This study demonstrates that adult women with major depressive disorder and a history of severe and repeated physical and/or sexual abuse in childhood had smaller left hippocampal volumes, compared to depressed women without a history of abuse and compared to healthy subjects. Hippocampal volumes in depressed women without a history of childhood abuse were similar to those of healthy women with neither an abuse history nor psychiatric illness.
The findings may explain both positive and negative findings in previous studies of hippocampal volume in major depressive disorder. The finding of smaller hippocampal volumes in depressed women with abuse in this study is similar to reports of smaller hippocampal volumes in some studies of patients with major depressive disorder (5
). The normal hippocampal volume in depressed women without abuse in this study is similar to reported negative findings in earlier studies (18
). Close examination of the MRI studies of patients with major depressive disorder suggests that hippocampal structural abnormalities may be restricted to subjects with treatment-resistant depression (15
), older women with major depressive disorder (5
), women with treatment-resistant depression (18
), and elderly depressed patients (16
), with some exceptions (14
). Patients with depression and comorbid illnesses such as PTSD are known to have a poorer response to antidepressants, compared to patients with depression alone. Findings of smaller hippocampal volumes in depressed women and in patients with treatment-resistant depression but not in mixed groups of patients with treatment-responsive depression raise the possibility that prepubertal childhood physical and/or sexual abuse could be associated with poor antidepressant response as well as with morphological abnormalities in the hippocampus in adulthood. Because, to our knowledge, no previous studies of hippocampal volume in major depressive disorder have documented the presence or absence of childhood physical and/or sexual abuse, it is possible that varying trauma histories may have contributed to the disparate findings in hippocampal morphometry. Hippocampal abnormalities could be a direct consequence of severe childhood trauma or could occur as a result of interaction with other factors, such as depression, alcohol use, or medical illness. In this study, however, significant differences in hippocampal volumes between depressed subjects with childhood trauma and comparison subjects were found after controlling for a past history of alcohol and other substance abuse.
The findings of this study are similar to those of a study by Stein et al. (28
) reporting smaller left hippocampal volumes in women with childhood sexual abuse, although the magnitude of the difference in hippocampal volume was greater in the present study (18% smaller mean volume versus 5% smaller mean volume than in normal comparison subjects). Because Stein et al. (28
) did not include a depressed group without abuse and only a third of the 21 subjects in the current study had childhood abuse and current major depression, definitive conclusions regarding the contribution of early trauma to hippocampal volume in depressed adults could not be drawn. Smaller hippocampi have been reported in adult subjects with PTSD secondary to combat (47
) and to childhood physical and/or sexual abuse (27
). In contrast, similar smaller hippocampal volumes have not been found in children with PTSD secondary to sexual abuse (51
) and in adults with PTSD after a motor vehicle accident (53
). Taken together, MRI studies in PTSD suggest that the severity, duration, frequency, and kind of trauma as well as the subject’s age during exposure to trauma and comorbid alcohol use (54
) could contribute to the contradictory findings about hippocampal volume in this disorder. We attempted to reduce variability in the study group by restricting inclusion to women with a history of severe, recurrent, and prolonged abuse that occurred before puberty. The volume of the left hippocampus was smaller than normal in this study as well as in prior studies that evaluated brain changes related to childhood trauma (27
). In contrast, smaller right hippocampal volumes were seen in subjects with postpubertal traumatic experiences (46
). The possibility that traumatic experiences before puberty may differentially affect the developing left hippocampus, particularly the head, needs to be examined.
The absence of a comparison group with early childhood trauma without current major depressive disorder or PTSD limits our ability to determine whether having a smaller left hippocampus is a risk factor for developing major depressive disorder or a consequence of abuse. Numerous preclinical studies support the possibility that morphological changes in the hippocampus are a consequence of stress. Exposure to chronic psychosocial stress and administration of hydrocortisone alter the morphology of apical dendrites and the synaptic structure of hippocampal neurons (reviewed in references 12
). Psychosocial stress, as well as glucocorticoids, inhibits neurogenesis in the dentate gyrus of the hippocampus (9
). Recent preclinical evidence supports the possibility that exposure to elevated levels of corticotropin releasing hormone (CRH) early in development results in progressive loss of hippocampal CA3 neurons (57
). Increased levels of CSF CRH seen in rats after maternal separation (58
), in nonhuman primates exposed to variable foraging demand (61
), and in humans with PTSD (62
) raise the possibility that elevated CRH levels could have a direct neurotoxic effect on hippocampus neurons in stress-related disorders.
Human studies have replicated increased HPA axis sensitization after childhood abuse. Women with current depression and a history of childhood physical and/or sexual abuse had greater increases in plasma cortisol and ACTH in response to the Trier Social Stress Test (39
). The importance of childhood abuse is further supported by the finding that subjects with major depressive disorder and without a history of childhood abuse had a normal cortisol response to a psychological stress paradigm (39
, unpublished 2002 manuscript of M. Vythilingam et al.). A similar enhancement of pituitary response to an endocrine challenge test—the CRH stimulation test—was seen in depressed children with ongoing abuse (65
) and in women with childhood abuse (40
), suggesting that persistent abnormalities in the HPA axis occur relatively early in life. Thus, increased levels of CRH and cortisol during repeated childhood abuse together with persistent hyperactivity and sensitization of the HPA axis in adulthood could damage hippocampal neurons in adult women with major depressive disorder. The lack of a smaller hippocampal volume in depressed women without a history of abuse in this study as well as in an independent sample of depressed subjects recruited at a different center (unpublished 2002 manuscript of M. Vythilingam, et al.) further highlights the deleterious effects of childhood abuse on brain development.
Smaller hippocampal volume could also be a risk factor for developing psychiatric disorders after exposure to overwhelming stress. Recent studies in humans and in nonhuman primates confirmed that about 40%–54% of the variance in hippocampal volume is genetically determined (66
). Morphological changes in the hippocampus have not been consistently observed subsequent to psychosocial stress or hydrocortisone administration (68
). Gilbertson et al. (70
) observed smaller hippocampal volume both in non-combat-exposed and in combat-exposed identical co-twins with PTSD and concluded that smaller hippocampi increase the vulnerability for developing PTSD in individuals exposed to trauma. Similar twin studies or prospective studies in high-risk populations will help resolve whether smaller hippocampal volume predisposes traumatized individuals to developing depression.
We demonstrated that smaller left hippocampal volume in women with major depressive disorder can be attributed to severe and repetitive physical and/or sexual abuse in childhood. Given the high prevalence of abuse in childhood, future studies evaluating hippocampal structure and function in depressed subjects should treat subjects with and without childhood abuse as separate groups. This strategy will help to increase homogeneity among subjects and to enhance reproducibility of biological findings in psychiatric illnesses. Future research should also focus on developing strategies to prevent and reverse structural brain changes after exposure to traumatic experiences in childhood.