Antidepressants May Prevent Hippocampus From Shrinking
Data from a pair of unrelated studies indicate that antidepressant medications—SSRIs in particular—may not only protect the brain from a loss of hippocampal volume that has recently been associated with depression, but may in fact reverse that loss by spurring neurogenesis—the birth of new neurons in the hippocampus.
The first of the studies, led by Yvette Sheline, M.D., an associate professor of psychiatry, radiology, and neurology at Washington University School of Medicine in St. Louis, appeared in the August American Journal of Psychiatry. Sheline and her co-investigators found that in a group of women with a history of clinical depression, the use of antidepressant medications appeared to protect the hippocampus from depression-associated damage.
Previous research has shown that the hippocampus is often smaller in people who have been clinically depressed than in those who have never had depression. Using high-resolution magnetic resonance imaging (MRI), Sheline’s team measured hippocampal volume in 38 women who had experienced an average of five episodes of major depression. In addition, each woman was interviewed on two occasions by independent investigators to determine the length of each depressive episode, as well as any pharmacologic treatment associated with each episode. (The team did not differentiate between medications, only use of an antidepressant versus no medication.) Not all of the subjects with depressive episodes had been treated with antidepressant medication.
Sheline found that on average, hippocampal volume was smaller than normal in depressed women and that the less time a woman had spent taking antidepressant medications, the smaller her hippocampus was likely to be.
The amount of volume loss was predictable, based on the number of days depressed compared with the number of days on antidepressant treatment.
“Our results,” Sheline said in a prepared statement, “suggest that if a woman takes antidepressants whenever she is depressed, depression would have less effect on the volume of her hippocampus. It is the untreated days that seem to affect hippocampal volume.”
The findings, Sheline noted, could have significant implications for treatment. Since the volume loss appears to be cumulative—that is, the more episodes of depression, the more volume loss—it is important to “recognize and treat depression right away to prevent damage.” She also suggests that it may be worthwhile for patients with recurring depression to continue taking antidepressant medication between depressive episodes.
“Many psychiatrists already recommend that some patients who are prone to depression remain on antidepressants permanently to protect against relapse,” Sheline explained. “These apparent neuroprotective effects provide a further argument for at least strongly considering doing so.”
She and her team are studying whether antidepressants may prevent damage to hippocampal neurons or restore previously lost volume.
Prevention vs. Repair
A report from a multicenter group led by Columbia University investigators may help to answer that question.
Rene Hen, Ph.D., an associate professor of pharmacology at Columbia and her colleagues reported in the August 8 issue of Science that it is the creation of new neurons that is critical to the action of antidepressants.
Hen’s team, funded by the National Institutes of Health, National Institute of Mental Health, and National Alliance for Research on Schizophrenia and Depression, used a mouse model to study new neuronal growth in the hippocampus. After treatment with the SSRI fluoxetine, the mice were observed (through feeding behaviors) to be less “anxious” when confronted with new environments. Normally, a mouse’s feeding behavior is delayed for a significant period when the animal is placed in a novel environment, which researchers deem to be an expression of anxiety provoked by the unfamiliar surroundings. This delay in feeding was significantly reduced by chronic administration of an SSRI; however, the effect was not noted immediately.
The reduction in the delay to feeding was noted to be significant only after four weeks of treatment. No difference was observed in feeding behaviors after five days of treatment with the SSRI, and only minimal reductions in the normal delay were noted after two weeks.
Long-Term Administration Preferable
Paralleling the delay in feeding-behavior changes, mice chronically treated with fluoxetine, but not those treated only briefly with the medication, showed a 60 percent increase in neurogenesis in key areas of the hippocampus.
The new data make sense, Hen said, in light of clinical observations that antidepressant medications often take weeks to exert any clinically noticeable effects.
“If antidepressants work by stimulating the production of new neurons, there’s a built-in delay,” explained Hen in a National Institutes of Health press release. “Stem cells must divide, migrate, and establish connections with postsynaptic targets—a process that takes weeks.”
NIMH Director Thomas Insel, M.D., noted, “This is an important new insight into how antidepressants work. We have known that antidepressants influence the birth of neurons in the hippocampus. Now it appears that this effect may be important to the clinical response.”
To determine whether the neurogenesis observed was critical to the behavioral response tied to antidepressant treatment, Hen and colleagues then selectively targeted the hippocampus of the animals with X-rays to kill proliferating cells. This blocked on average 85 percent of neurogenesis. Antidepressants given to these mice then had no effect on anxiety or depression-equivalent behaviors.
In addition, Hen’s team created a knock-out strain of mice missing the gene for the serotonin receptor 5-HT1A.
These mice, as adults, show anxiety-related traits such as exaggerated delay in feeding when placed in new environments.
Effects of Imipramine
When the 5-HT1A knock-out mice were treated with fluoxetine, no change was seen. However, the mice became less anxious after chronic treatment with the tricyclic antidepressant imipramine, which acts on norepinephrine rather than serotonin.
In addition, while the chronic fluoxetine significantly increased hippocampal neurogenesis in the normal mice, no change was seen in the knock-out mice. Both normal and knock-out mice treated with imipramine experienced increases in neurogenesis, Hen noted, which indicates that the 5-HT1A receptor may be required to mediate neurogenesis tied to fluoxetine, but not imipramine.
When the team chronically treated the mice with a serotonin 1A selective agonist, again, normal mice experienced increased neurogenesis, but knock-out mice did not.
“Our results suggest,” the researchers concluded, “that strategies aimed at stimulating hippocampal neurogenesis could provide novel avenues for treatment of anxiety and depressive disorders.”
The study, “Untreated Depression and Hippocampal Volume Loss,” is posted on the Web at http://ajp.psychiatryonline.org/cgi/content/full/160/8/1516. An abstract of “Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants” is posted at www.sciencemag.org/cgi/content/abstract/301/5634/805. ▪
Am J Psychiatry 2003 160 1516
Science 2003 301 805
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Published online: 5 September 2003
Published in print: September 5, 2003
Notes
The results of two new studies suggest that antidepressants work by directly reversing the loss of neuronal volume in specific brain regions, notably the hippocampus.
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