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Drug Transporter Gene Variants Predict Antidepressant Effectiveness

NEW YORK (GenomeWeb News) – Polymorphisms in a brain drug transporter gene can influence the effectiveness of antidepressants, German researchers announced today.
 
Manfred Uhr and his colleagues at the Max Planck Institute of Psychiatry reported online today in the journal Neuron that polymorphisms in a transporter gene called ABCB1 can influence — and potentially be used to predict — the effectiveness of certain antidepressants, including Forest’s selective serotonin reuptake inhibitor citalopram (Celexa) and Wyeth’s selective serotonin and norepinephrine inhibitor venlafaxine (Effexor).
 
“To our knowledge, our results provide for the first time evidence that genetic variants in the ABCB1 gene account for differences in the clinical efficacy of antidepressants, most likely by influencing their access to the brain,” the authors wrote.
 
In general, any one antidepressant only completely resolves depression symptoms in a third of those who get the drug. And a given drug’s ability to efficiently cross the blood brain barrier and enter the CNS seems to be one of several factors influencing efficacy.
 
The ABCB1 gene, also known as the multidrug resistance 1 gene, codes for a P-glycoprotein transporter belonging to the ATP-binding cassette transporter protein family. P-gp has a role in active transport across the blood brain barrier, pumping its target drugs out of brain cells and back into circulation, effectively lowering the drug concentration in the brain.
 
To assess which antidepressants are P-gp substrates, the researchers first created an in vivo assay using mice lacking the two homologs of the human ABCB1 gene. In the absence of P-gp, the transporter’s substrates are found at higher brain concentrations. For instance, brain concentrations of citalopram, venlafaxine, and the venlafaxine product d-venlafaxine were 3.0, 1.7, and 4.1 times higher respectively in mutant mice than in their wild type counterparts.
 
The team then performed a pharmacogenetic, human SNP association study of 443 individuals with depression, separating them into groups based on whether the antidepressant they were taking had been identified as a P-gp substrate.
 
By genotyping 95 ABCB1 SNPs selected either from the dbSNP or from Illumina’s Sentrix Human-1 100K BeadChips, the researchers were able to correlate ABCB1 polymorphisms with antidepressant efficacy after four to six weeks of antidepressant treatment. Using this approach, Uhr and his colleagues identified 11 ABCB1 gene variants that were significantly associated with depression remission.
 
Their results suggest that ABCB1 variability may be an important consideration, not only when administering antidepressants, but also when testing new therapeutics. “[T]he interdependence of P-gp substrate capacity and ABCB1 genotype needs to be considered in future drug development, because drugs that differ in their P-gp substrate capacity need to be evaluated in clinical trials where study populations are stratified according to the ABCB1 genotype,” they wrote.
 
As far back as the early 1960s, researchers have been trying to understand why some family members had similar outcomes with certain antidepressants. But research into antidepressant pharmacogenetics didn’t begin in earnest until the mid to late 1990s. Many of these studies initially focused on genes related to metabolizing enzymes — particularly enzymes in the cytochrome P450 family — or brain receptors.
 
Although a number of gene variants influencing drug response have been identified, it remains unclear if, and when, such findings will be applied in clinical practice.
 
Earlier this year, a US Centers for Disease Control and Prevention panel recommended against testing for cytochrome P450 when administering selective serotonin reuptake inhibitors. Based on the findings of a January 2007 paper, the Evaluation of Genomic Applications in Practice and Prevention Working Group argued that there was insufficient evidence to warrant genetic testing in that case.