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Postulating Traumatic Stress Disorders
Commentary
Biological Psychiatry
Postulating Traumatic Stress Disorders Murray B. Stein This special issue of Biological Psychiatry, “Understanding PTSD: From Mind to Molecules,” is focused on neurobiological studies that inform our scientific approach to posttraumatic stress disorder (PTSD). By virtue of the requirement that a lifethreatening stressor precede its onset, PTSD is distinguished from other mental disorders. Although mental health clinicians and researchers acknowledge the contributions (and presumably very complex interactions) of psychological, social, and biological factors in the generation of virtually all mental disorders, only PTSD (and the other trauma and stressorrelated disorders with it shares a chapter in DSM-5) has exposure to a traumatic stressor or stressors as a mandatory antecedent. In other words, PTSD is the quintessential biopsychosocially determined disorder; as such, it demands the efforts of a diverse and eclectic set of researchers and experimental methods to understand its etiology and consider novel approaches to its treatment. Such is the spirit of this special issue, where we have brought together a multitalented group of basic and translational researchers to share their insights into the nature of PTSD and its potential prevention and management. The time frame of inquiry begins very early in development, with Rodgers and Bale (1) describing an intriguing body of preclinical work positing the transgenerational transmission of stress through male germ cells; this work has been echoed in clinical studies demonstrating not only an increase in PTSD among adult offspring of survivors of extreme trauma (i.e., the Holocaust) but also a possible epigenetic reflection of that increased risk in glucocorticoid-relevant genes or their promoters (2). Bock et al. (3) review and insightfully integrate a body of animal and human literature that emphasizes possible molecular bases for prenatal stress exposures adversely affecting emotional and cognitive development of the brain. Zannas et al. (4) provide a comprehensive review of epigenetic studies relevant to PTSD and in so doing forge a path for future research in this area, highlighting opportunities and challenges that lie ahead. Together, these articles paint a picture of the brains of certain individuals being primed in utero to experience stressful life experiences differently than others. How can we begin to tie together these observations with findings of specific genetic vulnerabilities for PTSD that may operate through altering stress responsiveness (e.g., FKBP5 and allele-specific demethylation in association with childhood trauma exposure (5))? What is the physiologic and molecular nature of this altered brain response to stress? There is evidence that exposure of the hippocampus to glucocorticoids after stress results in a PTSD-like set of memory impairments that includes the inability to restrict fear to the appropriate context (i.e., there is an overgeneralization of the fear response (6)). Could it be that the hippocampus of individuals at risk for PTSD is exposed to functionally elevated levels of
glucocorticoids after trauma? If so, what is the effect of this exposure on learning and memory in individuals at risk for PTSD? Two articles in this issue, although not specifically pointing to stress hormones as the culprit, highlight the centrality of deficits in learning and memory to the expression of PTSD. Desmedt et al. (7) argue that PTSD may involve hypermnesia for certain aspects of the trauma but amnesia (or altered remembering) for contextual elements. They posit that this state of contextual amnesia is key to maintenance of the disorder and that this pathologic memory state may be explained by abnormal hippocampal-amygdalar interactions. Dunsmoor and Paz (8) review mechanisms by which altered conditioning might model many of the observed clinical features of PTSD, including poor fear inhibition and extinction and increased generalization. These alterations in fear learning and extinction are not unique to PTSD, as many of these same abnormalities are also seen in other anxiety-related disorders (9). However, recent research conducted in a large U.S. Marine sample suggests that some psychophysiologic features (e.g., poor safety signal discrimination) may be more strongly associated with PTSD than with other anxiety or depressive syndromes (10), raising hopes that relatively specific biosignatures of PTSD may be found. To this end, Michopoulos et al. (11) provide a state-of-theart review of the search for biomarkers for PTSD. Among these, the emphasis being placed on proinflammatory markers in PTSD is especially noteworthy (12,13); however, for every question about etiopathology this perspective answers, it raises two more about cause and effect (14). Larger, longitudinal studies are needed to help us discern “inflamed chicken” from “inflamed egg.” The search for genetic markers or predictors of PTSD is well underway, aided by the remarkable coming together of multiple research groups under the auspices of the Psychiatric Genomics Consortium to harness the needed sample sizes and standardized approaches to data analysis (15). When it comes to biomarkers for PTSD, we are not there yet, but a willingness to explore phenotypic definitions that do not slavishly adhere to DSM-5, but rather model more translationally tractable domains of the response to trauma (e.g., trauma-related loss vs. trauma-related threat) (16), will move us closer to that goal. However, none of this work will matter if we do not develop better tools to interrupt the development of PTSD after trauma exposure or hasten recovery once the disorder has taken hold. Dejean et al. (17) provide a masterful overview of the nittygritty of the cells and systems that underlie the expression and recovery from fear and how the advent of optogenetic techniques has enabled this level of understanding. They go on to describe novel neuroscience-informed approaches to PTSD treatment that could be investigated. For example, they hypothesize that brain stimulation techniques for PTSD, such as repetitive transcranial magnetic stimulation, could be more
SEE COMMENTARY ON PAGE 288
Published by Elsevier Inc on behalf of Society of Biological Psychiatry Biological Psychiatry September 1, 2015; 78:288–289 www.sobp.org/journal
http://dx.doi.org/10.1016/j.biopsych.2015.06.018 ISSN: 0006-3223
Biological Psychiatry
Commentary
selectively applied not only to specific regions but possibly also to specific classes of neurons, enhancing their impact. The contributions of Dejean et al. to this issue are complemented by the authoritative and forward-looking glimpse into translationally inspired treatments—“drugs and devices”—for PTSD by Bowers and Ressler (18). Included in their review is the important, and heretofore largely neglected, opportunity to study medications for secondary prevention of PTSD in persons at high risk after trauma exposure. Together, these articles should whet our appetites for larger randomized controlled trials—and more of them—to test these promising, biological target–oriented therapies and establish a role for them in the therapeutic armamentarium against PTSD.
Acknowledgments and Disclosures
6.
7.
8. 9.
10.
11.
MBS has received consulting fees from Janssen Pharmaceutica, Tonix Pharmaceuticals, and Pfizer Inc in the past 2 years. 12.
Article Information From the Anxiety and Traumatic Stress Disorders Program, University of California San Diego; and the Veterans Administration San Diego Healthcare System, La Jolla, California. Address correspondence to Murray B. Stein, M.D., M.P.H., Anxiety and Traumatic Stress Disorders, University of California San Diego, Mailcode 0855, 9500 Gilman Drive, La Jolla, CA 92093-0855; E-mail: mstein@ucsd. edu. Received Jun 22, 2015; accepted Jun 23, 2015.
2.
3.
4.
5.
14.
15.
References 1.
13.
Rodgers AB, Bale TL (2015): Germ cell origins of posttraumatic stress disorder risk: The transgenerational impact of parental stress experience. Biol Psychiatry 78:307–314. Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, et al. (2014): Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 171:872–880. Bock J, Wainstock T, Braun K, Segal M (2015): Stress in utero: Prenatal programming of brain plasticity and cognition. Biol Psychiatry 78:315–326. Zannas AS, Provençal N, Binder EB (2015): Epigenetics of posttraumatic stress disorder: Current evidence, challenges, and future directions. Biol Psychiatry 78:327–335. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Provençal CM, et al. (2013): Allele-specific FKBP5 DNA demethylation
16.
17.
18.
mediates gene-childhood trauma interactions. Nat Neurosci 16: 33–41. Kaouane N, Porte Y, Vallee M, Brayda-Bruno L, Mons N, Calandreau L, et al. (2012): Glucocorticoids can induce PTSD-like memory impairments in mice. Science 335:1510–1513. Desmedt A, Marighetto A, Piazza P-V (2015): Abnormal fear memory as a model for posttraumatic stress disorder. Biol Psychiatry 78: 290–297. Dunsmoor JE, Paz R (2015): Fear generalization and anxiety: Behavioral and neural mechanisms. Biol Psychiatry 78:336–343. Duits P, Cath DC, Lissek S, Hox JJ, Hamm AO, Engelhard IM, et al. (2015): Updated meta-analysis of classical fear conditioning in the anxiety disorders. Depress Anxiety 32:239–253. Acheson DT, Geyer MA, Baker DG, Nievergelt CM, Yurgil K, Risbrough VB, et al. (2015): Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines. Psychoneuroendocrinology 51:495–505. Michopoulos V, Norrholm SD, Jovanovic T (2015): Diagnostic biomarkers for posttraumatic stress disorder: Promising horizons from translational neuroscience research. Biol Psychiatry 78:344–353. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. (2014): Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 71:9. Michopoulos V, Rothbaum AO, Jovanovic T, Almli LM, Bradley B, Rothbaum BO, et al. (2015): Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. Am J Psychiatry 172:353–362. Segman RH, Stein MB (2015): C-reactive protein: A stress diathesis marker at the crossroads of maladaptive behavioral and cardiometabolic sequelae. Am J Psychiatry 172:307–309. Logue MW, Amstadter AB, Baker DG, Duncan L, Koenen KC, Liberzon I, et al. (2015): The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic stress disorder enters the age of large-scale genomic collaboration [published online ahead of print Apr 23]. Neuropsychopharmacology. Pietrzak RH, Naganawa M, Huang Y, Corsi-Travali S, Zheng MQ, Stein MB, et al. (2014): Association of in vivo kappa-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology. JAMA Psychiatry 71:1262–1270. Dejean C, Courtin J, Rozeske RR, Bonnet MC, Dousset V, Michelet T, Herry C (2015): Neuronal circuits for fear expression and recovery: Recent advances and potential therapeutic strategies. Biol Psychiatry 78:298–306. Bowers ME, Ressler KJ (2015): An overview of translationally informed treatments for posttraumatic stress disorder: Animal models of Pavlovian fear conditioning to human clinical trials. Biol Psychiatry 78: e15–e27.
Biological Psychiatry September 1, 2015; 78:288–289 www.sobp.org/journal
289
Biological Psychiatry
Postulating Traumatic Stress Disorders Murray B. Stein This special issue of Biological Psychiatry, “Understanding PTSD: From Mind to Molecules,” is focused on neurobiological studies that inform our scientific approach to posttraumatic stress disorder (PTSD). By virtue of the requirement that a lifethreatening stressor precede its onset, PTSD is distinguished from other mental disorders. Although mental health clinicians and researchers acknowledge the contributions (and presumably very complex interactions) of psychological, social, and biological factors in the generation of virtually all mental disorders, only PTSD (and the other trauma and stressorrelated disorders with it shares a chapter in DSM-5) has exposure to a traumatic stressor or stressors as a mandatory antecedent. In other words, PTSD is the quintessential biopsychosocially determined disorder; as such, it demands the efforts of a diverse and eclectic set of researchers and experimental methods to understand its etiology and consider novel approaches to its treatment. Such is the spirit of this special issue, where we have brought together a multitalented group of basic and translational researchers to share their insights into the nature of PTSD and its potential prevention and management. The time frame of inquiry begins very early in development, with Rodgers and Bale (1) describing an intriguing body of preclinical work positing the transgenerational transmission of stress through male germ cells; this work has been echoed in clinical studies demonstrating not only an increase in PTSD among adult offspring of survivors of extreme trauma (i.e., the Holocaust) but also a possible epigenetic reflection of that increased risk in glucocorticoid-relevant genes or their promoters (2). Bock et al. (3) review and insightfully integrate a body of animal and human literature that emphasizes possible molecular bases for prenatal stress exposures adversely affecting emotional and cognitive development of the brain. Zannas et al. (4) provide a comprehensive review of epigenetic studies relevant to PTSD and in so doing forge a path for future research in this area, highlighting opportunities and challenges that lie ahead. Together, these articles paint a picture of the brains of certain individuals being primed in utero to experience stressful life experiences differently than others. How can we begin to tie together these observations with findings of specific genetic vulnerabilities for PTSD that may operate through altering stress responsiveness (e.g., FKBP5 and allele-specific demethylation in association with childhood trauma exposure (5))? What is the physiologic and molecular nature of this altered brain response to stress? There is evidence that exposure of the hippocampus to glucocorticoids after stress results in a PTSD-like set of memory impairments that includes the inability to restrict fear to the appropriate context (i.e., there is an overgeneralization of the fear response (6)). Could it be that the hippocampus of individuals at risk for PTSD is exposed to functionally elevated levels of
glucocorticoids after trauma? If so, what is the effect of this exposure on learning and memory in individuals at risk for PTSD? Two articles in this issue, although not specifically pointing to stress hormones as the culprit, highlight the centrality of deficits in learning and memory to the expression of PTSD. Desmedt et al. (7) argue that PTSD may involve hypermnesia for certain aspects of the trauma but amnesia (or altered remembering) for contextual elements. They posit that this state of contextual amnesia is key to maintenance of the disorder and that this pathologic memory state may be explained by abnormal hippocampal-amygdalar interactions. Dunsmoor and Paz (8) review mechanisms by which altered conditioning might model many of the observed clinical features of PTSD, including poor fear inhibition and extinction and increased generalization. These alterations in fear learning and extinction are not unique to PTSD, as many of these same abnormalities are also seen in other anxiety-related disorders (9). However, recent research conducted in a large U.S. Marine sample suggests that some psychophysiologic features (e.g., poor safety signal discrimination) may be more strongly associated with PTSD than with other anxiety or depressive syndromes (10), raising hopes that relatively specific biosignatures of PTSD may be found. To this end, Michopoulos et al. (11) provide a state-of-theart review of the search for biomarkers for PTSD. Among these, the emphasis being placed on proinflammatory markers in PTSD is especially noteworthy (12,13); however, for every question about etiopathology this perspective answers, it raises two more about cause and effect (14). Larger, longitudinal studies are needed to help us discern “inflamed chicken” from “inflamed egg.” The search for genetic markers or predictors of PTSD is well underway, aided by the remarkable coming together of multiple research groups under the auspices of the Psychiatric Genomics Consortium to harness the needed sample sizes and standardized approaches to data analysis (15). When it comes to biomarkers for PTSD, we are not there yet, but a willingness to explore phenotypic definitions that do not slavishly adhere to DSM-5, but rather model more translationally tractable domains of the response to trauma (e.g., trauma-related loss vs. trauma-related threat) (16), will move us closer to that goal. However, none of this work will matter if we do not develop better tools to interrupt the development of PTSD after trauma exposure or hasten recovery once the disorder has taken hold. Dejean et al. (17) provide a masterful overview of the nittygritty of the cells and systems that underlie the expression and recovery from fear and how the advent of optogenetic techniques has enabled this level of understanding. They go on to describe novel neuroscience-informed approaches to PTSD treatment that could be investigated. For example, they hypothesize that brain stimulation techniques for PTSD, such as repetitive transcranial magnetic stimulation, could be more
SEE COMMENTARY ON PAGE 288
Published by Elsevier Inc on behalf of Society of Biological Psychiatry Biological Psychiatry September 1, 2015; 78:288–289 www.sobp.org/journal
http://dx.doi.org/10.1016/j.biopsych.2015.06.018 ISSN: 0006-3223
Biological Psychiatry
Commentary
selectively applied not only to specific regions but possibly also to specific classes of neurons, enhancing their impact. The contributions of Dejean et al. to this issue are complemented by the authoritative and forward-looking glimpse into translationally inspired treatments—“drugs and devices”—for PTSD by Bowers and Ressler (18). Included in their review is the important, and heretofore largely neglected, opportunity to study medications for secondary prevention of PTSD in persons at high risk after trauma exposure. Together, these articles should whet our appetites for larger randomized controlled trials—and more of them—to test these promising, biological target–oriented therapies and establish a role for them in the therapeutic armamentarium against PTSD.
Acknowledgments and Disclosures
6.
7.
8. 9.
10.
11.
MBS has received consulting fees from Janssen Pharmaceutica, Tonix Pharmaceuticals, and Pfizer Inc in the past 2 years. 12.
Article Information From the Anxiety and Traumatic Stress Disorders Program, University of California San Diego; and the Veterans Administration San Diego Healthcare System, La Jolla, California. Address correspondence to Murray B. Stein, M.D., M.P.H., Anxiety and Traumatic Stress Disorders, University of California San Diego, Mailcode 0855, 9500 Gilman Drive, La Jolla, CA 92093-0855; E-mail: mstein@ucsd. edu. Received Jun 22, 2015; accepted Jun 23, 2015.
2.
3.
4.
5.
14.
15.
References 1.
13.
Rodgers AB, Bale TL (2015): Germ cell origins of posttraumatic stress disorder risk: The transgenerational impact of parental stress experience. Biol Psychiatry 78:307–314. Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, et al. (2014): Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 171:872–880. Bock J, Wainstock T, Braun K, Segal M (2015): Stress in utero: Prenatal programming of brain plasticity and cognition. Biol Psychiatry 78:315–326. Zannas AS, Provençal N, Binder EB (2015): Epigenetics of posttraumatic stress disorder: Current evidence, challenges, and future directions. Biol Psychiatry 78:327–335. Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Provençal CM, et al. (2013): Allele-specific FKBP5 DNA demethylation
16.
17.
18.
mediates gene-childhood trauma interactions. Nat Neurosci 16: 33–41. Kaouane N, Porte Y, Vallee M, Brayda-Bruno L, Mons N, Calandreau L, et al. (2012): Glucocorticoids can induce PTSD-like memory impairments in mice. Science 335:1510–1513. Desmedt A, Marighetto A, Piazza P-V (2015): Abnormal fear memory as a model for posttraumatic stress disorder. Biol Psychiatry 78: 290–297. Dunsmoor JE, Paz R (2015): Fear generalization and anxiety: Behavioral and neural mechanisms. Biol Psychiatry 78:336–343. Duits P, Cath DC, Lissek S, Hox JJ, Hamm AO, Engelhard IM, et al. (2015): Updated meta-analysis of classical fear conditioning in the anxiety disorders. Depress Anxiety 32:239–253. Acheson DT, Geyer MA, Baker DG, Nievergelt CM, Yurgil K, Risbrough VB, et al. (2015): Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines. Psychoneuroendocrinology 51:495–505. Michopoulos V, Norrholm SD, Jovanovic T (2015): Diagnostic biomarkers for posttraumatic stress disorder: Promising horizons from translational neuroscience research. Biol Psychiatry 78:344–353. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. (2014): Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 71:9. Michopoulos V, Rothbaum AO, Jovanovic T, Almli LM, Bradley B, Rothbaum BO, et al. (2015): Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. Am J Psychiatry 172:353–362. Segman RH, Stein MB (2015): C-reactive protein: A stress diathesis marker at the crossroads of maladaptive behavioral and cardiometabolic sequelae. Am J Psychiatry 172:307–309. Logue MW, Amstadter AB, Baker DG, Duncan L, Koenen KC, Liberzon I, et al. (2015): The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic stress disorder enters the age of large-scale genomic collaboration [published online ahead of print Apr 23]. Neuropsychopharmacology. Pietrzak RH, Naganawa M, Huang Y, Corsi-Travali S, Zheng MQ, Stein MB, et al. (2014): Association of in vivo kappa-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology. JAMA Psychiatry 71:1262–1270. Dejean C, Courtin J, Rozeske RR, Bonnet MC, Dousset V, Michelet T, Herry C (2015): Neuronal circuits for fear expression and recovery: Recent advances and potential therapeutic strategies. Biol Psychiatry 78:298–306. Bowers ME, Ressler KJ (2015): An overview of translationally informed treatments for posttraumatic stress disorder: Animal models of Pavlovian fear conditioning to human clinical trials. Biol Psychiatry 78: e15–e27.
Biological Psychiatry September 1, 2015; 78:288–289 www.sobp.org/journal
289