Study uncovers the molecular events by which popular antidepressants work

Aug. 18, 2020

Some highly effective medications also happen to be highly mysterious. Such is the case with the antidepressant drugs known as selective serotonin reuptake inhibitors, or SSRIs: They are the most common treatment for major depression and have been around for more than 40 years, yet scientists still do not know exactly how they work.

Nor is it known why only two out of every three patients respond to SSRI treatment, or why it typically takes several weeks for the drugs to take effect—a significant shortcoming when you’re dealing with a disabling mood disorder that can lead to impaired sleep, loss of appetite, and even suicide. New research by a team of Rockefeller scientists helps elucidate how SSRIs combat depression. Their work, published in Molecular Psychiatry, could one day make it possible to predict who will respond to SSRIs and who will not, and to reduce the amount of time it takes for the drugs to act.

Major depression—also known as clinical depression—is firmly rooted in biology and biochemistry. The brains of people who suffer from the disease show low levels of certain neurotransmitters, the chemical messengers that allow neurons to communicate with one another. And studies have linked depression to changes in brain volume and impaired neural circuitry.

Scientists have long known that SSRIs rapidly increase the available amount of the neurotransmitter serotonin, leading to changes that go well beyond brain chemistry: Research suggests the drugs help reverse the neurological damage associated with depression by boosting the brain’s innate ability to repair and remodel itself, a characteristic known as plasticity. Yet the molecular details of how SSRIs work their magic remains a mystery.

Researchers set out to trace the chain of molecular events triggered by one of the most widely prescribed and effective SSRIs: fluoxetine, also known as Prozac. In particular, they wanted to see if they could tie the effects of the drug to specific changes in gene expression. The researchers treated mice with fluoxetine for 28 days, then measured the animals’ biochemical and behavioral responses to the drug.

Using a combination of behavioral tests and real-time RNA analysis, the researchers were able to monitor changes in the animals’ behavior and gene expression as they responded to the drug. Things started to get interesting on the ninth day of treatment: The activity of a gene called c-Fos began to increase markedly, and by day 14 the mice were showing telltale behavioral changes—they were moving around more, and took an interest in food even after being moved to a new environment. The timing of the behavior also aligned with well-established milestones in the treatment of human patients.

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