Why do antidepressants fail for some?
28 March, 2019
Research has revealed a biological explanation for why some people with depression do not respond to a class of antidepressants that doctors commonly prescribe. It has to do with fundamental differences in the nerve cells that produce and use serotonin.
Serotonin is the chemical messenger that has a major impact on feelings of happiness and wellbeing.
Scientists have long suspected that disruption in serotonin brain circuits is a key factor in major depressive disorder. Selective serotonin reuptake inhibitors (SSRIs) are a significant class of drug that seeks to remedy this disruption by increasing serotonin levels at nerve junctions.
However, for reasons that have been unclear, SSRIs do not work for around 30 percent of people with major depression. Now, researchers from the Salk Institute for Biological Studies in La Jolla, CA, and the Mayo Clinic in Rochester, MN, may have solved the mystery.
A Molecular Psychiatry paper describes how, by studying cells from hundreds of people with major depression, the team uncovered differences that could explain resistance to SSRIs.
"These results," says senior study author Fred H. Gage, who is president of the Salk Institute and also a professor in their Laboratory of Genetics, "contribute to a new way of examining, understanding, and addressing depression."
He and his colleagues believe that their findings also offer insights into other psychiatric illnesses that involve disruption of the brain's serotonin system, such as schizophrenia and bipolar disorder.
Depression and nerve cell response to SSRIs
Depression is a leading cause of disability that affects all ages and contributes in a major way to the "global burden of disease," according to the World Health Organization (WHO). The United Nations agency estimate that there are around 300 million people worldwide living with this widespread psychiatric condition.
In the United States, the National Institutes of Health (NIH) suggest that in 2017 around 17.3 million adults, or 7.1 percent of all adults, reported having "at least one major depressive episode" in the previous 12 months.
For the recent study, the scientists took skin cells from more than 800 people with major depression and turned the cells into stem cells.
They then coaxed the stem cells to mature into "serotonergic neurons," which are the nerve cells that make up the brain circuitry for producing and using serotonin.
The team compared serotonergic neurons of "SSRI non-responders" with those of "SSRI responders." The non-responders were those individuals with depression whose symptoms showed no improvement, while the responders were those whose symptoms showed the most dramatic improvement to treatment with SSRIs.
In previous work, the researchers had demonstrated that cells from SSRI non-responders had more serotonin receptors, causing them to overreact to the chemical messenger.
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