Thus, genetically susceptible individuals are at increased risk for stress-related disease.
Pathobiology of the stress response
The chain of events commonly referred to as the “fight-or-flight response” originally evolved to allow an organism to respond when its physical well-being was threatened. This “stress response” is mediated, in part, by the hypothalamic-pituitary-adrenal (HPA) axis that coordinates portions of the nervous and endocrine systems to direct available resources toward the task of overcoming or avoiding the threatening stimulus (stressor).
In the short term, the stress response is extremely adaptive because it shifts biological resources toward physiological functions that promote escape and survival. However, if the stress response becomes chronic because of repeated exposure to stressors, deficits at various levels of the negative feedback system, or both, the result is a sustained increase in the level of stress hormones and the initiation of pathological changes across multiple physiological systems. The consequence is increased vulnerability to stress-related diseases.5
Long-term consequences of ELS exposure
A preponderance of clinical data illustrates the long-term adverse effects of physical and sexual abuse on mental health. Women with a history of sexual abuse are more likely to manifest depressive-like behaviors after stressful life events than are women without such a history.6 In addition, the developmental timing of abuse may contribute to the clinical outcome of exposure to childhood trauma. For example, posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are equally likely to develop in girls abused before age 13. However, PTSD is more likely to develop in those who were abused after age 13.7 This divergence in clinical course may, in part, be linked to the development of the HPA axis and stress coping mechanisms.
In addition to the neuroendocrine and neurotransmitter alterations, there is evidence that ELS may alter brain structure. The hippocampus is a prominent substrate for glucocorticoid-mediated negative feedback on HPA axis activity. Changes in hippocampal cytoarchitecture after chronic stress have been associated with changes in both mood and cognition.8 ELS has been linked to decreased hippocampal volume and may be an important contributor to reduced hippocampal volume in depression.9-11 The concatenation of findings demonstrates that ELS alters the HPA axis and markedly increases the risk of depression and other disorders.
Preclinical studies provide insight into the mechanisms of stress-induced changes in behavior and have demonstrated that ELS exerts both acute and long-term effects on neuroendocrine, cognitive, and behavioral systems.12 Laboratory animals exposed to stressful conditions during development manifest adverse short- and long-term cognitive dysfunction and abnormal behavior associated with alterations of the normal physiology and genetic regulation of the HPA axis.13 Pathological stress responsiveness in adult mammals appears to be mediated in part through the effects of developmental stress on the neural systems that mediate the expression of fear.14 Moreover, the quality of maternal care early in development may be a moderating influence that exerts substantial effects on the ontogeny of the stress response in adult animals.15 Collectively, the data derived from rodent and nonhuman primate studies demonstrate that the effects of ELS continue into adulthood in the form of abnormal behavior and hyperresponsiveness of the HPA axis to environmental stressors.
CHECKPOINTS
■ The stress response shifts biological resources toward physiological functions that promote escape and survival; however, if the stress response becomes chronic because of repeated exposure to stressors, deficits at various levels of the negative feedback system, or both, the result is a sustained increase in the level of stress hormones and the initiation of pathological changes across multiple physiological systems. The consequence is increased vulnerability to stress-related diseases.
■ Posttraumatic stress disorder (PTSD) and major depressive disorder are equally likely to develop in girls who are abused before age 13; however, PTSD is more likely to develop in those who were abused after age 13.
■ Trauma exposure and neglect during both early life and adulthood substantially elevate adult risk for mood and anxiety disorders and alter hypothalamic-pituitary-adrenal (HPA) axis physiology. Exposure to a depressed mother either in utero or in the first months of life may also alter the HPA axis.
Genetic influences
Regardless of the developmental stage during which it occurs, exposure to violence and trauma alone does not produce adverse effects in all exposed women. Thus, the risk of PTSD and/or depression is, in part, heritable.16-18 A major research goal of psychiatric genetics is to understand how genetic variation, both independently and in concert with the environment, influences individual vulnerability to disease.
With respect to stress-related psychiatric illnesses, such as depression and PTSD, a great deal of work has focused on the identification of candidate genes whose allelic variants are thought to contribute to risk of disease in the presence of ELS, such as the serotonin transporter gene, and allelic variants within genes that code for elements of the HPA axis.16,19,20 For those individuals exposed to ELS, both gene 3 gene and gene 3 environment interactions likely influence the development of depression and other disorders. Notably, the genetic variants described by several studies only confer risk of depression and PTSD in the setting of childhood maltreatment. These data highlight the critical role of developmental timing and environmental influences on the expression of genetic risk of psychiatric illness.
Pleiotropic effects of ELS
The research described thus far demonstrates that trauma exposure and neglect during both early life and adulthood substantially elevate adult risk for mood and anxiety disorders and alter HPA axis physiology.21,22 However, the ramifications of ELS reach beyond mental health and behavior and have remarkable implications for a variety of common medical disorders. For example, ELS exposure increases the incidence of systemic inflammation and a variety of medical illnesses, including obesity, cardiovascular disease, cerebrovascular disease, diabetes mellitus, cancer, and autoim-mune disorders.23-27
Furthermore, a graded relationship appears to exist between exposure to trauma and psychiatric/physical health morbidity in adulthood.28 Although the biology of the interrelationships among ELS, mental illness, and physical illness is just beginning to be explored, the lifelong effects of ELS on both mental and physical health are well documented and the HPA axis is a likely mediator of both types of pathophysiology.
Multigenerational effects of violence and trauma
Abuse can reverberate among generations. It can adversely affect the fetus and maternal behavior; it can also have epigenetic effects. Exposure to a depressed mother either in utero or in the first months of life may alter the HPA axis.29 Our understanding of the effect of maternal state on the physical well-being of offspring has been greatly advanced by preclinical work with animal models. Carefully controlled studies have clearly established that exposing the pregnant female to a stressful or abusive environment is akin to directly exposing the fetus.30 The reported changes in brain morphology following gestational exposure to stress are consistent with changes found following severe forms of chronic stress in animal models or after trauma in humans.8,31
The effects of trauma cross the generational boundary and significantly alter the mental health of the subsequent generation. Some of these effects are likely caused by epigenetic changes in DNA, but evidence suggests that there are strong environmental effects of being raised by an abused parent.32,33 Furthermore, preclinical studies demonstrate the impact of altered maternal care on offspring.34 Additional work is necessary to elucidate the mechanisms underlying stress-induced changes in the HPA axis and the mental and physical consequences of these changes as they pass between generations.
Treatment implications of ELS exposure
The data described in this review indicate that patients with MDD or PTSD and a history of ELS may constitute unique endophenotypes with respect to course of illness. In addition, such patients may also require a unique treatment protocol. ELS has been found to have an impact on the clinical response of depressed patients to pharmacotherapy; the presence or absence of ELS in patients with chronic depression appears to moderate their response to pharmacotherapy and/or psychotherapy.35,36 Patients with depression and a history of ELS exhibit increased rates of relapse following successful treatment of depression.37 Furthermore, chronicity is a more common feature of depression in those with a history of ELS than in individuals without a history of childhood neglect or abuse.
Case Vignette
Erin is a 34-year-old married woman who was referred for psychotherapy by her psychiatrist. The youngest of 5 children, Erin grew up in a household with an alcohol(Drug information on alcohol)ic father (whom she suspects had bipolar disorder) and a mother with major depression. Three of Erin’s siblings were sexually abused by either her father or a friend of the family. Erin does not know whether she was sexually abused and reports that she has a very poor memory of her childhood. When she was 5 years old, her father committed suicide. At age 15, Erin was raped at a party. Shortly thereafter, she experienced her first major depressive episode and made a serious suicide attempt. Erin’s depression has persisted into her adult life, and she experiences transient episodes of binge eating, anorexia, and alcohol abuse.
Erin first sought psychiatric treatment at age 24. Over the next 7 years, she was treated with several antidepressants and mood stabilizers. After she experienced a debilitating postpartum major depressive episode, she was treated with an 8-session course of electroconvulsive therapy. Her depression persisted, and her psychiatrist referred her for psychotherapy to address distorted thinking and problems with emotion regulation.
Erin’s initial score on the Beck Depression Inventory (BDI) indicated that she was moderately to severely depressed. After 15 months of weekly treatment and pharmacotherapy, Erin’s BDI scores were within normal limits (representing a 75% improvement in scores), and she felt that her depression had diminished substantially. She and her therapist began to taper their sessions to once monthly, and she worked with her psychiatrist to taper and discontinue her antidepressant medications.
Four months after antidepressant discontinuation, she began to report some depressive symptoms, and within 2 months, she experienced a full relapse. She restarted her medication regimen, and returned to weekly psychotherapy. After 5 months, her BDI scores were again within normal limits; however, she elected to continue her medication and therapy regimens to prevent another relapse. Despite the fact that she was experiencing nearly full interepisode recovery, Erin and her treatment team decided that she functioned better and experienced greater symptom remission with regular ongoing therapy and a continuous medication regimen.
Conclusion
The research summarized here clearly demonstrates that exposure to stress before adulthood can result in persistent effects on both mental and physical health. Even before birth, children are particularly sensitive to the effects of stress, and this sensitivity continues after birth and throughout puberty. Exposure to violence and abuse can alter the function of the HPA axis throughout one’s life. These changes are accompanied by an increased incidence and severity of depressive and anxiety disorders as well as medical disorders. Thus, minimizing ELS would likely reduce the risk and severity of multiple mental and physical illnesses and stop the transgenerational cycle of abuse-related pathology. In addition, a better understanding of the mechanisms that underlie the pervasive effects of ELS will likely lead to improved behavioral and pharmacological treatment strategies.
