Preclinical Perspectives on Posttraumatic Stress Disorder Criteria in DSM-5

Abstract

Posttraumatic stress disorder (PTSD) now sits within the newly created “Trauma- and Stressor-Related Disorders” section of the Diagnostic and Statistical Manual of Mental Disorders (fifth edition; DSM-5). Through the refinement and expansion of diagnostic criteria, the DSM-5 version better clarifies the broad and pervasive effects of trauma on functioning, as well as the impact of development on trauma reactions. Aggressive and dissociative symptoms are more thoroughly characterized, reflecting increasing evidence that reactions to trauma often reach beyond the domains of fear and anxiety (these latter domains were emphasized in DSM-IV). These revised criteria are supported by decades of preclinical and clinical research quantifying traumatic stress–induced changes in neurobiological and behavioral function. Several features of the DSM-5 PTSD criteria are similarly and consistently represented in preclinical animal models and humans following exposure to extreme stress. In rodent models, for example, increases in anxiety-like, helplessness, or aggressive behavior, along with disruptions in circadian/neurovegetative function, are typically induced by severe, inescapable, and uncontrollable stress. These abnormalities are prominent features of PTSD and can help us in understanding the pathophysiology of this and other stress-associated psychiatric disorders. In this article we examine some of the changes to the diagnostic criteria of PTSD in the context of trauma-related neurobiological dysfunction, and discuss implications for how preclinical data can be useful in current and future clinical conceptualizations of trauma and trauma-related psychiatric disorders.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes important changes to the diagnostic criteria for posttraumatic stress disorder (PTSD). Although many of the symptoms remain consistent with DSM-IV-TR, the disorder has been moved to a new section entitled “Trauma- and Stressor-Related Disorders,” and the changes to the diagnostic criteria and their descriptions have expanded the section from just over one page to four pages. Much of the additional information is included under a subsection, “Posttraumatic Stress Disorder for Children 6 Years and Younger,” reflecting the greater attention to developmental differences in the manifestation of trauma symptomatology. Other key changes include: (1) removal of the requirement that the individual responded with fear, helplessness, or horror at the time of the trauma, (2) renaming the “re-experiencing” cluster symptoms as “intrusion” symptoms, (3) separating “avoidance” and “numbing” symptoms into two separate clusters, (4) subsuming “numbing” symptoms under a newly developed symptom cluster, “negative alterations in cognitions and mood,” (5) elaborating upon the “irritability or outbursts of anger” symptom to highlight the occurrence of verbal and physical aggression, (6) adding a specifier for a dissociative subtype.

These modifications represent at least two important changes in the conceptualization of how individuals respond to overwhelming trauma. First, the development of a separate category for trauma- and stressor-related disorders takes an important step toward acknowledging that trauma often has broad and pervasive effects on functioning beyond what can be adequately captured in a single diagnosis. Coupled with the greater emphasis on aggressive and dissociative symptoms within the diagnosis of PTSD, the presence of this new section reflects a deeper understanding that reactions to trauma can be pervasive and diverse, and that they often reach beyond our previous conceptualization of them as being limited to the domains of fear and anxiety, which DSM-IV emphasized.^1–16

Second, the inclusion of reactive attachment disorder and disinhibited social engagement disorder in the trauma- and stressor-related disorders section, coupled with the elaboration of the description of trauma symptoms in children within the PTSD criteria, begins to integrate the decades of preclinical and clinical research demonstrating the profound impact that developmental timing of trauma exposure has on trauma reactions, both at the time of initial exposure and in response to stress and trauma experienced later in life.^17–31 In this article we examine changes to the diagnostic criteria of PTSD in the context of animal models of trauma-related neurobiological dysfunction, and discuss implications for how preclinical data can be useful in current and future clinical conceptualizations of trauma and trauma-related psychiatric disorders.

HOW CAN PRECLINICAL RESEARCH INFORM THE REFINEMENT OF DIAGNOSTIC CRITERIA FOR PTSD?

Preclinical models that complement clinical research can greatly enhance our understanding of the neurobiological underpinnings of neuropsychiatric traits. While animal studies are limited in their capacity to model human psychiatric phenomena, consideration of preclinical data of the demonstrated effects of stress on neurobiology and behavior can help us to better understand human responses to severe stress or trauma.³² To confer this complementary and evidence-based insight, animal models of complex disorders such as PTSD must demonstrate a satisfactory degree of reliability together with face, construct, and predictive validity. That is, behavioral responses must be observable and measurable, emulate clinical symptomatology, and be corrected with pharmacological treatments that alleviate similar indications in patients with the disorder.³³

Preclinical models considered to phenotypically resemble clinical cases of PTSD in humans are characterized by long-lasting adaptations in stress and conditioned-fear responses, together with a generalized sensitization to stimuli following intense stress exposure.³⁴ In rodent models, simulation of a traumatic event can be induced via exposure to inescapable electric shocks, aggressive social confrontation, predator scent, or a short, varied sequence of stressors.^33,34 Animals exposed to such trauma typically demonstrate sensitized responses to novel stressful stimuli across neuroendocrine, cardiovascular, gastrointestinal, and immune systems for weeks to months after the exposure.³⁴ Increased sensitivity to pain, dysregulation of circadian biorhythms, greater depression-like behavior, and heightened fear and defensive reactivity are also observed.³⁵ Insights into the sensitizing effects of trauma exposure on systems involved in both physiological and affective stress regulation in animal models have provided the foundation for examining mechanisms of comorbidity of PTSD and a host of physical and psychiatric disorders, including cardiovascular and metabolic disease,^36,37 disrupted immune functioning,³⁸ chronic pain,^39–42 and depression.³¹

Cortisol and noradrenaline, adrenaline, and a host of other stress-mediated physiological sequelae work in concert to coordinate cellular responses in both the peripheral and central nervous systems, thereby facilitating an individual’s behavioral response to an immediate threat.^43–52 These physiological cascades concurrently modulate synaptic plasticity and epigenetic mechanisms governing future cellular responses to stress.⁵³ These adaptations enable individuals to rapidly recall memories and biological responses, facilitating their avoidance of, or coping with, similar threats in the future. From this perspective, the psychophysiological symptoms of PTSD reflect augmentation of biologically engineered adaptations in behavioral coping (e.g., hyperarousal, aggressive defense, avoidance, and persistent negative alterations in cognitions and mood).⁵⁴

Neurobiological adaptations—mediated by hyperactivation of both the hypothalamic-pituitary-adrenal axis and sympathetic nervous system during severe stress—attune neural systems, primed to facilitate cognitive and behavioral responses, to future threats.⁵⁵ These adaptations include augmenting memory consolidation at the cellular and systems level to prime an individual’s future fight, flight, or freeze response when faced with similar threats. Rapid recall of memories, both psychologically and physiologically, are critical to this adaptive response. PTSD symptomatology is not per se a disruption of this system but is, instead, reflective of an inherently efficient and enduring memory storage and retrieval system. From an evolutionary perspective, therefore, symptoms of PTSD, including intrusive memories of the traumatic event, avoidance of reminders of it, emotional numbing or dysregulation, hyperarousal, and exaggerated active versus passive coping, can be considered natural adaptations to extreme stress that fail to subside once the threat is removed. The enduring nature of these stress-mediated neuroadaptations, which are thought to underlie symptom persistence in vulnerable individuals, has led to suggestions that PTSD is a “forgetting” disorder, such that PTSD patients lose the ability to forget the trauma.³² Consequently, when they encounter trauma-associated cues, vivid memories of the traumatic event are reexperienced together with associated emotional states and physiological stress responses.

Preclinical research suggests mechanisms mediating PTSD and other trauma- and stressor-related psychopathology are founded in a functionally adaptive stress response system evolved to rapidly and effectively store fear-related memories and facilitate the rapid recall of situationally relevant physiological and psychological reactions.^56–58 Once an individual previously exposed to trauma is in a safer environmental context, the situationally adaptive response is to attenuate recall of trauma-related memories and associated system-wide physiological reactions. In PTSD, however, the all-too-effective recall of memories formed during exposure to extreme stress, together with the rapid coordination of physiological and behavioral responses, can be disabling later, when the individual is no longer facing the impending threat. Building upon the understanding of mechanisms afforded by animal models, clinical studies have begun to demonstrate parallels between deficits in attention, learning, and memory observed in humans with PTSD and alterations in brain systems and structures identified in animals as underlying these processes.^{10,34,59–61} Redefining PTSD as a “Trauma- and Stressor-Related Disorder” has helped to refine clinical criteria for diagnosis, better aligning the diagnosis with our understanding of the neurobiological mechanisms of stress reactivity and stress-mediated psychopathology.

REDEFINING PTSD AS A “TRAUMA- AND STRESSOR-RELATED DISORDER”

It has been argued for some time that the unique neurobiological adaptations to traumatic stress in PTSD validate its inclusion in a distinct diagnostic entity.^56,62,63 This perspective has been extended by the creation in the DSM-5 of a separate category for “Trauma- and Stressor-Related Disorders,” and the relocation of PTSD from “Anxiety Disorders” into this new section. These changes appear to reflect the growing appreciation that the characteristic symptom persistence of PTSD and other trauma- and stress-related disorders reflect allostatic overload to neurobiological stress-response systems^21,64,65 and the subsequent failure of re-adaptation to a safe environment at a neurophysiological level.⁶⁶ As discussed above, the cascading changes to neurobiological systems as a result of chronic or severe stress may manifest in changes to psychological and physiological functioning that reach far beyond symptoms of fear and anxiety. Indeed, behavioral neuroscience research across species suggests that when environmental stressors are too demanding and the individual is unable to effectively cope, poor health and psychopathology across multiple domains can result.⁶⁷

The creation of a DSM-5 section specifically for disorders reflecting trauma- and stress-related psychopathology also may reflect an acknowledgment of the variability in the expression of post-traumatic reactions. That overwhelming stress can induce significant and enduring changes in cognitions, feelings, and behavior^56,68–72 remains the fundamental construct of PTSD and the other stress-related disorders in DSM-5. However, the greater consideration of stress-related adaptations in the specific diagnostic criteria for PTSD in DSM-5 seems to reflect an increased awareness of the enduring impact of severe stress on mood and coping systems. The way in which an animal copes with stress is often colloquially referred to as the fight, flight, or freeze response, and reflects well-characterized confrontational and avoidant behavioral responses. In DSM-IV-TR, the role of the fear response in PTSD was acknowledged by its placement among the anxiety disorders. This emphasis on the role of fear and anxiety in PTSD has led to the development of effective therapies for PTSD that have built upon exposure and cognitive-behavior therapy for other anxiety disorders,^73,74 but it has also limited the development of therapies to address other trauma- and stress-related responses such as aggression or sleep disturbance.^75,76

Nonconfrontational behavioral responses to stress, such as the flight response or freeze response, are a means through which an individual can withdraw and avoid the threat, thereby both conserving energy and avoiding aggressive conflicts.⁷⁷ Many of the symptoms of PTSD in both DSM-IV-TR and DSM-5 reflect such withdrawal from, or “depressive” responses to, stress, although this emphasis is more pronounced in the DSM-5 criteria. By contrast, confrontational responses to stress, though well represented by aggressive and territorial posturing (particularly in animals),⁷⁸ have been conspicuously absent from previous DSM formulations of PTSD. The elaboration of the DSM-IV symptom “irritability or outbursts of anger” to the DSM-5 symptom “irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression toward people or objects” takes an important step toward addressing this omission.^79,80 A more thorough consideration of such confrontational responses as they apply to anger and aggression in PTSD may facilitate the development of treatments that more effectively target the profound impact that these “externalizing” behaviors⁸¹ have on interpersonal, occupational, and health-related outcomes.^{2,5,7,75,79,80,82–85}

STRESS SENSITIZATION AND TRAUMA-RELATED PSYCHOPATHOLOGY

All of the coping behaviors described above are triggered and regulated by stress and are fundamental features of PTSD pathophysiology. Indeed, a wealth of neurobiological data demonstrates that exposure to stress (or stress hormones) serves to modify the expression of these behaviors through alteration of hypothalamic-pituitary-adrenal axis feedback and monoamine neurotransmission.^86,87 The enduring nature of stress-induced neurobiological adaptations in PTSD represents a critical feature of this disorder.⁸⁶ Behavioral coping is mediated, in part, through genetics and fine-tuned by exposure to stress, particularly in early life. Adaptations that occur within the neuroendocrine systems are also modified by prior stress exposure and serve to regulate neural systems mediating mood and coping.

Such adaptations may be influenced by the developmental timing, chronicity, and characteristic of the trauma(s). For example, long-term childhood maltreatment by primary caregivers may result in neural, endocrine, cognitive, and behavioral alterations that are distinct from those occurring in response to a single, prolonged stressor in adulthood, such as exposure to combat.^{10,21,23–26,28,88,89} Preclinical models provide a valuable tool for elucidating the influence of gene × environment × development factors in the pathogenesis and symptomatic expression of PTSD.^90–93

Animal models of PTSD have contributed significant insight into the neurobiological mechanisms mediating fear conditioning, extinction learning, retention of extinction learning, and behavioral and neuroendocrine sensitization involved in the development or maintenance of PTSD.^94,95 Such studies have demonstrated that exposure to stress, particularly early in life, can result in enduring changes in neuroendocrine regulation and also in neurobiological reorganization within the mesocorticolimbic system.⁹⁶ While important similarities can be identified across multiple stress-sensitive disorders, a core and unique feature of PTSD is to be unable to forget trauma memories, and to experience, and be unable to inhibit, exaggerated physiological stress responses to associated stimuli.³² Classical associative fear conditioning, used extensively to model the traumatic memory features of PTSD in animals,⁹⁷ has shown that disruption of “for-getting” (extinction learning) is characterized by exaggerated amygdala responses together with deficits in frontal cortical and hippocampal function.⁹⁸ These functional and structural changes directly mediate memory recall and behavioral coping in the face of future stress and negatively affect the effectiveness of pharmacotherapies.⁹⁶

Amygdala hyperactivity promotes acquisition of fear associations and responses (both freezing in reaction to similar stimuli and aggressive behaviors when socially challenged), whereas deficits in frontal and hippocampal function prevent both the suppression of attentional responses to trauma-related stimuli and the behavioral adaptation to safe contexts.⁹⁸ These anatomical regions are thought to be particularly sensitive to the impact of severe stress via the direct actions of glucocorticoids and their facilitation of glutamate-mediated, long-term synaptic plasticity.^99–101 Relevantly, functional and structural differences have been observed in both the amygdala and hippocampus in both children and adults with PTSD.^{17,20,59,102–105} Preexisting risks for PTSD, including depression and early life stress, may prime these regional responses to stress, in part via differential methylation of glucocorticoid response genes.^53,106 Together with previously incurred structural and functional vulnerabilities, such insults may further serve to augment trauma-induced neuroadaptations. Although the relationship between genes, environment, and development in the etiology of PTSD is inherently complex, animal models provide a valuable means of elucidating pathophysiological mechanisms, identifying key biomarkers of vulnerability, and testing novel therapeutics.

PREVENTION AND TREATMENT IMPLICATIONS

Research into the neurobiology of susceptibility and resilience to development of PTSD in preclinical animal models provides novel avenues for treatment and prevention.^43,107–109 Psychotherapy is a critical first-line treatment for PTSD,¹¹⁰ and the mechanistic understanding of the effects of stress and trauma on functioning (based upon animal models) has been fundamental to the development and testing of these nonpharmacological interventions. For example, animal research on the impact of trauma on learning and memory has been used to develop trauma-focused therapies for PTSD such as cognitive processing therapy and prolonged exposure therapy.^73,74,111 Likewise, animal research has illuminated the neurobiological substrates of PTSD, opening the door for research examining the effects of psychotherapy on relevant neurobiological systems.^59,112–114

Moving forward, the more we understand the neurobiological mechanisms of stress and their implications for plasticity and treatment response, the broader our scope for treatment options becomes for both behavioral and somatic treatments. For example, pharmacotherapies that block the formation of trauma-related memories may help to prevent PTSD if given acutely and immediately post-trauma. Illustrating this point, morphine used acutely in early resuscitation and trauma care in US service members has been associated with a reduced risk of developing PTSD.¹¹⁵ Conversely, drugs that functionally induce an adaptive state in otherwise resistant neural circuits affected by trauma will potentially facilitate recovery and efficacy of psychotherapeutic approaches, as demonstrated in treatment-resistant depression.¹¹⁶

To date, the selective serotonin reuptake inhibitor class of antidepressants has most commonly been used in managing PTSD.^117,118 Possible treatments that directly modulate mechanisms implicated in synaptic plasticity include D-cycloserine, a broad-spectrum antibiotic and partial N-methyl-D-aspartate receptor agonist;^119–122 dehydroepian-drosterone, a precursor to male and female sex hormones (androgens and estrogens);^123–125 and neuropeptides such as corticotropin-releasing hormone and neuropeptide-Y.¹²⁶ Each of these compounds serves to regulate neuroendocrine and behavioral responses to stress and, through direct actions on mechanisms mediating synaptic plasticity, has promise as a therapeutic intervention for PTSD.

CONCLUSIONS

Broadly, the changes to the conceptualization of PTSD reflected in DSM-5 mirror the field’s ever deeper understanding of the long-term consequences of stress and trauma, and of the biological mechanisms underlying these changes, as derived from research using animal models over the past several decades. The critical role that trauma plays in cascading neurobiological changes underlying psychopathology, the importance of developmental timing in shaping posttraumatic outcomes, and the heterogeneity of emotional and behavioral dysfunction associated with exposure to severe trauma have all been elegantly interwoven into the new diagnostic criteria. Much work remains to be done, however, to integrate the knowledge we have gained from animal models into our diagnostic guidelines. Based on the above discussion, we conclude with some considerations for collaborative efforts between preclinical and clinical researchers. It is our hope that these collaborations will continue to lead us toward increasingly refined and nuanced formulations of the psychiatric effects of trauma in future versions of the DSM. The new DSM-5 structure separating out trauma- and stressor-related disorders potentially lays the groundwork for incorporating into the DSM framework both the impact of chronic trauma on personality development and the association of trauma with the onset of other psychiatric syndromes.

We recommend that in examining the implications of animal models for defining human responses to trauma, researchers and theorists continue to emphasize a developmental perspective on PTSD. Animal models demonstrate that early trauma exposure affects responsivity to later stressful events. Continuing to focus primarily on the effects of a single index event is, in light of the evidence, misguided. At the very least, this myopic view wastes valuable resources by discounting the vast literature suggesting that early experiences shape neurobiological systems in ways that contribute formatively to the development of PTSD and other forms of psychopathology. More critically, however, such a narrow perspective inappropriately localizes the genesis of dysfunctional behavioral responses in PTSD to the individual without effectively acknowledging the influence of both genes and environment on neurodevelopmental processes that prime an individual to effectively store and recall trauma- and stress-related memories. This narrow perspective not only creates obstacles to the development of effective interventions but also risks exacerbating trauma-related alterations in cognition and mood by implicitly blaming the individual for problems having a strong biological basis, such as persistent negative emotional states and aggressive behavior.

With creation of the “Trauma- and Stressor-Related Disorders” section, we are now better placed to conceptualize PTSD as one clinical manifestation of an underlying neurobiological adaptation to stress. In addition to aiding our understanding of the basic neurobiology of PTSD, preclinical studies can help determine the influence of genetic, environmental, and developmental factors in mediating an individual’s vulnerability to develop PTSD. Preclinical studies can also help to identify the mechanisms through which these mediating factors can be therapeutically disrupted, thereby providing opportunities both to identify novel drug targets and therapeutic interventions and to enhance our capacity to personalize treatments based on the unique phenotypic expression of PTSD. Importantly, as we better appreciate the mechanisms through which an inherently efficient stress response facilitates the hard wiring of fear memories and behavioral coping responses at the core of PTSD pathophysiology, we take an important step toward destigmatizing this devastating illness.