Mutant Enzyme Linked to Depression

13 December 2004 (All day)

Researchers are hot on the trail of a genetic variation that could explain why some people don't respond to antidepressant drugs that target the neurotransmitter serotonin. A new study has found that a group of severely depressed people were 10 times as likely as nondepressed people to have a version of a particular gene that reduces the production of serotonin in the brain.

The culprit in this study is a mutant version of the Tph2 enzyme, which synthesizes serotonin. A team headed by cell biologist Marc Caron of Duke University in Durham, North Carolina, previously found that cultured human brain cells expressing the mutant enzyme produced 80% less serotonin than did cells with the more common form of Tph2. In the current study, published online in Neuron on 9 December, they report that among a group of 87 patients with major depression, nine carried the mutation, compared with only three people in a control group of 219. The mutation appears to be specific to unipolar depression; no one in a group of 60 patients with manic depression, or bipolar disease, had it.

Caron says this is the first gene discovered in major depression with a documented effect, namely, lowering serotonin levels in the brain. The researchers say that the mutation could help predict who will respond to SSRIs--selective serotonin reuptake inhibitors such as Prozac--which restore flagging serotonin levels in people with depression. The drugs operate by preventing reuptake of serotonin by the cell that releases it so it will linger longer in the synapse to be taken up by other neurons.

But if there's not much serotonin released in the first place, the drugs can't do much good. Indeed, in the current study, seven of the subjects with the mutant variant failed to respond to SSRIs, and the other two required extremely high doses. What's more, based on preliminary work from his lab, Caron suspects that the mutation could play a role in paradoxical reactions that have been reported from SSRIs including extreme agitation, psychosis, and suicidal behavior. Such reactions have caused officials in both the United Kingdom and the United States to issue warnings about the risks of prescribing SSRIs to children and adolescents.

It's "a very exciting finding," says neuroscientist Huda Akil of the University of Michigan, Ann Arbor. Depression is likely influenced by many different genes in different people, she cautions. But if future, larger studies support the latest finding, says Akil, "it would represent a real breakthrough" that could help clinicians in detecting susceptibility to depression as well as tailoring drug treatment to patients' genetic profiles.

Related sites
Information about depression from the National Institute of Mental Health
More about SSRIs

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