Vol. 9, No. 4, 2003 Page 3&4
Antidepressant drugs appear to accomplish their job by stimulating the growth of new neurons, according to a team of Columbia University researchers.
Research already links long-term stress, anxiety, and depression to atrophy or death of neurons in the hippocampus, a structure in the brain's limbic system. In addition, studies have shown that some antidepressants increase cell genesis in the hippocampus. However, researchers were not sure if this new cell growth was directly responsible for the drugs' behavioral effects.
To find out, Rene Hen and colleagues conducted several experiments. In the first, they treated mice with antidepressants, and found that while the drugs had no short-term behavioral effects, long- term exposure (for a period of four weeks or longer) caused the mice to be less anxious. In addition, the mice exposed to antidepressants for a long period showed a 60 percent increase in a marker of new cell generation in the hippocampus.
To determine if this new cell growth directly changed the mice's behavior, the researchers used x-rays to selectively destroy proliferating cells, reducing neurogenesis by 85 percent. The irradiated mice, they say, failed to respond to antidepressant treatment in the same way as other mice. For instance, normal mice that are chronically stressed exhibit poor grooming behavior, a symptom that improves when the mice are treated with the antidepressant fluoxetine. In the irradiated mice, no improvement in grooming behavior occurred in similarly stressed mice given the drug.
Hen et al. next created mice lacking a gene that codes for a key subtype of serotonin receptor. These mice, unlike regular mice, exhibited no new cell genesis in response to long-term treatment with fluoxetine (which enhances the effects of serotonin), and their behavior was not affected by the drug. However, they did show behavioral responses and new cell growth in response to treatment with tricyclic antidepressants, which affect a different neurotransmitter (norepinephrine).
These findings, Hen and colleagues say, could explain why "drugs like Prozac and Zoloft take a month before acting and people can spend several months trying different drugs before finding the one that works for them."
In a separate study, Yvette Sheline and colleagues used magnetic resonance imaging (MRI) scans to measure the volume of the hippocampus in 38 women who had suffered an average of five episodes of major depression during their lives. Some of the women had been treated with antidepressants, while others had not. The researchers also interviewed the women to determine how long their episodes of depression had lasted, and how long they had taken antidepressants.
Sheline et al. found that while the depressed women had smaller hippocampal volumes than non-depressed women, the reduction was less marked in the subjects who had received antidepressant treatment. The researchers were able to predict the amount of hippocampal volume loss, based on the ratio of number of days of depression to the number of days on antidepressant treatment. They note that animal studies also show that antidepressants can protect against stress-induced reductions in hippocampal volume.
The researchers say it is not clear why the hipppocampus shrinks in people with depression, but the damage may result from high levels of chemicals such as cortisol (a stress-related hormone), or from damage to the connections between nerve cells.
Sheline and colleagues say that their findings about the neuro- protective effects of antidepressants show the importance of recognizing and treating depression early in the disease process. They also say their data indicate that treatment between episodes of depression could help protect the brain.
"Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants," L. Santarelli, M. Saxe, C. Gross, A. Surget, F. Battaglia, S. Dulawa, N. Weisstaub, J. Lee, R. Duman, O. Arancio, C. Belzung, and R. Hen, Science, Vol. 301, No. 5634, August 8, 2003, 805-9. Address: Rene Hen, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032.
"Creation of new neurons critical to antidepressant action in mice," news release, National Institute of Mental Health, August 7, 2003.
"Untreated depression and hippocampal volume loss," Y. I. Sheline, M. H. Gado, and H. C. Kraemer, American Journal of Psychiatry, Vol. 160, No. 8, August 2003, 1516-8. Address: Yvette Sheline, Department of Psychiatry, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, yvette@npg.wustl.edu.
"Antidepressant drugs may protect brain from damage due to depression," news release, Washington University School of Medicine, August 1, 2003.