Although the antidepressant medications known as selective serotonin reuptake inhibitors (SSRIs) have been on the market for nearly 40 years, no one knows for sure exactly how they work.
A new Princeton study on the action of Zoloft on yeast cells provides tantalizing evidence that depression is not solely linked to the neurotransmitter serotonin.
The findings, published in PLoS ONE, document how sertraline (known by the brand name, Zoloft) accumulated in the membranes of yeast cells. This accumulation occurred between the two lipid layers that make up the cellular membrane, causing a swelling and sharp curvature of the internal membrane. The finding is meaningful because yeast cells lack serotonin.
Although SSRIs are known to regulate serotonin, it is not completely understood how antidepressants interact with the body’s brain cells and what effect, if any, this activity has on treating depression. Antidepressant accumulation has been observed in the membranes of human cells, the researchers report, but is considered benign.
By observing this reaction to sertraline in an organism that does not contain the drug’s conventional target, Ethan Perlstein, Ph.D., and his co-authors have found significant evidence suggesting that antidepressants may have an active effect beyond regulating serotonin.
If the effects of the medication come from the membrane curvature, then the cell membrane could present an additional target for next-generation antidepressants.
“The serotonin transporter is one site where these drugs interact, but we show that’s not all they do,” Perlstein said. “These drugs have multiple effects on various targets in the cell — and one of the targets might be specific membranes themselves.”
More immediately, Perlstein said, the activity of the drug in a serotonin-free organism supports existing research suggesting that depression might also be linked to diminished secretions of brain-derived neurotrophic factor (BDNF), a protein found in the brain.
“Our work provides some grounding for this alternative hypothesis of depression by suggesting that the serotonin-based theory might be an oversimplification and that the cause of depression is not a closed story,” Perlstein said. “There is something else going on here.”
Source: Public Library of Science (PLOS)