Elsevier

Biological Psychiatry

Volume 46, Issue 11, 1 December 1999, Pages 1509-1522
Biological Psychiatry

The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders

https://doi.org/10.1016/S0006-3223(99)00224-3Get rights and content

Abstract

The relative contribution of genetic and environmental factors to the development of the major psychiatric disorders has long been debated. Recently, considerable attention has been given to the observations that adverse experiences early in life predispose individuals to the development of affective and anxiety disorders in adulthood. Corticotropin-releasing factor (CRF) is the central coordinator of the endocrinologic, autonomic, immunologic, and behavioral stress responses. When centrally administered, CRF produces many physiologic and behavioral changes reminiscent of both acute stress and depression. Moreover, CRF has also been implicated in the pathogenesis of a variety of anxiety disorders, mainly through CRF neurocircuits connecting the amygdala and the locus ceruleus. Clinical studies have provided convincing evidence for central CRF hypersecretion in depression, and, to a lesser extent, in some anxiety disorders. Evidence mainly from preclinical studies suggests that stress early in life results in persistent central CRF hyperactivity and increased stress reactivity in adulthood. Thus, genetic disposition coupled with early stress in critical phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual’s threshold for developing depression and anxiety upon further stress exposure. This pathophysiologic model may provide novel approaches to the prevention and treatment of psychopathology associated with stress early in life.

Introduction

From the past to present times, the relative contribution of disposition and experience to the pathogenesis of mental disorders has been explored in numerous studies. Evidence from these studies suggests a strong genetic contribution to the development of the major psychiatric disorders. In addition, a preeminent role of stressful life events has been documented for several disorders, especially mood and anxiety disorders, but schizophrenia as well. A number of studies have shown that the onset of depression is often preceded by stressful life events, and there is evidence that concomitant chronic stress enhances the effects of major life events on depression (Kessler 1997). Likewise, stressful life events along with recent minor difficulties have been identified as predictors of an episode of depression in a monozygotic female twin study (Kendler and Magee 1993). Moreover, genetically vulnerable individuals are more likely to develop major depression in response to stress than individuals without genetic loading (Kendler et al 1995).

The strong impact of untoward life events in childhood on the development of mood and anxiety disorders in adulthood has been well documented in recent years. One study comprising almost 2000 women revealed that women with a history of childhood sexual or physical abuse exhibited more symptoms of depression and anxiety and had more frequently attempted suicide than women without a history of childhood abuse (McCauley et al 1997). Another recent study reported that women who had been abused in childhood were four times more likely to develop major depression in adulthood than women who had not been abused (Mullen et al 1996). The magnitude of childhood abuse is correlated to the severity of depression in adulthood. Moreover, child abuse is associated with the early onset of depression and a greater likelihood for chronic depression Young et al 1997, Zlotnick et al 1995.

Childhood abuse also has been shown to predispose for the development of several anxiety disorders in adulthood, including panic disorder and generalized anxiety disorder Portegijs et al 1996, Stein et al 1996. Moreover, posttraumatic stress disorder (PTSD), an anxiety disorder consisting of symptoms of intrusion, avoidance, and increased arousal related to the experience of a traumatic event, has also been related to childhood adversities; PTSD may be a direct consequence of the experience of childhood abuse. Childhood abuse, however, appears to increase an individual’s risk to develop PTSD in response to extreme stressors in adulthood Bremner et al 1993, Browne and Finkelhor 1986, Zaidi and Foy 1993.

In addition to childhood physical and sexual abuse, parental loss and other childhood adversities have also been related to the development of depression and anxiety disorders, including PTSD, in adulthood Kendler et al 1993, Kessler and Magee 1993, McCranie et al 1992. Several studies have shown that depression and anxiety disorders are often comorbid in individuals with a history of childhood adversities, whereas there is little specificity regarding the consequences of different kinds of experiences Mullen et al 1996, Saunders et al 1992.

Based on these observations, we assume that genetic predisposition coupled with early adverse experiences in critical phases of development induce a persistent vulnerability to the effects of stress later in life and, thus, increase vulnerability of an individual to develop mood and anxiety disorders. This stress vulnerability was posited to be mediated by persistent changes in stress-responsive neurobiological systems involved in both mood and anxiety disorders.

Section snippets

Corticotropin-releasing factor

It is likely that persistent changes in central nervous system (CNS) corticotropin-releasing factor (CRF) systems mediate the association between stressful experiences and the development of mood and anxiety disorders. The 41–amino acid sequence of CRF was isolated and characterized by Vale et al (1981). Subsequent immunohistochemical and radioimmunoassay mapping suggested a heterogeneous distribution of CRF neurons throughout the CNS (see Owens and Nemeroff 1991 for review; Figure 1). Cell

CRF and the stress responses

Endocrinologically, the stress response is largely characterized by activation of the hypothalamic–pituitary–adrenal (HPA) axis. Stress-activated neurotransmitter systems are believed to stimulate both the synthesis and secretion of CRF into the hypothalamo–hypophysial portal circulation. The CRF binds to receptors of the adenohypophysial corticotrophs and thereby stimulates the production and release of the pro-opiomelanocortin (POMC) derivatives derivatives, adrenocorticotropin (ACTH) and

Clinical findings in depression

Increased HPA-axis activity in major depression is one of the most robust findings in the history of biological psychiatry (see Table 1). Board et al (1957) reported increased adrenocortical activity in depressed patients, and this finding has now been replicated in numerous studies (Holsboer 1991). After the intake of a standard dose of dexamethasone, a synthetic glucocorticoid that suppresses pituitary–adrenal activity through negative-feedback inhibition in healthy subjects, the majority of

Clinical findings in anxiety disorders

Stress early in life appears to predispose to the development not only of depression, but to several anxiety disorders as well. Findings from basic research provide compelling evidence for a role for CRF in mediating states of anxiety (vide supra). Clinical studies in patients with several anxiety disorders, including panic disorder, generalized anxiety disorder, and obsessive–compulsive disorder (OCD), are less conclusive than the findings reviewed previously in depression (see Table 1).

Preclinical and clinical findings in early life stress

Given the relationship between severe childhood adversity and the development of mood and anxiety disorders, for which a neurobiological substrate has been posited, preclinical and clinical studies of the neurobiological effects of early adverse experiences would appear to provide the best opportunity to elucidate the precise pathogenesis (see Table 2). Among rodent models of early life stress are repeated brief removals of rat pups from their mothers during the neonatal period. Whereas the

Summary and future directions

An interaction of genetic and environmental factors has long been postulated to determine an individual’s vulnerability to developing affective and anxiety disorders. A strong relationship between early adverse experiences and the development of these disorders in adulthood appears well documented. Both endocrine and behavioral responses to stress are predominantly controlled by CNS CRF systems. Corticotropin-releasing factor neurons in limbic and brain stem regions appear to mediate, at least

Acknowledgements

The authors are supported by NIH MH-42088, NIH MH-50113, and DFG He2561/2-1.

This work was presented at the scientific satellite conference, “The Role of Biological and Psychological Factors on Early Development and Their Impact on Adult Life,” that preceded the Anxiety Disorders Association of America (ADAA) annual meeting, San Diego, March 1999. The conference was jointly sponsored by the ADAA and the National Institute of Mental Health through an unrestricted educational grant provided by

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