Hippocampal and amygdala volumes did not significantly decrease over 3 years among patients or participants in the control group, and these volumes did not significantly differ in the study population. Thus our study cannot confirm that hippocampal volumes diminish during depressive episodes, as suggested in cross-sectional in vivo neuroimaging studies in elderly patients6,7
and in younger patients with major depression.8–10
Our main finding was that patients with recurrent depression who have a smaller hippocampal volume experienced a negative clinical outcome within the first 3 years after an acute depressive episode. Moreover, in a cross-sectional analysis Sheline and colleagues6
observed a correlation between smaller hippocampal volumes and a longer cumulative duration of illness. Thus hippocampal volumes and the course of a depressive episode may be related. Our findings supported the hypothesis that brain alterations such as reduced hippocampal volumes may predispose patients to the development of depression and a poor clinical outcome without full remission from depression. Thus stressful life events or other factors that influence neuronal development (e.g., pre-, peri-or postnatal infections; genetic vulnerability) may change hippocampal structures in a way that would render patients more vulnerable to the development of major depression.
Other studies support the hypothesis that a smaller hippocampus may predict psychiatric disease with more severe symptoms. Lyons and colleagues26
stated that paternal genetics, but not early stress, appeared to account for much of the variance in hippocampal size in squirrel monkeys. Experimental studies showed that monkeys with smaller hippocampal volumes responded with greater increases in adrenocorticotropic hormone levels after social manipulation.27
Interestingly, Gilbertson and colleagues28
found that smaller hippocampal volumes constituted a risk factor for the development of stress-related psychopathology because the severity of post-traumatic symptoms was negatively correlated with the hippocampal volume in both patients with post-traumatic stress disorders and the patients' unexposed identical twins.
We found that larger hippocampal volumes were associated with a good clinical response and with a low relapse rate over the 3 years. Relatively larger hippocampal volumes may prevent relapses in patients with recurrent depression. In line with this hypothesis, larger hippocampal volumes have been found to be associated with less executive dysfunctioning29
and memory impairment.30,31
Interestingly, this effect was seen in particular among patients with recurrent depression. It may be that patients with first depressive episodes are not defined well enough clinically because, compared with patients with unipolar recurrent depression, they may also have bipolar disorders with other neurobiological correlates.
Based on the stress-toxicity hypothesis of depression32
and on cross-sectional studies of the relation between duration of illness and hippocampal volumes,15
we might have expected a volume decline at least among patients who continued to experience depression during the 3 years of follow-up; however, we found no significant reduction of hippocampal volumes. These results indicated that there was no volume decline during depressive episodes and that total hippocampal and amygdala volumes were very stable over time. Only a small decline in the hippocampal volume with increasing age has been found in in vivo33–36
and postmortem studies37
that reported little or no hippocampal volume changes with increasing age. In particular, hippocampal volume decline was seen in patients with Alzheimer disease, which showed a progressive hippocampal decline owing to neurodegenerative processes.34
Therefore, the failure to find significant differences during a 3-year period among participants in a control group or among patients with major depression, in which most of the patients were remitted from depression, was not astonishing. It may be that subregions of the hippocampus, such as the gyrus dendatus or region CA3, are more sensitive to neuroplastic changes, as reported in studies of animals.2–4
Therefore, methods such as voxel-based morphometry or high-resolution MRI (e.g., 3 T or more), are required to detect changes in these subregions.
Recently, we found an association between the brain-derived neurotrophic factor polymorphism and hippocampal volumes, which was independent of a diagnosis of depression,38
suggesting that the volume of the hippocampus may be determined early during neuronal development. This finding, together with the main finding of our present study, suggested that the hippocampus may be resistant to disease effects, but that neuroplastic processes may cause subtle changes. Such small effects were seen among patients who had been taking antidepressants for a long time. We found that left hippocampal volumes increased significantly even after we performed a Bonferroni adjustment in those patients who took their antidepressants over the whole 3-year period, which indicated that the antidepressants had active effects (e.g., through neuroplastic processes), which have been suggested based on results of experimental studies.2,5
Our study supports the finding from a structural MRI study in 20 patients with post-traumatic stress disorder that the mean hippocampal volume increased by about 4.6% after a 36- to 48-week trial involving treatment with paroxetine.39
However, in patients with major depression, no significant change in hippocampal volumes was found after a mean of 7 months (SD 3 mo) of successful treatment with serotonin reuptake inhibitors, in particular with fluoxetine, compared with the pretreatment investigation.40
It may be that morphological changes are more likely to be seen after a longer time period, as in our study, than after a few months of treatment. However, we do not know of any evidence that antidepressants act unilaterally on neurogenesis or neuroplastic processes. Thus we have to regard our finding with caution. Future studies involving larger samples are necessary to investigate this question.
We found that amygdala volumes were not significantly altered among patients with a first depressive episode or with recurrent depression. This finding was in line with earlier studies, including our own investigations, which failed to find altered amygdala volumes in patients with recurrent depression10,18
and showed smaller19
or even larger amygdala volumes16
among patients with a first depressive episode. One explanation for these inconsistent findings may be that the amygdala can be less reliably measured than the hippocampus.
Our study had a few limitations. All patients took antidepressants for at least 6 months after their depressive episodes, as recommended clinically. This may be one reason why we failed to find progressive changes in hippocampal volumes because, at this very early stage, the possible protective effects associated with the use of antidepressants might have been present in all patients. Another limitation was our relatively small sample; however, to date we are not aware of a larger follow-up investigation using structural MRI. In addition, we had to define large and small hippocampal volume groups post-hoc after baseline investigations; however, no normal values are available at the present time. Furthermore, hippocampal volumes that 1 or 2 units of standard deviation smaller than those of participants in the control group nearly did not exist in patients with major depression. Thus it is unlikely that hippocampal volume will be used as a diagnostic tool in the near future. It may be the case that mainly patients with good clinical outcomes participated in the follow-up investigation, whereas nonremitted patients with poor clinical outcomes did not. This study bias might explain the failure to find significantly reduced hippocampal volumes in the overall patient group.
In summary, the present data indicate that relatively smaller hippocampal and amygdala volumes might predispose patients with recurrent depression to a poor treatment response and to vulnerability for relapses.