A new study shows that the widely used antidepressant fluoxetine does more than boost serotonin levels: it changes how brain cells manage their energy and rebuild their connections, potentially helping the brain “loosen up” and adapt during depression treatment.
The study was carried out in collaboration between the University of Eastern Finland and the University of Helsinki, and the results were published in Neuropsychopharmacology.
Using cell type–specific transcriptome profiling, researchers found that after two weeks of treatment, a special class of brain cells, called parvalbumin interneurons, which help keep brain activity balanced, became less rigid in the prefrontal cortex. Their mitochondria, the tiny power plants of cells, showed reduced expression of genes linked to energy production, while genes related to plasticity were upregulated. At the same time, the protective perineural nets that normally restrict plasticity weakened. Together, these changes may allow the brain to enter a more plastic, or adaptable, state, though the causal links between them remain to be clarified.
This is important, since depression is linked to overly rigid brain circuits that resist change, and by softening these circuits and altering how their mitochondria function, fluoxetine may create a window of plasticity or flexibility in the brain. The findings also suggest new biological markers, such as mitochondrial changes or weakened perineural nets, that could one day guide or improve treatment.
“The findings point to a new understanding of how antidepressants may help people recover: not only by lifting mood, but by giving the brain room to rewire its circuits by altering its energy systems,” says the study leader, Senior Researcher Juzoh Umemori from the University of Eastern Finland.
Fluoxetine is widely sold under the brand name Prozac, but is internationally available under many different brand names.
Gene and Cell Technology research group
Research article:
Jetsonen, E., Didio, G., Suleymanova, I. et al. Chronic treatment with fluoxetine regulates mitochondrial features and plasticity-associated transcriptomic pathways in parvalbumin-positive interneurons of prefrontal cortex. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02219-8