The Magic of Knowing the Genetic Variations

The study led by Manfred Uhr found that certain variants in the gene for a protective transporter protein that drives drugs and other substances out of the brain supports the efficacy of the antidepressants such as citalopram (trade name Celexa) and venlafaxine (Effexor).

“Antidepressants are the first-line treatment for major depression, but their overall clinical efficacy is unsatisfactory, as remission … occurs in only one-third of the patients after a trial with an adequately dosed single drug, and remission rates further decline following successive treatment failures,” wrote the researchers.

The research conducted over a mice model investigated the function of transporter protein, called P-gp that prevents entry of antidepressants into the brain.

They first knocked out genes for the transporter protein in mice and administered the antidepressants to the animals.

The researchers found that brain concentrations of citalopram and venlafaxine were regulated by P-gp—that the antidepressants were thus “substrates” of the transporter.

In another study conducted over 443 patients on the antidepressants, they looked for variants in the human gene that were linked to reduced efficacy of the drugs. Their genetic analysis identified 11 such variants.

“To our knowledge, our results provide for the first time evidence that genetic variants in the [gene for P-gp] account for differences in the clinical efficacy of antidepressants, most likely by influencing their access to the brain,” they wrote.

“From a clinical point of view, the findings warrant that patients receiving a drug that is a P-gp substrate for the treatment of brain diseases are genotyped to exclude the possibility that a patient receives a drug that fails to enter the CNS to an extent required for efficacy,” researchers wrote.

The findings appear in the January 24, 2008, issue of the journal Neuron.

Source-ANI
SPH /GA