Study Maps How SSRIs Affect Two Types of Serotonin Neurons in Opposite Ways

Antidepressants are among the most widely prescribed medications in the world, yet how they actually work in the brain remains poorly understood. A new study is helping fill that gap by mapping the gene-expression changes that SSRIs induce in serotonin-producing neurons—and finding that not all of those neurons respond the same way.

The research focused on fluoxetine, one of the most commonly prescribed SSRIs, and its effects on the Dorsal Raphe Nucleus, the brain's main serotonin-producing region. Using spatial transcriptomics, a technique that reads out gene activity at high resolution, the team mapped how different types of serotonin neurons in that region responded to both short-term and long-term treatment.

"Rather than treating the serotonin system as a single uniform population, we used spatial transcriptomics to read out gene activity at high resolution and map different types of serotonin neurons in the same brain area," said Iskra Pollak Dorocic, senior author on the study published in Molecular Psychiatry. "That allowed us to see that these neurons are far more diverse than a single label suggests, and importantly that they do not all respond to the drug in the same way."

The study identified two distinct serotonin neuron subpopulations that moved in opposite directions in response to the drug. One group showed increased expression of the neuropeptide prodynorphin (Pdyn) after short-term treatment—an effect that diminished with longer exposure. Pdyn signaling has previously been linked to stress-induced depressive symptoms in other parts of the brain, and the researchers suggest this temporary increase could be connected to the negative effects some patients experience when first starting SSRI treatment, such as increased anxiety or worsening mood.

A second population responded differently. These neurons expressed the neuropeptide thyrotropin-releasing hormone (TRH), and their activity increased only after prolonged treatment. TRH signaling has previously been linked to anti-depressive functions elsewhere in the brain, pointing to a possible role in the therapeutic effects that typically emerge after several weeks on an SSRI.

Dorocic said the two-track response maps onto the clinical experience of many patients: "We found that two distinct serotonin neuron populations are pushed in opposite directions by the same drug, one early and transiently, and one slowly over weeks. That mirrors the clinical picture, where unpleasant effects often come first and relief comes later, and it gives us concrete molecular candidates to interrogate next."

The genes, pathways, and cell types identified could help guide future research into the biological mechanisms underlying depression, and may eventually support the development of more targeted antidepressant treatments with fewer side effects.