Sadly, parental neglect and child abuse are very common in the United States and worldwide. Patients abused or exploited in childhood, who experience neglect or the loss of a parent during childhood, are haunted by these experiences.
Considerable evidence from laboratory animal and clinical studies indicate that stressful or traumatic events early in development have long-lasting effects on brain development. In particular, the neural and endocrine systems mediating the response to stress exhibit persistent alterations after adverse childhood events.
Clinically, patients with a history of childhood trauma often struggle with variable symptom complexes including both depression and anxiety. In this article, we review evidence that depression in patients with a history of early life stress (ELS) is biologically and clinically distinct from depression in patients without childhood abuse or neglect.
Data linking ELS to depression
Conservative estimates suggest that every year in the United States more than 1 million children are exposed to sexual or physical abuse or severe neglect.1 Unfortunately, this is only the tip of the iceberg. Emotional abuse is by definition comorbid with sexual and physical abuse and may occur alone at even higher rates.
Psychiatric sequelae of child abuse have been studied in adult survivors in considerable detail (Table). Women abused as children report greater numbers of depression, anxiety, somatic, and substance abuse symptoms compared with women without such a history.2 Not only are these women at increased risk for attempted suicide, but they attempt suicide at a rate that is proportional to the number of early life traumatic events that occurred during childhood.3 Men also are at increased risk for depression in the wake of child abuse.4
Sexual abuse in particular is a marker of especially severe childhood trauma. Depressed women who were sexually abused as children report more childhood physical abuse, childhood emotional abuse, parental conflict, and an earlier onset of depression than depressed women without a history of sexual abuse.5
Finally, recent data drawn from the National Comorbidity Survey suggest that child abuse and neglect may independently elevate risk for several stress-related diseases including cardiac disease, peptic ulcer, autoimmune disease, diabetes mellitus, and lung disease.6
Table
Early life stress as a risk factor for mood and anxiety disorders
| Child abuse and neglect are predictors of episodes of major depression in identical twins |
| Women with a history of childhood abuse are more than twice as likely to develop depression as non-abused women |
| Childhood abuse is related to the development of anxiety disorders in adulthood |
| Childhood physical abuse predisposes for combat-related posttraumatic stress disorder (PTSD) |
| Stress early in life may induce a vulnerability to stress later in life, resulting in an increased risk for stress-related disorders |
Depression and the biology of stress
Preclinical research using laboratory animals and clinical research with humans has provided significant insight into the relationship between the pathophysiology of depression and the neurobiology of stress. A burgeoning database suggests that disruption of the neural systems mediating the stress response plays a significant role in the etiology of certain forms of depression and anxiety.7 Much of this work has focused on the preeminent role of corticotropin-releasing factor (CRF) in this process (Figure).
CRF is one of the principal mediators of the mammalian stress response. One CRF system is composed of neurons of the paraventricular nuclei of the hypothalamus that project nerve terminals to the median eminence, where they secrete CRF into the hypophyseal portal system. CRF is then transported within the portal system to the anterior pituitary where it acts on corticotrophs to increase adrenocorticotrophic hormone (ACTH) secretion, thereby controlling hypothalamic-pituitary-adrenal (HPA) axis activity.8 CRF is also found in extrahypothalamic brain areas where it functions, in concert with the hypothalamic CRF system, as a neurotransmitter in coordinating the behavioral, autonomic, and immune responses to stress.9
Direct central nervous system (CNS) administration of CRF in laboratory animals, typically rodents or nonhuman primates, results in activation of the autonomic nervous system leading to elevation of peripheral catecholamines, modification of gastrointestinal activity, increased heart rate and increased blood pressure. In addition, changes in behavior similar to those observed in human depression occur, including disturbed sleep patterns, reduced food intake, decreased reproductive behavior, and enhanced fear conditioning.10,11
In humans, elevated CRF concentrations are found in the cerebrospinal fluid (CSF) of patients with depression12,13 and of combat veterans with posttraumatic stress disorder (PTSD).14,15 Further, postmortem studies of suicide victims have revealed decreased density of CRF receptors in the frontal cortex,16 decreased expression of CRF receptor mRNA and increased CRF concentrations in the frontal cortex when compared with controls,17 and increased concentrations of cisternal CSF CRF.18 Collectively, these clinical data are consistent with the hypothesis that CRF is chronically hypersecreted in patients with depression or PTSD.