EARLY LIFE STRESS AND DEPRESSION Childhood trauma may lead to neurobiologically unique mood disorders
Adults with a history of child abuse or neglect may respond differently than other depressed patients to the usual treatments.
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
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.
Figure Biological and behavioral effects of chronic CRF hypersecretion
A distinct ‘ELS depression’?
Depression has a complex etiology based on interacting contributions from genes and the environment19 that may ultimately result in biologically and clinically distinct forms of depression.20 Exposure to stress, particularly during neurobiologically vulnerable periods of development, may be one means whereby the environment influences the development of depression in genetically susceptible individuals.21
Heredity. Kendler and colleagues22 studied 1,404 female adult twins and observed that childhood sexual abuse was associated with both an increased risk for major depression and a marked increased sensitivity to the depressogenic effects of stressful life events. Moreover, research in human gene-environment interactions has identified a functional polymorphism in the promoter region of the gene for the serotonin transporter which appears to moderate the influence of stressful life events on the development of depression and potential for suicide.23,24
Environment. Similarly, a key variable in determining the clinical outcome of childhood trauma may be the developmental timing of the abuse. Women abused before age 13 are at equivalent risk for developing PTSD or major depressive disorder (MDD), whereas women abused after age 13 are more likely to develop PTSD.25
Thus a major challenge in depression research is to understand the biological mechanisms that mediate the effects of trauma during development through the genetic windows of vulnerability and resilience.
Animal models of ELS have been studied to elucidate the neurobiological consequences of early life trauma in adult humans. This work has largely been performed in rodents and nonhuman primates using a variety of experimental paradigms.
Although a comprehensive review of these data is beyond the scope of this article, ELS in laboratory animals has consistently been found to produce both short- and long-term adverse neurobiological and endocrine effects as well as cognitive dysfunction and abnormal behavior.21 One possible mechanism mediating these effects is a persistent hyperresponsiveness of different components of the HPA axis following exposure to stress.
Studies in adult women have sought to uncover the long-term effects of ELS (prepubertal physical or sexual abuse) on reactivity of the HPA axis in response to the Trier Social Stress Test, a standardized psychosocial stress test.26 It consists of the subject giving a 10-minute speech and performing a mental arithmetic task in front of a panel of stern-appearing evaluators. Variables measured include heart rate, plasma ACTH, and cortisol concentration at intervals before and after the performance component of the test. The four groups in this study included:
- women without psychiatric illness or history of ELS serving as a control group (CON)
- depressed women without a history of ELS (non-ELS/MDD)
- depressed women with a history of ELS (ELS/MDD)
- non-depressed women with a history of ELS (ELS/non-MDD).
The largest ACTH and cortisol responses and increases in heart rate following this stress exposure were seen in the ELS/MDD group. In fact, the ACTH response of these women was more than 6 times greater than that observed in the control group. The ELS/MDD group of women also had greater rates of comorbid PTSD (85%) in comparison to the other experimental groups as well.
These data are consistent with the hypothesis that ELS produces enduring sensitization of the HPA axis and autonomic nervous system response to stress. This phenomenon may constitute an important etiological element in the development of stress-related adult psychiatric illnesses such as depression or PTSD.
To further explore the hypothesis that ELS alters set points of the HPA axis, we sought to characterize the effects of standard HPA axis challenge tests (CRF stimulation test and ACTH1-24 stimulation test) in a similar population of women.27 Depressed women with a history of ELS and depressed women without a history of ELS both exhibited a blunted ACTH response to infusion of exogenous CRF. Conversely, women with a history of ELS but without current depression had an increased ACTH response following CRF infusion.
With respect to the ACTH1-24 stimulation test, abused women who were not depressed had lower plasma cortisol levels at baseline and after administration of ACTH1-24. Similar to the findings of our previous study,26 women with MDD and a history of ELS were more likely to report current life stress and to also have comorbid PTSD than women with ELS who were not depressed. Blunting of the ACTH response to exogenous CRF in depressed women with a history of ELS may in part be secondary to acute downregulation of pituitary CRF receptors as a result of chronic CRF hypersecretion.
More recently, Carpenter and colleagues28 evaluated the relationship between the perception of ELS and CSF CRF in patients with depression and healthy control subjects. The perception of ELS predicted CSF CRF concentration independent of the presence or absence of depression. Further, and most interestingly, the developmental timing of the stress exposure was predictive of either relatively increased or decreased CSF CRF. ELS before age 6 was associated with elevated CSF CRF, whereas perinatal and preteen exposure to stressful events was associated with decreased CSF CRF.
Brain structure changes? In addition to the neuroendocrine changes observed in patients with ELS, there is evidence that ELS may also alter brain structure. Reduced hippocampal volume is found in some but not all patients with unipolar depression.29 In patients with a history of depression who also have hippocampal atrophy, the extent of atrophy is greater in patients with higher total lifetime duration of depression.30,31
Patients with ELS also have been found to have decreased hippocampal volume.32,33 However, previous structural imaging studies have not controlled for the presence of ELS when attempting to determine the relationship between depression and structural changes in the hippocampus, and this methodologic confound may explain in part the inconsistent relationship between altered hippocampal volume and depression.
To evaluate this hypothesis, hippocampal volume was measured in depressed women with and without a history of ELS and in a control group of women. Reduced hippocampal volume was found to occur solely in depressed women with a history of ELS. Depressed women without ELS and women from the control group had similar hippocampal volumes.34 These data suggest that previous reports of reduced hippocampal size in patients with depression may in fact be related to a history of ELS rather than depression.
The data discussed in this paper indicate that patients with depression and a history of ELS may constitute a unique subgroup among depressed patients as a whole. A growing body of evidence suggests that depressed patients with ELS may also be unique with respect to their response to treatment.
ELS has been found to impact the clinical response of patients to pharmacotherapy with either dysthymia or depression.35,36 Further, patients with depression and a history of ELS have been reported to exhibit increased rates of relapse following treatment of depression.37 The course of depression in individuals with ELS is often characterized by chronicity.
ELS and therapeutic response, Recently, our group has sought to determine whether ELS in patients with chronic depression moderates their response to pharmacotherapy or psychotherapy.38 In this study, data from a large multicenter trial39 originally designed to compare the relative efficacy of pharmacotherapy (nefazodone), psychotherapy (Cognitive Behavioral Analysis System of Psychotherapy), or their combination in the treatment of chronic depression was reanalyzed by stratifying patients based on the presence or absence of ELS. In the overall sample of patients with chronic depression, psychotherapy and pharmacotherapy were comparable in efficacy but significantly less effective than their combination.