to the effect of suicidality was separate from any mental health diagnosis. So we need to pay attention to that for sure.
Shaili Jain: That there could be this hidden danger.
Katie Webb: Right. Not to make the false assumption that just because a patient is saying they do not have a mental health diagnosis does not mean that they’re not having normal reactions to trauma.
Shaili Jain: What are the top three take home messages for clinicians who are on the front line?
Katie Webb: Healthcare professionals are really busy, and so I think that’s part of the challenge.
First, it is really important that professionals set aside a little bit of time to educate themselves on this issue. I think we all need to be aware of the dynamics of MST. Be aware that for many MST survivors, they have not had positive or helpful responses from systems and peers when they have disclosed their MST history in the past and that can account for how they act around you, as a healthcare professional.
Be aware that they may be reticent to share details. They may downplay whatever it is that they’re reporting because of the responses they have received before. Just maintaining an open and non-judgmental stance can be really key in creating an environment that’s safe for people to get engaged with care. A good example would be regarding male survivors. I think the VA healthcare system can parallel society in that there is a myth that rape doesn’t happen to men. Invalidation of male rape can happen in really subtle ways in the healthcare setting – maybe a healthcare professional sees a male patient and assumes they do not need to do a screen for MST. Just being aware that oftentimes survivors have been ignored, not believed, or in an environment where they are made to think their experience could not have happened because they’re men.
Secondly, knowing screening is really important. Screen for MST and screen for suicidality. I know screening is done in primary care, but I like the idea of screening in mental health, too. Oftentimes, survivors think that MST is not a medical problem, so when primary care physicians screen for it patients will answer no because they view it as having nothing to do with their doctor’s visit.
Finally, after screening, I think educating and engaging the veteran and mitigating that past experience of feeling like they’re alone and like they don’t have social support is very important.
Shaili Jain: Do you think that nowadays there is less stigma around MST? From both sides, the healthcare professional and the patient?
Katie Webb: I think people want to be more open. I think their intentions are in the right place, but because sexual trauma is such a loaded topic, people carry around a lot of assumptions about what is sexual trauma and what isn’t.
For example, I was having a conversation with a really well intentioned healthcare provider who was talking about all the great work they had done with a sexual assault survivor, and they said, “You know, sexual harassment, that’s not really MST. That doesn’t count.”
So where was this coming from? It was coming from misperceptions about what it means to be sexually harassed. I think that’s really a challenge. I think there is still this innocent but dangerous assumption that this doesn’t happen to men or it may only happen to a certain type of man, but not a man’s man.
I think the education piece remains central.
Shaili Jain: Can you share how MST has impacted lesbian, gay, bisexual, and transgender (LGBT) veterans?
Katie Webb: The research parallels some of the discrimination that LGBT people face in that there isn’t a lot of research on MST in LGBT veterans. We do know that, to some extent, LGBT veterans are more likely to have experienced childhood sexual abuse (CSA) than their heterosexual counterparts. CSA is also a risk factor for experiencing MST.
We know that the “don’t-ask-don’t-tell culture” created a very dangerous environment. Again, thinking about how social support is so key after trauma, if LGBT veterans can’t really be fully honest about who they are and then are often isolated from social support, that is not a good situation. We know that sexual minorities are targeted for MST in the military and then have little social supports in the aftermath. They are put in a bind – they can’t even state why they were targeted for MST for fear they might be discharged from the military.
I think it’s great that “Don’t ask, Don’t tell” was repealed. I think it’s great that they’re now allowing transgender people in the military. I think we also have to acknowledge it’s a really slow culture shift to match some of the policy changes. It would be reasonable to expect that some of that is still going on.
Also, when you factor in the stress of being a minority to begin with, that can mean you are more likely to have a mental health problem after a traumatic experience, too.
Shaili Jain: It strikes me that LGBT veterans who have MST would be very high risk for suicide.
Katie Webb: Right, and then when you think about that and you think about trauma sequelae and how those unhelpful responses might be even more extreme with the LGBT population, it makes total sense that they will experience a lot of mental health distress. Unfortunately, how that can get translated is, “There’s something really wrong with me.”
It’s our job to flip that and say, “No, you’re the one making sense, it is your surroundings that don’t.”
Shaili Jain: I cannot help but draw parallels between recent research reports of college campus rapes and military sexual trauma. From my perspective as a psychiatrist, there are some striking similarities between these two types of sexual violence. MST raises similar issues to college rapes in that victims are often inexperienced younger people who are living away from home for the first time and are thrown into environments where it may be unclear what types of behaviors and boundaries are acceptable. There are also institutional factors that play a role in how the victim is treated and justice is served. Can you comment on these parallels? In particular, how generalizable is the VA experience to non-veteran populations?
Katie Webb: I agree, there are so many parallels. Probably with MST you see a little bit more extremity in everything.
For example, to some degree on college campuses, you’re living and working with your peers, just like in the military – you’re battle buddy is your room mate or your officemate or your chore mate. Both settings encourage unit cohesion, but I think in the military that’s more extreme because if your unit doesn’t get along, you’re more likely to die. I think in the military that creates this pressure, particularly on minorities, e.g. women, to bond in ways that definitely push the limit and push what’s acceptable.
I think you raise a very legitimate fact that younger people are still developing, they are still forming their schematics of how the world works. This is then used against them, as a tool that can be blaming. “Well, you don’t know how the world works. Maybe you misunderstood the situation.” Then that really creates this manipulative dynamic that I think perpetrators can use and systems can use, so that is a striking similarity.
Colleges and the military try to keep the issue within their system of discipline, whether it be campus police or a military court system. I think military survivors of sexual trauma and college survivors of sexual trauma are isolated and blamed. Oftentimes, the powers that be say, “Well, we responded. We kept the survivor safe by transferring them to a new base.” They transfer the victim away from people they know with detrimental impacts on their careers. Sometimes, a college student may transfer to a new college and interrupt their goals while perpetrators stay put. If the survivor chooses not to report, they may have to continue to co-exist with the perpetrator. The same thing can occur on college campuses.
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.
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.
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.
More than thirty-five years after the 1980 recognition of PTSD in the Diagnostic and Statistical Manual of Mental Disorders (DSM), the data are unequivocal: Today there can be no doubt about the validity of PTSD as a diagnostic entity. Yet, the disorder remains steeped in controversy, and more recently, there have been growing complaints that PTSD is being overemphasized in our society and over diagnosed in our hospitals.
PTSD can be found in its current avatar in the 2013 version of the DSM, called the DSM-5. Dr. Friedman is founder and former Executive Director of the National Center for Posttraumatic Stress Disorder and Professor of Psychiatry and of Pharmacology and Toxicology at the Geisel School of Medicine at Dartmouth. He was a member of the American Psychiatric Association’s (APA) DSM-5 Anxiety Disorders Work Group and chair of the Trauma and Dissociative Disorders Sub-Work Group.
Recently, I asked him about his work for the DSM-5 sub-work group.
Dr. Jain: The first question that I had was about the DSM-5 work group. The reason I ask about this is because I think, for a lay audience or scientists outside of our field, they may not be familiar with how much work went into the DSM-5. I was hoping you could speak a little bit about what that entailed, the scope of that mission, and the timeline of that whole effort.
Dr. Friedman: Basically, the DSM-5 had a work group for each diagnostic cluster. In the DSM-4, PTSD was an anxiety disorder, and the anxiety disorder group is the largest group of diagnoses. There were initially about a dozen of us who were asked to work on the anxiety disorder diagnoses. These were not just Americans, we had Europeans and people from Asia and other continents working with us.
When we looked at all these different anxiety disorder diagnoses, everything from panic disorder to obsessive compulsive disorder, and from tick disorders to PTSD, we felt that there was such a broad swath of diagnoses, and frankly, many of these diagnoses did not seem to belong together. So we divided ourselves into three work groups. There was the anxiety disorder work group, which looked at “classic” anxiety disorders (i.e., panic disorders, social anxiety, generalized anxiety disorder, agoraphobia, etc). Then there was a second group that looked at obsessive compulsive spectrum disorders. Finally, the third group, that I was asked to chair, was looking at what we came to call trauma and stress related disorders, and we were also asked to look at dissociative disorders.
We basically addressed the following: PTSD, acute stress disorder, reactive attachment disorder, and disinhibited social engagement disorder. We also looked at dissociative disorders, particularly de-realization and depersonalization disorder, dissociative amnesia, fugue states, and dissociative identity disorder.
Dr. Jain: Can you give me a sense of the timeline? When did you start work on this?
Dr. Friedman: It was a 5-year process. We began in 2008, and we knew that the DSM-5 had to be published in time for the May 2013 American Psychiatric Association meeting.
Dr. Jain: What was the process? Were you combing through all of the literature and picking out the higher quality studies? What were the sources for the work group?
Dr. Friedman: It was very conservative. It other words, there had to be very compelling research evidence to make any changes to the DSM-4. In terms of the process itself, for each diagnosis position papers were written and published in appropriate scientific journals. The position paper was a very thorough and careful literature review. Furthermore, we tried to make the process as open and transparent as possible, so on two separate occasions, the working criteria for each diagnosis of the different DSM-5 work groups were published on the American Psychiatric Association website. The entire clinical scientific community was invited to comment to raise objections, and these were taken very seriously. There were also field trials that were conducted. In our group, the field trials were really more about clinical utility. How easy was it for practitioners to use these criteria? What was the inter-rater reliability between one clinician and another who was looking at the same patient? It turned out PTSD emerged as having one of the highest inter-rater reliabilities. Also, our work group decided to do some research on its own.
Dr, Jain: Can you summarize the most important changes that eventually ended up being made for PTSD? I know your work group was looking at many disorders, but please comment specifically about PTSD.
Dr. Friedman: I think that the most important change was moving PTSD out of the anxiety disorders cluster. Our review of the data indicated that all posttraumatic clinically significant psychiatric symptoms don’t fit neatly into a DSM-III/DSM-IV fear-related anxiety disorder paradigm. A second important change was opening up the A criterion so that it was not a narrow fear-based anxiety disorder. The way we did that was by eliminating the A2 criterion, which required the following response after exposure to a traumatic event: fear, horror, or helplessness. By getting rid of this A2 criterion, we really opened things up to other acute posttraumatic emotional reactions. Also, in DSM-IV, you could have PTSD without reporting a single avoidance symptom. Now you have to have at least one avoidance symptom in order to have PTSD. We also stipulated that if PTSD was secondary to witnessing the sudden death of a loved one, that death had to have been under accidental or violent circumstances.
Dr. Jain: For me as a clinician there is this issue of partial PTSD that comes up all the time. We are seeing patients who do not necessarily meet the criteria in the DSM-5, but there is something going on, and they have considerable dysfunction. How do you think clinicians like me should approach those cases?
Dr. Friedman: I agree with you completely. The DSM-5 work group agrees with you completely. We very much wanted to have a sub threshold PTSD diagnosis. When we went into the literature, there are about 60 papers, including some that I have done with Paula Schnurr, looking at partial PTSD. The problem for DSM-5 is that there has never been a standard case definition of partial PTSD that has been used widely. Different investigators had different definitions of sub threshold PTSD.
As I told you earlier, given the very strong empirical rational that was required for any addition to be made, the APA concluded there was not sufficient evidence of a specific sub threshold PTSD diagnosis that had been validated in the literature. I do hope that we can soon develop a widely accepted case definition for subthreshold PTSD so that the needed research can be conducted to guide the next DSM consideration of subthreshold PTSD.
I agree with you that we see these patients who have been exposed to major traumatic events. They have many PTSD symptoms, it is clearly a trauma-related problem, but they do not exceed the diagnostic threshold for PTSD. What are we supposed to call them? In DSM-5, the diagnosis “other specified trauma or stress related disorder” would be the proper diagnosis. So there is a place for such cases in the DSM-5. Once we get a good case definition and we have the data, I think that there will be an actual sub threshold diagnosis in DSM.
Dr. Jain: One thing that I have noticed is there is a fundamental assumption about the DSM-5 which gets forgotten: it is a manual meant to be used by people who have specific clinical training. What scares me is when I see people finding bits of the DSM-5 and diagnosing themselves (or others) when they don’t have such training. Can you comment?
Dr. Friedman: You are correct. The DSM-5 is an ongoing manual under the aegis of the American Psychiatric Association. Diagnosis should only be done by people that are qualified to make diagnoses. That is why people go to medical school, whether they are making a psychiatric diagnosis or a surgical diagnosis or a pediatric diagnosis. The diagnostic criteria are to guide qualified people to be able to make diagnostic distinctions. The whole reason to do that is because diagnosis A may be better served by treatment A, and diagnosis B may actually have better outcomes if you use treatment B.
These distinctions are extremely important, and you need a professional in order to make these. On the other hand, I think it is important and useful for lay people, policy makers, journalists, and family members to have some idea about specific diagnoses so that if they, or a loved one, is exhibiting a specific set of symptoms, they can go to a qualified professional to see whether or not they are correct.
Dr. Jain: There are growing complains that PTSD is being overemphasized in our society and maybe over diagnosed in our hospitals. I think people who are not appropriately qualified might be making the diagnosis. There is a huge amount of variability in the mental health training of clinicians throughout any given hospital system. A classic example that I run into all the time is when someone has assumed that just because somebody served in a warzone, they must have PTSD. We know that that is an erroneous assumption. Actually, the opposite is true. The majority of people who served in a warzone will not develop PTSD. I am curious. Do you feel it is overemphasized and over diagnosed, and if so, what do you think the reasons might be?
Dr. Friedman: There are different contexts in which the PTSD term is used. There is the way that you and I have been discussing it, in terms of the very strict DSM-5 diagnostic criteria. There is also the public health context. For example, following a terrorist attack, we know that the risk for developing PTSD or other problems is heightened, so it makes sense to be looking for PTSD. But we need to look with very accurate instruments and with well-trained individuals making that diagnosis. We have screening measures, like the Primary Care PTSD Screen (PC-PTSD), but that is where the diagnostic evaluation should begin, not where it should be concluded.
So, if a person comes in and says, “I am having terrible nightmares about the murder that I witnessed yesterday.” Well, that is normal during the immediate aftermath of a traumatic event. Most people are going to have PTSD symptoms after experiencing such an event, which will usually dissipate. In that case the clinician can be reassuring but should also caution the patient that if such symptoms persist, further evaluation is necessary.
I think one of the major roles that we clinicians play is we are teachers. When someone comes into our office, we need to make that into a teachable moment. It does not bother me if someone comes in and he or she is a thoughtful person who looked at the Internet, maybe read your blog, and said, “I think I have PTSD.” That is okay with me. It is my job to make a careful evaluation and either validate or refute that assumption. It is my responsibility to tell them why they do or don’t have PTSD, and then make some recommendation for what they should do.
I think there is a rush to judgment sometimes. It is certainly reasonable for a clinician who has seen a traumatized patient, to ask the question, is this PTSD? But then they either have to follow through with a careful diagnostic evaluation or refer the patient to a mental health professional who will do the diagnostic assessment.
We developed the Clinician-Administered PTSD Scale (CAPS), which is the gold standard for making a diagnosis. The CAPS is only to be administered by a specifically trained clinician. It is not something that you can hire a college graduate to do. The important thing is the CAPS has behavioral anchors. If a patient said, “I am not sleeping well,” you want to say, “How many hours of sleep are you getting? What wakes you up? When are you sleeping? When are you not sleeping?” Only a trained clinician is going to have the awareness and the training and the skill to really use these diagnostic criteria in the way they are meant to be used.
Dr. Jain: You brought up that point about the positive PTSD screens. Sometimes, I think there is a misperception that because it is a positive screen, it automatically means someone has PTSD. Another issue is, as you know, we have a shortage of mental health professionals across the country. Sometimes, I think PTSD gets over diagnosed because there are not enough mental health professionals to see patients when they screen positive.
Dr. Friedman: I want to say something about screens. What many people do not understand is that screens are designed to be biased toward false positives. What you want to do with a screen is you want to include all the people who might have the diagnosis, whether it is high blood pressure, cervical cancer, PTSD etc. The expectation with the screen is that many of the people who screened positive are not going to have the diagnosis. You do not want to leave out anybody who might.
Dr. Jain: Like you said, interpreting that screen—that is the piece that I feel sometimes contributes to this overemphasis of the diagnosis.
Dr. Friedman: It’s understanding the utility and the limitations of the screen or of a self-report instrument. We’ve got some really good assessment instruments in mental health. We have the PCL and the PHQ-9. Again, these are all self-report. They do not have behavioral anchors like the CAPS (which is a structured interview administered by a trained clinician). For example, if a patient checks a four and states, “I am having terrible sleep,” the clinician has to use the behavioral anchors to drill down and clarify exactly what does that individual mean. One person’s four might be someone else’s two.
Dr. Jain: Any final thoughts?
Dr. Friedman: We do not have a stake in preserving the DSM-5 diagnosis in perpetuity. If there is better data that comes along, that is great. If the DSM-5 has raised questions that have motivated people to generate that data, that is great too. That is what science and clinical science is all about. I think that is an important contextual issue that people often miss.
The National Vietnam Veterans Readjustment Study (NVVRS) was conducted in 1983 as a response to a congressional mandate for an investigation of PTSD and other postwar psychological problems among Vietnam veterans. More than 25 years after the original NVVRS study was conducted, researchers reassessed more than two thousand of the original study participants for symptoms of PTSD. What made this research unique was that the long-term course of PTSD in military personnel had not previously been evaluated in a nationally representative sample. This follow up study, called the National Vietnam Veterans Longitudinal Study (NVVLS), found a current prevalence of PTSD in 4.5% of male and 6.1% of female combat Vietnam era veterans. Extrapolating these figures suggests that more than a quarter of a million Vietnam veterans still struggle every day with the consequences of PTSD forty years after that war ended.
The study was led by Charles R. Marmar, MD, the Lucius N. Littauer Professor and chair of the department of Psychiatry at NYU Langone Medical Center and director of its Steven and Alexandra Cohen Veterans Center, a leading program in the study of PTSD. A pioneer in the field of PTSD research, his work has led to breakthroughs in our understanding of PTSD through the study of police officers, soldiers in combat, veterans, and civilians who have been exposed to sudden, usually life-threatening, events.
Recently, I spoke to Dr. Marmar about the implications of the NVVLS study and about his 40 year career as a PTSD researcher.
Dr. Jain: For my first question, can you start by commenting on the large percentage of Vietnam veterans you and your team studied that has never suffered from PTSD linked to war? I feel sometimes that percentage gets lost in some of the headlines and media coverage of PTSD research.
Dr. Marmar: Yes. It is a little difficult to give a precise overall estimate, but if you look across our data from both the first wave of our study (collected between ’84 and ’88) and then the second wave (collected between 2011 and 2013), it is roughly a 75% and 25% split. Of course it depends precisely on how you define PTSD, and that has changed over the years, but you could say that approximately 3/4 of Vietnam veterans who served in the warzone never developed significant levels of stress, anxiety, or depression related to their military service. They were relatively resilient. Now, that is only an average across all 3.1 million men and women who served. There is a lot of variability depending on who you were, how old you were, how many times you were deployed, and what your service duties entailed. In a warzone deployment, there are three broad roles: combat, combat support, and service support. All three roles come under the definition of a warzone, but the number of people who are actually repeatedly at the tip of the sword is a smaller percentage, and that factors in to the individual risk calculation.
Dr. Jain: Yes. Actually as you talk, something comes into my mind about recent returnees from the conflicts in Afghanistan and Iraq. Military rank appears crucial. Lower ranking military members are exposed to higher doses of trauma and are therefore more vulnerable. Is that something that you looked at in the Vietnam study or is that something you can offer some feedback on?
Dr. Marmar: In general, older, more educated war fighters of higher rank are able to tolerate the intensity of combat and are more resilient. Also, as you indicated, in general, their levels of repeated combat exposure are lower if they were squad leaders rather than squad members.
Dr. Jain: Dr. Hoge’s editorial that accompanied the article described your research as “methodologically superb.” Can you comment a little bit from a researcher’s perspective on the strength of your study and how it is different to previous efforts to document the prevalence or course of PTSD in this population?
Dr. Marmar: Firstly, we believe it is the only study in the world (with the possible exception of studies conducted by Solomon et al with the Israeli Defense Force) which followed, in an epidemiologically sound way, a representative sample of every man and every woman who served in a major conflict. The study was not done by recruiting people from VA hospitals and clinics or by advertising on Craig’s list, etc. So it takes into account the differences between community samples and VA seeking patients, as these are two very different groups. This study was drawn top down from military records. It included people from all 50 states, Guam, and Puerto Rico, and it included urban, suburban, rural, and extremely remote veterans. So, for example, we have included participants from the remote aspects of the Big Island of Hawaii, all the way to Manhattan. It is a truly representative sample in this regard. Secondly, we oversampled for women and minorities. This gave us more statistical power to look at these populations too. Thirdly, the study is exceptionally successful in its implementation. We had zero contact with our cohort for 25 years. We never contacted a single one of them on a single occasion and still retained just under 80% of them for the follow up 25 years later. The study has many excellent features, but the most important features are that it has true representational sampling, over representation of women and minorities, and its high retention rate over 25 years.
Dr. Jain: That’s what makes it a very important piece of science in our understanding of the prevalence and course of PTSD.
Dr. Marmar: It also tells you something profound about the participants’ commitment to the research. Another thing is it is very deep, because we have up to 5-hour household interviews, survey interviews, and 3-hour clinical interviews on a sub-sample. For this follow up study, we had a 1-hour self-report package, 1 to 2-hour interview by professional survey interviewers, and 3 to 5-hour clinical interviews done by my team at NYU. We used a team of highly qualified PhD clinical interviewers, and they were able to interview people by telephone so that we could sample, in the clinical interview, people from all over the country. It is very hard to do that if you ask participants to come into regional medical centers.
Dr. Jain: Can you talk a little bit about sub threshold (or partial) PTSD? Clinicians see that all the time—patients who might not meet the diagnostic criteria, but that does not mean they do not have symptoms that have a significant impact on their quality of life. Sub threshold (partial) PTSD is something I believe you chose to measure in the study. Can you tell us a little bit about your findings?
Dr. Marmar: What we do know is that roughly as many Vietnam veterans have partial PTSD today as have full PTSD. We define partial PTSD very strictly. We had a very well-defined algorithm of what constitutes partial PTSD. The important things to note are that the overall symptom levels are relatively high in the partial group, and their functioning difficulties in work and love are also high. In fact in our work, and in some prior publications, the levels of dysfunction are quite similar in people with partial and full PTSD. Levels of medical comorbidity may be quite similar, too. So partial PTSD is very important. The other thing we found is that roughly 5% of the Vietnam veterans alive today, who served in the war, meet full criteria for PTSD, but an equal number meet partial criteria. We also found that roughly 1/3 of Vietnam combat veterans with PTSD today also have full current comorbid major depressive disorder. That is almost identical to the rate of comorbid major depression that we found in the partial group. You can see that there is a heavy burden of symptoms, comorbidities, and dysfunction in the partial group. A big study about partial PTSD, published in 2001 in the American Journal of Psychiatry, reported similar findings.
Dr. Jain: From your findings it is definitely something we need to be more aware of and on the lookout for to make sure these patients are also getting services where indicated or having their symptoms addressed.
Dr. Marmar: Absolutely. I think this is an important and potentially underserved group. They probably function a little better, maybe overall, than those with the full, more severe form, but there is still a heavy burden of illness. We have statistical models which examine the extent to which full PTSD is a risk factor for medical comorbidity and premature death. An important follow up question would be: Does carrying a diagnosis of chronic partial PTSD over years to decades shorten your life? I think physicians should be very concerned about the physical and medical problems of veterans with partial PTSD: cardiovascular risk, stroke risk, metabolic load, diabetes, and cancer.
Dr. Jain: Right. Yes. There is this whole other body of literature that is emerging that really fleshes out this sensitive relationship between PTSD and physical illness.
Dr. Marmar: In a study we did that was published in JAMA in 2009, my colleague Beth Cohen and I downloaded the VA national database and looked at 250,000 OEF/OIF veterans enrolled in VA healthcare nationally. We asked a simple question: If you compare veterans with no current mental health diagnosis, what do these medical risk factors look like in those with PTSD alone, depression alone, and comorbid PTSD and depression? At that time, around 2009, we had these pretty young, recently returning Iraq and Afghanistan veterans, and we found huge, two to three times increases in levels of dyslipidemia, type 2 diabetes, obesity, and other problems in those with psychiatric illness.
Dr. Jain: One of the wonderful things about working in the VA is that, as a system, it cares about PTSD. It funds not only clinical programs, but many research efforts too. In addition to that, there is political and societal motivation to support the funding of studies such as yours. As a physician, I am well aware that PTSD is not just an issue for veterans. It is an issue across our culture, across our society. It is an issue globally. Because so much cutting edge research on PTSD is done in veteran populations, it can contribute to a societal myth that PTSD is only a veteran issue. Your study offers a much needed contribution to advancing the science of PTSD, but it raises another question in my mind: Would the results be that different in a civilian population?
Dr. Marmar: It is difficult to say. War fighters are repeatedly exposed to personal life threat. It is somewhat less common in a civilian world. War fighters not only had their own life in danger, but they are required, by their service to their country, to take the lives of other people. This adds a different dimension to trauma than say, being a sexual assault survivor (which, of course, is horrible), or a vehicle accident or national disaster survivor. Killing is different than just having your life in danger. This has been written about more recently as the “moral injury” of war. In general, clinically, I think you would agree that there are easier cases that are more easily treated, and more difficult cases that are more difficult to treat. That is true in every aspect of the practice of medicine. In trauma, people who are repeatedly exposed to trauma early in life and who perpetuate violent acts, as part of the trauma experience, actually are different, and they have a different form of PTSD that is more complex, more chronic, and, generally, more treatment refractory.
Dr. Jain: Jonathan Shay wrote about the specific plight of Vietnam veterans in his 1994 book, Achilles in Vietnam: “such unhealed PTSD can devastate life and incapacitate its victims from participation in the domestic, economic, and political life of the nation. The painful paradox is that fighting for one’s country can render one unfit to be its citizen.” Shay’s anecdotal observations seem prophetic when considered in the light of your recent study. Can you comment about what your research showed about the quality of life of Vietnam veterans who still have combat related PTSD?
Dr. Marmar: I would say the effect on quality of life is very profound. Think, by analogy, about the study of the effects of psychotic symptoms among patients with the schizophrenia spectrum disorders. As you know, early on when the concept of schizophrenia was being developed, the focus initially was on the rather dramatic positive symptoms: delusions, hallucinations, the jumbled thinking, and so on. But actually as you begin to analyze what is related to functional disability, it is often more the negative symptoms of schizophrenia: the amotivational syndrome, apathy, detachment, dysphoria, and depression. I would say, in some ways, that is true for PTSD. The nightmares and flashback, the startle reactions—these positive symptoms are very disturbing. But the negative symptoms, which include numbing, detachment, inability to express and receive affection, erosion of the ability to enjoy things, and so on—those negative symptoms are very devastating to function. They often lead to withdrawal, fractured family, and alienation, and they are often associated with heavy alcohol and drug misuse. The negative symptoms are very important.
Dr. Jain: Right. That has a knock-on effect on capacity to work, capacity to parent, and capacity to engage in social relationships. In that way, I think it really speaks to how PTSD as a disease entity that goes beyond the individual human and their own biology and really extends and infiltrates our society.
Dr. Marmar: Yes. Very very much so. I mean, for every war fighter who is traumatized, there are 10 to 20 people in their lives that are part of their social fabric that are affected to varying degrees: parents, siblings, spouses, children, grandchildren. That is a huge network. They are all affected.
Dr. Jain: Again, coming back to your JAMA study, I feel like someone who is thinking both from the perspective as a clinician and researcher. I think intuitively, a lot of clinicians have been seeing this type of picture for decades, but what is validating is to have an excellent, well-designed, very rigorous scientific study which gives us that support for what we have been seeing on the ground. In my understanding, that is what your study has done. Can I ask how many years you been doing PTSD work?
Dr. Marmar: I have more than 40 years of experience as a trauma clinician and researcher. In a way, my professional history parallels that 40-year Vietnam study. I am probably more energized and passionate about my trauma research today than when I started 40 years ago.
Dr. Jain: Why do you think that is?
Dr. Marmar: It took a long time to really grasp the depth of what this subject was really about. We did not have all the tools. We did not have the sophisticated epidemiological studies. We did not have advances in translational neuroscience to probe the neurocircuitry, neuroendocrinology, or the neurogenetics for the illness of PTSD. I am very excited that the world is captivated by PTSD, and we have the tools now to make very dramatic advances, for example, to develop panels of blood and brain imaging biomarkers that would definitively say who does not have PTSD, who has partial PTSD, who has regular PTSD, etc. We will crack that code in your academic lifetime. It is an exceptionally rich and open field, and there is an opportunity to make huge contributions.
Post-traumatic Stress Disorder (PTSD) has been described as a disorder of memory. It has become quite apparent that there are two types of memory in PTSD: the first being the involuntary intrusions of the trauma, and the second being the voluntarily recalled memories that constitute the trauma story, also known as the trauma narrative. Both are fundamentally different in their quality and form. The involuntary intrusions are vivid, highly emotional, and involve a sense of reliving the original trauma. In contrast, the voluntarily recalled trauma narratives do not share this same intensity, but their content is notable for being significantly disorganized. Such disorganization can be found very soon after the traumatic event and hence is not attributable to poor recall, but to the very nature of these traumatic memories themselves. In essence, there is an inability to put into words the most emotional part of a traumatic event, a period of time which could have lasted anywhere from several seconds to several hours. Traumatic memories are also unstable, so what is under voluntary and involuntary control varies over time. For this reason, the recall of trauma over different points in time creates different trauma accounts, with such discrepancies being more noticeable as the symptoms of PTSD become more severe.
For such disorders of memory, a natural follow up question is what are the molecules and chemical building blocks that our memories are made from? Unlike taking a blood sample, a saliva swab or a sample of bone marrow, there is no simple way to sample brain tissue from a live human. For this reason, neuroscientists have relied on animal models to discover what goes on in the brain when memories are made. The work of Eric R. Kandel forms the basis for much of what we understand about how memories are formed. Dr. Kandel was awarded the 2000 Nobel Prize in Physiology or Medicine for his extensive body of pioneering work investigating the synaptic connections between nerve cells in sea slugs. His work has illuminated some of the basic molecular mechanisms underlying learning and memory in animals and is central to understanding not only normal memory, but also disorders that affect memory, such as PTSD. More recently, Dr. Kandel and his colleagues identified a molecule, a prion protein called CPEB, (cytoplasmic polyadenylation element-binding protein 3) that plays a key role in the maintenance of long-term memories in the sea slug Aplysia and in mice. In a 2015 study, Kandel and his colleagues trained mice to memorize a way to navigate through a maze, then the researchers knocked out the mouse homolog of the CPEB gene called CPEB3 and this knocked out the maintenance of long-term memories and caused the mice to forget how to navigate the maze.
Dr. Kandel is a Professor at Columbia University, the Kavli Professor and Director of the Kavli Institute for Brain Science, Co-Director of the Mortimer B. Zuckerman Mind Brain Behavior Institute and a Senior Investigator at the Howard Hughes Medical Institute. I spoke with him about this recent publication and the relevance of such findings to disorders of memory, such as PTSD.
Dr. Jain: The first question I had was about prions. They have a really bad reputation in the world of medicine as being associated with horrific diseases like Creutzfeldt-Jakob Disease (CJD) and Bovine Spongiform Encephalopathy (BSE). Your work has shown that in order to maintain long term memory, we need local protein synthesis at the synapse. You and your colleagues have identified the CPEB protein as a functional prion which has this role of keeping memory indefinitely. Could you talk a little bit more about functional prions and how they differ from prions that cause pathological changes in the brain?
Dr. Kandel: Well, functional prions differ from pathological prions in two ways. First, in pathological prions, the conversion from the soluble form to the aggregated self-perpetuating form is spontaneous. In functional prions, it is regulated by a physiological signal. Secondly, in pathological prions, once the prions assume an aggregated self-perpetuating form, prion proteins then kill the cell. They are then released by the dying cell and taken up by other cells, they kill the next cell and are passed on from one cell to another like an infection. The functional prions are not only turned on by a physiological signal, but when they are turned on and reach the aggregated self-perpetuating form that is their normal function. They are inactive when they are not in the aggregated form. So they fulfill their normal function, which in this case is regulating local proteins synthesis.
Dr. Jain: Taking this one step further, when we think specifically about a psychiatric disorder, such as PTSD, can you speak a little bit as to what these recent findings mean in terms of understanding what the molecular basis for PTSD might be?
Dr. Kandel: Before we come to PTSD, we now have information on Age Related Memory Loss indicating that one of the key defects is upstream from CPEB-3, the same functional prion that we found important for maintaining normal memory.
PTSD very likely has prion mechanisms. Joseph Rayman in our lab identified a second prion in addition to CPEB that seems to play a role as a protective factor in PTSD. We have not done enough to talk about it and it has not been published yet.
Dr. Jain: Neuroscience data comes from studies using animal models (sea slugs, mice etc.). Can you speak a little bit to those of us who are not so familiar with cutting edge neuroscience methodologies, how do we infer from animal models what might be happening in the human brain?
Dr. Kandel: Well, one cannot be certain unless one explores the molecules directly in the human brain, but there is a homologue in the human brain. There is no obvious reason for thinking it does not have a similar function, but until one tests it one cannot know for sure.
Dr. Jain: We hear about these amazing discoveries about these prions and homologues in humans. What is your vision for how basic science research will actually translate clinically into impacting people living with memory disorders?
Dr. Kandel: We are already there in some areas. We have far to go in other areas, but I will give you an example. We have a pretty good understanding of Alzheimer’s disease. We know the toxicity of beta amyloid. We do not know why the drugs that are directed against beta amyloid do not work, but one possibility that is being seriously entertained is that by the time the patient comes to see a physician, they have had the disease for ten years. That is a very long time and you lose a lot of nerve cells in ten years, and drugs do not bring nerve cells back once they are dead.
We need to diagnose the disease earlier and a major effort now, in Alzheimer’s research, is early diagnosis. Imaging, cerebral spinal fluid, genetic warning signals etc.
The other thing is it has proven possible to define an independent disorder, age related memory loss. Recent work from our lab, and that of Scott Small, ,has shown there is a separate entity, independent of AD, called Age Related Memory Loss. We have identified the molecular pathways involved in that disorder. We have treatments that work very effectively in animals. I think the time is going to come soon when these will be tried in people.
All of these came out from a basic science and work with experimental animals. So even though we are in the very early stage of understanding the really complex functions of the brain, we are making progress and all of this will hopefully have some therapeutic impact.