Understanding Resilience and Preventing and Treating PTSD

10 – 1,2,8 FKBP5 FKBP5 More re- 14 May/June 2018 17 • environment 15– Â Asetof 13 The best example of Number 3 • 11,12 educes glucocorticoid recep- cial focus on resilience in the and neurotrophic factors (e.g., Vo lu me 2 6 te gene is the one coding for ctor [BDNF] gene), among many with longitudinal studies emerging more re- 2 In the last decade, studies have increasingly focused 6,7 interactions modifying risk for PTSD. haplotypes has been found toin interaction modify with risk the for severity PTSD of childhood in trauma. adults an extensively studiedFKBP5, candida a chaperone protein that r tor (GR) sensitivity to circulating cortisol. on understanding the mechanisms underlyingvarious phenotypic resilience levels and at their interaction, incorporating genomic, psychosocial, and neurobiological perspectives. While recent developments ining, the much study remains of to resilience beent are discovered review is and excit- not understood. meant The to be pres- in exhaustive; it resilience summarizes research, progress withface a of spe psychologically traumaticvention experiences, and and treatment on of theumatic posttra stress pre- disorder (PTSD). GENOMICS The heritability component for PTSD30% has to 40%; been trauma estimated severity at andfluence frequency PTSD significantly in- risk. Earlier twin studiesdate were followed gene by studies, candi- which identified several gene is only one of several genesPTSD, found including to affect genes resilience related oradrenal risk to for the (HPA) hypothalamic-pituitary- axis,and monoamines dopaminergic (e.g., system genes), serotonin transporter brain-derived neurotrophic fa others, including inflammatory-response genes. cently, large-scale research collaboration led by the Psychiatric cently. populations, Avast 2,3 on (Ms. Horn); 2,4,5 iversity of Oreg of Medicine at Mount Sinai (Dr. Feder). Some of the key early studies of resil- 22 July 2017; revised manuscript received 10 1 neurobiology, prevention, PTSD, resilience, treatment Adriana Feder, MD, Department of Psychiatry, Icahn slifespan. ’ Copyright © 2018 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited. Copyright © 2018 President and Fellows of Harvard College. Unauthorized reproduction EVIEW www.harvardreviewofpsychiatry.org

R Resilience is defined as theSome dynamic ability of to the adapt key successfully early inadults, studies studies the of testing face resilience interventions of were to adversity, observationalthe trauma, promote studies or underlying resilience in genomic significant in and children. threat. neurobiological They different mechanisms. populations, were Neuralience and and followed are molecular a by studies also research recent in in preclinical upsurge increasingly modelsand of identifying of human active studies resil- studies on stress of resilience adaptations canrisk in be populations. harnessed resilient to Further, animals. develop treatment new Knowledge interventions preventiveare gained focused interventions consistently to on from linked enhance to enhancing animal resilience psychological in potentially resilience can at- modifiablewith enrich protective posttraumatic currently stress factors available disorder treatment (PTSD). that interventions Translating for our individuals tionally expanding promises knowledge of to the yield neurobiology novel of therapeuticvast resilience strategies field addi- for of resilience treating research spanning this genomic, disabling psychosocial, andhave condition. neurobiological levels, led This and and review discusses how can summarizes findings lead the to newKeywords: preventive and treatment interventions for PTSD. Sarah R. Horn, BA, and Adriana Feder, MD the Department of Psychology, Un

Resilience research gradually progressed from descriptive range of subsequent studiescharacterized in key psychosocial children factors and associatedience, with later including resil- in the importance adults of acaregiver positive during bond development, with as a well primary ascognitive emotion regulation, flexibility, perceptions of purpose andthe control, availability and of social support for resilienceamong across other the lifespan, factors reviewed below. ience were conducted in the 1970schopathology in stemming children at from risk diverse for risk psy- parental serious factors, mental including illness or having beenphanage, raised in and an or- alsowho in nevertheless identified showed normative subgroups development. of such children 158 Department of Psychiatry, Icahn School Original manuscript received December 2017, accepted2018; for revised manuscript received publication 31 January subject 2018. toCorrespondence: revision 9School January of Medicine at MountNew Sinai, York, NY One 10029. Gustave Email: L. [email protected] Levy Place,© Box 2018 President 1230, and Fellows of Harvard College DOI: 10.1097/HRP.0000000000000194 From Resilience is broadly defined assuccessfully the dynamic in ability the to adapt facethreat. Resilience of is adversity, complex trauma, andized or on might a continuum, significant be with the best potential foran conceptual- it individual to change across THE STUDY OF RESILIENCE

and Treating PTSD Understanding Resilience and Preventing studies to investigating how to promote resilience in different

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Genomics Consortium–Posttraumatic Stress Disorder group and family stability have been shown to promote resilience (PGC-PTSD) has made it possibletoachievelargesamplesizes following exposure to early-life adversity by regulating for conducting genome-wide association studies (GWASs).11 emotional and neurobiological development, highlighting The largest multiethnic GWAS in PTSD, including over 20,000 clear opportunities for preventive interventions for high- samples from 11 studies, has recently found a shared genetic risk risk youth.27,29,30 When trauma occurs during develop- between PTSD and schizophrenia, and possible shared risk ment, the timing and duration of exposure to adversity is with bipolar and major depressive disorders.18 Ongoing col- key, as is the timing of preventive interventions.31,32 Because laborations will make it possible to achieve the larger sample of heightened brain plasticity, infancy and adolescence are de- sizes needed to identify genetic risk for PTSD at the genome- velopmental periods that are especially sensitive to both wide level.15,18 trauma exposure and positive interventions.31 Over the past decade it has become evident that other in- Of note, exposure to manageable, nontraumatic stressful fluences beyond genetic sequence are central to gene expression events during development might actually enhance resilience. and function. Epigenetic modifications affecting the structure This phenomenon, termed stress inoculation, was initially re- of chromatin (how tightly DNA is wound around histones)— ported in young monkeys exposed to weekly short maternal for example, via DNA methylation and histone methylation separations over ten weeks. Despite behavioral and biological or acetylation—can facilitate or limit the accessibility of tran- evidence of acute stress during separations, by the age of three scription factors to genes, thus enhancing or suppressing gene the animals showed more adaptive behaviors and biological expression. Epigenetic modifications often occur in response stress responses over time, as well as larger ventromedial pre- to environmental exposures, especially during early develop- frontal cortex (PFC) volume, a brain region subserving emo- ment, ultimately enhancing resilience or vulnerability to stress tion regulation and fear extinction.33 Learning to cope with and trauma into adulthood. In the earliest demonstration of stress has been linked to expression of specific genes in brain epigenetic changes during early development in rodents, regions involved in learning and emotion regulation.34 In Michael Meaney and collaborators19 found lower methyla- humans, an individual’s perceived degree of control over a tion of the GR promoter region in the hippocampus in off- stressor is known to be of key significance, and exposure to spring of high licking, grooming, and arched-back nursing manageable stress levels is thought to enhance resilience to dams—which was associated with higher GR expression future stressors.35 and lower anxiety-like behaviors and HPA-axis activation in the offspring, thus resulting in enhanced resilience. These PSYCHOSOCIAL FACTORS IN ADULTHOOD studies and many others have contributed to our understanding Some of the most widely replicated and potentially modifiable of the mechanisms underlying the influence of early-life environ- protective factors linked to psychological resilience include emo- ment on resilience into adulthood via epigenetic mechanisms.20 tion regulation, cognitive flexibility and reappraisal, positive Of note, some of the same genetic variations that increase the emotions, and the ability to harness social support.35 Emotion risk for mental illness upon exposure to early adversity also regulation has been linked to greater executive function,2,36 appear to enhance psychosocial function in positive and sup- broadly defined as the ability to plan and complete a task, and portive developmental environments, possibly mediating the required for quick and effective responses to threat, which degree of individual sensitivity to environmental influences in is crucial for survival and well-being.37–39 Effective implicit general.21,22 Increasingly sophisticated studies in animal models (automatic) emotion regulation involves top-down cortical are elucidating molecular mechanisms underlying resilient phe- regulation of subcortical fear-processing structures,39 and notypes23 and have discovered genotype Â epigenetic Â envi- supports cognitive flexibility (the ability to adapt one’sthink- ronment interactions.24 Further, some molecular adaptations ing to face new situations), cognitive control,40,41 and adap- have been uniquely identified in resilient phenotypes and are ab- tive (or constructive) coping.9,42 Cognitive reappraisal is a sent in more vulnerable animals.25 New epigenome-wide anal- conscious (explicit) emotion-regulation strategy employed by yses are emerging from collaborative studies in humans.15,26 resilient individuals; it involves noticing negative thoughts and replacing them with a more positive perspective.43 Positive re- DEVELOPMENTAL YEARS appraisal has also been linked to lower anxiety symptoms in Psychological factors identified in studies of resilient children trauma-exposed individuals44 and is a central component of include higher cognitive and executive functioning, advanced cognitive-behavioral therapy (CBT) for individuals with PTSD. maturity, rapid response to danger, and positive relationships Dispositional positive affect, characteristic of resilient in- with peers, among others.2,3,7 While a comprehensive review dividuals, has been linked to greater social connectedness, of this important topic is beyond the scope of the present re- psychological well-being, constructive problem solving, and view, both early adversity and mitigating environmental fac- adaptive coping with stress.45–47 Positive emotions enhance re- tors have been consistently shown to affect the development silience48,49 and promote broader associative thinking (the op- of stress response systems, brain structure and function, and posite of rumination), thus supporting active coping with consequently psychological and behavioral responses to stress.50 Positive emotions have also been found to decrease stress into adulthood.27,28 In particular, caregiving quality autonomic arousal and facilitate efficient cardiovascular

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recovery following stress exposure,51 and to protect against and facilitate efficient cardiovascular recovery following stress the negative impact of stress on general health.45,52 The capac- exposure,51 protecting individuals against the negative impact ity to experience positive emotions is closely linked to reward of stress on general health.45,51 responsiveness.48,49,53 Positive affect and reward play a cen- The HPA axis and locus coeruleus–norepinephrine (LC-NE) tral role in modulating cognitive control and maximizing exec- system are key components of the stress response system, en- utive function, crucial for effective responses to threat.41,54 abling the organism to react and adapt in the face of stress. The availability of social support and the ability to es- Early-lifestressisknowntoaffect“HPA-axis programming” tablish and nurture a supportive social network have re- and has been linked to chronically elevated corticotropin- peatedly been linked to resilience.55 High levels of social releasing hormone (CRH) levels, resulting in decreased resil- support reported by resilient individuals function as a ience to subsequent exposure to adversity and trauma.77 In safety net in stressful situations,9,56 including in military addition, the dopaminergic system, known to mediate reward and war settings.57 Conversely, low social support and low responses, is increasingly understood to play a role in regulat- social integration have been identified as strong risk factors ingfearlearningandanxietybyactingasa“brake” on fear for PTSD.58,59 Further, individuals with PTSD commonly responses.78 The “threshold” beyond which the capacity to experience difficulties with interpersonal relationships and adapt is taxed differs for each individual and might also differ intimacy, partially explained by impairments in social across the lifespan.55 Interaction between genetic makeup, cognition,60–62 and decreased sensitivity to positive social early-life environment, and the timing, intensity, and chronicity stimuli.63 A focus on increasing social support and engage- of stress and trauma exposure can result in the development of ment with others is of key importance in treating individ- PTSD and other stress-related disorders. uals with PTSD. Other key neuropeptide and neurotransmitter signaling A range of other psychosocial factors has been linked to re- systems include neuropeptide Y (NPY), BDNF, endocannabi- silience. Higher coping self-efficacy, the perception that one is noid, oxytocin, and glutamatergic/gamma-aminobutiric acid able to manage or recover from a stressful event, has been (GABA)ergic systems. Higher levels of plasma NPY, an anxi- linked to positive adjustment and lower PTSD symptoms af- olytic neuropeptide thought to counteract the effects of CRH ter trauma exposure.64,65 Related constructs include a sense in the amygdala, hippocampus, and hypothalamus,79 were of control or mastery over stressors—found to be associated found to correlate with better performance during rigorous with lower perceived threat and physiological responses to military training in a study of highly resilient Special Forces stress—and the ability to face one’sfears.66,67 In addition, ac- soldiers.80 Studies in individuals with PTSD have reported al- tive coping has been found to support resilience, whereas terations in plasma and cerebrospinal fluid NPY levels.81 avoidant coping is linked to PTSD.68–70 The last decade has BDNF, a neuropeptide that promotes hippocampal and PFC also witnessed a growing interest in mindfulness, the ability function,82 was found to be differentially expressed in the nu- to focus one’s awareness on the present moment, while no- cleus accumbens (a key reward region in the brain) of resilient ticing, observing, and describing sensations, thoughts, and mice after exposure to chronic social-defeat stress, an animal feelings, as a protective factor associated with better physi- model of stress-related psychopathology. Resilient mice have cal and mental health.71,72 Additionally, a solid sense of pur- been found to upregulate KCNQ potassium channels within pose and the ability to find meaning in the face of challenges the ventral tegmental area, ultimately preventing heightened might facilitate emotional recovery from negative experi- BDNF signaling within the nucleus accumbens;25 these find- ences.73 It is known that traumatic experiences can shatter ings have led to a new randomized, controlled trial (RCT) a person’s assumptions about safety and predictability, also in humans, currently under way. Animal studies are increas- affecting their sense of purpose in life.70,74 The ability to ingly identifying such neuroplastic changes at the molecular make sense of a traumatic experience—meaning making— level within fear and reward centers, constituting active adap- has been recognized as important to psychological recovery tations in resilient animals.23 in treating PTSD.75 Chronic stress has been shown to induce changes in glutamate-system function, associated with synaptic atrophy NEUROBIOLOGY in the hippocampus and PFC in animal models, an effect that Biological responses to stress involve complex adaptive sys- is rapidly reversed by administration of N-methyl-D aspartate tems of interrelated hormones, neurotransmitters, and neuro- (NDMA) glutamate receptor antagonist ketamine.83 Oxyto- peptides acting in concert. Resilience is understood to depend cin, a neuropeptide that promotes social attachment, is also on the efficient activation and termination of the stress re- involved in attenuation of the fear response.84 Endocan- sponse. Notably, key resilience factors, such as cognitive nabinoid signaling regulates stress responses, including at- reappraisal and positive emotions, may buffer against the tenuating stress-induced activation of the HPA axis, and deleterious effects of trauma and adversity. Habitual cogni- possibly mediating stress controllability.85,86 The develop- tive reappraisal has been linked to lower levels of reported an- ment of novel treatment interventions targeting these and ger and physiologic arousal in healthy adults,76 and positive other signaling systems is the focus of active ongoing research, emotions have also been found to decrease autonomic arousal discussed below.

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THE IMMUNE SYSTEM can be strengthened or weakened, and potentially updated The immune system has reciprocal communication with the with new information afforded by experience.107 These changes, HPA axis and has been increasingly implicated in stress and associated with induction of brain plasticity,107 represent op- resilience. Following stress, glucocorticoids regulate the im- portunities for modifying the meaning, centrality, or emo- mune response by inhibiting production of pro-inflammatory tional valence of traumatic memories. cytokines (e.g., interleukin-6 [IL-6]).87 In turn, cytokines in New research continues to uncover the surprising degree the brain and circulating cytokines activate the HPA axis.88 of plasticity of the human brain, enabling ongoing develop- Immune-system mediators have also been shown to play a role ment of novel interventions to “train” or strengthen specific in adult neurogenesis, learning, and memory.89,90 Several brain circuits known to function abnormally in individuals studies in individuals with PTSD have found evidence of al- with stress-related psychopathology.108–112 Of note, neuro- tered immune function, including elevated C-reactive protein imaging studies to date have primarily focused on individuals (CRP),91–96 with one study linking CRP polymorphisms to with PTSD, with less emphasis on resilient, trauma-exposed PTSD symptomatology.97 A meta-analysis found that PTSD comparison groups. Further, incorporating a third, healthy is associated with increased inflammatory biomarkers, al- control group with no or low exposure to trauma is essential though psychotropic medication use and comorbid depres- to the design of resilience studies, as it helps to identify factors sion were significant moderating factors.98 Arecentstudyin specific to the resilient or vulnerable groups, and also the Gulf War veterans found alterations in peripheral inflamma- common effects of trauma exposure in both exposed groups. tory activity associated with both reduced hippocampal vol- Neuroimaging studies have identified automatic (implicit) ume and higher PTSD symptom severity.99 emotion regulation as a core dysfunction in stress-related disor- Compared to individuals with current PTSD, recent stud- ders, including PTSD, accomplished through top-down regula- ies have reported lower plasma levels of pro-inflammatory tion of amygdala activation by the ventral anterior cingulate IL-6 as well as CRP in women recovered from PTSD (compa- cortex (ACC).37,113–115 For example, in an functional magnetic rable to levels in nontraumatized controls),100 and higher resonance imaging (fMRI) study, trauma-exposed individuals levels of anti-inflammatory IL-10 in resilient individuals.101 without PTSD (more resilient), compared to the PTSD group, Additional evidence suggests that psychosocial factors consis- exhibited significantly higher rostral ACC activation during tently associated with resilience, such as higher perceived sense an emotional conflict (incongruent) contrast while performing of mastery102 and a composite self-report measure of social an implicit emotional-interference task.115 Another series of engagement, awareness of self and others, meaning in life, neuroimaging studies has focused on neural circuits underlying and physical health behaviors might mitigate systemic inflam- effortful (explicit) emotion regulation in healthy volunteers and mation in the face of significant lifetime exposure to trauma psychiatric populations, involving conscious attempts to mod- and adversity.103 Dispositional positive affect, a psychosocial ulate the intensity of emotional responses.116 In fMRI studies, factor associated with resilience, has also been linked to lower resilient women with a history of sexual assault demonstrated levels of inflammatory cytokines.104 While preliminary, these higher prefrontal activation than the control group with PTSD results indicate that more resilient individuals might have during explicit cognitive reappraisal of aversive images,117 and more adaptive immune-system function. veterans with PTSD, compared to combat-exposed controls, In a recent, elegant study employing variations of the showed reduced dorsolateral PFC activation during cognitive social-stress paradigm in mice—an animal model of resilience— reappraisal of aversive images.118 Positive appraisal style and peripheral immune-system differences measured before exposure positive reappraisal are of particular interest as coping strate- to social stress were found to predict resilience and also, in addi- gies associated with resilience.119 A recent neuroimaging study tional experiments involving depletion of IL-6 from leukocytes, found that positive reappraisal ability, or “finding positive to promote resilience.105 These interesting findings suggest meaning in negative experiences,” is associated with enhanced potential novel avenues for the treatment of PTSD—in partic- connectivity between the ventromedial PFC and the amygdala, ular, ones aimed at reducing peripheral inflammation.105,106 striatum, and dorsal PFC, regions subserving reward valuation.120 Further, cognitive reappraisal has also been linked to NEURAL CIRCUITRY lower amygdala and higher prefrontal/parietal activation in Research on the neurocircuitry of fear has advanced greatly in response to negative stimuli.121 recent decades, delineating the roles of the amygdala, hippo- The neurocircuitry of reward has been implicated in other campus, and ventromedial PFC in mediating conditioning, studies of resilience and PTSD. Self-reported positive emo- reconsolidation, and extinction. tions have been found to correlate with neural responsiveness Individuals suffering from PTSD experience significant dis- to reward in fMRI studies of patient and nonpatient sam- tress when exposed to trauma reminders, “overgeneralizing” ples.48,49,122 In behavioral studies, individuals with PTSD re- the original fear cues to other similar cues in their environment, ported lower reward anticipation and lower satisfaction which also trigger fear responses. Of particular relevance for when rewarded,123 and exhibited avoidance of positive PTSD, recent studies have shown that memory is dynamic in- affective (i.e., rewarding) stimuli during performance of an stead of fixed. Each time a stored memory is reactivated, it approach-avoidance task.124 Neuroimaging studies have

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further documented reward-related circuit abnormalities— and intervention efforts, reviewed below and summarized for example, in the nucleus accumbens and medial PFC— in Table 1. in individuals with full and subthreshold PTSD,125–128 and have reported a link between PTSD symptom increase after Caregiver and Family-Based Interventions exposure to stressful military service and decreased response Protective factors identified in studies of resilience during de- to reward in the nucleus accumbens in a longitudinal study velopment have been incorporated into the design of youth- of healthy soldiers.129 Stress-induced reward-system dysreg- based interventions. Given the centrality of positive caregiving ulation is thought to increase vulnerability to stress-related as a buffering factor during development,136 many interven- disorders49,53—an observation that has been further sup- tion paradigms for high-risk youth focus on improving par- ported by candidate-gene studies.130,131 Further, imbal- enting skills and attachment patterns, strengthening family anced neural responses to risk and reward might constitute bonds, and enhancing caregiver responsiveness.137,138,151 a biomarker of stress vulnerability.129 Three interventions that have targeted parenting skills to en- Although resilient individuals are thought to possess “ro- hance resilience include Multidimensional Treatment Foster bust” neural reward circuitry function, to date only one neu- Care for Preschoolers (MTFC-P),137 Attachment and Biobe- roimaging study, with a small sample size, has examined havioral Catch-Up (ABC),138,139 and Kids’ Club and Mom’s neural circuits of reward in highly resilient individuals (Spe- Empowerment.140,141 Each of these programs targets specific cial Forces soldiers), compared to civilian controls (n = 11 aspects of parenting skills. For example, Multidimensional per group), while performing a monetary incentive delay Treatment Foster Care for Preschoolers, designed for foster task.132 Interestingly, while civilians showed greater right care children aged three to six years, centers on bolstering subgenual PFC and ventral striatum activation during reward supportive caregiving and positive-parenting skills, such as anticipation, the Special Forces soldiers showed no differen- responding consistently and contingently to positive and neg- tial activation in reward-processing regions between the ative behaviors.137 The ABC program, designed for foster high-reward and no-reward conditions. A longitudinal fMRI care children, aims to improve attachment patterns and regu- study in a sample of 200 nonpatient, student volunteers found latory capacity in young children by instructing caregivers to an interaction between ventral striatal reactivity to positive be highly responsive and sensitive in their interactions with feedback and recent stressful life events in predicting self- them through recognizing the children’s needs, reducing the reported state-positive emotions, supporting a protective effect frequency of frightening parental behaviors, and addressing of higher reward-related neural responses against reductions the parent’s own issues.138,139 Both interventions have been in positive affect when facing stressful life events.49 Addi- shown to improve attachment security and to normalize corti- tional neuroimaging studies of reward circuitry and brain sol patterns in children.136,139,140,152 Finally, Kids’ Club and function underlying other psychological factors central to re- Mom’s Empowerment, an intervention for mothers and chil- silience are needed, including social cognition and connected- dren exposed to intimate partner violence, has also demon- ness with others.133 strated significant improvements in positive parenting.140,141 As reviewed above, the study of resilience incorporates In addition to targeting positive and responsive caregiving multiple levels of inquiry, including research on genetic deter- to enhance resilience, a “family resilience framework” high- minants, gene Â environment interactions, gene expression, lights three domains of family functioning to be addressed functional differences observed across multiple integrated in resilience-oriented family intervention programs: communi- stress response systems, and psychosocial characteristics ob- cation processes, organizational patterns, and belief systems.153 served in resilient individuals. Emerging neuroimaging and For example, FOCUS, a brief intervention for families coping genome-wide studies promise to advance our understanding with traumatic exposures and loss, has been administered na- of the neurobiology of resilience, with the ultimate goal of de- tionally to military families and has been implemented in com- veloping novel intervention strategies to enhance resilience. munity, clinical, and school settings.142 FOCUS utilizes core Additionally, research on resilience-based interventions is es- psychosocial resilience factors such as meaning making, prob- sential to clarify potential mechanisms underlying adaptive lem solving, and social support to promote family resilience.142 responses to stress and trauma, and to broaden the range of The program has resulted in decreased distress and symptom- available preventive and treatment approaches for trauma- atic behaviors in parents and children, and increased children’s exposed individuals. prosocial behaviors and families’ resilience processes.143

ENHANCING RESILIENCE I: DEVELOPMENTAL School-Based Interventions RESILIENCE-BASED INTERVENTIONS School-based programs to enhance resilience represent an Without early intervention, childhood adversity can significantly opportunity to bolster support in the child’s natural social increase an individual’s risk for developing mental and physical networks.154–156 These programs also capitalize on well-known health disorders, including PTSD and depression.134–136 The psychosocial factors to enhance resilience, such as cognitive re- developmental period is marked by increased plasticity and appraisal, defined above as a conscious emotion-regulation heightened responsiveness to resilience-based prevention strategy that involves noticing negative thoughts and replacing

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Table 1 Examples of Resilience-Boosting Interventions for Children and Adolescents Intervention type Program example Population Intervention summary Resilience factors targeted Caregiver- and Multidimensional Foster preschool Children’s playgroup Supportive and consistent family-based Treatment Foster Care children and foster parenting 137 Facilitate school for Preschoolers caregiver(s) readiness (supplemented by Attachment security Therapist administered individual behavioral Parent stress levels sessions) Attachment and Foster preschool 10 weekly, in-home sessions Attachment security Biobehavioral children and foster Sensitive caregiving Catch-Up138,139 caregiver(s) Children’sregulatory Therapist administered Child protective capacity services involved Kids’ Club and Mom’s School-age children 10-session program Social competence 140,141 Empowerment and their mothers over 5 weeks Facing fears Therapist administered exposed to intimate Group format (separate partner violence Social and emotional groups for mothers adjustment for mothers and children) Parenting skills FOCUS142,143 Families coping with Narrative sharing process Meaning making Therapist administered traumatic exposures Strengths-based approach Problem solving and loss; military families; families Social support with chronic illnesses School-based Bounce Back144 Multicultural 10 sessions Cognitive-reappraisal School-based school-age children CBT-based skills therapist delivered exposed to traumatic events Reduction of PTSD and anxiety symptoms Mindfulness-based 7th- and 8th-grade Structured program of Coping skills, emotion stress reduction145 males in a low-income mindfulness instruction awareness Trained instructor urban area delivered Community-based Positive Youth High-risk and general Five Cs: competence, Individual strengths, Development146,147 community youth confidence, character, positive adult-youth Trained mentors connection, caring relationships, Engage youth in self-regulation skills community (prosocial approach) Communities That High-risk and Prevent adolescent Family management Care148–150 general community behavior and health styles, social support, Trained mentors youth problems (e.g., drug and academic abuse prevention) engagement CBT, cognitive-behavioral therapy; PTSD, posttraumatic stress disorder. them with a more positive perspective. Bounce Back, a 10- stress in high-risk youth populations. In a small RCT of MBSR session CBT intervention for trauma-exposed children in elemen- for seventh- and eighth-grade males in a low-income urban area, tary school, was shown to significantly reduce PTSD, depression, participants receiving this intervention showed improved coping and anxiety symptoms compared to a delayed intervention skills compared to those who received a health education pro- condition. Notably, the intervention was also successfully de- gram.145 A review noted that since 2005, at least 14 studies of livered by school-based therapists, demonstrating its potential school-based intervention programs have directly trained stu- for more widespread scalability.144,157 School-based interven- dents in mindfulness, with associated improvements in several tion programs have also begun to adopt mindfulness-based resilience-related domains, such as emotion regulation, academic stress reduction (MBSR) to improve mental health and reduce skills, and social skills, and decreases in anxiety and stress.158

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School-based psychosocial interventions have been studied about stress control, coping skills, cognitive restructuring, in children with PTSD symptoms, but few have measured re- and support seeking. silience as an outcome beyond symptom reduction. One pro- Hardiness training similarly focuses on enhancing a sense gram for war-exposed children focused on enhancing social of control by teaching attitudes and skills that reduce threat and peer support. In this teacher-delivered intervention, par- perception, help reframe stressful situations as opportunities ticipating children showed reduction in PTSD symptoms for growth, and enhance coping abilities.169 Hardiness, which and greater adaptive functioning.156 A separate study of Sri incorporates coping self-efficacy, meaning making, and cogni- Lankan children utilized a quasi-RCT design for students aged tive reframing, has been linked to decreased PTSD symptoms 9 to 15 years with high tsunami exposure. Compared to a in deployed soldiers.170 Recent resilience-training programs waitlist control group, students in the active condition (focused for soldiers have focused on meaning making and personal on cognitive-behavioral skills, meditation, and processing trau- strengths.171,172 A different approach, designed to enhance matic experiences) had not only decreased PTSD and depres- performance under stress and aligned with the concept of stress sive symptoms but also increased hopefulness.159 inoculation, involves extremely taxing captivity-simulation exercises employed as preparedness training for soldiers.80,173 Community-Based Interventions Mindfulness programs have also been investigated as pre- Another hallmark of preventive interventions for youth is an ventive strategies for trauma-exposed adults. Mindfulness- emphasis on identifying and developing positive individual Based Resilience Training (MBRT) for first responders aims strengths, such as the Positive Youth Development (PYD) to reduce negative health outcomes and enhance resilience. programs centered on the “5Cs” of competence, confi- In a pilot study for law enforcement officers, MBRT improved dence, connection, character, and caring, in addition to em- sleep quality and reduced burnout levels, perceived stress, and 147,160 phasizing strong bonds with adults. The 4-H study, a fatigue.174 In secondary analyses, increased resilience partially PYD evaluation project, followed 1700 fifth-grade children mediated the effect of increases in mindfulness on decreased participating in community youth-development programs and levels of burnout.175 Mindful Awareness and Resilience Skills examined their developmental trajectories throughout the sec- Training (MARST), a program designed for foster care workers 147 ond decade of life. The Communities That Care (CTC) effort, and family support counselors, aims to increase resilience by a different program developed to prevent adolescent problem be- focusing on mindfulness, positive cognitive-reappraisal skills, havior, including substance abuse, guides communities to select, and awareness of positive emotions.176,177 test, and implement effective preventive interventions addressing A novel preventive intervention that originated from the 148,149 high-risk children. The CTC model is now being adapted study of neurocognitive mechanisms—attention-bias modifi- 150 for community child-maltreatment prevention. cation training (ABMT)—is based on observations that in Psychosocial interventions for youth in juvenile justice services, stressful environments, resilient soldiers focus attention on also at heightened risk for PTSD, are increasingly recognized as threats, whereas a tendency to direct attention away from 161 critical services for this population. Trauma-Adapted Multidi- threat might be associated with greater risk for PTSD.178 In mensional Treatment Foster Care is a behavioral intervention that an RCT with soldiers, ABMT designed to enhance attention targets adaptive social support (e.g., engagement in prosocial to threat, when administered pre-deployment or immediately activities and decreased contact with antisocial peers) and a prior to combat, mitigated combined risk of PTSD and the positive relationship with a caregiving adult. In RCTs, this development of depressive symptoms after combat expo- program has been shown to reduce delinquent behaviors and sure.179 A very different approach—administering a pharma- 162–164 mental health problems. cologic agent prior to trauma exposure to prevent or mitigate stress-related symptoms—might now be within reach. For ex- ENHANCING RESILIENCE II: RESILIENCE-BASED ample, the NMDA glutamate receptor antagonist ketamine INTERVENTIONS FOR ADULTS has recently been shown to induce stress resilience in rodents when administered one to two weeks prior to stress exposure, Pre-trauma Training and Other Preventive Approaches suggesting possible applications for occupational groups with Preparedness training for occupational groups frequently ex- high exposure to potentially traumatic events.180,181 posed to potentially traumatic situations (e.g., first responders, military personnel) aims to bolster resilience through targeting Early Post-trauma Interventions specific skills (e.g., firefighting) and stress-management skills Many years after discouraging results from earlier psycholog- (e.g., relaxation training, cognitive reframing), and are thought ical debriefing studies,182 a recent upsurge of research on pre- to work through enhanced coping self-efficacy and a height- ventive interventions administered shortly after a traumatic ened sense of control.165,166 Examples of preparedness training event has aimed to prevent the development of PTSD symp- include Stress Inoculation Training (SIT) pre-deployment for toms.183 A brief video intervention focusing on coping strate- military personnel167 and the Mental Agility and Psychological gies for women survivors of sexual assault, administered Strength (MAPS) training program for first responders in within 72 hours of the assault, was associated with lower PTSD Western Australia,168 both centering on psychoeducation symptoms both six weeks and six months later, primarily in

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women with a prior history of rape.184 A separate approach posttraumatic growth beyond simple reduction of PTSD symp- utilizing a modified exposure therapy paradigm in the emer- toms.196 Further, translating our expanding knowledge of the gency department hours after trauma exposure was found to neurobiology of resilience promises to yield novel therapeutic mitigate the emergence of PTSD reactions, particularly in rape strategies for treating PTSD197 (see Text Box 1). victims.185 Using a combined genotype risk score, those at higher genetic risk for PTSD who did not receive the interven- Psychosocial and Cognitive-Training Strategies to tion had higher PTSD symptom levels.186 Enhance Resilience There is also an active interest in developing early pharma- Numerous studies identifying the buffering effect of social cologic interventions to help prevent or mitigate first onset of support against stress and trauma have contributed to the de- PTSD symptoms after trauma exposure.183,187 In studies to velopment of interventions focused on building social support date, the beta-adrenergic blocker propranolol administered and relationship skills. Examples include an intervention for shortly after trauma to try to prevent initial consolidation of veterans with PTSD and their marital partners, incorporating traumatic memories failed to reduce PTSD incidence but did partner-based exercises focused on effective communication, attenuate physiological responses.188 Studies of pharmacologic intimacy, and anxiety reduction,205 and Skills Training in Af- agents showing promise for the secondary prevention of PTSD fective and Interpersonal Regulation, piloted in veterans with include RCTs of hydrocortisone administration (thought to en- military sexual trauma and PTSD.198 For survivors of sexual hance synaptic plasticity),189,190 naturalistic studies of morphine assault and intimate partner violence, social support that pro- administration,191,192 and intranasal oxytocin studies.63,193 Pre- motes self-esteem is critical206 to counter potential negative clinical studies have also identified NPYas a promising agent, as feedback from their social circle via victim blaming.207,208 it has consistently shown to attenuate stress responses and, more Of note, in a recent RCT, interpersonal psychotherapy for recently (in animal models), the development of PTSD-like individuals with PTSD, emphasizing the interpersonal after- symptoms.81,194,195 Further research is needed before early math of trauma, showed similar efficacy as prolonged expo- secondary prevention can be implemented in clinical practice. sure, the gold-standard treatment.209 Other resilience-boosting interventions such as stress inoculation training, mentioned above, incorporate active prob- Resilience-Based Interventions for PTSD Psychotherapeutic, resilience-based interventions for adults lem solving, cognitive reappraisal, and relaxation training to who have developed PTSD aim to enhance social support, pos- assist trauma survivors. In female sexual assault survivors, this approach was associated with reductions in PTSD and itive emotions, physical exercise, emotion regulation, meaning 210,211 making, and purpose in life. Building upon and utilizing these depressive symptoms. The Moving Forward program skills therapeutically may help bolster resilient functioning and for veterans with PTSD provides training in effective problem solving and emotion regulation, and has been found to yield improvements in social problem solving and resilience mea- Text Box 1 sured by the Brief Resilience Scale.212 Recent studies have also How Resilience Research Can Benefit PTSD Treatment: begun to examine the potential of incorporating positive Some Examples of Novel and Potential Interventions mood induction to increase the effectiveness of exposure 199 Psychotherapy therapy interventions. Social support: Skills Training in Affective and Interpersonal Meaning-making interventions, which involve integrating ’ Regulation, promoting social engagement, skills, and a traumatic experience into the survivor s broader belief sys- 213–215 functioning198 tem, have also been employed in the treatment of PTSD. Positive emotions: Incorporating positive mood induction Originally developed by Viktor Frankl, logotherapy has been into exposure therapy199 adapted for the treatment of combat-related PTSD, supporting Emotion regulation/purpose in life: emotion-regulation individual strengths and guiding combat survivors in a per- 216 therapy, focusing on mindful emotion-regulation skills sonal search for meaning and purpose. Narrative-based and on what is meaningful in life to the patient200 therapies, such as Skills Training in Affective and Interpersonal “Training the brain” Regulation, also incorporate meaning making and the en- Attention-bias modification training and attention-control hancement of emotion regulation and social support.217 training201,202 Emotion-regulation therapy, developed to treat individuals Cognitive-emotional training109,110 with anxiety and depressive disorders, incorporates mindful Pharmacotherapy emotion-regulation skills and a focus on what is, for the patient, 200 Pharmacologic augmentation of psychotherapy203 meaningful in life, with potential applications for PTSD. Intranasal neuropeptide Y81 Mindfulness, yoga, and meditation, linked to increases in 218,219 Intranasal oxytocin63,204 positive affect and improved immune system function, Discovery of novel pharmacological targets in animal models have increasingly been studied as interventions for PTSD. of resilience25 Dialectical behavior therapy,220 which emphasizes mindfulness- based skills, has been successfully adapted for PTSD, particularly

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for survivors of childhood abuse and for individuals with recently, in a rodent model of PTSD, intranasal NPY adminis- complex PTSD presentations.221,222 Yoga integrates physical tration immediately prior or following traumatic stress expo- exercise (known to be protective against chronic stress223), is sure showed protective effects on behavioral, neuroendocrine, often incorporated into mindfulness and meditation-based and molecular changes.79 Intranasal NPY is currently being in- paradigms, and has been found to yield improvement in vestigated as a potential treatment for PTSD.81 The glutamate PTSD symptoms, positive affect, and resilience in preliminary NMDA receptor antagonist ketamine, shown in animal studies studies for PTSD.224,225 to reverse synaptic atrophy in the PFC stemming from chronic The last few years have seen the emergence of cognitive- stress,83 has demonstrated efficacy for treatment-resistant de- emotional training interventions, aimed at reducing abnor- pression240 and, more recently—in the first proof-of-concept malities in attention to threat and emotion processing that RCT—for PTSD.241 RCTs of repeated intravenous adminis- were identified in earlier cognitive and neuroimaging studies tration of ketamine over two to four weeks for patients with of individuals with stress-related disorders.109,201 Preliminary PTSD are currently under way. Other promising novel phar- findings from a study in combat veterans with PTSD suggest macotherapies for PTSD currently under study include intrana- that attention-control training, rather than attention-bias sal oxytocin administration63,204 and compounds targeting the modification training, might help normalize attention alloca- endocannabinoid system.242,243 tion and improve PTSD symptoms.202 Cognitive-emotional training, another novel intervention with promising initial re- FUTURE DIRECTIONS sults in patients with major depression, awaits additional test- Resilience research is blossoming as the field embraces ining in relation to PTSD patients.110 creased interdisciplinary collaboration and translational studies aimed at enhancing preventive efforts, expanding currently Emerging Pharmacotherapeutic Strategies available treatments for PTSD, and aiming beyond symptom PHARMACOLOGIC AUGMENTATION OF PSYCHOTHERAPY Gold-standard, reduction to boost resilience and coping. Psychosocial factors evidence-based psychotherapies for PTSD are based on expo- long known to enhance resilience, such as hardiness, coping sure techniques within CBT paradigms. Neuroimaging studies self-efficacy, social support, cognitive reappraisal, and meaning suggest that CBT may reduce PTSD symptoms by decreasing making, are increasingly incorporated into new intervention activation of the amygdala and increasing activation of the rostral ACC.226 Increasingly, studies are investigating phar- designs for children and adults. macological augmentation strategies to enhance the efficacy of Neural and molecular studies in preclinical models of resil- exposure-based psychotherapy, thought to work through ex- ience are increasingly identifying active adaptations in resilient 25,244 thereby providing valuable insight into potential tinction learning.203 D-cycloserine, a partial agonist at the gly- animals, avenues for novel pharmacological interventions to mitigate cine regulatory site of the NMDA glutamate receptor that was the effects of stress and trauma. Additionally, combined ge- found to enhance fear extinction in preclinical studies, has nomic and molecular studies, along with new genome-wide shown some promise for anxiety and obsessive-compulsive studies in large samples of trauma-exposed individuals, will disorders, but results from PTSD studies have not supported the clear efficacy of D-cycloserine for that purpose.227–230 Pro- ultimately enable both identification of individuals at high pranolol, discussed above under secondary prevention, has ad- risk for stress-related psychopathology and the development ditionally been tested in conjunction with trauma-memory of novel intervention strategies designed for newly identified targets. Key examples of this approach are the studies on the reactivation in attempts to block or reduce reconsolidation of FKBP5 Â Â the trauma memory in individuals with PTSD, with mixed re- gene, which discovered genetic epigenetic envi- sults to date.231–234 Results from preclinical studies suggest the ronment interactions in individuals exposed to childhood trauma, associated with a differential risk for PTSD in adult- potential utility of other agents in combination with psycho- 7 — hood. These findings lay the groundwork for the develop- therapeutic intervention for PTSD including endocannabinoids, FKBP5 estrogen, methylene blue, and histone deacetylase inhibitors— ment of antagonists, currently being tested in rodent models of early trauma exposure.245 In the future, it might most of which have not yet been studied in humans with this also be possible to enhance or suppress the expression of spe- combined approach.203 There is also renewed interest in study- cific genes associated with onset or chronicity of PTSD.197 ing ±3,4-methylenedioxymethamphetamine (MDMA)-assisted 235,236 Our advancing understanding of fear conditioning, recon- psychotherapy, with initial promising results. solidation, and extinction mechanisms emerging from both INVESTIGATIONAL PHARMACOTHERAPIES Currently available med- animal and human studies also has clear translational impli- ications for treating PTSD are insufficiently effective for many cations for PTSD—in particular, findings from recent studies patients,237,238 though findings from studies of the neurobiol- demonstrating that memory retrieval can induce brain plastic- ogy of resilience have suggested potential novel pharmaco- ity.107 Reactivated trauma memories can be “updated” with logic approaches. For example, evidence from studies in new information, potentially modifying their meaning or emo- resilient Special Forces soldiers and in patients with PTSD, tional impact on the individual; alternatively, pharmacologic mentioned above, indicates that the anxiolytic neuropeptide intervention has the potential to block reconsolidation of NPY might be involved in enhancing resilience.80,239 More trauma memories.107 Further, as reviewed above, pharmacologic

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augmentation can potentially enhance extinction learning.203 goal in the field of resilience is to broaden treatment strategies This active area of research is complex and not without risk, es- for individuals with PTSD and other stress-related disorders pecially because pharmacologic intervention can also strengthen beyond symptom reduction to bolstering well-being and resil- trauma memories, depending on the timing of drug administra- ience. New intervention programs for the military and other tion, mechanism, and emotions elicited during trauma recall.203 populations with high trauma exposure are increasingly incor- Additionally, the development of cognitive-emotional porating mindfulness, meaning making, cognitive reappraisal, training interventions—based on our growing understanding and the promotion of adaptive coping. Equally important, of neural circuity subserving attention, perception, and regulation the development of new screening and early-identification of emotion—holds significant promise for the prevention and strategies, along with efforts targeted at optimization, dissem- treatment of stress-related disorders, including PTSD. A growing ination, and implementation of new interventions, will need number of clinical trials promise to yield novel pharmacological to advance alongside the fast-paced growth of preventive and interventions aimed at reducing dysfunction in stress response treatment strategies. systems by targeting key neurotransmitter, hormone, and neuropeptide systems as well as immune responses.197 New stud- “ ” ies also aim to identify a biomarker panel for PTSD across Declaration of interest: Dr. Feder is listed as a coinventor on a the stress response system (including genomic, neuroendo- use patent application of ketamine for treating PTSD. crine, and immune biomarkers) to facilitate the identification of high-risk individuals and the diagnosis of PTSD, and to op- 246–249 REFERENCES timize intervention design. 1. Southwick SM, Bonanno GA, Masten AS, Panter-Brick C, The extant and rich literature on the consequences of early- Yehuda R. 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