David Baxter PhD
Late Founder
The Neurobiology of Child Abuse and Neglect
by Andrew Wilner, MD
Neuropsychiatry Review, Vol. 9, No. 6 June 2008
WASHINGTON, DC? Since the days of Sigmund Freud, clinicians have observed that early-life trauma may lead to adult psychopathology. At the 161st Annual Meeting of the American Psychiatric Association, Charles Nemeroff, MD, PhD, presented recent research that suggests a neurobiologic underpinning for this association.
Dr. Nemeroff, Professor and Chairman of the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine in Atlanta, noted that child abuse is one of the major factors contributing to depression. ?Child abuse or neglect is, unfortunately, a very common problem,? he said. ?Four out of every 20 girls will be abused and one or two of every 20 boys. The peak age of vulnerability is 7 to 13. In the United States, approximately 500,000 children are sexually abused each year. This is a worldwide phenomenon across all socioeconomic classes.?
EARLY ABUSE MAY LEAD TO LATER MENTAL HEALTH PROBLEMS
These early experiences of abuse may have lasting and important effects on an individual?s mental health, according to Dr. Nemeroff. He cited the results of a retrospective cohort study of 17,337 adults (54% female; mean age, 57) who completed a survey regarding childhood abuse, household dysfunction, and suicide attempts. Among this group, the lifetime prevalence of at least one suicide attempt was 3.8%. Risk factors for suicide included death of a parent, domestic violence, early-life trauma, incarceration of a parent, physical abuse, sexual abuse, and substance abuse in the home. A single adverse event increased the chance of suicide two to five times. If a person had all seven risk factors, the likelihood of a suicide attempt increased to 35.2%, demonstrating a powerful and graded relationship between early-life trauma and depression.
In a study of 125 depressed women, those with childhood sexual abuse were more likely to have attempted suicide and/or engaged in deliberate self-harm and become depressed earlier in life. These women were also more likely to have panic disorder and to report a recent assault.
The negative effect of these early-life experiences may be partially accounted for by changes in the neurobiology of corticotropin-releasing factor (CRF), according to Dr. Nemeroff. An increase in CRF can cause behavioral effects such as agitation, anxiety, decreased sexual behavior, depression, loss of appetite, loss of sleep, and other biologic effects. Early-life adverse events may result in hypersecretion of CRF and a down-regulation of the CRF receptor in the pituitary gland.
Maternal deprivation is a form of early-life stress that can be reproduced in the laboratory. In experiments with rat pups separated from their mothers for 15 or 180 minutes per day, the pups separated from their mothers the longest (180 minutes per day) had significant increases in CRF mRNA in the hypothalamus. Adult rats separated from their mothers as pups had a decrease in cell proliferation and immature neuron production in the dentate gyrus of the hippocampus. If corticosterone is lowered below control values in these rats, suppression of cell proliferation can be reversed. These findings suggest that early adverse experiences inhibit structural plasticity via hypersensitivity to glucocorticoids and diminish the ability of the adult hippocampus to respond to stress.
?These observations are important, because they suggest that CRF receptor antagonists may be useful in the prevention and treatment of psychopathologic conditions related to early-life stress,? said Dr. Nemeroff.
A study from Dr. Nemeroff?s laboratory found that women with a history of childhood abuse exhibited increased pituitary adrenal and autonomic responses to stress compared with controls. Forty-nine women (ages 18 to 45) were divided into four groups: 12 controls; 13 women with major depression and a history of sexual or physical abuse as children; 14 women without depression with a history of sexual or physical abuse as children; and 10 women with depression but no history of abuse.
The women were stressed with the Trier Social Stress Test, which requires the subject to give a public address and do an arithmetic problem. Women with early-life stress and depression had the highest increase of adrenocorticotropic hormone (ACTH) and cortisol after stress compared with the other three groups. These women also had the highest heart rate after stress. The group with early-life stress but no depression had the second highest elevations of ACTH and cortisol, suggesting that the early-life trauma may be the main reason for the ACTH increase, as opposed to the depression. Women with early-life stress were more likely to have acyclic chronic pelvic pain, fatigue, and multiple physical symptoms than were controls.
Dr. Nemeroff noted that children who are traumatized are at risk for depression and PTSD. However, adults who develop PTSD but did not have early trauma may have a different disease and require different treatment.
A GENETIC COMPONENT
Genetic variation may also influence susceptibility to depression and PTSD. In a study of 422 indigent patients from a general medical clinic, patients with moderate to severe child abuse were significantly more likely to have depression compared with those who had experienced mild abuse. Fifteen single nucleotide polymorphisms (SNPs) of the corticotropin-releasing hormone type 1 (CRHR1) receptor gene were studied, and significant gene x environment interactions with multiple individual SNPs were found (eg, rs110402) that mediated whether an individual exposed to child abuse would become depressed.
In another study of 900 patients, four SNPs in the stress-related gene FKBP5 (rs9296158, rs3800373, rs1360780, rs9470080) significantly interacted with the severity of child abuse to predict the level of adult PTSD symptoms. This finding suggests a gene/childhood environment interaction for adult PTSD.
Dr. Nemeroff concluded, ?We need to educate parents on how to take care of children and reduce the rate of child abuse. The adolescent brain isn?t fully mature and is uniquely vulnerable to insult from alcohol, drugs of abuse, and abuse and neglect. An improved environment can have tremendous beneficial effects, including increased sprouting and synaptogenesis. Psychosocial interventions early can buffer the consequences of inheriting unfavorable genetic polymorphisms.?
Suggested Reading
by Andrew Wilner, MD
Neuropsychiatry Review, Vol. 9, No. 6 June 2008
WASHINGTON, DC? Since the days of Sigmund Freud, clinicians have observed that early-life trauma may lead to adult psychopathology. At the 161st Annual Meeting of the American Psychiatric Association, Charles Nemeroff, MD, PhD, presented recent research that suggests a neurobiologic underpinning for this association.
Dr. Nemeroff, Professor and Chairman of the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine in Atlanta, noted that child abuse is one of the major factors contributing to depression. ?Child abuse or neglect is, unfortunately, a very common problem,? he said. ?Four out of every 20 girls will be abused and one or two of every 20 boys. The peak age of vulnerability is 7 to 13. In the United States, approximately 500,000 children are sexually abused each year. This is a worldwide phenomenon across all socioeconomic classes.?
EARLY ABUSE MAY LEAD TO LATER MENTAL HEALTH PROBLEMS
These early experiences of abuse may have lasting and important effects on an individual?s mental health, according to Dr. Nemeroff. He cited the results of a retrospective cohort study of 17,337 adults (54% female; mean age, 57) who completed a survey regarding childhood abuse, household dysfunction, and suicide attempts. Among this group, the lifetime prevalence of at least one suicide attempt was 3.8%. Risk factors for suicide included death of a parent, domestic violence, early-life trauma, incarceration of a parent, physical abuse, sexual abuse, and substance abuse in the home. A single adverse event increased the chance of suicide two to five times. If a person had all seven risk factors, the likelihood of a suicide attempt increased to 35.2%, demonstrating a powerful and graded relationship between early-life trauma and depression.
In a study of 125 depressed women, those with childhood sexual abuse were more likely to have attempted suicide and/or engaged in deliberate self-harm and become depressed earlier in life. These women were also more likely to have panic disorder and to report a recent assault.
The negative effect of these early-life experiences may be partially accounted for by changes in the neurobiology of corticotropin-releasing factor (CRF), according to Dr. Nemeroff. An increase in CRF can cause behavioral effects such as agitation, anxiety, decreased sexual behavior, depression, loss of appetite, loss of sleep, and other biologic effects. Early-life adverse events may result in hypersecretion of CRF and a down-regulation of the CRF receptor in the pituitary gland.
Maternal deprivation is a form of early-life stress that can be reproduced in the laboratory. In experiments with rat pups separated from their mothers for 15 or 180 minutes per day, the pups separated from their mothers the longest (180 minutes per day) had significant increases in CRF mRNA in the hypothalamus. Adult rats separated from their mothers as pups had a decrease in cell proliferation and immature neuron production in the dentate gyrus of the hippocampus. If corticosterone is lowered below control values in these rats, suppression of cell proliferation can be reversed. These findings suggest that early adverse experiences inhibit structural plasticity via hypersensitivity to glucocorticoids and diminish the ability of the adult hippocampus to respond to stress.
?These observations are important, because they suggest that CRF receptor antagonists may be useful in the prevention and treatment of psychopathologic conditions related to early-life stress,? said Dr. Nemeroff.
A study from Dr. Nemeroff?s laboratory found that women with a history of childhood abuse exhibited increased pituitary adrenal and autonomic responses to stress compared with controls. Forty-nine women (ages 18 to 45) were divided into four groups: 12 controls; 13 women with major depression and a history of sexual or physical abuse as children; 14 women without depression with a history of sexual or physical abuse as children; and 10 women with depression but no history of abuse.
The women were stressed with the Trier Social Stress Test, which requires the subject to give a public address and do an arithmetic problem. Women with early-life stress and depression had the highest increase of adrenocorticotropic hormone (ACTH) and cortisol after stress compared with the other three groups. These women also had the highest heart rate after stress. The group with early-life stress but no depression had the second highest elevations of ACTH and cortisol, suggesting that the early-life trauma may be the main reason for the ACTH increase, as opposed to the depression. Women with early-life stress were more likely to have acyclic chronic pelvic pain, fatigue, and multiple physical symptoms than were controls.
Dr. Nemeroff noted that children who are traumatized are at risk for depression and PTSD. However, adults who develop PTSD but did not have early trauma may have a different disease and require different treatment.
A GENETIC COMPONENT
Genetic variation may also influence susceptibility to depression and PTSD. In a study of 422 indigent patients from a general medical clinic, patients with moderate to severe child abuse were significantly more likely to have depression compared with those who had experienced mild abuse. Fifteen single nucleotide polymorphisms (SNPs) of the corticotropin-releasing hormone type 1 (CRHR1) receptor gene were studied, and significant gene x environment interactions with multiple individual SNPs were found (eg, rs110402) that mediated whether an individual exposed to child abuse would become depressed.
In another study of 900 patients, four SNPs in the stress-related gene FKBP5 (rs9296158, rs3800373, rs1360780, rs9470080) significantly interacted with the severity of child abuse to predict the level of adult PTSD symptoms. This finding suggests a gene/childhood environment interaction for adult PTSD.
Dr. Nemeroff concluded, ?We need to educate parents on how to take care of children and reduce the rate of child abuse. The adolescent brain isn?t fully mature and is uniquely vulnerable to insult from alcohol, drugs of abuse, and abuse and neglect. An improved environment can have tremendous beneficial effects, including increased sprouting and synaptogenesis. Psychosocial interventions early can buffer the consequences of inheriting unfavorable genetic polymorphisms.?
Suggested Reading
- Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291-1305.
- Bradley RG, Binder EB, Epstein MP, et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry. 2008;65(2):190-200.
- Dube SR, Anda RF, Felitti VJ, et al. Childhood abuse, household dysfunction, and the risk of attempted suicide throughout the life span: findings from the Adverse Childhood Experiences Study. JAMA. 2001;286(24):3089-3096.
- Gladstone GL, Parker GB, Mitchell PB, et al. Implications of childhood trauma for depressed women: an analysis of pathways from childhood sexual abuse to deliberate self-harm and revictimization. Am J Psychiatry. 2004;161(8):1417-1425.
- Heim C, Newport DJ, Heit S, et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA. 2000;284(5):592-597.
- Mirescu C, Peters JD, Gould E. Early life experience alters response of adult neurogenesis to stress. Nat Neurosci. 2004;7(8):841-846.
