Antidepressant drugs may protect brain from damage due to depression
St. Louis, Aug. 1, 2003 -- Studying women with histories of clinical depression, investigators at Washington University School of Medicine in St. Louis found that the use of antidepressant drugs appears to protect a key brain structure often damaged by depression.
Previous research has shown that a region of the brain involved in learning and memory, called the hippocampus, is smaller in people who have been clinically depressed than in those who never have suffered a depressive episode. Now, researchers have found that this region is not quite as small in depressed patients who have taken antidepressant drugs.
The study, led by Yvette I. Sheline, M.D., associate professor of psychiatry, radiology and neurology, appears in the August issue of the American Journal of Psychiatry. The hippocampus is a part of the brain's limbic system, a group of structures important to emotion and motivation. Using high-resolution magnetic resonance imaging (MRI), Sheline's team measured hippocampal volumes in 38 women who had experienced an average of five episodes of major depression in their lifetimes. Only some of those episodes had been treated with antidepressant drugs.
"In addition to their brain scans, each woman was interviewed on two occasions by independent interviewers to determine how long each depressive episode lasted and how much, if any, of that episode was treated with antidepressants," Sheline says.
The team compared hippocampal volumes to the number of days on or off treatment. They found that on average, hippocampal volume was smaller than normal in depressed women, and that the less time a woman had spent taking antidepressants, the smaller her hippocampus. The amount of volume loss was predictable, based on the number of days depressed versus the number of days on antidepressant treatment.
"Our results suggest that if a woman takes antidepressants whenever she is depressed, depression would have less effect on the volume of her hippocampus," Sheline says. "It is the untreated days that seem to affect hippocampal volumes."
Animal studies also have demonstrated that antidepressant drugs can protect against stress-induced decreases in hippocampal volumes. Why the hippocampus shrinks is not clear. It may be that brain chemicals released during depression, such as cortisol, damage brain cells. Or it could be that depression damages the connections between nerve cells, resulting in a smaller volume. But however the damage is done, Sheline says it is clear from this study that antidepressant drugs can limit volume loss.
"We've shown in other studies that people with hippocampal damage also have problems with certain memory tests," she says. "And large epidemiology studies have shown that major depression is a risk factor for the later development of Alzheimer's disease. So it seems clear that volume loss in the hippocampus can have very negative effects, not to mention the devastating problems caused by depression itself."
Sheline and colleagues did not look at specific antidepressants to compare whether one was better than another at preserving hippocampal volumes, but any antidepressant seems to protect the brain better than no treatment.
Sheline says because volume loss in the hippocampus 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. It also may be worthwhile for patients to continue taking antidepressants between episodes of depression.
"Many psychiatrists already recommend that some patients who are prone to depression remain on antidepressants permanently to protect against depression," Sheline explains. "These apparent neuroprotective effects provide a further argument for at least strongly considering remaining on antidepressants."
Currently, Sheline's team is looking at whether antidepressant drugs prevent damage to hippocampal neurons or whether they may potentially restore previously lost volume. It is unclear whether drugs can restore volume that was lost, but she says this research demonstrates that without treatment, hippocampal volume loss in depressed patients was more extensive than it was in those who took antidepressant drugs.
Common antidepressants such as Prozac lift mood by spawning new brain cells, suggests a new study. The finding might give rise to more potent drugs that directly boost nerve production.
The report attempts to solve a conundrum: why many antidepressants take several weeks to take effect despite boosting brain chemicals within days. This applies to selective serotonin re-uptake inhibitors (SSRIs), which raise available levels of the nerve-to-nerve signal serotonin, and tricyclic antidepressants, which bump up norepinephrine levels.
The drugs work by triggering the birth of new nerve cells in the hippocampus, normally associated with learning and memory, argue René Hen of Columbia University, New York, and his team. In mice, they found, jamming new nerve birth scuppers some of antidepressants' uplifting effects.
To cripple neuron production, the group trained an X-ray beam on some animals' hippocampus; this treatment kills only dividing cells. X-rayed mice suffered more fear and stress after month-long courses of Prozac — an SSRI — or of the tricyclic antidepressant imipramine.
The study offers some of the best evidence that the new cells are responsible for at least some of the mood-lifting effects of antidepressants; rather than being merely a side-effect. "This is as good as it gets right now," says brain researcher Elizabeth Gould at Princeton University in New Jersey.
Critics point out that the drugs may have other effects in the brain that help to fight depression. What's more, it is difficult to mimic the human disorder by testing anxiety in mice. "We have no idea how relevant this is to human depression," says Daniel Weinberger, who studies mental illness at the National Institute of Mental Health in Bethesda, Maryland.
Making connections
An estimated 121 million people worldwide suffer clinical depression; almost one in ten in some developed nations. Antidepressants are the world's third most widely prescribed drugs.
The idea that antidepressants might generate new hippocampal neurons was first proposed in 2000. Hen suggests that young neurons may stave off depression because they are more adept at forming and re-forming connections, helping the brain to accommodate stress.
A new generation of mood-enhancing drugs might even be designed to prompt hippocampal cells to divide, he speculates.
References
1.Santarelli et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301, 805 - 809, (2003).