Brain not required for antidepressant to act

Brewer’s yeast cells don’t have the brain chemical serotonin — or brains, for that matter — but that doesn’t stop the single-celled fungus from responding to an antidepressant in unexpected ways. A new study finds that the antidepressant piles up in yeast cells, distorting normally curved membranes and triggering the cells to start eating themselves.

These single cells are far removed from the vastly more complex human brain. But studying how drugs affect yeast might help scientists better understand how antidepressants work, says study coauthor and evolutionary pharmacologist Ethan Perlstein of Princeton University.

Perlstein and his colleagues focused on sertraline, sold as Zoloft, part of a class of antidepressants called selective serotonin reuptake inhibitors, or SSRIs. These drugs are thought to boost mood by increasing the levels of serotonin floating around between nerve cells. Sertraline latches on to a molecule called the serotonin transporter, part of which sits on the outside of nerve cells and slurps up serotonin. By gumming up the serotonin transporter, sertraline leaves more free serotonin.

Yeast have none of this. “A molecule like Zoloft should be completely innocuous to a yeast cell, in the way that an antibiotic would be innocuous to a viral infection,” Perlstein says.

But when Perlstein and his team gave the cells a low dose of sertraline labeled with a radioactive tracer, the drug accumulated inside membranes that surround the cell’s organelles and the yeast cell itself. These hot spots of drug buildup distorted the normal curvature of the membranes and seemed to trigger a quality-control check in which the cell starts breaking itself down, a process called autophagy, the team reports online April 18 in PLoS One.

It’s unknown whether a similar process happens in human cells, nor is it clear whether the process would be helpful or harmful, Perlstein says. Autophagy could trigger some beneficial changes, he says. If so, the results might eventually enhance scientists’ understanding of how SSRIs work.

Unlike other psychoactive drugs, antidepressants can take weeks to kick in, suggesting that a complex process is at work, Perlstein says. “You cannot simply talk about this as a serotonin thing. You cannot dismiss the activity of these molecules in systems and cells that don’t have serotonin,” he says. “It’s telling you that something else is going on.”

Neuroscientist Randy Blakely of Vanderbilt University in Nashville, who has developed mice with serotonin transporters that are impervious to certain SSRIs, urges caution when applying the results to humans. “We have to recognize that yeast membranes are very different from human membranes, or vertebrate membranes in general,” he says.

For now, there isn’t evidence that sertraline accumulates and triggers autophagy in people, Blakely says. “I don’t know of data that would indicate that similar events occur in the brain,” he says. “In fact, epidemiological data indicates that these medications are among the safest we have in the treatment of mental illness.”