Hippocampal Volume Loss and Major Depression

Mood disorders range from major depressive disorders to major manic episodes. These disorders are both unipolar and bipolar. One main area of mood disorder research is that of unipolar major depression. Major depression can last just one episode or it can be a disorder, which can last for years with multiple depressive episodes over this extended period. The psychological aspects of depression are well understood but the biological foundations are less understood. As some evidence of this, the DSM-IV manual does not include any neurological information concerning major depression. In this handbook, depression is treated purely as a mental condition without an explanation of the biological aspects of the disorder. On the other hand, there are many psychopharmaceuticals prescribed to people with depression, which suggests that there is more than a cursory acknowledgment of the biological basis of this mental illness. However, this biological focus is mainly a focus on neurotransmitters and not anatomy. Recently, there have been numerous studies conducted to investigate the relationship between brain structure and depression (see Videbech & Ravnkilde, 2004). One of the structures most often studied in connection with depression is the hippocampus, which is a key structure for memory. The purpose of this paper is to investigate whether the hippocampus specifically is negatively impacted in depressed patients.

Frodl et al. (2002) investigated hippocampal changes in patients with first episode major depression. The authors had 30 adult depressed subjects (mean age = 40.3) and 30 matched controls (mean age = 40.6). The mean time of the depressive episode for the depression group was 0.71 years. The researchers collected MR images for all subjects. They compared the hippocampal volumes of the depressed group with the control group with ANCOVAs. Depressed men had significantly smaller left hippocampal volume than did healthy male subjects but right hippocampal volume was not significantly different. Female depressed subjects had significantly larger right hippocampal volume than did their matched controls and left volume did not differ, which implicates differing effects of depression on men and women. There was a significant left-right hippocampal volume disparity in the depressed patients but there was not one in the healthy subjects. Overall, the difference in hippocampal volume was not significant between the depressed and control groups though. There was also no significant correlation between age and hippocampal volume for either group but this finding goes against that of other research (Frodl et al.). On the other hand, between groups there was a significant reduction of hippocampal white matter volume. In other words, both male and female depressed patients had on average a reduction in the hippocampal white matter compared to the control subjects.

The authors concluded that there are likely physiologic gender differences in how males and females react to stress, which would explain why depressed males had smaller hippocampal volume and females did not. They believe this may be an example of the protective effects of estrogen against stress seen in other studies. In any case, there was a tendency for both depressed males and females to have significant left-right hippocampal asymmetry and reduced white matter. They concluded that this represents the beginning of left hippocampus volume loss and disrupted axonal transmission, respectively. The researchers could not conclude, however, that depression caused the volume loss. It may be that the loss came in response to stress or some other factor, which in turn predisposed the depressed subjects to major depression. Alternatively, the depression could have been the catalyst for the reduction (Frodl et al., 2002). Further longitudinal research is needed to uncover the causal relationship between depression and hippocampal volume.

Lloyd, Ferrier, Barber, Gholkar, Young, and O’Brien (2004) also looked at hippocampal volume change in depression, but with a distinction between early-onset (before age 60) and late-onset (after age 60) patients. Their study had 51 depressed (23 early- and 28 late-onset) and 39 control subjects. A 1.0 Tesla MRI scanner was used to acquire brain images for all subjects. The authors found that early-onset depressed patients did not have significantly smaller hippocampal volume compared to controls. Late-onset patients did have a 7% to 10% hippocampal volume reduction compared to control subjects, which was a statistically significant reduction. However, this significance was lost when hippocampal volume was age-corrected. These results were inconclusive at best. Once again, the direct cause of hippocampal volume loss cannot be determined from the results of this study. The authors did conclude that their findings do tend to show that hippocampal volume is more greatly affected in late-onset depression than it is in early-onset depression.

Both of the previously studies did not find conclusive evidence of overall hippocampal loss in major depression but Frodl et al. (2002) did find evidence for left side loss in males. Neither of these studies has addressed the effects of depression over time though. Frodl et al. (2004) conducted a study to overcome this shortcoming. They looked at hippocampal and amygdala changes in depressed patients over the course of one year. They had 30 depressed patients and 30 healthy control subjects. They found a significant difference between left and right hippocampal volumes. In addition, patients who were not remitted at the 1-year follow-up had significantly smaller hippocampal volume compared to the remitted patients. In addition, nonremitted patients had smaller right hippocampal volumes at baseline and 1-year testing compared to control subjects. There was no significant reduction in hippocampal volume over the 1-year period for any of the groups, however. The authors concluded that, “our findings support the hypothesis that subtle brain lesions such as reduced hippocampal volumes may predispose patients to a poor clinical outcome without full remission from depression” (p. 497). Therefore, they are in favor of the theory that reduced hippocampal volume serves as a predisposing factor for major depression. These researchers did find evidence of hippocampal reduction in depressed patients but no evidence that depression caused the loss.

There still seems to be uncertainty concerning hippocampal volume loss and depression. From the previous three studies, there is evidence for some loss but this evidence is not convincing. However, the three review studies are hardly a comprehensive review of the literature in this field. What evidence is there for hippocampal loss in other studies? Kanner (2004) conducted a literature review to see if depression was more than just a psychiatric disorder, that it is in fact neurologic with psychiatric symptoms. He states, “The most frequent findings [of research concerning depression and brain structure changes] have consisted of a decrease in the volume of the hippocampus, prefrontal cortex, and basal ganglia” (Kanner, 2004, p. 637). The author cites a number of studies that show a relationship between major depressive disorder and hippocampal volume loss. There is also evidence of a relationship between severity of depression and hippocampal volume (Kanner, 2004).

The researcher further maintains that there are high prevalence rates of depression in people with neurologic disorders (e.g., up to 50% of stroke patients become depressed). These rates are even much higher than those of non-neurologic medical patients (Kanner, 2004). This is very interesting because it does seem to imply a strong neurological basis for depression. If someone receives an acquired brain injury to her head, a frequently occurring side effect is depression. This may still, however, be evidence that head injury is more psychologically impacting (i.e., it is harder to mentally accept) than is other bodily injury or disease. However, Kanner presents the results of many studies that show very high rates of depression in neurological disorder patients and deduces that this implies that depression is foremost a neurologic disorder and the psychiatric symptoms are secondary to but not separate from pathology. Understanding the relationship between depression and neurologic abnormalities (e.g., reduced hippocampal volume) is difficult. Frodl et al. (2004) state that reduced hippocampal volume serves as a predisposing factor for major depression. Kanner believes that the relationship is most likely bi-directional; neurologic dysfunction leads to depression and depression leads to neurologic dysfunction. This will likely be the conclusion of the relationship – just as scientists now understand that behavior results from both nature and nurture.

Is there further evidence for the neurological basis of depression? In a well-conducted meta-analysis of hippocampal volume and depression studies, Videbech and Ravnkilde (2004) found strong evidence for hippocampal volume reduction in depressed patients, especially those with repeated depressive episodes. The authors included 12 studies of unipolar depression that met their data criteria for meta-analysis. They found an average hippocampal volume reduction of 8% in the left hemisphere and 10% in the right. In addition, Videbech and Ravnkilde found “that the higher the proportion of patients with recurrent depression, the smaller the volume of the right hippocampus” (p. 1959). These are interesting results in light of the inconclusive findings of Frodl et al. (2002) and Lloyd et al. (2004). Videbech and Ravnkilde’s results are not explained by any one study in the meta-analysis (i.e., there is not one study with extreme results that is skewing the meta-analysis) nor by gender or age differences. These authors did not offer a firm conclusion concerning the cause of hippocampal volume loss though and stated that more longitudinal research is needed.

While there are seemingly contradictory findings in studies of hippocampal volume loss and depression (cf. Lloyd et al., 2004; and Videbech & Ravnkilde, 2004), recent literature reviews (see Kanner, 2004) and meta-analyses (see Videbech & Ravnkilde) show clear evidence for reduction of hippocampal volume in major depressive disorder patients. Even so, there still is need for further research to understand the causal relationship between hippocampal volume loss and depression. This research is promising; as the neurological aspects of depression are understood better, treatments that are more effective can be developed to help those suffering from major depression.


Frodl, T., Meisenzahl, E. M., Zetzsche, T., Born, C., Groll, C., Jager, M., Leinsinger, G., Bottlender, R., Hahn, K., & Maller, H. (2002). Hippocampal changes in patients with a first episode of major depression. American Journal of Psychiatry, 159, 1112-1118.

Frodl, T., Meisenzahl, E. M., Zetzsche, T., Hahne, T., Banac, S., Schorr, C., Jager, M., Leinsinger, G., Bottlender, R., Reiser, M., & Maller, H.-J. (2004). Hippocampal and amygdale changes in patients with major depressive disorder and healthy controls during a 1-year follow-up. Journal of Clinical Psychiatry, 65, 492-499.

Kanner, A. M. (2004). Is major depression a neurologic disorder with psychiatric symptoms? Epilepsy & Behavior, 5, 636-644.

Lloyd, A. J., Ferrier, I. N., Barber, R., Gholkar, A., Young, A. H., & O’Brien, J. T. (2004). Hippocampal volume change in depression: Late- and early-onset illness compared. British Journal of Psychiatry, 184, 488-495.

Videbech, P., & Ravnkilde, B. R. (2004). Hippocampal volume and depression: A meta-analysis of MRI studies. American Journal of Psychiatry, 161, 1957-1966.

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