In some ways the most provocative, but also the most controversial, data linking the HC to MDD have been from magnetic resonance imaging studies of the volume of the HC in patients with MDD; these studies are summarized in .23,24,25,26,27,29,30,70,71,72,73,74,75
Despite variation in the measurement techniques and patient samples, when we combined results from studies measuring the HC alone using a meta-analytic technique, we showed that depressed patients had significantly decreased left and right hippocampal volumes compared with controls ().76,77,78,79
Fig. 2: Magnetic resonance spectroscopic images of the left hippocampus in a healthy control subject and in a patient with recurrent depression. The size of the difference shown here is unusually large, with most positive studies reporting a reduction (more ...)
Genetic vulnerability, early abuse and chronic stress predispose individuals to depression. These factors might also predict a small HC in samples of depressed patients with these variables. The possibility that a small HC may predate onset of psychiatric illness has not been evaluated in samples of patients with strong family histories of MDD. The notion that a small HC may confer vulnerability to stress-associated disorders, however, has been recently assessed in a study of individuals exposed to combat who had nonexposed monozygotic twins. HC volume in the trauma-exposed and
in the nonexposed, asymptomatic twin correlated negatively with severity of post-traumatic stress disorder in the twin who had been exposed to trauma.80
These data suggest that genetic factors lead to small HC volumes and confer vulnerability to psychiatric illness as a consequence of this reduction. Whether genetic vulnerability is expressed in part through a small HC that confers vulnerability to MDD is unknown, but the sample in which this may be most readily tested comprises individuals with strong family histories of MDD.
A literature beyond the scope of this summary has established the association between early trauma or abuse and depression.81
Several recent studies have focused on early abuse and HC function and volume in MDD. Vythilingam et al24
recently studied 21 women with a significant history of prepubertal physical or sexual abuse and current MDD. Prepubertal abuse is associated with long-term dysregulation of the hypothalamic–pituitary–adrenal axis, in contrast to postpubertal abuse, for which such an association has been less consistently described. Depressed women with past abuse had a 15% reduction in left HC volume compared with healthy control subjects; in contrast, women with MDD but no history of abuse had HC volumes similar to those of healthy controls. These data are consistent with those from other studies that examined women who had a history of prepubertal abuse; in general, past abuse is associated with reduced HC volume.24,81,82
Unfortunately, the samples of women studied to date have been heterogeneous with respect to past severity, duration and treatment history of depression. Therefore, although it appears that prepubertal abuse may be associated with reduced HC volume, it may also be the case that prepubertal abuse is associated with severe or recurrent depression, which results in reduced HC volume.
Chronic or recurrent depressive episodes may also lead to HC volume reduction. Sheline et al29
reported that total duration of past illness predicted degree of HC volume reduction when duration of illness was assessed as number of days spent ill; others have reported that volumetric reductions were greater in patients with a chronic course of depression and a large number of weeks spent ill compared with those who recovered fully with a shorter overall duration of illness,83
although not all investigators have reported such a relation.72
Our cross-sectional study of patients with either a first episode or multiple past episodes of depression suggested that patients with multiple episodes were more likely to have smaller HC volumes; a nonlinear relation between HC volume and number of past episodes further suggested that most of the volume loss occurred within the first few episodes.23
These data are consistent with recent reports that patients with schizophrenia have the greatest volumetric changes in the period shortly after onset of illness.84
A key related question is whether effective treatment starting early in the illness can slow or prevent the rate of volume loss in this illness. A recent study reported an association between HC volume loss and time spent with untreated depression but no association between HC volume and time during which depression was being treated, suggesting that volume loss may be arrested by antidepressant treatment.59
Further studies are necessary to clarify whether, in fact, effective treatment can minimize HC volume loss. Further studies are also required to reconcile the observed volume reductions in imaging studies with postmortem studies that have reported only moderate apoptosis in this region.66
It is possible, for example, that cell loss by apoptosis is a significant event over many years of illness, whereas retraction of the neuron's dendritic tree might be observed earlier in the course of illness and might partially account for the observed volume loss with the lack of significant cell death in depressed patients.