Bending, not Breaking: A Prescription for Resilience to Anxiety

Dennis S. Charney, MD

This interview was conducted by Norman Sussman, MD, on March 8, 2006.

What initially piqued your interest in the study of posttraumatic stress disorder (PTSD)?

In the late 1980s, my Yale colleagues and I started work on PTSD at the Department of Veteran’s Affairs Medical Center in West Haven, Connecticut. Through the efforts of Matthew J. Friedman, MD, PhD, Terence M. Keane, PhD, and Fred Gusman, MSW, we were awarded a division of the National Center for PTSD. This center enabled us to begin to look at the biologic consequences of severe stress, such as combat, on human biology. Through that work we found that stress could actually alter the neurochemistry and structure of the brain in humans. For example, in a 1995 study led by Bremner,¹ our group published a report demonstrating that the hippocampus of PTSD patients was reduced in size. Subsequently, up to 20 studies have looked at hippocampal volume. Although this result has not been observed in every single group of patients, it is widely accepted in PTSD that, at least in some patients, severe stress can alter the size of the hippocampus.

Our research was built upon basic science work by several scientists, most notably Robert Sapolsky, PhD, and Bruce S. McEwen, PhD. They both demonstrated in animal models that severe stress could alter hippocampal structure and function.^2-5 In parallel to investigating the effects of stress on human brain structure, we also began to look at how combat stress and other forms of stress affect the neurochemistry of the brain and the body. We found that severe stress in humans can alter neurochemical systems, such as the norepinephrine and benzodiazepine systems, in ways that might be long lasting and relate to common symptoms of severe stress.

Are there any consistent findings of physiologic or biochemical markers specifically for posttraumatic stress?

There are findings that clearly are more common in patients with PTSD. Reduced hippocampal size can be a consequence of stress, but also might be a risk factor for development of PTSD. An investigation by Gilbertson and colleagues⁶ in twins showed that in some individuals, having a reduced hippocampal size before stress exposure may predispose them to PTSD. Thus, reduced hippocampal size for the development of PTSD may be both a risk factor and a consequence of stress.

Other replicated findings include a hyper-responsiveness of the brain norepinephrine system. Studies by our group, led by Southwick⁷ and Bremner,⁸ showed that the drug yohimbine, which activates the norepinephrine system, produces abnormal neurochemical and brain metabolic responses consistent with a chronically elevated norepinephrine function in the brain. More recently, a study by Neumeister and colleagues,⁹ while working with me at the National Institute of Mental Health, revealed that a specific polymorphism of the a_2C adrenoreceptor gene may relate to enhanced norepinephrine turnover. Studies are planned to determine if this polymorphism is more common in patients with PTSD.

We and others have also observed elevations in cerebral spinal fluid corticotrophin-releasing hormone, which has been shown to be a peptide that produces the symptoms or effects in laboratory animals akin to anxiety and depression.¹⁰ In addition, Yehuda¹¹ has repeatedly found abnormal regulation of the hypothalamic pituitary adrenal axis in PTSD.

How did you go from looking at the negative effects of stress to studying resilience?

My colleagues and I had spent many years working on the aforementioned studies to determine the biology of anxiety, depression, or PTSD. Then, almost 10 years ago, we began to wonder if we could learn from people who had been exposed to severe forms of stress but did not develop anxiety disorders, PTSD, or depression. We wanted to discover the biologic and psychologic factors that enabled these patients to be resilient in the face of severe stress. When I was at Yale working with Andy Morgan, PhD, Steven Southwick, MD, and others, we began to consider how to investigate the biologic and psychologic basis of resilience to stress.

The first group we studied were the United States Special Forces.^12-14 Primarily through the work of Morgan, we developed a relationship with the Army and the Navy to study the Special Forces. We studied them in the context of very stressful training exercises, and began to identify the neuropeptides and steroids that might relate to resilience in the face of stress. For example, we found that elevations in neuropeptide Y, which is an endogenous anxiolytic neuropeptide, seemed to relate to an ability to perform better under stress. We also found that elevations of the adrenal steroid dehydroepiandrosterone (DHEA) in response to stress seemed to relate to a more positive or effective performance under stress. This model of studying people who have been trained to be resilient under severe stress yielded findings that might underlie the neurobiology of resilience. If neuropeptide Y or DHEA relate to stress resilience, they might be targets for effective treatments to prevent the negative effects of stress.

As a follow-up to work with the Special Forces, my research group, including Meena Vythilingam, MD, and Southwick, began a series of studies at the National Institutes of Health (NIH) involving prisoners of war (POWs) from Vietnam.¹⁵ We were interested in this group because we became aware that despite the trauma of being a POW, the torture associated with it, and the many years being in solitary confinement, the American POWs from Vietnam ended up functioning very well when they got out, and the incidence of PTSD and depression was much lower than expected. We figured that if we could study these men even years after they got out, both from a psychologic and biologic perspective, we would learn a lot about resilience. We brought the POWs to NIH and conducted hours of videotaped interviews, a variety of neuropsychologic tests, and brain imaging tests to begin to understand how they could have handled such a terrible experience and come out in many cases even stronger than before.

How can the research on resilience be applied in the treatment of patients with stress?

My colleagues and I have expanded our work to include women who have overcome severe trauma, particularly sexual and physical abuse. We have begun to study individuals who have faced serious medical problems and dealt with those problems with courage and resilience. We have found that many of the elements of resilience that we identified in the American POWs from Vietnam were also present in these other groups. Consequently, Southwick and I have developed a prescription for resilience that we think contains the key ingredients toward becoming a more resilient person. It might also have implications for the prevention and treatment of stress induced psychopathology.

We have found that one characteristic present in many resilient people is optimism, even in dire situations. While in some people optimism appears to be genetic, it can also be learned. For example, cognitive-behavioral therapy in part is designed to enable people to view their situation in a more positive light and to see ways out of a difficult situation. Having a moral compass or a set of beliefs that few things can shatter can get a person through very tough times. Faith or spirituality has some overlap with a moral compass, and for some people can be comforting and provide a sense of optimism and hopefulness in the face of difficult situations. Another ingredient is cognitive flexibility, meaning that when a person experiences severe trauma, he or she can use that as a growth experience. The person can ask how he or she can grow from the experience and learn more about himself or herself while going through tough times. Many of the POWs we studied said that even though those 6–8 years was a terrible experience, they learned things about themselves that they could not have learned almost any other way, and that it prepared them to face challenges later in life. Essentially, having cognitive flexibility enables a person to see that failure is an opportunity for growth. Resilient people face their fears. Courage, for example, is not the absence of fear. Rather, it is being afraid but acting despite that fear.

Do antidepressants or anti-anxiety drugs help with resilience?

We do not know that yet. Such studies are just in their beginning stages. Several groups are now looking at the roles that medication and psychotherapy may have in enhancing resilient factors to fight against depression or anxiety.

Is one’s personality or ability to be successful or executive related to ability to be resilient?

We have found that social support, particularly via close meaningful relationships, can be important to a person’s resilience to stress. The POWs used a tap code as a way of communicating non-verbally through cell walls using an algorithm. The tap code kept many of the POWs’ spirits up, even when they were in solitary confinement. Everyone needs a tap code. Everybody needs people in their lives to help them get through the tough times. Another characteristic we have found in resilient people is that many of them faced stress earlier in their lives and were able to master it. Subsequently, each time a person faces a difficult situation, he or she can reflect on how it was dealt with before and utilize those skills again.

Where would you like your work on resilience to lead?

I want to discover the biochemistry, neurochemistry, and genetics that underlie resilience. We focus on vulnerability genes in relation to mental illness, but we need to identify stress protective genes. I am also interested in the psychologic aspects of resilience. I think we have under-recognized the fact that we can train people to become more resilient. This has important implications for how we raise our children to become resilient adults.

Dr. Charney is a consultant to Abbot, AstraZeneca, Bristol-Myers Squibb, Cyberonics, GeneLogic, Institute of Medicine, Neurogen, Neuroscience Education Institute, Novartis, Orexigen, Organon, Otsuka, Quintiles, and Sepracore; has a confidentiality agreement with Forest and Novartis; and receives grant support from Emory and NIH/DRR.

References

1. Bremner JD, Randall P, Scott TM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry, 1995;152(7):973-981.

2. Sapolsky RM. Why stress is bad for your brain. Science. 1996;273(5276):749-750.

3. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57(10):925-935.

4. McEwen BS, Magarinos AM. Stress effects on morphology and function of the hippocampus. Ann N Y Acad Sci. 1997;821:271-284.

5. McEwen BS. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann NY Acad Sci. 2004;1032:1-7.

6. Gilbertson MW, Shenton ME, Ciszewski A, et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci. 2002;5(11):1242-1247.

7. Southwick SM, Krystal JH, Bremner JD, et al. Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54(8):749-758.

8. Bremner JD, Innis RB, Ng CK, et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54(3):246-254.

9. Neumeister A, Charney DS, Belfer I, et al. Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans. Pharmacogenet Genomics. 2005;15(3):143-149.

10. Bremner JD, Licinio J, Darnell A, et al. Elevated CSF corticotrophin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry. 1997;154(5):624-629.

11. Yehuda R. Post-traumatic stress disorder. N Engl J Med. 2002;346(2):108-114.

12. Morgan CA 3rd, Wang S, Southwick SM, et al. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biol Psychiatry. 2000;47(10):902-909.

13. Morgan CA 3rd, Wang S, Mason J, et al. Hormone profiles in humans experiencing military survival training. Biol Psychiatry. 2000;47(10):891-901.

14. Morgan CA 3rd, Rasmusson Am, Wang S, Hoyt G, Hauger RL, Hazlett G. Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol Psychiatry. 2002;52(2):136-142.

15. Charney DS. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry. 2004;161(2):195-216.