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Vol. LVII, No. 24
December 2, 2005

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Depression Research Changing Minds

People used to think that depression is a kind of personal weakness, something you can will away. Research has helped lift the stigma attached to it by showing that depression has measurable physical effects. It raises the risk of heart disease, high blood cholesterol and high blood pressure; in fact, the chance of someone dying after a heart attack is 4 times greater if he or she is depressed. Our understanding of what's actually going on in the brain during depression has also taken remarkable strides. Researchers are now using this new knowledge in the hope of changing the way depression is treated in the future.

Advanced imaging techniques showing activity within the brain have revealed areas that behave differently in depressed people. This knowledge is guiding researchers in designing newer methods for treating depression that target particular brain regions. In one technique called deep brain stimulation, thin wires are surgically implanted into an area called the subgenual cingulate region. A small current run through the wires improved depression in a small study. Such surgery may be impractical for large numbers of people, but it proves the principle that a small electric current in this area of the brain can help treat depression.

Another technique that doesn't require surgery is called transcranial magnetic stimulation. In TMS, a small electromagnet rests on the scalp and induces a current in the brain. The device can be fairly well focused on specific brain regions and doesn't seem to cause side effects. TMS has been promising in small studies, and a large-scale NIMH-funded study is now under way to test it more rigorously.

Other research teams are making progress using molecular approaches. Scientists were intrigued by the fact that it often takes people days or weeks to get better with selective serotonin reuptake inhibitors (SSRIs) even though these drugs work very quickly to block serotonin reuptake from synapses. Dr. Husseini Manji, director of NIMH's Mood and Anxiety Disorders Program, explained that we now know these medications ultimately work by affecting signaling pathways within neurons that alter gene expression.

The genes that account for the improvements these antidepressants bring seem to be those involved in cell growth and survival. While nerve cells in the brain don't die with depression, they do "shrivel up," as Manji put it — they have fewer dendritic branches and the dendritic spines onto which synapses are made. Drugs targeting these neuroplasticity and cellular resilience pathways are now being developed and tested. Manji is optimistic that new medications will be available within the next few years.

Researchers hope that understanding the genes involved in depression will also help doctors make better treatment decisions. Antidepressants like SSRIs and talk therapy are currently the most common treatments for depression, but different people respond differently to them and doctors often have little guidance in designing effective treatment regimens. Manji believes that as few as 4 or 5 genes might one day enable doctors to predict, with a simple blood test, which treatments will work best for which people.

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