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Can Unique Animal-Human Study Identify New Targets for Predictors of Depression?

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The European Union is betting €7.3 million ($8.7 million) that a unique animal-human study will be able to identify new drug targets for depression, and pinpoint polymorphisms that contribute to the disease.

“At the end of it, we will have genes that we will expect will predict response to treatment,” said Bill Deakin, a professor of psychiatry at the University of Manchester in the UK who coordinates the study, called Newmood.

The 5-year study, which involves 13 research groups in the United Kingdom, Spain, France, Italy, Germany, the Netherlands, Estonia, Poland, and Hungary, will observe and compare gene-expression profiles for mice, rats, and humans diagnosed with depression. Any genes that show up in all three organisms will be further analyzed.

This approach is novel because it looks for changes that are shared between animal models and depressed patients, Deakin said. “There aren’t any major array studies in experimental animals of this kind.”

The hope is to find new drug targets for depression, mainly because existing drugs are based on dated research. For example, most antidepressants today work through the serotonin synapse. “We have known that for the last 40 years,” said Deakin. New drugs are also needed to treat treatment-resistant depression. In addition, the researchers hope to find genes with polymorphisms in humans that indicate a predisposition to depression.

The study, which began recently, will be “both hypothesis-driven and a search,” said Deakin. The researchers will start by measuring the expression of 800 genes in mouse and rat models of depression using microarray technology from GeneScore, a Paris-based startup. The genes cover almost all neurotransmitter systems, as well as trophic factors, cytokines, developmental regulators, and cell adhesion molecules — “all the ones conceivably related to” depression, Deakin said. In addition, the scientists plan to study gene expression in postmortem human brains from patients who committed suicide or suffered from chronic depression.

In a second step, the scientists plan to knock out those genes that were over- or under-expressed both in the animal models and in human brains to see if the mice develop features of depression, such as fearful behavior, insensitivity to rewards, or helplessness. “We hope [these genes] will have nothing to do with serotonin,” Deakin said. Also, the researchers want to study if polymorphisms of these genes are present in patients with depression.

In the end, the researchers want to produce a “depression chip” carrying all the genes they discovered in their search, to be used in screens for new antidepressant drugs, Deakin said.

Another project recently funded with €7.5 million from the EU, called Gendep, will look for genetic variations in humans that predict treatment response to antidepressants, according to Deakin. This project will involve a large European clinical trial. “The end product of both of them will be that we will know which genetic polymorphisms predict response to which kinds of treatment, so they will indeed be personalized,” he said.

— JK

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