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Columbia neuroscientists have shown for the first time that antidepressants work by stimulating the birth of new neurons in the brain, according to the study's senior author, Dr. Rene Hen, associate professor of pharmacology.

If so, more direct-acting drugs could be developed to promote the birth of new cells and shorten the lag time between the start of therapy and the lifting of mood. "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. During that time they're still depressed, so faster-acting drugs would be a great benefit," Dr. Hen says. The study appeared in the Aug. 8 issue of Science.

Most antidepressants prescribed today increase the amount of serotonin or noradrenaline – two neurotransmitters in the brain that may be undersupplied in people with depression. The commonly used serotonin reuptake inhibitors (SSRIs), for example, increase serotonin level between two neurons by preventing removal of the neurotransmitter from the synapse.

Everyone agrees that these drugs alleviate depression because they raise levels of serotonin and/or noradrenaline, Dr. Hen says, but what happens next is unclear. Raising neurotransmitter levels alone is not responsible for improving mood because levels rise days after drug therapy starts, while depression doesn't begin to lift until after several weeks of therapy.

Clues to what really happens began emerging a few years ago when other researchers found that several weeks of antidepressant treatment promoted the birth of new neurons in the hippocampus of mice. Because the time interval between the start of treatment and the maturity of new cells is similar to the time lag between the start of treatment and mood change in people, many researchers hypothesized that the new cells are responsible for the drugs' effects on depression.

To test this hypothesis, Dr. Hen and a postdoctoral researcher in the lab, Dr. Luca Santarelli and a graduate student, Michael Saxe, gave antidepressants to mice that had lost the ability to produce new hippocampal neurons. They then measured two behaviors believed to be related to depression: interest in food and interest in grooming. In normal mice, antidepressants increase food consumption and coat care, while mice under stress lose interest in both.

After four weeks on the antidepressants, however, the behavior of the neurogenesis-impaired mice did not change with either of the two drugs tested: Prozac and imipramine, an older tricyclic. The results, Dr. Hen says, "show there is a need for neurogenesis to cause antidepressant-like effects in mice" and suggest that new neurons may also be necessary for the drugs' mood-altering effects in people.

To be certain that neurogenesis is behind the efficacy of antidepressants, however, Dr. Hen says the experiment should be repeated using a different method to stop neurogenesis. In the current study, X-ray irradiation directed at the subgranular zone of the hippocampus prevented the development of new cells.

Though the researchers conducted several control experiments, including ones that irradiated other brain structures, "one could still argue there are side effects in the part of the brain we X-rayed that are really causing our results," Dr. Hen says. The lab is trying to develop a transgenic mouse that can't create new hippocampal neurons during adulthood to address those concerns.

If confirmed, new antidepressants that directly stimulate neurogenesis could work faster than the current drugs that work through serotonin receptors. But such drugs would still take a couple of weeks to change mood since it takes time for new neurons to mature and reach their targets. Dr. Hen says even faster-acting drugs would have to wait until researchers understand how the new neurons act on the hippocampus.

"Figuring out how the new neurons affect hippocampal circuitry to reduce depression is our biggest challenge now," Dr. Hen says. "We'll have to understand the function of these new neurons, to see if they're different from the old neurons or see how they alter the existing circuits. It requires re-thinking the role of the hippocampus, which is usually only associated with learning and memory, not mood."

If neurogenesis alleviates depression, does an inability to make new neurons cause depression in the first place? Other researchers have found that people with depression have less hippocampus volume than people without depression. And stress – believed to be a major factor in the development of depression – has also been shown to reduce neurogenesis in laboratory animals.

Dr. Hen says depression may have multiple causes: "It could be a decrease in neurogenesis, or a change in some other hippocampal property. Lack of neurogenesis is probably not the only, or even the main, cause. However, our findings point to the importance of the hippocampus. Any abnormality there may make people vulnerable to depression."

The research was supported by the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Alliance for Research on Schizophrenia and Depression.


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