Genetic difference predicts antidepressant response

The researchers said their findings indicate that genetic testing could help predict the responses of patients to particular antidepressants. More broadly, they said, such tests could help predict the efficacy of any drugs used to treat neurological disease.

Manfred Uhr and colleagues published their findings in the January 24, 2008, issue of the journal Neuron, published by Cell Press.

“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. “This situation is particularly alarming in view of the fact that major depression constitutes one of the greatest disease burdens worldwide and is anticipated to be the second leading global disease burden by the year 2020, trailing only cardiovascular disease.”

One reason for such poor response rates, said the researchers, is that protective transporter proteins pump such substances as drugs and some hormones back into the bloodstream, preventing them from crossing the blood-brain barrier.

In their studies, the researchers explored the function of one such transporter protein, called P-gp, in preventing the 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.

Studying 443 patients on the antidepressants, they next searched for variants in the human gene that correlated with 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.

“The general conclusion to be drawn is that any drug administered to treat CNS diseases should be analyzed for its P-gp substrate status, which can be determined by using …knockout mice. 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.”

The researchers also suggested that development of future antidepressants should take into account whether the candidate drugs are transported by P-gp. And, clinical trials of antidepressants should be designed to take into account the P-gp genetic status of patients in the trial.

Source: Cell Press

New study replicates association between genetic variation and antidepressant treatment response
Pharmacogenetics, the study of genetic variation that influences an individual's response to drugs, is an important and growing focus in all of medical research, including psychiatry. It is a complex field, however, revealed by the lack of consistent and replicable findings across multiple studies, but some encouraging results are beginning to emerge. A new study scheduled for publication in the June 15th issue of Biological Psychiatry evaluated genetic markers in the treatment response of antidepressants and this work implicates the same markers as found in a prior trial.
Discovery of 'overdrive' protein could broaden drug design options
New research by scientists at the University of North Carolina at Chapel Hill shows for the first time that an important family of proteins known to function at the cell surface also functions at a site within the cell.
St. John's wort relieves symptoms of major depression
New research provides support for the use of St. John's wort extracts in treating major depression. A Cochrane Systematic Review backs up previous research that showed the plant extract is effective in treating mild to moderate depressive disorders.
Herbal menopause therapy a good fit for breast cancer patients?
When it comes to understanding the effectiveness and safety of using herbal therapies with other drugs, much is unknown. Now, a University of Missouri researcher will study how black cohosh - an herbal supplement often used to relieve hot flashes in menopausal women - interacts with tamoxifen, a common drug used to treat breast cancer.
No longer depressed, or on meds
Henry Quant was just 5 years old and bedridden with chronic fevers when he began taking pills for anxiety and depression. His mother knew that the drugs helped, but they made her nervous.
American kids most medicated
American children are approximately three times more likely to be prescribed psychotropic medication than children in Europe. A new study published today in BioMed Central's open access journal Child and Adolescent Psychiatry and Mental Health claims that the differences may be accounted for by regulatory practices and cultural beliefs about the role of medication in emotional and behavioural problems.
Sex differences seen in response to common antidepressant
Women with depression may be much more likely than men to get relief from a commonly used, inexpensive antidepressant drug, a new national study finds. But many members of both sexes may find that it helps ease their depression symptoms.
Antidepressants need new nerve cells to be effective
Researchers at UT Southwestern Medical Center have discovered in mice that the brain must create new nerve cells for either exercise or antidepressants to reduce depression-like behavior. In addition, the researchers found that antidepressants and exercise use the same biochemical pathway to exert their effects.

Genetic difference predicts antidepressant response

Related stories:

News discussion: