The hippocampal maps in the present study provide novel findings regarding regional hippocampal alterations in unmedicated patients with major depression. Specifically, overall hippocampal volume was preserved in unmedicated depressed patients, concomitant with localized (non-significant) increases in CA1 subfields and portions of the subiculum bilaterally in depressed patients relative to controls. However, the sample was heterogeneous, and several clinical variables, particularly severity of depression and age, made independent contributions to hippocampal morphology and volume.
The notion that hippocampal volume reduction may be a consequence of depression has been influential in guiding recent animal, postmortem and clinical examinations of the pathophysiological basis of depression (Campbell and MacQueen, 2004
). The findings of the present study support this, as we find that increased depression severity was associated with left hippocampal atrophy; however, hippocampal reduction did not characterize this sample of relatively young, currently unmedicated depressed outpatients overall. Indeed, we found a trend toward increased hippocampal volume in unipolar patients previously treated with atypical antipsychotics, which may reflect postulated neuroprotective effects of these agents (Thompson et al., 2009
). Although caution is clearly warranted in interpreting these findings, given the small number of subjects previously treated with antipsychotics, these findings suggest that not only current drug treatment status, but past history of psychotropic medication usage, may be important in assessing structural neuroanatomical differences in patients with mood disorders.
In a large sample of bipolar patients, Jones et al. (2009)
found that current antipsychotic use was associated with significantly larger temporal white matter volumes; specifically, bipolar subjects taking antipsychotics had larger white matter volumes than bipolar subjects not taking antipsychotics or healthy comparison subjects. Sheline et al. (2003)
observed that longer duration of untreated depression was associated with hippocampal volume reduction, which provides some tentative evidence that antidepressants may have a neuroprotective effect. In addition, Frodl et al. (2008)
found a significant left hippocampal volume increase in a subgroup of depressed patients who took antidepressants over a 3-year period. In contrast, Yucel et al. (2008b)
found that medication-exposed patients with unipolar major depression, and those with multiple episodes, had smaller subgenual prefrontal cortical volumes than patients with no exposure to medication and healthy controls, suggesting that illness burden and short-term medication exposure may mediate brain alterations in anterior cingulate regions. Thus, although previous studies have observed effects of current medication use, this is the first study, to our knowledge, to suggest that prior use of atypical antipsychotics may have a persistent effect on hippocampal structure. While caution is clearly warranted in interpreting these trend-level findings, we felt that their inclusion was important to encourage investigation of such effects in other studies. To confirm this suggestive finding, longitudinal studies that assess the same individuals repeatedly over time are needed.
The results of the present study are generally consistent with a recent meta-analysis (McKinnon et al., 2009
), which found that studies including young adult patients showed equivalent hippocampal volumes between MDD patients and controls, which may be due to reduced burden of illness in this population. In addition, other studies are consistent with ours in showing that specific clinical characteristics of the sample may affect neuroanatomical findings (Frodl et al., 2002
; Ballmaier et al., 2008
; MacQueen et al., 2008
). Another recent study of medial temporal structures in major depressive illness (Keller et al., 2008
) found that depressed patients with psychosis had a significantly smaller mean amygdala volume relative to depressed patients without psychosis and healthy comparison subjects, but no differences between depressed patients without psychosis and healthy comparison subjects. Similar to our findings, they observed no group differences in hippocampal volume. Nevertheless, our findings contrast with those of Alexander et al. (2005)
, who studied a comparably sized sample of unmedicated patients with major depressive illness, and found smaller posterior (but not anterior) hippocampal volume in clinically remitted MDD patients as compared with controls. Notable differences between our samples include symptomatic status, as Alexander and colleagues included only clinically remitted patients, whereas 65% of the patients in the present study were in a depressive episode at the time of investigation. In addition, although we had a similar proportion of subjects who were medication-naïve, no subjects in the Alexander et al. (2005)
study had been previously treated with antipsychotics.
Hippocampal differences may be somewhat localized and difficult to detect in small, heterogeneous samples using global measures (McDonald et al., 2004
). The identification of regional alterations in hippocampal structure may thus help to elucidate the underlying pathophysiological mechanisms associated with depression, and also indicate functional systems that may be selectively disturbed in the illness. Our findings indicated depression-associated atrophy in the left hippocampus that was particularly pronounced in the subiculum and CA1 subfields. Using a rigorous measurement protocol for tracing the hippocampus, Maller et al. (2007)
reported differential volume loss in the tail of the hippocampus in MDD patients relative to healthy controls. This region approximately corresponds to the CA1 subfields that we found to be affected by depression severity. Notably, MacQueen et al. (2008)
also found that, in patients with recurrent MDD, larger volume in the hippocampal body/tail (but not the head) was associated with better treatment response at 8 weeks, suggesting that localized hippocampal alterations may be associated with clinical response. In a study of late-onset depression using methods similar to ours, Ballmaier et al. (2008)
found that regional surface contractions were significantly pronounced in late- relative to early-onset depression, particularly in the anterior of the subiculum and lateral posterior of the CA1 subfield in the left hemisphere. These findings, as well as our own, are consistent with postmortem studies, which have identified neuronal abnormalities in the subiculum in the brains of depressed individuals (Rosoklija et al., 2000
), as well as in distinct layers of hippocampal subfields, with most pronounced changes in CA1 regions, followed by CA2 and CA3 subfields (Stockmeier et al., 2004
). The CA1 and CA2 subfields may be particularly vulnerable to vascular damage (Duvernoy, 1988
), which is consistent with findings of local volume reductions in late-onset depression (Ballmaier et al., 2008
) and with the hypothesis that ischaemic small-vessel disease may be implicated in the pathogenesis of elderly depression (Lyness, 2002).
Certain limitations of the present study should be noted. First, only some of the subjects were medication-naïve. Although samples were small for subgroup analyses, we nevertheless found a significant association between regional hippocampal volume reduction and depression severity, as well as a suggestive relationship between prior treatment with atypical antipsychotics and hippocampal volume. As our study was cross-sectional, it cannot be ruled out that the observed group differences were attributable to other factors. However, it is tempting to speculate that these suggestive findings may reflect postulated effects of neuropil increase related to atypical antipsychotic treatment, manifested as subtle volumetric increases on MRI. Using the same methodology for hippocampal mapping in a sample of patients with bipolar disorder, we previously found that unmedicated bipolar patients showed localized deficits in the right hippocampus, in regions corresponding primarily to the CA1 subfields, as compared with both normal controls and lithium-treated bipolar patients (Bearden et al., 2008
). Finally, we did not assess neurocognitive function in this sample, so the functional significance of these hippocampal alterations remains to be established.
One prior study (Ballmaier et al., 2008
) has assessed the relationship between regional hippocampal morphology and memory performance in elderly depressed patients, using the CVLT (California Verbal Learning Test). This study found a strong correlation between delayed verbal memory and left-sided regional atrophy in the CA1 subfield and subiculum in patients with late-onset depression, which may resemble the patterns found in early Alzheimer's disease. However, these elderly depressed patients did not show deficits on memory measures relative to comparison subjects, suggesting that regional hippocampal atrophy patterns and their associations with memory performance could become apparent before clinical evidence of cognitive decline. Although it is unknown whether this sample of relatively young, unmedicated depressed patients suffered from memory impairment at the time of the present study, the patterns of localized atrophy we found in relation to depression severity are highly consistent with the regional findings of Ballmaier et al. (2008)
, suggesting that hippocampal CA1 subfields and the subiculum may be particularly vulnerable to the effects of depression. Hypercortisolaemia and ischaemia have both been hypothesized to contribute to hippocampal damage in major depression (MacQueen et al., 2003
; Sheline et al., 2003
). It has also been proposed that impaired neurogenesis may contribute to mood symptoms in major depression (Sapolsky, 2004
). Although admittedly speculative, this may be the mechanism underlying our finding of more pronounced hippocampal deficits associated with increasing depression severity. However, whether these changes are reversible with symptomatic improvement is unknown. Longitudinal studies are clearly needed to better understand the time course of hippocampal changes in relation to symptomatic and cognitive changes in major depressive illness.