Our analyses, which in some cases included more than 2000 scanned participants, confirm the findings of meta-analyses of hippocampus volume in patients with MDD published before 2004.14,15
The 20 new studies published between 2004 and 2007 included in our analysis allowed for a systematic examination of demographic and clinical factors that may mediate hippocampal volume in patients with MDD. We found differences in hippocampus volume only for those patients with MDD whose illnesses persisted longer than 2 years or who experienced more than 1 disease episode. Interestingly, this effect was limited to samples comprising children and middle-aged and older adults, whereas the hippocampus volumes of young adults were equivalent among MDD patients and controls. The results cannot be explained by the inclusion of patients with bipolar disorder, comorbid psychiatric diagnoses or previous electroconvulsive therapy, because removal of these patients from the sample did not alter our findings. Moreover, there was no evidence that a publication bias toward positive findings contributed to these results.
Equivalent hippocampus volume in patients with less than 2.1 years of illness or only 1 disease episode is consistent with the notion that small hippocampus volumes are associated with protracted illness. Five studies demonstrated this relation. Two studies38,47
reported a significant inverse correlation between left hippocampus volume and illness duration, a finding in accordance with an earlier report of a logarithmic relation between hippocampus volume and duration of illness in adult patients with MDD.37
Another study reported that volume in the left hippocampus showed a marginally significant relation with duration of illness in a group of drug-free patients with MDD.31
Finally, Sheline and colleagues9
reported that a greater total number of days ill predicted left hippocampus volume size in female patients with a recurrent history of MDD.
Other studies, however, have not found evidence of an effect of illness duration on hippocampus volume.16,18,19,22,23,25,27–29,47,60,62
These negative findings may reflect small sample sizes,20,62
the inclusion of patients with bipolar disorder,22
and samples comprised of primarily young adult patients20,29,61
and of patients with a low number of illness episodes.29
In particular, younger patients with limited disease exposure may have yet to experience the pattern of hippocampal volume loss reported in patients with protracted illness. This suggestion is in line with Videbech and Ravnkilde's15
earlier meta-analysis showing an association between total number of depressive episodes and hippocampus volume, a finding replicated here. In contrast to the earlier report, however, with the inclusion of additional studies, we found this relation to hold bilaterally, as opposed to being significant for the right hippocampus only.
Medication status may play an important role in modulating hippocampus volume in MDD and, consequently, some studies did not find a relation between extended illness course and small hippocampus volume. A systematic examination of differences in hippocampus volume among patients who did and did not receive pharmacotherapy was not possible; however, preclinical literature suggests that antidepressant medication may have neurotroprotective effects,63
a finding mirrored in preliminary work in patient populations. Notably, in the studies included here, the differences in hippocampus volume between patients and controls were greatest for patients with a moderate compared with an extensive duration of illness (6.5% v. 3%). It is possible that presumed long-term treatment with antidepressant medication in these patients may have resulted in hippocampus volume increase and a partial reversal of tissue loss. One study reported that time spent untreated predicted small hippocampus volume, whereas time treated with antidepressants did not correlate significantly with hippocampus volume.17
Patients with posttraumatic stress disorder had increased hippocampus volume following a year of treatment with paroxetine.5
Lithium augmentation is sometimes used concurrently with antidepressant treatment in patients with MDD. Bipolar patients receiving short-term treatment with lithium had larger hippocampus volumes than did matched controls when assessed cross-sectionally,11
and in a related study, bipolar patients had increases in hippocampus volume over 2–4 years of lithium therapy.12
An alternative explanation, however, is that MDD represents a process equivalent to accelerated aging, where the differences between patients and controls are greatest in middle adulthood but then plateau as both patients and controls age. Longitudinal studies are required to examine the effect of medication and other treatment methods on hippocampus volume over time.
Of interest is the finding that hippocampus volumes did not differ between young adults with MDD and matched controls. Moreover, these participants experienced substantially less hippocampal volume loss than did middle-aged adults. One explanation is that young adults have a reduced burden of illness compared with older participants, and the limited data available on the duration of illness and number of illness episodes in the young adult population support this hypothesis.20
These data, however, are incomplete. Studies reporting hippocampal volume loss in this population may reflect a confounding of illness duration and age, where young adults with an extended course of illness are more likely to show atrophy. An alternate explanation is that the young adult period confers a period of reduced vulnerability to the effects of MDD on hippocampus volume. Specifically, hypercortisolemia, linked to hippocampus volume loss in prolonged MDD,64
is more common with advancing age,65
rendering the aged hippocampus particularly vulnerable to the effects of protracted stress.66
Hippocampal volume loss has also been reported in other neuropsychiatric illnesses (e.g., schizophrenia, posttraumatic stress disorder, bipolar disorder); it will be interesting to determine whether similar findings emerge for young adults when compared developmentally (for a review see Sala et al.67
Children with MDD had small hippocampus volumes relative to matched controls. This period of rapid brain development68
may represent a special period of neural vulnerability to the stress associated with MDD, or there may be unique pathophysiological processes associated with pediatric onset MDD. There was no evidence, however, that this population had small hippocampus volumes before or proximate to onset of illness; the mean duration of illness was 2.45 (SD 0.39) years, comparable to the aggregate onset data (information on number of episodes unavailable). The studies of children with MDD, therefore, do not discriminate between the possibility that small hippocampus volume antedates or follows clinical symptoms in this population.
Although we found no evidence that the presence of comorbidity contributed to differences in hippocampus volume, studies involving patients with comorbid disorders were few in number and heterogeneous in comorbid diagnoses. A stringent test of publication bias found no evidence that differences in hippocampus volume are attributable to the biased reporting of positive findings. Indeed, it is noteworthy that the literature concerning hippocampus volume reductions contains a substantial number of negative findings,24,62
possibly mediated by the clinical and demographic factors identified here. Finally, it will be important to explore further the effects of comorbidity in MDD by conducting replicable, systematic studies examining participants with MDD and comorbid conditions (e.g., substance abuse, posttraumatic stress disorder, social anxiety disorder).
Our findings extend the results of previous meta-analyses14,15
that revealed little evidence of an effect of slice thickness on differences in hippocampus volume between patients with MDD and controls. We confirmed this finding; both levels of MRI resolution continued to reveal hippocampus volume reductions in our updated analysis.
One limitation to our meta-analysis is the small size of many of the clinical and demographic subgroups, which may have limited statistical power to detect between-group differences. This is reflected in the fact that only a small number of comparisons between average hippocampal volume loss in each of the subgroups forming the clinical variables achieved significance. In our study, differences in rates of volume loss did not differ significantly across the subgroups formed by examining the age of onset, illness episodes and illness duration analyses.
In summary, this analysis of more than 2000 scanned participants found that hippocampus volumes are smaller in patients with MDD than in controls, but duration of illness plays an important role, as this difference is detectable only in patients who have an illness of greater than about 2 years duration or more than 1 episode of illness. Difference in hippocampus volumes is detectable in children, middle-aged and older adults, but not in young adults, where reduced burden of illness may play an important role. To date, studies examining the hippocampus in MDD have been mostly conducted cross-sectionally. Longitudinal studies that track patients over disease onset and through follow-up, particularly those involving systematic reporting of medication status and comorbidity, are urgently needed. Careful collection and reporting of data concerning burden of illness will also be essential if future studies are to advance our understanding of the factors that mediate small hippocampus volume in patients with recurrent MDD.