By the Blouin News Science & Health staff

A gene that may compromise the efficacy of antidepressant drugs

by in Medicine, Research.

An employee of a research institute. Reuters/ Fabrizio Bensch

An employee of a research institute. Reuters/ Fabrizio Bensch

A University of Sussex study found a gene alteration which influences how strongly people remember negative memories. The study published in The Journal of Neuroscience, shows an alteration in the gene that produces the brain chemical substance noradrenaline, which heavily impacts the outcome of reboxetine intake, an antidepressant drug. These findings demonstrate genes impact on antidepressant response and efficacy.

The more an event is associated with strong emotions, the stronger its trace remains in our memory. However, studies on patients with depression or anxiety disorders suggest that there is a heightened recall of negative events. Noradrenaline is a stress hormone as well as a neurotransmitter (postman delivering signals between a neuron and a target cell), and it is one of the brain substances incriminated for depression and anxiety. In addition, the antidepressant drug reboxetine specifically affects the levels of noradrenaline in the brain and reduces the recall of negative memories.

From a genetic point of view, one of the genes implicated in noradrenaline release which affects emotional memory is the alpha-2B adrenoceptor gene (ADRA2B). Studies have shown that a gene alteration (variant) is related to increased activation of part of the brain after exposure to a stressful event. It is possible that such genetic factors influence the efficacy of drugs. However, scientists have no clue about the relationship between genetic variants and pharmacological agents and if both are affecting emotional responses.

In the present study funded by Brighton and Sussex Medical School, Professor of Experimental Psychology Theodora Duka and her colleagues examined the hypothesis that a variant form of the ADRA2B gene moderates the effect of reboxetine on emotional memories in a healthy population. To avoid gender differences on emotional processing, the team conducted the study only within a male population with no previous history of psychiatric or neurological disorders. Participants received a genetic test to see if they had the ADRA2B variant and they were randomly divided in two groups: those receiving reboxetine and those receiving a sugar pill (placebo).

After two hours, enough time for the drug to circulate in the bloodstream, one set of positive, negative, and neutral images was presented on a computer screen. The images were randomly chosen within two available sets matched for valence, content or arousal. Thirty minutes later, the researchers subjected the participants to a recall memory test; men had to write down a brief description of each picture they could remember. At the end, all sets were presented and men had to recall whether they have seen each picture before or not.

The researchers found that while reboxetine attenuated negative recall in men with the common form of ADRA2B, it did not have any effect in men-carriers of the variant gene form. All participants remembered the positive and negative pictures better than the neutral ones, but the carriers of the ADRA2B variant recalled more negative pictures and this did not change when they were administered reboxetine. The antidepressant drug simply did not work on carriers of the gene variant.

“This study elegantly demonstrates the importance of the concept of aversive memory in psychiatric disease and paves the way for further experiments dealing with the molecular underpinnings of antidepressant efficacy,” says Andreas Papassotiropoulos, MD and memory researcher at the University of Basel who did not participate in the study.

The interest should fall now on understanding how antidepressants affect the way emotional information is processed in order to predict the most effective antidepressant prescription according to the individual’s genetic profile. At the same time, these findings provide some possible explanations for the moderate efficacy of antidepressants and for cases of treatment-resistant depression. Now researchers have to explore the ADRA2B variant impact on the reboxetine effectiveness in other populations including women and patients with anxiety as well.