Elsevier

Biological Psychiatry

Volume 49, Issue 12, 15 June 2001, Pages 1023-1039
Biological Psychiatry

The unmet needs in diagnosis and treatment of mood disorders in children and adolescents
The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies

https://doi.org/10.1016/S0006-3223(01)01157-XGet rights and content

Abstract

Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to subsequent stress as well as to the development of depression and anxiety. A number of preclinical studies suggest that early life stress induces long-lived hyper(re)activity of corticotropin-releasing factor (CRF) systems as well as alterations in other neurotransmitter systems, resulting in increased stress responsiveness. Many of the findings from these preclinical studies are comparable to findings in adult patients with mood and anxiety disorders. Emerging evidence from clinical studies suggests that exposure to early life stress is associated with neurobiological changes in children and adults, which may underlie the increased risk of psychopathology. Current research is focused on strategies to prevent or reverse the detrimental effects of early life stress on the CNS. The identification of the neurobiological substrates of early adverse experience is of paramount importance for the development of novel treatments for children, adolescents, and adults.

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

References (144)

  • M.D De Bellis et al.

    A.E. Bennett Research Award. Developmental traumatology.Part II: Brain development

    Biol Psychiatry

    (1999)
  • L.D Dorn et al.

    Response to oCRH in depressed and nondepressed adolescentsDoes gender make a difference?

    J Am Acad Child Adolesc Psychiatry

    (1996)
  • A.J Dunn et al.

    Physiological and behavioral responses to corticotropin-releasing factor administrationIs CRF a mediator of anxiety or stress responses?

    Brain Res

    (1990)
  • R Famularo et al.

    Psychiatric diagnoses of maltreated childrenPreliminary findings

    J Am Acad Child Adolesc Psychiatry

    (1992)
  • C Feiring et al.

    Age and gender differences in children’s and adolescents’ adaptation to sexual abuse

    Child Abuse Negl

    (1999)
  • S Feldman et al.

    Neural mechanisms involved in the corticosteroid feedback effects on the hypothalamo-pituitary-adrenocortical axis

    Prog Neurobiol

    (1995)
  • V.J Felitti et al.

    Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study

    Am J Prev Med

    (1998)
  • P.A Fisher et al.

    Preventive intervention for maltreated preschool childrenImpact on children’s behavior, neuroendocrine activity, and foster parent functioning

    J Am Acad Child Adolesc Psychiatry

    (2000)
  • D.D Francis et al.

    The role of corticotropin-releasing factor—norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress

    Biol Psychiatry

    (1999)
  • C Heim et al.

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

    Biol Psychiatry

    (1999)
  • E Hollander et al.

    Serotonergic function in social phobiaComparison to normal control and obsessive-compulsive disorder subjects

    Psychiatry Res

    (1998)
  • J Kaufman

    Depressive disorders in maltreated children

    J Am Acad Child Adolesc Psychiatry

    (1991)
  • J Kaufman et al.

    The corticotropin-releasing hormone challenge in depressed abused, depressed nonabused, an normal control children

    Biol Psychiatry

    (1997)
  • J Kaufman et al.

    Serotonergic functioning in depressed abused childrenClinical and familial correlates

    Biol Psychiatry

    (1998)
  • J Kaufman et al.

    Effects of early adverse experiences on brain structure and functionClinical Implications

    Biol Psychiatry

    (2000)
  • J.H Kehne et al.

    Effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization anxiolytic test in rat pups

    Neuropharmacology

    (2000)
  • L.G Kirby et al.

    Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus

    Neuropsychopharmacology

    (2000)
  • C.O Ladd et al.

    Long-term behavioral and neuroendocrine adaptations to adverse early experience

    Prog Brain Res

    (2000)
  • A Martin et al.

    Pharmacotherapy of early-onset depression. Update and new directions

    Child Adolesc Psychiatr Clin N Am

    (2000)
  • P.E Mullen et al.

    The long-term impact of the physical, emotional, and sexual abuse of childrenA community study

    Child Abuse Negl

    (1996)
  • D.J Newport et al.

    Neurobiology of posttraumatic stress disorder

    Curr Opin Neurobiol

    (2000)
  • O Agid et al.

    Environment and vulnerability to major psychiatric illnessA case control study of early parental loss in major depression, bipolar disorder and schizophrenia

    Mol Psychiatry

    (1999)
  • L Arborelius et al.

    CRF, depression and anxiety

    J Endocrinol

    (1999)
  • Arborelius L, Plotsky PM, Nemeroff CB, Owens MJ (2000): Increased 5-HT cell firing responsiveness to citalopram in...
  • D.G Baker et al.

    Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder

    Am J Psychiatry

    (1999)
  • C.M Bánki et al.

    Cerebrospinal fluid neuropeptides in mood disorder and dementia

    J Affect Dis

    (1992)
  • L.S Brady et al.

    Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications

    J Clin Invest

    (1991)
  • A Breier et al.

    Early parental loss and development of adult psychopathology

    Arch Gen Psychiatry

    (1988)
  • J.D Bremner et al.

    Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder

    Am J Psychiatry

    (2000)
  • J.D Bremner et al.

    Hippocampal volume reduction in major depression

    Am J Psychiatry

    (2000)
  • J.D Bremner et al.

    Magnetic resonance imaging-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder

    Am J Psychiatry

    (1995)
  • P.D Butler et al.

    Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus

    J Neurosci

    (1990)
  • C Caldji et al.

    Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat

    Proc Natl Acad Sci U S A

    (1998)
  • M Carlson et al.

    Psychological and neuroendocrinological sequelae of early social deprivation in institutionalized children in Romania

    Ann N Y Acad Sci

    (1997)
  • P.B Chappell et al.

    Alterations in corticotropin-releasing factor-like immunoreactivity in discrete barin regions after acute and chronic stress

    J Neurosci

    (1986)
  • J.D Coplan et al.

    Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressorsImplications for the pathophysiology of mood and anxiety disorders

    Proc Natl Acad Sci U S A

    (1996)
  • R.J Davidson et al.

    Dysfunction in the neural circuitry of emotion regulation—a possible prelude to violence

    Science

    (2000)
  • M.D De Bellis et al.

    Hypothalamic pituitary adrenal dysregulation in sexually abused girls

    J Clin Endocrinol Metabol

    (1994)
  • M.D De Bellis et al.

    Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopression in patients with major depression

    Am J Psychiatry

    (1993)
  • M.D De Bellis et al.

    N- Acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD

    Am J Psychiatry

    (2000)
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