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Antidepressants don't work for you? This could be why

What causes depression has been oversimplified, resulting in drugs that treat stress but not necessarily depression, according to new research out of Northwestern University.

What causes depression has been oversimplified, resulting in drugs that treat stress but not necessarily depression, according to new research. shattered.art66/Flickr

Depression researcher Eva Redei presented research at the Neuroscience 2009 conference in Chicago this week that calls into question two tenets of depression science: that stressful life events are a major cause of depression, and that an imbalance in neurotransmitters triggers depressive symptoms.

For decades, drugs have been developed around these beliefs, leading to antidepressant medications that are actually designed to relieve stress. But stress-related genes have almost no overlap with depression-related genes, reports Redei, the David Lawrence Stein professor of psychiatry at Northwestern University's Feinberg School of Medicine in Chicago. (Full disclosure: Northwestern is my alma mater.)

That means those antidepressants work if you're stressed, but not necessarily if you're depressed.

"This is a huge study and statistically powerful," Redei says. "This research opens up new routes to develop new antidepressants that may be more effective. There hasn't been an antidepressant based on a novel concept in 20 years."

Redei's conclusion is based on studies of rats with behavioral and physiological abnormalities that are found in humans with major depression. Using microarray technology, Redei was able to isolate and identify the specific genes related to depression in the hippocampus and amygdala--regions of the brain associated with depression.

Redei then exposed four different strains of rats to chronic stress for two weeks, and identified which genes increased or decreased in response to this stress in all four strains. She now had one set of depression-related genes and one of stress-related genes.

To test the long-held belief that stress is a major cause of depression, Redei looked for similarities between these two sets of genes. Out of more than 30,000 genes on the microarray, 254 were related to stress and 1,275 to depression. Only 5 were found in both samples.

"This finding is clear evidence that at least in an animal model, chronic stress does not cause the same molecular changes that depression does," Redei says. She is now looking at the genes that differ in the depressed rats so that she can narrow down targets for drug development.

Antidepressants are also often ineffective, Redei says, because they aim to boost the neurotransmitters serotonin, norepinephrine, and dopamine, whose reduced levels have been associated with depression. But this strategy is now also being called into question.

In the second part of the study, Redei found that the biochemical events that result in depression were starting all the way back in the development of neurons, not in neurotransmitters. She says her animal model of depression did not show significant differences in the levels of genes controlling neurotransmitters' functions. In other words, medications are working as Band-Aids on the effect, as opposed to treatments of the cause.

"If depression was related to neurotransmitter activity, we would have seen that," she says.

Of course, her research depends on whether depression in human brains behaves similarly to depression in rats. "The similarities between these regions of the human and rodent brain are remarkable," she says. "The hippocampus and amygdala are part of the so-called ancient lizard brain that controls survival and are the same in even primitive organisms."