Summary: A new study uncovers a key biological process targeted by SSRIs, suggesting new clinical applications. The study found that SSRIs affect membrane trafficking in cells, which might explain their broader effects.
Remarkably, a single dose of fluvoxamine in mice enabled drug delivery across the blood-brain barrier. This discovery could lead to SSRIs aiding in the delivery of drugs for conditions like dementia.
Key Facts:
- SSRIs impact the ability of cells to transport materials via membrane trafficking.
- A single dose of fluvoxamine can facilitate drug delivery across the blood-brain barrier in mice.
- This finding suggests potential new uses for SSRIs in treating hard-to-reach conditions like dementia.
Source: King’s College London
Since the 1980s, selective serotonin reuptake inhibitor (SSRI) antidepressants have been the backbone of treatment for depression and other mental health conditions worldwide, with tens of millions of annual prescriptions in the UK alone. Yet their mechanisms of action—and their wider effects across the body—are still not fully understood.
Now, a study led by King’s researchers has been published in Molecular Psychiatry, identifying a key biological process targeted by SSRIs and proposing the use of these drugs in new clinical applications.
In this work, all currently prescribed SSRIs were tested on various types of cells grown in Petri dishes, using similar drug concentrations to those found in blood of patients treated for depression. Unexpectedly, almost all antidepressants affected the ability of cells to transport material in and out of their environment through a process called membrane trafficking.
Moreover, a single injection of an antidepressant fluvoxamine in mice enabled a fluorescent compound that would normally stay outside the brain to accumulate inside the brain, crossing the cell barrier separating the brain from the rest of the body.
Dr. Oleg Glebov, King’s IoPPN said, “Given how little is known about the wider effects of antidepressants, we wanted to understand more about how these drugs affect the cells in our brains and bodies. What we found was that most antidepressants regulate the same key biological process across many tissues, which likely has little to do with their effect on depression.
“Furthermore, our data suggests that a single antidepressant dose may be enough to effectively open up the blood-brain barrier for delivery of other drugs. We hope that this finding may help improve clinical efficacy and drive down the treatment cost for new drugs against dementia, which currently are unavailable to millions of people who need them.
“Besides that, we are excited to explore whether antidepressants may help deliver drugs into other hard-to-reach corners of the body.”
Exactly how SSRIs control membrane trafficking remains unclear, and finding out the molecular-level intricacies will require collaboration across multiple scientific disciplines. Likewise, whether SSRIs are actually any good for delivering other drugs in humans will need to be determined in the clinic.
Nevertheless, it is entirely possible that this study can signal the start of a brand new career for these venerable 30+ year-old drugs—this time, helping other drugs do their job.
About this neuropharmacology research news
Author: Oleg Glebov
Source: King’s College London
Contact: Oleg Glebov – King’s College London
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability” by Oleg Glebov et al. Molecular Psychiatry
Abstract
Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability
As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear.
Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below.
We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression.
Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo.
These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.