Childhood Maltreatment and Psychopathology: A Case for Ecophenotypic Variants as Clinically and Neurobiologically Distinct Subtypes

Some of the strongest evidence for an association between exposure to childhood maltreatment and the development of major depression can be found in the Adverse Childhood Experiences study (31), which showed that risk for depression increased in a graded, dose-dependent fashion with the number of maltreatment-related adverse childhood experiences. Exposure to one or more adverse childhood experiences accounted for 54% of the population attributable risk fraction for current episodes of depression (1) and 67% for suicide attempts (32). Having five or more adverse experiences increased the relative risk of receiving a prescription for an antidepressant 2.9-fold (6). Long-term prospective studies also indicate about a twofold greater risk attributable to maltreatment (2, 4, 5) (see Figure 2A). These findings are consistent with results of twin studies showing that heritability plays only a minor role in risk for moderate or even severe depressions (33).

Maltreatment increases the risk for depression in both males and females, although some studies suggest a greater risk for depression in physically abused females than in physically abused males (34, 35). Hence, the greater female prevalence may be due, at least in part, to greater sensitivity to physical abuse and more frequent exposure to childhood sexual abuse (36).

Important clinical differences exist between depressive illnesses with and without childhood maltreatment. Depressions emerge earlier and have a more sustained course (13, 37) in maltreated individuals. These individuals also have more severe mood, neurovegetative, and endogenous symptoms and more comorbidities, particularly substance abuse (13, 22, 37, 38). Psychotic features are also more common, as are suicide attempts and deliberate self-harm (39).

Maltreated patients with depression also differ with respect to treatment response. A recent meta-analysis of depression outcome studies (13) confirmed that childhood maltreatment unequivocally predicts poor treatment outcome. However, it is also possible that maltreated patients with depression respond preferentially to therapies that are less effective for patients with depression who have no history of maltreatment. In a large clinical trial (40), chronically depressed participants received either pharmacotherapy with nefazodone, psychotherapy using the cognitive-behavioral analysis system of psychotherapy, or both treatments in combination. Psychotherapy was clearly superior to antidepressant monotherapy in the subset of participants with childhood trauma, and nefazodone provided little added benefit. In contrast, chronically depressed patients with no history of trauma or loss responded more favorably to nefazodone than to psychotherapy, and they benefited from combination treatment. On the other hand, in another study (41), maltreatment was associated with a poorer response to interpersonal therapy than to cognitive therapy or medication, and with rapid relapse. With hindsight, we can see that factors found over the years to predict treatment resistance in depression (i.e., early onset, comorbid anxiety and substance use disorders, axis II diagnoses, and presence of psychotic features) are the same factors now known to be characteristic of the maltreatment-related ecophenotype.

Neurobiological studies are beginning to provide compelling reasons for considering depression with a maltreatment history as a distinct subtype. Reduced hippocampal size is one of the more prominent neuroimaging findings in major depression. However, Vythilingam et al. (16) reported that reduced hippocampal size was present only in the subset of depressed individuals who had a history of maltreatment. On balance, there is now more consistent evidence for reduced hippocampal size in adults with a history of maltreatment than in adults with major depression. Furthermore, reduced hippocampal volume in maltreated individuals in the absence of depression or any psychiatric history has been observed in recent large-sample studies (42, 43). In short, what has been regarded as a key finding in major depression may instead be a consequence of early stress that serves in turn as a risk factor. Indeed, reduced hippocampal volume can precede and partially mediate risk for depression with early stress (44).

Amygdala activation during exposure to sad or negative faces is another neuroimaging finding linked to major depression (45) that may be limited to depressed individuals with a history of maltreatment (24). Indeed, bilateral amygdala reactivity to emotional expression is enhanced by a history of emotional maltreatment whether or not the individual has depression (46).

Genetic and epigenetic risk factors may also be distinctly different in patients with major depression with and without a history of maltreatment. A comprehensive meta-analysis by Karg et al. (47) found strong support for a gene-by-environment interaction involving the serotonin transporter promoter polymorphism and risk for depression when the environmental experience was childhood maltreatment but only marginal support when the environmental experience involved postchildhood stressful events.

Epigenetic hypermethylation of the Nr3C1 gene results in decreased expression of glucocorticoid receptors and potential hypersecretion of cortisol during stress. Interestingly, Nr3C1 has been found to be hypermethylated in postmortem tissue from suicide victims with a history of maltreatment, but not in suicide victims without maltreatment or in nonsuicide comparison subjects (48).

While some have speculated that individuals without maltreatment who develop depression do so because of a dense family history and a high heritable risk, this supposition is not supported by our unpublished data or by the observation that less severe forms of depression show little evidence of heritability (33). However, nonmaltreated depressed individuals may show an array of noninherited rare copy number variants—short stretches of DNA that are deleted or duplicated between individuals that contribute disproportionately to risk (49).

Finally, depressed patients differ in their risk for autoimmune, metabolic, and cardiovascular disorders based on maltreatment history. This may be related to chronic low-grade inflammation. Longitudinal data show that depression and inflammation are strongly coupled in depressed individuals with maltreatment but not in those without maltreatment (4).

Sexual abuse, physical abuse, and witnessing domestic violence are types of maltreatment that may fulfill the DSM-IV A1 criterion for a traumatic event (50), and they are major risk factors for the development of PTSD (Figure 2B). Scott et al. (2) reported an adjusted odds ratio of 4.86 for lifetime diagnosis of posttraumatic stress disorder in a prospective study of adults with a history of maltreatment. Furthermore, individuals who experienced both childhood adversity and adult traumatic events have been found to be more likely to develop PTSD than those who experienced either type of adverse event alone (51).

However, in recent years there has been growing concern about how well the DSM-IV conceptualization of posttraumatic stress, which is based on exposure to acute life-threatening events in soldiers, applies to maltreated children. Youngsters often experience traumatic or highly stressful events during a substantial portion of their life, which may be perpetrated by one or more family members rather than a faceless enemy. This has led to two important observations. First, DSM-IV criteria are not sufficiently developmentally sensitive. Severely maltreated children often do not meet full diagnostic criteria, as they frequently show symptoms in only two of three category clusters, but may be as impaired as children who meet full criteria (52). Furthermore, risk for posttraumatic stress in children appears to be influenced by frequency of exposure and multiplicity of exposure types rather than the degree to which they witnessed actual or threatened death or serious injury or experienced a threat to their physical integrity. Hence, children may be “traumatized” by repeated exposure to types of maltreatment that do not meet the A1 criterion for a traumatic event, such as emotional abuse (50).

Second, as van der Kolk (50) and others have articulated, traumatized children also show a complex array of problems, such as affective dysregulation, disturbed attachment patterns, behavioral regression, somatic symptoms, and altered attributions and expectancies that are not included in the current DSM conceptualizations and often lead to a host of comorbid diagnoses. Developmental trauma disorder has been proposed as a diagnostic category that more faithfully captures the critical events and clinical presentation of posttraumatic sequelae in chronically maltreated children (50).

However, developmental trauma disorder is best restricted to maltreated individuals with features of posttraumatic stress (see the online data supplement for further discussion). As noted above, many maltreated individuals are more accurately characterized as depressed, and timing of exposure may be a critical determinant. Schoedl et al. (53) found that individuals reporting sexual abuse after age 12 had a 10-fold greater risk of severe PTSD in adulthood than individuals reporting sexual abuse before age 12. Conversely, depressive symptoms were more severe in individuals reporting sexual abuse before age 12 than in those reporting it after age 12 (53).

Multiple lines of evidence suggest that maltreated individuals with PTSD continue to differ from their nonmaltreated counterparts in adulthood. They show greater symptom complexity (54), more comorbid mood disorders (55), and more severe dissociation (56, 57) or alexithymia (58), leading to the designation “complex PTSD” (54, 59, 60). There may also be important neurobiological and genetic differences.

A key neuroimaging finding in PTSD, particularly in combat veterans (61), has been reduced hippocampal volume. However, a study of monozygotic twins discordant for combat exposure found reduced hippocampal volume in combat-exposed individuals with posttraumatic stress as well as in their unexposed twins without posttraumatic stress (62). While these results may be confounded by individual drinking history or personality factors common to both twins, it is also possible that reduced hippocampal volume resulted from shared early stress and functioned as a risk factor for posttraumatic stress. As noted above, reduced hippocampal volume has been observed with considerable consistency in adults with a history of maltreatment. While some early studies with small sample sizes found reduced hippocampal size in maltreated adults with PTSD but not those without (63), recent studies with larger samples report reductions that are unrelated to posttraumatic stress (42, 43). Additional neuroimaging findings in PTSD, including amygdala hyperreactivity and reduced medial prefrontal and anterior cingulate response (61), have also been observed in individuals with a history of childhood abuse, including those without PTSD or any psychopathology (43). Studies are clearly needed to ascertain the degree to which these neuroimaging findings are specific to PTSD, are specific to PTSD in the context of a history of maltreatment, or are a more general consequence of exposure to childhood maltreatment.

Similar to findings for depressive illness, a number of genetic polymorphisms appear to modulate risk for PTSD in individuals with a history of maltreatment. The most compelling involves polymorphisms of FKBP5, which regulates cortisol-binding affinity and the nuclear translocation of the glucocorticoid receptor (64, 65). Interestingly, Xie et al. (65) reported that among individuals with the TT genotype of rs9470080, those with no maltreatment history had the lowest risk for PTSD as adults, and those with a maltreatment history had the highest. This suggests that the search for genetic risk factors may be elusive if study subjects are not subtyped by maltreatment history.

The National Comorbidity Replication Study showed that childhood sexual or physical abuse was associated with a 2.03- to 3.83-fold increase in risk for specific phobias, social anxiety disorder, generalized anxiety disorder, and panic disorder with or without agoraphobia (7) (Figure 2C). Childhood adversity accounted for 32.4% of the population attributable risk fraction for anxiety disorders (3). Moreover, exposure to multiple types of childhood adversity increased the likelihood of receiving a prescription for an anxiolytic by twofold (6).

The impact of exposure to childhood maltreatment on the clinical presentation and treatment of anxiety disorders has been understudied. Patients with an anxiety disorder and a history of maltreatment have significantly higher rates of concurrent major depression (37, 66), more significant impairment in social functioning, higher state and trait anxiety scores (66), greater chronicity (37), greater symptom severity, and poorer quality of life (67). Severity increases with the number of types of maltreatment experienced, and emotional abuse and neglect are especially salient risk factors for social anxiety disorder (67, 68). Lastly, in a clinical trial with paroxetine, social anxiety patients with a history of emotional abuse were the most likely to drop out of treatment (68).

Neuroimaging studies in individuals with anxiety disorders, particularly disorders involving intense fear and panic, such as panic disorder, specific phobias, and social anxiety, report evidence for amygdala hyperreactivity, which may stem from underactivity of the prefrontal cortex and insufficient inhibition of the amygdala (69, 70). Overactivation of the insula, a paralimbic region associated with perception of somatic sensations, has also been observed (70, 71). However, as indicated above, heightened amygdala activation has been observed in fMRI studies of adults without psychopathology if they were exposed to childhood maltreatment (43, 46). Moreover, a recent report (72) found that threatening faces produced overactivity in both the amygdala and the anterior insula in maltreated children with normal levels of anxiety. Hence, amygdala and insula findings are not specific to individuals with anxiety disorders. An alternative hypothesis is that enhanced amygdala and insula response to threat emerges as a consequence of exposure to childhood maltreatment and serves as a risk factor for the later development of anxiety disorders.

A substantial body of research shows the important role of maltreatment on risk for drug abuse and dependence (8, 9) (Figure 2D–E), although the nature of the association may be complicated by high rates of substance abuse in maltreating parents and by the possibility of prenatal exposure, prenatal malnutrition, and prematurity. A well-controlled epidemiological and co-twin study of women (8) found that nongenital childhood sexual abuse was associated with a 2.9-fold increase in risk for drug dependence and that sexual abuse involving intercourse was associated with a 5.7-fold increase. Risk was related to the number of different types of maltreatment an individual experienced. Compared with individuals with no adverse childhood events, adults with five or more adverse childhood events are seven to 10 times more likely to report illicit drug use problems, addiction to illicit drugs, and injection drug use (9). The population attributable risk fractions for these outcomes were 56%, 64%, and 67%, respectively (9). Results from the National Longitudinal Study of Adolescent Health and the National Youth Survey provide prospective evidence for a causal relationship between physical abuse and early adulthood substance abuse (73, 74).

A moderate number of studies have reported differences between substance-abusing individuals with and without a history of maltreatment. The maltreated ecophenotype is associated with an earlier age at initiation, a greater likelihood of engagement in risky sexual behaviors (75), a greater risk for recent incarceration (76), greater ratings of psychological distress (77), and a greater risk for comorbid personality disorders (78). Physical maltreatment appears to be a particularly salient risk factor for the development of substance abuse (35) and progression to injection drug use (79).

Substance abusers with a history of maltreatment respond more poorly to treatment, with greater use of substances during treatment and more persistence of substance-related problems after discharge (80–82). Integrative therapies have been developed to address the combined impact of substance abuse and trauma-related psychopathology (83).

Key neuroimaging findings in substance abusers suggest the possibility of a “dopamine deficiency” that may manifest as reduced activation of the ventral striatum (nucleus accumbens) during rewarding or pleasurable tasks (84, 85). Furthermore, deficits in brain regions implicated in salience attribution (the orbitofrontal cortex) and inhibitory control (the anterior cingulate gyrus) may underlie the patterns of compulsive and impulsive behaviors that characterize addiction (86). Although these factors have not been well studied in maltreated individuals, the few relevant studies report reduced sensitivity to reward and decreased basal ganglia response (87), as well as structural and resting blood flow deficits in the ventral striatum, the anterior cingulate, and the orbitofrontal cortex (43, 88, 89). Further research is needed to ascertain whether these deficits are common to substance abusers in general or more specific to the subset with a history of childhood maltreatment.

As indicated above, there is a growing body of reproducible findings linking childhood maltreatment to structural and functional brain differences. The most consistent finding is that of alterations in the corpus callosum, characterized by reduced midsagittal area (90–94) or decreased fractional anisotropy (diminished integrity) on diffusion tensor scanning (95, 96) (Table 1). Another reasonably consistent finding is reduction in hippocampal volume in adults (16, 93, 97–105) but not younger children (91, 92, 106, 107) with a history of maltreatment (Table 2). The hippocampus is likely the most stress-sensitive structure in the brain, and translational studies show that stress or glucocorticoids act on the hippocampus to suppress neurogenesis in the dentate gyrus and provoke remodeling of pyramidal cells in portions of the cornu ammonis, particularly CA3. A recent study (105) found that childhood maltreatment was associated with volume reductions in the same subfields in a relatively large population of young adults, suggesting that the same mechanisms may be at work.

There are also associations between exposure to early maltreatment and the attenuated structural or functional development of the neocortex (93, 108–113), including the anterior cingulate (109, 114–116), the orbitofrontal (89, 116, 117) and dorsolateral prefrontal cortex (88, 115), and the visual and auditory cortex (Table 3).

While maltreatment may be associated with alterations in the striatum/basal ganglia (87, 88, 114) and cerebellum (118, 119), most studies have not reported structural differences in the amygdala (91–93, 97, 102, 114). However, increased amygdala volume has been reported in children with institutional deprivation or rearing by chronically depressed mothers (120–122), while smaller amygdala volumes have been observed in adults with childhood trauma and borderline personality disorder or dissociative identity disorder (100, 101, 103, 104). Nevertheless, there is good evidence of enhanced amygdala reactivity in maltreated individuals (17, 43, 46, 72).

Second, there appear to be sensitive periods when these regions are maximally susceptible to the effects of stress. Following this path of inquiry, our group examined the relationship between age at exposure to sexual abuse and observed alterations in brain morphology in a preliminary sample of young adult women (93). We found the hippocampus to be maximally susceptible to maltreatment in women exposed between the ages of 3 and 5 years. However, when maltreatment occurred at ages 9–10, the midportion of the corpus callosum was maximally susceptible, and at ages 14–16, the prefrontal cortex was affected. Thus, there appear to be specific windows of vulnerability in development that determine the negative effects of exposure. These observations are supported by translational research showing that synaptic density in the hippocampus but not the prefrontal cortex of rats is sensitive to the effects of early (preweaning) stress, while the opposite is true with regard to peripubertal stress (123, 124). Rao et al. (125) provided additional support for an early hippocampal sensitive period in humans, reporting that degree of parental nurturance at age 4, but not at age 8, predicted hippocampal volume at age 14.

Third, the effects of maltreatment on brain functioning may not appear immediately after exposure (124). Several studies have reported reductions in the gray matter volume of the hippocampus in adults with a history of maltreatment but not in maltreated children (Table 2). This pattern of results is consistent with translational studies showing that effects of early stress on the hippocampus first emerge during the transition between puberty and adulthood (124). The delay between exposure and neurobiological change may be particularly relevant, as a comparable time lag often occurs between exposure and emergence of depression or posttraumatic stress disorder (126).

Fourth, maltreatment also appears to affect the development of sensory systems and pathways that process and convey the adverse experience. For example, parental verbal abuse is associated with decreased fractional anisotropy in the arcuate fasciculus, which interconnects Wernicke’s and Broca’s areas (127), and with alterations in gray matter volume in the auditory cortex (112). Conversely, witnessing domestic violence is associated with a reduction in gray matter volume in the primary and secondary visual cortex (128) and with decreased fractional anisotropy in the inferior longitudinal fasciculus, which interconnects the visual cortex and the limbic system to shape our emotional and memory response to things that we see (129).

Figure 3 places these findings in context by showing that many of the identified neuroanatomical abnormalities are interconnected and are components of a circuit regulating response to potentially threatening stimuli. Briefly, the thalamus and sensory cortex process threatening sights and sounds and convey this information to the amygdala (130). Prefrontal regions, particularly the ventromedial and orbitofrontal cortex, modulate amygdala response, perhaps turning it down with the realization that something is not actually a threat or, in other cases, irrationally amplifying it (130). The hippocampus also processes this information and plays a key role in retrieving relevant explicit memories (130). The amygdala integrates this information and signals the paraventricular nucleus of the hypothalamus, which in turn regulates autonomic (e.g., heart rate) and pituitary-adrenal hormonal responses and signals the locus ceruleus, which regulates the intracerebral noradrenergic response. The hippocampus, through the subiculum and bed nucleus of the stria terminalis, also modulates paraventricular response, particularly to psychological stressors (131).

Hence, childhood maltreatment, by affecting the development of key components of this system, reprograms response to subsequent stressors. The influence of maltreatment on autonomic and hypothalamic-pituitary-adrenal response to psychological stressors has been evaluated in a series of studies using the Trier Social Stress Test. Heim et al. (132) first reported that women with a history of physical or sexual abuse had heightened cortisol, ACTH, and heart rate response to stress challenge. Subsequent studies have generally painted a different picture, with evidence emerging for a blunting of cortisol response in adults with a history of maltreatment (133–136). Nevertheless, some individuals show an augmented response, consistent with an enhanced fight-or-flight reaction, and others show a blunted response, consistent with freezing. This divergent pattern of response may be influenced by the type (137) and timing (138) of maltreatment.

Simultaneous to disruptions in brain development that occur with exposure to mistreatment are alterations in the development of psychological structures. Alterations have been observed in the form of poor self-concept, feelings of worthlessness, and negative views of the world. Furthermore, victims of maltreatment show deficits in what is called deontic reasoning (reasoning about duties and obligations we owe one another), which puts victims at increased risk for future victimization (139). Victims of maltreatment are also more likely to show insecure attachment, associated with diminished expectations of support as well as poor emotion regulation capacities (140).