Focus Points • The study of resilience has shifted from a reductionistic, problem-oriented approach focused on finding treatments for illness, to one that emphasizes prevention and nurturing of strengths to promote wellness. • Determinants of resilience are multi-factorial, including neurobiologic, genetic, temperament, and environmental influences. • The Connor-Davidson Resilience Scale, a 25-item self-rated instrument, has been tested in both community and clinical samples with good internal consistency and test-retest reliability. • The resilience-enhancing, or saliostatic, effect of treatment has been reported in individuals with posttraumatic stress disorder taking the selective serotonin reuptake inhibitors fluoxetine or sertraline, the serotonin norepinephrine reuptake inhibitor venlafaxine extended release, the selective g-aminobutyric acid reuptake inhibitor tiagabine, or combined sertraline and cognitive-behavioral therapy. • Combined treatment is commonly recommended, although empirical support is limited.

Abstract

In human terms, resilience is an ability to cope with stress and varies with context, time, age, gender, and cultural origin. Resilience shifts the focus of psychological investigation onto increasing the positive rather than reducing the negative. Inquiry into resilience has evolved from descriptions of resilient qualities, to discovery of the process to attain resilience, to uncovering the motivation to reintegrate in a resilient manner. Much of the research on resilience has focused on children in settings such as family violence, extreme poverty, war, and natural disasters. A coherent pattern of characteristics associated with successful adaptation has emerged. Salient characteristics include commitment, dynamism, humor in the face of adversity, patience, optimism, faith, and altruism. As such, resilience may represent an important target of treatment in anxiety, depression, and stress reactions. Resilience can be quantified, but available measures need to be validated transculturally. There exist many possible determinants of resilience, including neurobiologic, genetic, temperament, and environmental influences. Resilience is modifiable on individual and cultural levels. Posttraumatic stress disorder is an example of a serious disorder associated with impaired stress coping that can improve with treatment.

Introduction

In the field of medicine, most intervention and inquiry has focused on the examination and cure of illness. In recent years there has been a shift from a reductionistic, problem-oriented approach to one that stresses prevention and the nurturing of strengths. The study of resilience has emerged from this change in orientation that focused on finding treatments for illness to attempts to promote wellness.¹

The study of resilience did not arise from theory, but rather through the empirical identification of characteristics of survivors of trauma and other adversities.¹ Inquiry into resilience has evolved from its first simplistic attempts to describe resilient qualities and to answer the question, “What characteristics determine whether people will thrive in the face of adversity?” In human terms, resilience is an ability to cope with stress. Resilience focuses on strengths that are already present, not on weaknesses and what is absent. As such, resilience may represent an important target of treatment in anxiety, depression, and stress reactions.

Resilience is a multi-faceted human characteristic that varies with context, time, age, gender, and cultural origin.^2-5 Salient characteristics include commitment, dynamism, humor in the face of adversity, patience, optimism, faith, and altruism. Past successes serve as wellsprings; stress is viewed as a challenge. Resilient individuals and communities engage the support of others, are able to tolerate negative affect, adapt, identify, and work toward meaningful goals.^3,6-8 In addition, resilience in childhood and adolescence has been associated with positive outcomes in adulthood.⁸

In its second phase the study of resilience has sought to uncover the process of attaining resilient qualities. Resilience theory holds that there is a force within every individual that drives them to seek self-realization, unselfishness, wisdom, and harmony with a spiritual wellspring of strength. A resiliency model developed by Richardson and colleagues9 is depicted in Figure 1.  This model illustrates the means by which individuals respond to life disruptions and stressors through both conscious and unconscious processes. Beginning at a state of biopsychospiritual balance or “homeostasis,” an individual adapts mind, body, and spirit to their current life situation. Internal and external stressors are ever present, and the individual’s ability to cope with these experiences is influenced by adaptations to previous disruptions. Under some circumstances, such adaptations or protective factors are ineffective and result in disruption of homeostasis. The response to this disruption over time is a reintegrative process, leading to one of the following four outcomes: the disruption represents an opportunity for growth, in which the adaptation to the disruption leads of a new, higher level of homeostasis; reintegration with return to the baseline level of homeostasis; recovery from the disruption with loss, establishing a lower lever of homeostasis; or a dysfunctional state in which maladaptive processes, such as self-destructive behaviors, are used to cope with stressors. The attainment of growth, knowledge, and self-understanding is termed resilient reintegration and refers to the adaptive coping process.



The question the third phase of resiliency theory attempts to answer is, “What is the motivation to reintegrate in a resilient manner and where do I find it?” This phase is much less quantitative and more “fuzzy,” according to skeptics. Answers to this question arise from a foundation that is centuries old and originate, in part, from Eastern medicine, theology, and philosophy.⁹  The purpose of this article is to summarize the primary determinants of resilience, to examine the means to measure it, and to describe the effect of various therapeutic interventions on resilience.

Determinants       

Biological

Stress can be characterized in several ways: duration (acute, chronic), responsiveness (adaptive, hyperadaptive, nonresponsive), and severity (mild, moderate, severe, and extreme). The effects of stress can be manifested in psychological symptoms, physiological symptoms, or both. Much of the neurobiological research in the field has focused on the consequences of severe psychological stress and stress-related psychopathology, such as posttraumatic stress disorder (PTSD) and depression in treatment-seeking populations. Little work has focused on neurobiological processes related to resilience and vulnerability to psychological stress, in general, and to specific forms of psychopathology, in particular.

Human responsiveness to stress may be attenuated by learned or adaptive skills, retraining, or indifference to future stress. Researchers have described an adaptive physiologic model for response to acute stress whereby one’s internal milieu fluctuates to meet both perceived and anticipated demands, albeit with a changing set point because of the need for homeostatic maintenance.^10,11 Failure of homeostatic mechanisms to terminate the acute adaptive physiologic response produced by neurochemical stress mediators results in the brain and body bearing the burden of adapting to physiological and psychological challenges. This burden has been termed “allostatic load” and represents the cumulative physiological burden borne by the body and brain in efforts to adapt to stressors.¹¹ McEwen and Stellar¹⁰ hypothesized that while the impact of this load on individual physiologic systems may be minimal, the cumulative effects of mild-to-moderate impairment in multiple systems could result in substantial health risk. A measure of allostatic load has been proposed and includes 10 biomarkers associated with physiologic activity. The markers were drawn from a variety of regulatory systems that have been linked to disease processes that occur with aging (Table 1).¹² In longitudinal studies, this measure was found to be significantly associated with four major health outcomes (eg, new cardiovascular disease, decline in cognitive and in physical functioning, and mortality),^12,13 thereby supporting McEwen and Stellar’s hypothesis regarding the deleterious effects of allostatic load. It is important to note that this model focuses on physiologic outcomes with long-term stress and has not been applied to the investigation of neurobiological risk factors for psychopathology.



Charney¹⁴ addressed this issue in a recent review in which he offered a framework for developing a psychoneurobiological measure for allostatic load. This integrative model of resilience and vulnerability incorporates neurochemical response patterns to acute stress along with neural mechanisms that mediate reward, fear conditioning, social behavior, and important functional interactions between these systems. For example, using inhibitory avoidance, or contextual fear, as the stressor, Table 2 provides a summary of the neurochemical response pattern to this acute stressor, associated neural mechanisms, and functional interactions related to psychopathology and resilience.¹⁴



In terms of a neurochemical profile, the activity of  a number of neurotransmitters, neuropeptides, and hormones work to promote resilience (eg, dehydroepiandrosterone [DHEA], neuropeptide Y, galanin, serotonin [5-HT], and benzodiazepine receptors), while others work to undermine it (eg, corticotropin-releasing hormone [CRH], locus coeruleus-norepinephrine system). However, some neurochemicals serve both functions (eg, cortisol, dopamine), depending on the circumstances and neuroanatomic site of action. For example, CRH is an important neurochemical stress mediator with complex effects. CRH is released from the hypothalamus with stress, activating the release of cortisol and DHEA via the hypothalamic-pituitary-adrenal axis. CRH-containing neurons are also located at numerous other sites throughout the brain and it is here that the extra-hypothalamic effects of CRH associated with the stress response are exhibited: activation of fear behaviors, increased arousal and motor activity, inhibited neurovegetative function, and reduced reward expectations. Two CRH receptors are found in different brain regions and evidence from animal models suggests they have opposing functions, with activation of CRH-1 receptors demonstrating anxiogenic effects and activation of CRH-2 receptors demonstrating anxiolytic effects.¹⁵ Thus, CRH increases cortisol and DHEA levels, activates the locus coeruleus-norepinephrine system, and activates anxiogenic CRH-1 receptors and anxiolytic CRH-2 receptors. Persistently elevated levels of CRH have been found in association with PTSD and major depression and may relate to chronicity of symptoms of fear, anxiety, and anhedonia. However, it is possible that reduced CRH levels and adaptive changes in CRH-1 and CRH-2 receptors may result in less vulnerability to stress and greater resilience.^16-18 For further reading regarding this topic, we refer readers to Charney’s¹⁴ review of the psychobiological mechanisms of resilience and vulnerability.

Genetic

Science has yet to provide satisfactory explanations for differences in normal and abnormal behavior in humans. Underlying biological mechanisms have not been adequately elucidated, but recent advances in molecular genetics and neuroimaging have begun to offer possible explanations for individual differences in stress responsivity. Much interest has focused recently on the serotonin transporter gene (SLC6A4). In humans, the short “s” allele of the promoter region of the serotonin transporter gene (5-HTTLPR) has been associated with reduced 5-HT transporter expression and function and with anxiety in healthy subjects.^19,20 This finding with the 5-HTTLPR polymorphism has been replicated in numerous studies and verified in mice lacking SLC6A4. Typically, the effect of this gene on subjective measures of personality is modest, accounting for a small proportion of the total variance.²¹

At the behavioral level, Hariri and colleagues²² found that individuals who are heterozygous or homozygous for the s allele of 5-HTTLPR exhibit greater amygdalar activity in response to fear-inducing stimuli compared with individuals homozygous for the long allele.  The difference between the two genotypes was ~5-fold, accounting for 20% of total variance. This effect size (ES) was ~10-fold greater than in experiments using personality measures. These results suggest a complex linkage between gene networks and multiple environmental factors such as education, socioeconomic circumstances, parents, peer groups, and siblings, which impact brain development and function, and ultimately influence behavior.^22,23

Evidence for an association between the 5-HTTLPR polymorphism and depression is inconclusive,²⁴ but such a relationship could moderate the serotonergic response to stress. Caspi and colleagues²⁵ performed a prospective epidemiologic study investigating possible genetic vulnerability to depression with the 5-HTTLPR polymorphism and a potential gene-by-environment interaction, examining if the 5-HTTLPR polymorphism moderated the influence of life stress on depression. The study sample was comprised of a large birth cohort in New Zealand followed longitudinally over 26 years. At age 26, subjects were assessed for the presence of major depression and for stressful life events. Compared to subjects homozygous for the long allele, subjects with one or two copies of the s allele of the 5-HTTLPR polymorphism exhibited more depressive symptoms, diagnosable major depression, and suicidality in relation to stressful life events in adulthood. Furthermore, childhood maltreatment was also found to predict major depression in adulthood, but only in subjects with the s allele.²⁵ These findings provide evidence of a gene-by-environment interaction in which an individual’s response to environmental insults, either early in life or in adulthood, is moderated by his or her genetic makeup.

These studies demonstrate how changes in a regulatory promoter region—not coding regions—may influence brain function and behavior. This type of variation, along with others yet undiscovered, may well play a prominent role in individual differences. It is well known that people react differently to stressful life experiences. Theories of depression have predicted that an individual’s sensitivity to stressful events depends on their genetic composition.²⁶ Behavioral geneticists have documented that the risk of depression after acute stress is increased among people at high genetic risk and diminished among people at low genetic risk.²⁷ How specific genes or gene networks, in concert with environmental variables, aggravate or shield the effects of acute stress is unknown. These studies also indicate that trials that use neurochemical, neuroimaging, and genetic approaches may help to elucidate the relationships between phenotype, genotype, and psychobiologic reactions to stress.¹⁴

Findings from the field of genetic epidemiology have also helped us to begin to understand the role of genetic influences in psychopathology. For example, over the last century, findings from twin, adoption, and family studies have demonstrated that genes influence the etiology of most disorders. Research has demonstrated that the inheritance of most psychiatric disorders is complex and that single gene variants of psychiatric illnesses are rare. Most cases of psychiatric illness can be attributed to the joint actions of gene networks and environmental risk factors which impact brain development and function, and ultimately influence behavior.

Thus, variable expression is a common feature of psychiatric disorders. Genes may never predict who will become ill with a psychiatric disorder. However, if genes and gene regulators are discovered, they may be used in conjunction with other known risk factors to identify individuals at risk for mental illness. If that becomes possible, individuals at greatest risk could potentially be selected for primary prevention protocols to possibly block the expression of the gene and thereby the onset of disease.²⁸

In contrast to our limited understanding of the genetics of psychiatric disorders, even less is known about the inheritance of mental health well-being, or resilience. One could surmise that mental health well-being may be associated with the absence of genes that cause specific disorders. Research by Kendler and colleagues²⁹ focused on whether there are genes and environmental risk factors that contribute to health or wellness. Should researchers succeed in the discovery of health-inducing genes and environmental factors, such a discovery would signal a tectonic shift in psychiatric research that would place as much emphasis on wellness as illness.³⁰

Temperament

Temperament appears to be another determinant of resilience. One of the early series of investigations that stimulated interest in this field was Werner’s⁸ work with the children of Kauai. This prospective longitudinal investigation examined the developmental course of high-risk and resilient children from a 1955 birth cohort on the island of Kauai, Hawaii.  The relative influence of risk and protective factors changed during various life phases. Males displayed more vulnerability than females in their first decade and less during their second decade. At the beginning of their fourth decade, another shift appears under way. Certain protective factors seem to have a more general effect on adaptation than do specific risk factors.⁸ Protective factors include sociability, intelligence, social competence, internal locus of control, warmth and closeness of affectional ties, active emotional support within the family network, social support, and characteristics of school, work, and church.

Other studies of child temperament, environment, and resilience have supported Werner’s findings. In a study involving twin pairs, results demonstrated that maternal warmth, activities that stimulated children, and outgoing temperament promoted positive adjustment in children exposed to socioeconomic deprivation. These findings also demonstrated that resilience is partially heritable and that protective processes operate through genetic and environmental effects.³¹

Another study examined the effects of child temperament and stressful family environment on behavioral problems among preschool children. Results showed that children with the most internalizing and externalizing behavioral problems had the most difficult temperaments and were raised in high conflict family environments. Children with the most difficult temperaments lived in highly expressive families and were the most aggressive, whereas children with easy temperaments had fewer behavioral problems, regardless of family environment. These results suggest that both protection and vulnerability are associated with temperament: a difficult temperament may operate as a vulnerability factor for internalizing and externalizing behavior problems, whereas an easy temperament may function as a protective mechanism for these problems.³²

Environmental

While genetic factors may be important risk factors for stress coping and resilience, environmental factors are important as well. For example, while over 50% of adults in the United States will experience a trauma during their lifetime that could be associated with the development of PTSD, epidemiologic studies reveal that the lifetime prevalence of PTSD in the United States is only 7% to 8%.³³ It is unclear why some individuals develop PTSD and other posttraumatic pathology while others do not. Furthermore, it is unclear why some individuals can cope and function well under stress while others are overwhelmed and function poorly under similar circumstances.

Specific risk factors for resilience have not been systematically assessed; however, a variety of risk factors for PTSD have been identified in the literature. In reviewing 38 published studies, Shalev³⁴ grouped these factors into general categories of pretrauma vulnerability, event-related characteristics, magnitude of the stressor, preparation for the event, immediate reactions to the event, and posttrauma factors. More recently, Brewin and colleagues³⁵ conducted a meta-analysis of 14 separate risk factors for PTSD, examining the moderating effects of various sample and study characteristics. Three categories of risk factors emerged: factors predictive of PTSD in some populations but not in others (eg, gender, age at trauma, and race); factors that predicted PTSD more consistently but to a varying extent depending on the study population and methods applied (eg, education, previous trauma, and general childhood adversity); and factors with more uniform predictive effects (eg, psychiatric history, reported childhood abuse, and family psychiatric history). In general, the ES of all risk factors was modest. Environmental factors operating during or after trauma, such as trauma severity, lack of a social support structure, and additional life stress had stronger effects than pretrauma factors.³⁵

Although the meta-analyss suggested statistically significant differences, further characterization of a minimally clinically important difference is necessary. These results suggest a trend, but further prospective studies are required to substantiate and delineate the extent of their effect. Further work in characterizing factors such as the time of a preceding event, the patient’s initial reaction, support systems, and development of adaptive coping skills is necessary. The investigators identified combinations of factors that were suggestive of the impact on risk. However, no one factor is likely to be predictive of an outcome.³⁵

Measurement

Interventional studies have traditionally focused on morbidity, as opposed to health promotion. The measurement of resilience or facets of resilience has been undertaken by a number of researchers,^6,36 but the scales developed have been limited in scope and lack generalizability. With the growing emphasis on mental health promotion, the need for a well-validated, reliable, simple tool to help quantify resilience and to assess its response to treatment is evident.

The Connor-Davidson Resilience Scale (CD-RISC) is an instrument that consists of 25 self-rated items.³⁷ Each item is rated from 0 (not at all true) to 4 (true nearly all of the time). The scoring range is between 0 and 100. Higher scores correspond to greater resilience. The scale builds upon the work of previous research on hardiness,⁶ action orientation, self-efficacy, confidence, adaptability,3 patience, and endurance in the face of adversity,⁷ as well as on the characteristics of historical figures who embody the concept of resilience.³⁸

The CD-RISC has been tested in both community and clinical samples and has demonstrated good internal consistency and test-retest reliability. When compared to other measures, the scale exhibits validity relative to stress and hardiness and reflects different levels of resilience in differentiated populations. The general population mean is 80, whereas lower mean scores are observed in various treatment-seeking populations: primary care, 72; psychiatric outpatients, 68; generalized anxiety disorder, 62; major depression, 58; and PTSD, 50.³⁷ Clinical improvement is accompanied by up to a 25% increase in resilience, depending on the level of global improvement. Improvements in CD-RISC score were noted in proportion to overall clinical global improvement. The greatest increase was noted in subjects with the highest global improvement; CD-RISC scores decreased in individuals with minimal or no global improvement.³⁷ According to its developers, the scale demonstrates that resilience is quantifiable, modifiable, and can improve with pharmacologic and psychotherapeutic interventions.

The CD-RISC may prove useful in both clinical and research settings. Three areas where CD-RISC might be helpful were identified: investigation of the neurobiology of resilience; clinical practice with interventions to bolster resilience; and in settings to investigate strategies for coping with stress. The authors also noted several limitations of the CD-RISC scale. Neither information about the process of resilience, nor the theory of resilience is provided. The scale has not been validated against objective measures of resilience such as neurochemical responses to stress,³⁷ in children or adolescents, or across different cultures.

Treatments

After a discussion of the determinants of resilience and its measurement, a salient question is, “How can we increase resiliency?” This question has particular relevance to those at risk for stress-related disorders, including survivors of trauma and others with a predisposition to anxiety or depression. Perhaps there are individual characteristics that can be fostered to help such individuals recover more quickly. Passing reference has been made to the belief that selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) both promote resilience, but in the absence of direct measurement of this effect.^39,40 More recently, a number of interventions have demonstrated improvement in resilience using psychometrically validated instruments, but current data are limited largely to studies in individuals with PTSD.

An early report of the effect of pharmacotherapy on resilience was noted by Connor and colleagues⁴¹ who undertook a 12-week, placebo-controlled trial of fluoxetine in civilians with PTSD. Among the outcomes assessed were several features beyond basic PTSD symptoms, notably stress vulnerability (Sheehan’s Stress Vulnerability Scale), which may also be considered a measure of resilience.^42,43 At week 12, fluoxetine was more effective than placebo in reducing vulnerability to the effects of stress (P<.01). The authors opined that resilience to the effects of stress may be regarded as a potential protective factor against feeling overwhelmed in the face of pressure or setback and that their findings suggested that the serotonergic drug fluoxetine conferred a resilience-building effect.

The resilience-enhancing, or saliostatic, effect of treatment has been reported with a number of other interventions in individuals with PTSD. Using CD-RISC described above, results from open-label clinical trials have yielded moderate to strong treatment effects. These findings include treatment with the selective g-aminobutyric acid reuptake inhibitor tiagabine (ES=1.05), the SSRIs fluoxetine (ES=0.68) and sertraline (ES=0.81), and combined sertraline and cognitive-behavioral therapy (ES=0.55), with an overall ES of 0.76.44 Resilience characteristics that showed the greatest changes were related to confidence, control, coping, knowing where to turn for help, and adaptability. Items showing the least change were related to religious and existential aspects of resiliency, effort, acting on a hunch, decision-making, and goals. Among the predictors of response to treatment were baseline CD-RISC score and the item assessing “sense of humor.”⁴⁴ Resilience-building effects have also been observed with the SNRI venlafaxine extended release. Pooled results from two large multicenter randomized controlled trials of patients with PTSD found that total CD-RISC score and treatment were significant predictors of both response and remission.⁴⁵

Conclusion

Resilience shifts the focus of psychological investigation and inquiry onto increasing the positive rather than reducing the negative. Much of the research on resilience has focused on children and adults in settings such as family violence, extreme poverty, war, and natural disasters. A coherent pattern of characteristics associated with successful adaptation is emerging. These include sound intellectual functioning, the ability to cope with emotions, self-esteem, optimism, altruism, humor, and an engaged and active coping style in the face of adversity.

There exist many possible determinants of resilience, including neurobiologic, genetic, temperament, and environmental influences. Resilience can be quantified, but available measures need to be validated transculturally and in children and adolescents. Resilience is modifiable on individual and cultural levels. Individuals who successfully cope and adapt are able to maintain reward expectations in an unrewarding milieu, regulate fear conditioning and extinction in the face of uncontrollable stress, and maintain effective bonding and attachments following interpersonal abuse or loss. Posttraumatic stress disorder is an example of a serious disorder with impaired stress coping, which improves with treatment.

References

1. Richardson GE. The metatheory of resilience and resiliency. J Clin Psychol. 2002;58:307-321.
2. Seligman ME, Csikszentmihalyi M. Positive psychology. An introduction. Am Psychol. 2000;55:5-14.
3. Rutter M. Resilience in the face of adversity. Protective factors and resistance to psychiatric disorder. Br J Psychiatry. 1985;147:598-611.
4. Garmezy N. Stress Resistant Children: The Search for Protective Factors. Recent Research in Developmental Psychopathology. Book supplement no. 4 to J Child Psychol Psych. Oxford: Pergamon Press; 1985.
5. Garmezy N, Rutter M. Acute stress reactions. In: Rutter M, Hersob L, eds. Child and Adolescent Psychology: Modern Approaches. Oxford: Blackwell; 1985.
6. Kobasa SC. Stressful life events, personality, and health: an inquiry into hardiness. J Pers Soc Psychol. 1979;37:1-11.
7. Lyons J. Strategies for assessing the potential for positive adjustment following trauma. J Trauma Stress. 1991;4:93-111.
8. Werner EE. The children of Kauai: resiliency and recovery in adolescence and adulthood. J Adolesc Health. 1992;13:262-268.
9. Richardson GE, Neiger B, Jensen S, Kumpfer K. The resiliency model. Health Educ. 1990;21:33-39.
10. McEwen BS, Stellar E. Stress and the individual. Mechanisms leading to disease. Arch Intern Med. 1993;153:2093-2101.
11. Sterling P, Eyer J. Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J, eds.  Handbook of Life Stress, Cognition, and Health. New York, NY: John Wiley & Sons; 1988:629-649.
12. Seeman TE, McEwen BS, Rowe JW, Singer BH. Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proc Natl Acad Sci U S A. 2001;98:4770-4775.
13. Karlamangla AS, Singer BH, McEwen BS, Rowe JW, Seeman TE. Allostatic load as a predictor of functional decline. MacArthur studies of successful aging. J Clin Epidemiol. 2002;55:696-710.
14. Charney DS. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry. 2004;161:195-216.
15. Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci. 2002;22:193-199.
16. Baker DG, West SA, Nicholson WE, et al. Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry. 1999;156:585-588.
17. Nemeroff CB. Recent advances in the neurobiology of depression. Psychopharmacol Bull. 2002;36(suppl 2):6-23.
18. Bremner JD, Licinio J, Darnell A, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry. 1997;154:624-629.
19. Lesch KP, Mossner R. Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol Psychiatry. 1998;44:179-192.
20.  Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527-1531.
21. Murphy DL, Li Q, Engel S, et al. Genetic perspectives on the serotonin transporter. Brain Res Bull. 2001;56:487-494.
22. Hariri AR, Mattay VS, Tessitore A et al. Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002;297:400-403.
23. Hamer D. Genetics. Rethinking behavior genetics. Science. 2002;298:71-72.
24. Lesch KP. Neuroticism and serotonin: a developmental genentic perspective. In: Plomin R, DeFries JC, Craig IW, McGuffin P, eds. Behavioral Genetics in the Postgenomics Era. Washington, DC: American Psychiatric Association; 2003:389-424.
25. Caspi A, Sugden K, Moffitt TE et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386-389.
26. Costello EJ, Pine DS, Hammen C et al. Development and natural history of mood disorders. Biol Psychiatry. 2002;52:529-542.
27. Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry. 1999;156:837-841.
28. Tsuang MT, Faraone SV. The future of psychiatric genetics. Curr Psychiatry Rep. 2000;2:133-136.
29. Kendler KS, Roy MA. Validity of a diagnosis of lifetime major depression obtained by personal interview versus family history. Am J Psychiatry. 1995;152:1608-1614.
30. Tsuang MT. Genes, environment, and mental health wellness. Am J Psychiatry.. 2000;157:489-491.
31. Kim-Cohen J, Moffitt TE, Caspi A, Taylor A. Genetic and environmental processes in young children’s resilience and vulnerability to socioeconomic deprivation. Child Dev. 2004;75:651-668.
32. Tschann JM, Kaiser P, Chesney MA, Alkon A, Boyce WT. Resilience and vulnerability among preschool children: family functioning, temperament, and behavior problems. J Am Acad Child Adolesc Psychiatry. 1996;35:184-192.
33. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048-1060.
34. Shalev AY. Stress versus traumatic stress: from acute homeostatic reactions to chronic psychopathology. In: van der Kolk BA, McFarlane AC, Weisaeth L, eds.  Traumatic Stress. New York, NY: Guilford Press; 1996:77-101.
35. Brewin CR, Andrews B, Valentine JD. Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol. 2000;68:748-766.
36. Wagnild GM, Young HM. Development and psychometric evaluation of the Resilience Scale. J Nurs Meas. 1993;1:165-178.
37. Connor KM, Davidson JR. Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety. 2003;18:76-82.
38. Alexander C. The Endurance: Shackleton’s Legendary Antarctic Expedition. London: A. Knopf; 1998.
39. Ravindran AV, Griffiths J, Waddell C, Anisman H. Stressful life events and coping styles in relation to dysthymia and major depressive disorder: variations associated with the alleviation of symptoms following pharmacotherapy. Prog Neuro Psychopharmacol Biol Psychiatry. 1995;19:637-653.
40. Healy D, Healy H. The clinical pharmacologic profile of reboxetine: does it involve the putative neurobiological substrates of wellbeing? J Affect Disord. 1998;51:313-322.
41. Connor KM, Sutherland SM, Tupler LA, Malik ML, Davidson JR. Fluoxetine in post-traumatic stress disorder. Randomised, double-blind study. Br J Psychiatry. 1999;175:17-22.
42. Sheehan DV, Raj AB, Sheehan KH, Soto S. Is buspirone effective for panic disorder? J Clin Psychopharmacol. 1990;10:3-11.
43. Sheehan DV. The Anxiety Disease. New York, NY: Charles Scribners Sons; 1983.
44. Davidson JR, Payne VM, Connor KM et al. Trauma, resilience and saliostasis: effects of treatment in post-traumatic stress disorder. Int Clin Psychopharmacol. 2005;20:43-48.
45. Davidson J, Stein DJ, Rothbaum BO, Pedersen R, Tain XW, Musgnung J. Resilience as a predictor of remission in PTSD patients treated with venlafaxine XR or placebo. Poster presented at: Annual Meeting of the Anxiety Disorders Association of America; March 23-26, 2006; Miami, Florida.