Genetic changes key in antidepressant drugs: study

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http://www.reuters.com/article/scien...86929320080123

By Michael Kahn
LONDON (Reuters) - Changes in a gene that protects the brain from foreign substances may affect whether commonly used antidepressants work -- and a simple test could help doctors prescribe the right drug, researchers said on Wednesday.
The findings could also help doctors adjust doses to make the drugs more effective while cutting down on harmful side effects, said Florian Holsboer, director of the Max Planck Institute for Psychiatry in Munich, who led the study.
"This is the first step into personalized antidepressant treatment according to genetic makeup," Holsboer said. "The gene test can help the clinician when he makes a choice for the antidepressant he gives to the patient."
Depression is a leading cause of suicide and affects about 121 million people worldwide, according to the World Health Organization.
Previous studies have looked at a link between genetic mutations and antidepressants but did not differentiate between drugs, Holsboer said in a telephone interview.
The German team looked at how changes in the ABCB-1 gene affected three widely used treatments: Forest Laboratories Inc's
Celexa, Wyeth 's Effexor and Remeron from Dutch chemicals group Akzo Nobel's Organon pharmaceutical unit.
ABCB-1 is important because it protects the brain from molecules that do not belong and codes for a protein called P-gp, which pumps away substances trying to enter, Holsboer said.

To see how this protein functioned in regulating the three antidepressants, the researchers created mice lacking the ABCB-1 gene and gave the animals the drugs.
They found that the gene and the protein blocked Celexa and Effexor but not Remeron. The researchers do not know why but said the drugs' different chemical makeup could be the reason.
"If the genes are mutated the 'pump' may be better or worse," Holsboer said. "If it is not a good pump the antidepressant may have less problem entering the brain."
The researchers next studied 443 patients on antidepressants to pinpoint the mutations. They found 11 variations of the gene, of which two are particularly important because of their key role in how the protein works, Holsboer said.
This knowledge could lead to a genetic test to help the 30 percent of people who do not respond to antidepressants, he added.
"This situation is particularly alarming in view of the fact that major depression constitutes one of the greatest disease burdens worldwide," the researchers wrote in the journal Neuron.