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Depression genes show when the drugs won't work

October 5, 2006 By Michael Hopkin This article courtesy of Nature News.

Anxious mice could point to better treatment for human conditions.

When depressed or chronically anxious people are prescribed drugs to treat their condition, it can take weeks before they know whether the pills have worked or not. Now psychiatrists have laid the foundations for a genetic test that could bypass that trial-and-error process by identifying patients who will not respond to particular drugs.

The researchers focused on a brain mutation that predisposes humans to depression and related disorders. They engineered mice to express the same mutation and found that the mice displayed classic signs of rodent anxiety. What's more, when given the widely prescribed drug fluoxetine, also called Prozac, the mice showed little improvement.

If the same happens in humans, it might help to explain why around 60% of patients given drugs for depression do not respond to the first medication that they are prescribed, say the researchers, led by Francis Lee, of Weill Medical College of Cornell University in New York.

Beating the blues

A range of drugs called selective serotonin-reuptake inhibitors (SSRIs) are widely used to treat depression. They all work by increasing the amount of serotonin, a chemical linked to emotional state, available to neurons in the brain.

But evidence is emerging that serotonin may not be the whole story. In 2003, for example, it was reported that fluoxetine may also work by bolstering neuron growth in the hippocampus, a region associated with learning and memory (see ' New nerves may fight depression').

The new research builds on the idea that neuron growth is important for alleviating depression and its related symptoms. The mice in the study had a mutation in the gene encoding brain-derived neurotrophic factor (BDNF), which is secreted from brain cells and guides neuron growth. The mice were more anxious spending less time exploring open spaces and were not helped by fluoxetine, Lee and colleagues report in Science1.

Humans with a specific mutation in the same gene are more prone to depression, as well as learning and memory difficulties. Surprisingly, as many as 30% of Caucasians may carry this mutation, but no one has investigated whether Prozac works well for this particular group or not.

Picking the pills

By screening for this brain mutation in humans with depression, doctors might improve their success rate in prescribing treatments something that would be desirable, given that the drugs take several weeks to work even in successful cases. "Because antidepressants have a delayed onset of action, knowing which class to initiate treatment with would be beneficial," Lee says.

But it will be a long time before we have such a test, argues Sarah Bailey, a pharmacologist at the University of Bath, UK. "That kind of pharmacogenomics is something for the future," she says. Doctors should go on prescribing SSRIs for now, she adds. "SSRIs are very effective for treating a whole range of things."

The researchers should next test the mutant mice for symptoms of depression as well as of anxiety, says Bailey. "This paper hasn't looked at depression, which is a bit surprising," she says. Although the two often go hand in hand, "we don't really know whether the molecular mechanism is the same of different", she explains. "Some people just get anxious, some depressed, some both."

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  1. Chen A.-Y., et al. Science, 314 . 140 - 143 (2006).


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