A new study reveals how antidepressants have opposite effects on different groups of serotonin-producing brain cells, providing new insight into why selective serotonin reuptake inhibitors (SSRIs) can cause unpleasant side effects at the start of treatment, but lead to symptom relief over time.
Antidepressants are among the most widely prescribed drugs in the world. More than one in 10 people in Sweden currently uses antidepressants, with SSRIs being the most common type.
However, surprisingly little is known about what these drugs actually do in the brain. Our study aimed to map the changes in gene expression that SSRIs cause in their primary target, serotonergic neurons in the brain. ”
Iskra Polak Doročić, Assistant Professor, Department of Chemistry and Biophysics, Stockholm University
Change mapping
This study focused on fluoxetine, one of the most widely prescribed SSRIs, and examined its effects on the dorsal raphe nucleus, a major serotonin-producing region of the brain. The research group used a cutting-edge technology called spatial transcriptomics (LE1.1) to map changes in gene activity after short- and long-term treatment.
“Rather than treating the serotonin system as a single homogeneous population, we used spatial transcriptomics to read out gene activity at high resolution and map different types of serotonin neurons in the same brain region. This showed that these neurons are much more diverse than a single label would suggest, and importantly, not all respond to drugs in the same way,” says Iskra Pollak Dorocic.
two different paths
This study revealed widespread changes in gene expression following SSRI treatment. Most notably, the researchers identified two distinct subpopulations of serotonin neurons that responded differently to the drug.
- One group showed increased expression of the neuropeptide prodynorphin (Pdyn) after short-term treatment. Pdyn signaling has previously been associated with stress-induced depressive symptoms in other parts of the brain. However, this effect decreases with longer exposure to antidepressants. This study suggests that this temporary increase in Pdyn may be associated with adverse effects, such as increased anxiety and worsened mood, that some patients experience when they first begin SSRI treatment.
- A second population of serotonin neurons had the opposite response. These cells instead expressed the neuropeptide thyrotropin-releasing hormone (TRH), whose activity increased only after long-term treatment. TRH signaling has previously been linked to antidepressant function in other parts of the brain. The results of this study suggest that TRH may play a role in the therapeutic effects of SSRIs, which typically occur after several weeks of treatment.
good and bad effects
This finding highlights the complexity of the brain’s serotonergic system and suggests that different serotonergic neurons may contribute to different stages of antidepressant response.
“We found that two distinct populations of serotonin neurons are driven in opposite directions by the same drug, one early and transiently and one slowly over several weeks. This reflects the clinical picture in which unpleasant effects often come first and relief comes later, and gives us a concrete molecular candidate to investigate next,” says Iskra Polak Dorocic.
The genes, pathways, and cell types identified in this study provide valuable clues for future research into the biological mechanisms underlying depression. The findings could also help develop more targeted antidepressants with fewer side effects and improved efficacy.
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Reference magazines:
Henningson, C. Others. (2026). Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonergic neurons. molecular psychiatry. DOI: 10.1038/s41380-026-03644-x. https://www.nature.com/articles/s41380-026-03644-x
