Biomarkers for complex post-traumatic stress disorder: translational and evolutionary perspectives

Summary

Complex PTSD (C-PTSD) is a chronic mental condition resulting from prolonged traumatic stress, characterized by the typical PTSD symptoms plus disturbances in mood, identity, and interpersonal relationships. It affects about 2-8% of the global population, with higher prevalence in vulnerable groups like refugees and childhood abuse survivors. Current treatments improve some PTSD symptoms but are ineffective for the additional C-PTSD symptoms. Understanding the neurobiology of C-PTSD is essential for developing better treatment options.

Study at a glance

Abstract

Post-traumatic stress disorder (PTSD) is a chronic mental illness that occurs following exposure to traumatic stressors such as combat, disasters, or assault. It is characterized by a triad of reexperiencing of the trauma, avoidance of triggers for such recollections, and increased vigilance towards threats (1). In 1992, Judith Herman described a variant of PTSD that occurred in persons who had undergone prolonged or repeated traumatic stress, such as hostages, prisoners of war, concentration camp survivors, or victims of chronic familial abuse or violence. Apart from the classical "triad" seen in PTSD, these patients experienced somatic, dissociative, and mood symptoms, alterations in identity, and disturbed interpersonal relationships. She proposed the term "complex PTSD" to describe such cases (2).A syndrome akin to "complex PTSD" was proposed for inclusion in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) under the name "Disorders of extreme stress, not otherwise specified" (DES-NOS). The alterations in mood, identity and relationships described by Herman were also included in the tenth edition of the World Health Organization (WHO)'s International Classification of Diseases and Disorders (ICD-10) with the label "Enduring personality change after catastrophic experience (F62.0)." However, DES-NOS was not included in the final version of DSM-IV, and ICD-10 category F62.0 was rarely used in practice (3). Based on research over the next two decades, the concept of complex PTSD was refined and validated in diverse settings. Complex PTSD (C-PTSD) was redefined as a syndrome consisting of both the PTSD triad, and a second triad of disturbances in self-organization (DSO), characterized by disturbances of mood (numbing or increased reactivity), difficulties in interpersonal relationships, and a negative self-image. Such symptoms were defined as occurring in the context of complex trauma -that is, trauma which is repeated or prolonged. This definition of complex PTSD has been included in the most recent WHO classification of mental disorders (ICD-11). It is estimated that about 2-8% of the world's population suffers from C-PTSD, with much higher rates observed in vulnerable groups such as refugees and survivors of childhood abuse (4)(5)(6).Optimal treatment strategies for C-PTSD are still in development. Pharmacological treatments for PTSD may improve symptoms in the PTSD triad, but do not have proven benefits for DSO. Trauma-focused psychotherapies improve PTSD triad symptoms, depression, anxiety, and insomnia, but their effect on overall quality of life -a measure of DSO -is low (7). There are also significant variations in efficacy between psychotherapies based on different theoretical models and techniques (8). Novel therapies such ketamine and psilocybin have been suggested as alternatives, but though they have some benefits in PTSD, their efficacy in C-PTSD has not been evaluated (9,10). The development of more effective treatments for this chronic and disabling condition would require a better understanding of the neurobiology of C-PTSD, particularly in relation to symptoms of DSO, which do not appear responsive to currently available treatments (11).The past four years have seen remarkable advances in our understanding of the pathophysiology of PTSD. Initial work focused on dysregulation of monoamine neurotransmitters such as serotonin (5-HT, and on altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis (12). It is now known that a host of complex physiological and biological alterations occur in PTSD, including alterations in glutamatergic and peptidergic transmission, increased oxidative stress, immuneinflammatory dysregulation, and accelerated cellular aging. These changes appear to arise from an interaction between genetic variants influencing these pathways, "sensitizing" experiences such as childhood adversity, and exposure to one or more traumatic stressors (5,13,14). These far-reaching systemic changes explain the strong associations between PTSD and other medical and neurological disorders (15).Relatively less is known about the biological substrates of C-PTSD. It can be assumed that the "classical" symptoms of PTSD seen in these patients have the same putative origin as those of noncomplex PTSD, and many early studies on the biology of PTSD included patients with undiagnosed C-PTSD, such as veterans or refugees. In contrast, little is known about the neural or biochemical bases for DSO (16). Experts in the field agree that comprehensive research is warranted, and certain important initiatives, such as a biobank aimed at comparing PTSD and C-PTSD, have already been launched (17).Dissociative symptoms, characterized by disturbances in identity or in the integration of psychological functions, are commonly seen in C-PTSD, and may be correlated with DSO. A candidate gene study found an association between dissociative symptoms in PTSD and the FKBP5 gene, involved in regulating glucocorticoid receptor responsiveness to stress, but none of the patients in this study was specifically evaluated for C-PTSD (18). More promisingly, a genome-wide association study (GWAS) found possible associations between "dissociative PTSD" -a condition similar to C-PTSD -and the genes encoding adenylyl cyclase 8 (ADCY8) and dipeptidyl-peptidase 6 (DPP6). The former gene has been associated with fear-based memories and synaptic plasticity, while the latter is linked to synaptic integrity. Variants in these genes may confer vulnerability to C-PTSD, but this hypothesis requires formal verification (19).Potential biomarkers of PTSD, prior to the inclusion of C-PTSD in psychiatric nosology, have been studied extensively. Structural and functional imaging has revealed altered functioning of the brain's default mode, salience, and central executive networks in patients with PTSD (20). Studies of peripheral blood markers have found consistent evidence of low baseline cortisol, elevated levels of pro-inflammatory cytokines such as interleukin-1 and tumor necrosis factor alpha, reduced antioxidant activity, and elevated indices of the metabolic syndrome (21,22). More recently, At first sight, it may seem difficult, if not impossible, for an animal model to replicate the features of PTSD, particularly those of the DSO domain, which require high levels of conscious awareness and cognition (37). Nevertheless, evidence of a C-PTSD-like phenotype has been observed in several mammalian species, including rodents, equines, and primates. In these species, prolonged or repeated trauma has been associated with impairments in emotional responses and social behavior which resemble two of the three domains of DSO (38)(39)(40)(41). For example, in prairie voles, which exhibit monogamous behavior similar to that seen in humans in the wild, prolonged stress led to impaired pair bonding with female partners, and "indiscriminate huddling" with other female voles (41). Such animals also exhibit features of PTSD such as increased vigilance and exaggerated startle responses. These changes have been associated with a wide range of chronic trauma exposures, including experimental repeated stress, captivity, forced work, or maltreatment by humans (39,40).Based on these results, rodent studies have been carried out to examine the physiological and biochemical correlates of exposure to chronic or recurrent trauma. Experimental stressors used to induce a "C-PTSD-like" phenotype in these animals include predator scent stress (PSS), stressrestress, and combinations of more than one type of stressor. Peripherally, chronic traumatic stress is associated with reduced serum and adrenal cortisol and altered adrenocortical histology, which correlates with levels of observed anxiety (42). Centrally, exposure to recurrent traumatic stress has been associated with increased cerebellar noradrenaline levels, reduced levels of dopamine in the brainstem, hypothalamus and hippocampus, and increased hypothalamic corticotrophin-releasing hormone (CRH) (43,44). In addition, chronic trauma appears to be associated with increased expression of the neuropeptide vasopressin (AVP) in the paraventricular nucleus (PVN) of the hypothalamus, and more specifically in the magnocellular portion of the PVN (44)(45)(46). Such trauma is also associated with reduced oxytocin expression in the nearby supraoptic nucleus (SON), which correlates with impaired pair-bonding behavior (41). While alterations in monoamine transmitters and HPA axis hormones have been observed in non-complex PTSD, alterations in AVP and oxytocin may be particularly relevant to C-PTSD, as they may represent an evolutionary "bridge" between animal and human phenotypes of this condition.As C-PTSD is often linked to childhood abuse or neglect, animal models of childhood adversity, may also be used to approximate this disorder in mammals. Rats exposed to early maternal separation show evidence of increased fear conditioning and impaired social behavior, which are consistent with the two dimensions of C-PTSD. These changes are associated with blunted vasopressin release, reduced expression of the neurotensin 1 receptor, and overexpression of the chloride channel NKCC1 (47-50). Moreover, these changes may be reversible through the administration of oxytocin (49, 50). These results are broadly consistent with those seen in animals with other forms of chronic trauma. Nevertheless, these findings should be interpreted with caution, because early childhood adversity is associated with a wide range of psychiatric disorders besides C-PTSD (47).Viewed at a surface level, the behaviors exhibited by persons with C-PTSD seem grossly maladaptive. For example, why do many of those affected by this disorder avoid help-seeking, idealize their abusers (the so-called "Stockholm syndrome"), or enter subsequent relationships where there is a high risk of experiencing abuse? (2, 51) Such paradoxical phenomena may be explicable in terms of the appeasement displays seen in animals, which lead to a "conditional reconciliation" between aggressor and victim and ensure individual survival and well-being. For example, in a fight between male chimpanzees, appeasement of the defeated or "subordinate" male protects it against death or mutilation, and ensures its survival in the larger group. In situations characterized by traumatic "entrapment," where the victim cannot easily "escape" from the abuser, similar behaviors may become established in humans and dominate over more "adaptive" strategies such as seeking help outside the immediate social circle. Such situations include intimate partner violence (IPV) and childhood physical and sexual abuse, both of which are strongly associated with C-PTSD. In the words of Cantor and Price (2007), "appeasement is the most likely endophenotype for complex PTSD." (52) The exact forms that these appeasement displays may take depend on interactions between evolutionarily primitive (hypothalamic and brain stem) brain structures that mediate a general, undifferentiated appeasement response, and more recently evolved (limbic and cortical) structures that modify its expression and lead to a disturbance of self-concept (52, 53). Such a model is attractive because it provides a plausible explanation for the DSO dimension of C-PTSD: many aspects of this dimension, such as shame, dissociative symptoms, and submissiveness towards aggressors, can be understood as variations of appeasement (54).If the above hypothesis is true, then biological alterations associated with appeasement or subordinate status in animals may be implicated in the pathogenesis of C-PTSD, and even serve as biomarkers. In this context, it is helpful to briefly review what is known about the biological correlates of these behaviors. In mammals exhibiting cooperative behavior, acute defeat in a conflict is associated with increased cortisol, whereas a more stable subordinate status is associated with lower levels of cortisol than those seen in dominant animals (55). Similar changes have been observed in male capuchin monkeys, where dominant males had elevated levels of testosterone and cortisol compared to subordinates (56). In female rhesus monkeys, appeasement behavior is inversely correlated with 5-HT1A binding potential in the OFC, and a functional polymorphism (short or s variant) of the 5-HT transporter gene SLC6A4 was linked to a decrease in appeasement behavior with age (57).Neural correlates of subordinate social status have also been studied in non-mammalian species. In the cichlid fish species Neolamprologus pulcher, subordinate fish had higher levels of arginine vasotocin, the analogue of AVP. In addition, levels of isotocin, the analogue of oxytocin, were negatively correlated with affiliative social behavior (58). In the electric fish Gymnotus omarorum, alterations in hypothalamic vasotocin are also associated with the establishment of dominantsubordinate social hierarchies (59). These findings are consistent with research in rodents, which have also found associations between AVP and oxytocin receptor densities in the limbic system and hypothalamus and social dominant / subordinate status (60,61).A tentative synthesis of these findings is that C-PTSD-like phenotypes in animals, whether in the wild or in experimental settings, are associated with alterations in serotonergic transmission, HPA axis function, and dysregulation of the similar neuropeptide transmitters oxytocin and AVP. The latter two are particularly significant because they play a central role in social behavior in both animal humans, including affiliation, social bonding, and appeasement and submission displays (62,63). Alterations in these peptide transmitters are likely to be associated with the DSO symptoms that are specific to C-PTSD, and more particularly with disturbances in interpersonal and social relationships (41). Such alterations may reflect a dysregulation in evolutionarily ancient neurochemical processes mediating submission and appeasement displays, triggered by exposure to prolonged trauma in an interpersonal setting (51).If C-PTSD reflects a dysregulated or morbid form of appeasement behavior, does this arise from chronic trauma, from antecedent vulnerability factors, or from both? Research on the epidemiology of C-PTSD has shown that it is more prevalent in those who occupy a "subordinate" position in human social hierarchies -women, migrants, persons abandoned by their parents in childhood, and those with a lower socioeconomic or educational status (64)(65)(66). Animal studies of early maternal separation also show evidence of altered neuropeptide signaling and deficits in social behavior, even if they do not exhibit features of PTSD (47, 50). Together, these findings suggest that C-PTSD may result from the superimposition of PTSD on a prior state of deficits in social organization, which result from psychosocial disadvantage and are further exacerbated with the onset of PTSD symptoms. This hypothesis is entirely consistent with the available evidence, but it requires verification through the assessment of DSO symptoms -and their biological correlates -in children and adults belonging to "subordinate" social groups, both with and without C-PTSD (52, 64).A tentative synthesis of animal and human research into C-PTSD, indicating possible points of converge and their "deep" evolutionary roots, is presented in Figure 1. In this model, complex trauma activates both the mechanisms responsible for PTSD symptoms, and a behavioral system involved in appeasement and submission displays in the face of threats to one's survival. The latter system may have been sensitized by prior psychosocial adversity or disadvantage. Dysregulation of this system leads to the DSO symptoms that characterize C-PTSD. Such dysregulation may involve altered expression of the genes identified in human research on C-PTSD. For example, the HAP1 gene codes for huntingtin-associated protein 1, which helps maintain the integrity and connectivity of 5-HT neurons (67). Altered expression of this protein may alter serotonergic transmission, leading to dysfunctional appeasement behavior.(Insert Figure 1 here.)The conclusions advanced above are tentative, and need to be verified in human subjects. Research on alterations in oxytocin and AVP in patients with PTSD have yielded mixed results, but none of these studies have specifically examined C-PTSD: most of these were conducted in veterans with acute trauma related to combat situations (68)(69)(70)(71)(72). Genetic variants in oxytocin and vasopressin receptors (OXTR and AVP1a) appear interact with mother-child attachment to influence vulnerability to PTSD in children exposed to an armed conflict. Such a finding may be of relevance to the genesis of C-PTSD, which often occurs in relation to parental neglect and abuse (73).The above model also has implications for effective treatment of the DSO symptom domain in C-PTSD. Clinical trials of agents acting at AVP or oxytocin receptors in PTSD have also yielded conflicting but suggestive findings. A controlled clinical found that an of the receptor, not from in PTSD symptoms, but this study not include with C-PTSD the other administration of a of AVP to persons with PTSD led to increased responsiveness their or partner This that AVP social behavior in this population trials of oxytocin in PTSD have found that this may improve social cognition and It is plausible that AVP or oxytocin, or their may the interpersonal deficits seen in C-PTSD, though this to be animal models have identified a possible interaction between 5-HT and these in studies of social of the serotonin appears to the social deficits by prolonged stress and social status is associated with altered 5-HT1A receptor in the and hypothalamus are treatments for PTSD, and improve social functioning over a of two though less than psychological A patients with PTSD by trauma in an interpersonal setting physical or sexual abuse in childhood or found that the was to this result is significant because C-PTSD commonly results from interpersonal trauma More recently, which 5-HT release, as an at and 5-HT has been found to improve DSO symptoms such as impaired and mood used as an to in PTSD In has on social behavior and oxytocin and vasopressin This may represent a potential in the of C-PTSD, but it is a controlled with a high potential for and a It may be possible to these by of as they in their serotonin and oxytocin release, while at receptors and has from these research in an animal model of C-PTSD has found that leads to In humans, is used to depression, though it has also helpful in PTSD to treatments The benefits of in PTSD appear to with changes in glutamatergic but has on including serotonin and oxytocin to it is possible that C-PTSD may to where other treatments have In animal model of C-PTSD, the of an experimental of receptor 1 the of behavioral following predator This was associated with reduced levels of 5-HT in the and dopamine in the of may represent a for of 5-HT alterations in patients with findings above are also relevant to the psychosocial treatment of C-PTSD. DSO symptoms are a biological reflect trauma and psychosocial psychological should not on the traumatic but on social and and In childhood neglect is associated with both and C-PTSD, which can to DSO. Animal research has shown that can the of early maternal and this may be a for C-PTSD in In similar benefits may be through social and the affected social particularly in persons belonging to More recently, it has been suggested that C-PTSD may to that in and personality development. This known as has been a wide range of traumatic including and evidence that on through the of social and the of and may improve in those from C-PTSD is known about the biological correlates of though it has been that oxytocin can this be in the research into the biological of C-PTSD is still in its early and the conclusions above are likely to change as further it is not the findings in humans with C-PTSD can be with the biochemical changes observed in animal models of this studies of C-PTSD in humans involve significant both in terms of definition and of the type of complex trauma the of animal models of C-PTSD has not been established particularly with to DSO symptoms. the between appeasement or submission displays in animals and C-PTSD in humans, though consistent with the available evidence, a more is about both the biology these this hypothesis may be or advances may help in some of these research has the of models in in patients with PTSD. this work is still in its early such models have been found in PTSD based on clinical and biochemical and in genes related to immuneinflammatory in PTSD Such may be in to in clinical and from patients with C-PTSD, with a specific on indices of peptidergic and serotonergic transmission, and PTSD is a of significant and and is often to in clinical from recent animal research that the symptoms to this condition are related to alterations in oxytocin, and the of evolutionary these changes can be linked to evolved behavioral involved in appeasement and submission displays that ensure survival a social is with a from or this model requires further it as a of dysregulation of these transmitters and their receptors in patients with C-PTSD, which serve as biomarkers of this condition or its symptom evidence from human research that and strategies can have on these the disturbances of self-organization that are of C-PTSD. Such should not be in a work as of a treatment that therapies and to ensure the and overall and and PTSD

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