St. Louis, June 11, 1999 -- Investigators at Washington University School of Medicine in St. Louis have found that a key brain region is significantly smaller in people who have suffered from clinical depression. Reporting in the June 15 issue of The Journal of Neuroscience, they say people who have been depressed have smaller volumes in a seahorse-shaped brain structure called the hippocampus that is important in learning and memory.

Using three-dimensional magnetic resonance imaging (MRI), the scientists found that otherwise healthy women with a history of depression had smaller hippocampal volumes than those who never had been depressed.

"In a previous, smaller study, we found a relationship between depression and loss of volume in the hippocampus, so we anticipated this finding," said lead author Yvette I. Sheline, M.D., assistant professor of psychiatry, radiology and neurology. "But we also expected to see an effect from aging. We thought the hippocampus would be somewhat smaller in our older subjects who had never been depressed, but instead we saw significant volume loss only in patients with a history of depression."

The investigators scanned the brains of 48 women ranging in age from 23 to 86. Half had a history of clinical depression. The others never had been depressed. None from either group had hypertension, diabetes, substance abuse or other conditions linked to destruction of brain cells. By excluding people with those conditions, Sheline expected to see only the effects of depression and aging in the hippocampus. Instead, there was volume loss only in those who had been depressed.

Women with a history of depression had hippocampal volumes between 9 percent and 13 percent smaller than never-depressed controls. Those with a history of depression also scored lower on tests of verbal memory, a process linked to hippocampal function.

Hippocampal volumes were even smaller in patients who had been depressed more often. Although none of the subjects was clinically depressed at the time of testing, the average woman in the study had experienced almost five episodes of depression in her lifetime, with one subject having lived through 18 bouts of clinical depression.

"The finding that depression can result in volume loss and that more depression can result in even greater volume loss underscores the importance of treating and preventing depression," Sheline said. "Treatment not only can prevent suffering and restore quality of life. It also appears that treating depression may limit long-term damage."

Although Sheline and colleagues found significant loss of volume in the hippocampus, total brain volume was unchanged.

The researchers also found loss of volume in part of the amygdala, a brain structure associated with emotion. Again, while the total volume of the amygdala was the same, the volume in the region called the amygdala core nucleii was smaller in those who had been depressed.

Other investigators have found that depressed patients make too much cortisol, a stress hormone or glucocorticoid important to proper hippocampal function. Sheline and others believe excessively high levels of glucocorticoids may have toxic effects on the hippocampus. But she cannot yet rule out the possibility that a person at risk for depression may start with a smaller hippocampus.

"If I were to speculate, I would say that the fact that multiple episodes of depression produce greater volume loss in the hippocampus suggests that there probably is some sort of damaging effect from depression," she said. "It also is possible that there is some other variable genetic perhaps that would predispose vulnerable people to this sort of damage. That also may be the case. But to prove it, we would need to take MRI scans of people before they have ever had depression."

Sheline and colleagues are beginning to re-scan some of the subjects from this study to learn whether hippocampal volumes fluctuate over time. They also are looking at seretonin receptors in the hippocampus and other brain structures. The seretonin receptor on neurons is one of the sites where antidepressant drugs are likely to work. Sheline wants to clarify the extent to which depression contributes to a decline in the number of seretonin receptors in the hippocampus and other brain structures even when the number of neurons in those regions remains the same.

Shheline YI et al. Depression Duration but not Age Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major Depression. The Journal of Neuroscience, vol. 19, no. 12, pp. 5034-5043, June 15, 1999.