SSRIs may pack more punch at the cellular level than believed

"We hope that our study begins to illuminate the full breadth of pharmacological effects of antidepressants on cellular physiology starting with the simple unicellular eukaryote, budding yeast," said Ethan O. Perlstein, Ph.D, a researcher involved in the work from the Lewis-Sigler Institute for Integrative Genomics at Princeton University in New Jersey. "Furthermore, our work validates the notion that simple model organisms may be useful for the study of complex human disease."

Knowing that a high concentration of sertraline (Zoloft®) is toxic to yeast cells, scientists applied a lethal dose to millions of these cells and fished out a few cells that became resistant to the drug. Researchers then identified the underlying mutations in those cells and applied genetic, biochemical, and electron microscopic imaging techniques to characterize the molecular basis of resistance. Their results suggest that SSRIs may actually affect more than one process in a cell, including non-protein targets such as phospholipid membranes. Additionally, the study's results demonstrate that sertraline targets intracellular membranes and modulate pathways involved in vesicle trafficking that are present in both yeast and human cells. Vesicle trafficking plays an important role in how neural synapses develop and function. More work is necessary, however, to determine the exact clinical relevance of this secondary drug target.

"There's no question that SSRIs help thousands of people with mental health problems," said Mark Johnston, Editor-in-Chief of the journal GENETICS, "but as this research shows, there is still some mystery about how they help us. This study a key first-step toward giving us a comprehensive answer to how SSRI's work, and it may open doors to entirely new therapies."