The unmet needs in diagnosis and treatment of mood disorders in children and adolescentsThe role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies
Introduction
The past decades have witnessed an increasing societal awareness of the presence and high incidence of child maltreatment, which has now been pronounced a public health problem of epidemic dimensions (Margolin and Gordis 2000). According to the National Center of Child Abuse and Neglect, approximately 1.5 million verified cases of child maltreatment are reported annually in the United States; more than half of these cases represent instances of neglect, and about 700,000 cases are incidents of sexual, physical, or emotional abuse (Sedlack and Broadhurst 1996). In addition to child maltreatment, large numbers of children experience the loss of a parent (Agid et al 2000) or live with a mentally ill parent likely unable of providing continuous parental care (Goodman and Gotlib 1999). In view of estimates that 5% to 16% of women are sexually or physically abused during pregnancy Cokkinides et al 1999, Goodwin et al 2000, Hedin and Janson 2000, McFarlane et al 1996, it can also be assumed that a significant number of children are exposed to prenatal stress.
Compelling evidence from a variety of studies suggests that early life stress constitutes a major risk factor for the development and persistence of mental disorders. Increased rates of major depression, posttraumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder, and other behavioral disorders have been reported for maltreated children (e.g., Famularo et al 1992, Pelcovitz et al 1994). Representative of many other studies, a community-based study of almost 2000 adult women revealed that those with a history of childhood sexual or physical abuse, but not adulthood rape or physical assault, 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). Syndromal major depression and anxiety disorders, including panic disorder and PTSD, are frequent in adults with a history of childhood abuse (e.g., Felitti et al 1998, Mullen et al 1996, Saunders et al 1992, Stein et al 1996). Similar findings have been reported for other instances of early life stress. For example, early parental loss has been found to be related to unipolar and bipolar depression, as well as anxiety disorders, beyond familial or genetic factors Agid et al 1999, Kendler et al 1992, Kendler et al 1993. Moreover, prenatal stress has been related to an increased risk for major depression in adulthood (Hulshoff et al 2000). Early life stress has also been associated with increased risk for other disorders, including schizophrenia and substance abuse Agid et al 1999, Felitti et al 1998, Kendler et al 2000 as well as diabetes, heart disease, and immune disorders Felitti et al 1998, Francis et al 1999, Wallace 1987. The manifestation or worsening of these psychiatric and classical medical disorders in adulthood is often related to acute life events or ongoing stress Hammen et al 1992, Mooy et al 2000, Norman and Malla 1994, Twisk et al 1999. Thus, it may be suggested that adverse experience during development may induce a vulnerability to the effects of stress later in life, predisposing these individuals to develop a wide array mental and physical disorders that are known to manifest or worsen in relation to acute or chronic life stress.
Vulnerability to stress and disease is surely not the exclusive consequence of an adverse early environment, but is well documented to be influenced by genetic factors (see Francis et al 1999). Thus, the concatenation of genetics, early life stress, and ongoing stress may ultimately determine individual stress responsiveness and the manifestation of psychiatric disorders. Thus, an epidemiologic twin study indicated that the manifestation of major depression occurs as a function of genetic disposition, early trauma, and recent life stress (Kendler et al 1993). Early adverse experiences may “shape” a preexisting genetic vulnerability to stress and disease, resulting in a stable phenotype, with a certain risk to develop one or another syndrome in response to further stress exposure (see Figure 1). By what means can early adverse experiences shape a vulnerable phenotype? It is likely that early adverse experiences induce a persistent sensitization of stress-responsive neural circuits. There are a number of excellent recent reviews on the neurobiological consequences of early developmental stress in animals Francis et al 1999, Kaufman et al 2000, Ladd et al 2000. This review seeks to provide an update of preclinical findings and summarizes available clinical data on the neurobiological consequences of early life stress in children and adults.
Section snippets
Neural circuits implicated in stress, depression, and anxiety
The relationship between early life stress and the development of major depression and anxiety disorders, as well as other mental and physical disorders, may be hypothesized to be mediated by persistent changes in corticotropin-releasing factor (CRF) neurotransmission and alterations in other neurotransmitter systems implicated in the regulation of the stress responses (e.g., Nemeroff 1999). Because of its strategic distribution throughout the central nervous system (CNS), the 41 amino acid
Preclinical findings on the neurobiological consequences of early life stress
Given the preclinical evidence for a role of CRF in the mediation of stress and emotion, it may be plausible that early adversities induce persistent changes in CRF neural circuits that are associated with the development of depression or certain anxiety disorders. Preclinical studies using rodents or nonhuman primates are indispensable to improve our understanding of the consequences of early life stress because experimental variation of early environment in humans is obviously precluded on
Comparison of preclinical findings on the neurobiological consequences of early life stress with the neurobiology of mood and anxiety disorders
The accumulating evidence from preclinical studies on early life stress suggesting persistent changes in brain regions pivotal to the mediation of stress and emotion has raised the question of whether patients suffering from depression or anxiety disorders exhibit similar neurobiological alterations.
Although many of the long-term consequences of early life stress in animals bear significant similarities with the neurobiological changes observed in adult patients with depression and some anxiety
Are the neurobiological consequences of early life stress reversible?
As we have shown, accumulating evidence from preclinical and clinical studies suggests that early life stress induces persistent sensitization of CRF neurocircuits, resulting in a phenotype with increased vulnerability to stress, depression, and anxiety. Pharmacologic agents that target central CRF systems may reverse the neurobiological consequences of early life stress and may therefore be useful in the prevention and treatment of disorders related to early life stress in children and adults.
Conclusion
An unacceptably large number of children in our society are subjected to early adverse experiences, exposing these children to an increased risk for the development of depression or anxiety disorders, as well as other disorders, that may persist throughout adulthood. We have summarized findings from preclinical and clinical studies suggesting that early life stress induces long-lived hyperactivity and sensitization of CNS CRF and other neurotransmitter systems, resulting in enhanced endocrine,
Acknowledgements
Supported by The Conte Center for the Neurobiology of Mental Disorders and NIH MH Grant No. 42088.
Aspects of this work were presented at the conference, “The Unmet Needs in Diagnosis and Treatment of Mood Disorders in Children and Adolescents,” October 17–18, 2000, in Washington DC. The conference was sponsored by the National Depressive and Manic-Depressive Association through unrestricted educational grants provided by Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb Company, Forest
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