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“People suffering from depression are in great distress and find it very difficult to go through the process of treatment adjustments, which can take weeks or months,” said Shomron, who heads the Genome High-Throughput Sequencing Laboratory at TAU’s Sackler Faculty of Medicine. “We chose to focus on paroxetine, a very common drug for depression, which is sold in Israel under the trade names Seroxat, Paxxet, Paxil, Parotin and Paroxetine-Teva. We were looking for a faster, easier and more effective way to find out how [paroxetine] would affect a particular patient.”

Paroxetine belongs to the SSRI family of drugs that inhibit the re-absorption of serotonin in the brain, the best-known and most popular of which are Prozac and Cipralex. “These drugs do not help all those suffering from depression, and in many cases one must keep trying drugs from other families by trial and error. Meanwhile, the patients and their families suffer,” explained Gurwitz, who heads the National Laboratory for the Genetics of Israeli Populations at Sackler.

One of the interesting things about the research is that it did not involve people suffering from depression. Rather than examine the effect of the drug on patients, the researchers added paroxetine to 80 samples of cultured white blood cells taken from healthy volunteers.

The results showed that in some cases the drugs inhibited cell division in the cultures significantly, while in others the delay was relatively minor. The researchers then focused on those cases with the most extreme responses: the 10 cultures that were most affected by the addition of paroxetine, and those least affected. The aim was to see whether there were significant differences between the two extremes on the genetic and molecular levels. By using a genetic chip, the researchers were able to perform a comprehensive molecular profile of all the selected samples.

“The result surprised us so much that we started to check if we’d made some mistake,” said Shomron. “We discovered that the single biggest difference between the two groups was the level of expression of a gene known as CHL1. Until then, no one had ever linked that particular gene to depression.”

Dr. Gurwitz noted, however, that the protein encoded by the gene CHL1 is recognized in scientific literature as essential for creating synapses (connections between neurons) in the brain. “Our findings suggest that depression may be caused not by lack of serotonin, as is written today in medical books, but because of damage to the synapses, probably resulting from a lack of proteins that repair synapses damaged by stress,” he says.

Giving the researchers a boost is a large clinical study recently published in the United States involving some 1,400 patients treated with the antidepressant Citalopram. Those findings also suggest a link between the gene CHL1 and the response to depression treatment.

Since the 1990s, Gurwitz said, hundreds of genetic studies have dealt with antidepressants. “But almost all of them began with the assumption that the main cause of depression is a lack of serotonin in the brain.” The approach of the two Israelis was totally different, he said. “We chose to look at all the genes of the human genome, about 25,000 genes and see which are affected by antidepressants. We believed the genetic diversity between people would surely be reflected in their response to drugs, which can be measured in vitro.”

The two said that this new insight could lead to a new type of antidepressant, which, instead of boosting serotonin levels in the brain – which are associated with depression, but probably not the cause – could improve the process of repairing damaged synapses.