SSRIs may activate vagus nerve dependent gut-to-brain serotonin signaling.

When Prozac was introduced in 1987, it made a big splash as the first selective serotonin reuptake inhibitor (SSRI) antidepressant for the treatment of major depressive disorder.

Prozac and Sarafem are brand names for a drug called "fluoxetine," which was first discovered by Eli Lilly in 1972. Since the patent for this drug expired in 2001, fluoxetine is available as a generic FDA-approved prescription for depression, obsessive-compulsive disorder, panic attacks, and some eating disorders.

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Historically, most experts and consumers thought fluoxetine worked by inhibiting the reuptake of serotonin in the brain, and that the antidepressant effects of this drug occurred solely from the "neck up." However, there is still a surprising amount of uncertainty about how SSRIs actually work.

Because 90 percent of the human body's serotonin is produced in the gut, one current theory is that fluoxetine might boost the amount of serotonin produced "below the neck."

While the 21st-century debate about SSRIs rages on, a drug-free alternative for treatment-resistant depression called "vagus nerve stimulation (VNS)" was approved by the FDA in 2005 for severe unipolar and bipolar depression. VNS typically involves a small, silver-dollar sized device that is surgically implanted below the skin near the collar bone and works like a pacemaker to stimulate the vagus nerve.

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In recent years, researchers at McMaster University's Brain-Body Institute (Canada) have been investigating a possible link between SSRI antidepressant medications, serotonin levels in the gut, and the role that vagus nerve stimulation might play in boosting gut-to-brain transport of serotonin, which appears to rely on the vagus nerve.

Notably, after a vagotomy—which surgically cuts off gut-to-brain communication via the vagus nerve—SSRIs lose their ability to relieve depression-like symptoms in mice.

As part of the bidirectional gut-brain axis, afferent vagal nerves send signals from the bottom-up. There is reason to believe that these vagus nerve pathways might serve as a type of "serotonin superhighway" between the gut and the brain.

A few days ago, the team at McMaster University—who've been conducting research in mice about how SSRIs and the vagus nerve might work in tandem—published a study, "Oral Selective Serotonin Reuptake Inhibitors Activate Vagus Nerve Dependent Gut-Brain Signalling," in the journal Scientific Reports. The title of this paper sums up the main takeaway of this research: SSRIs may activate the vagus nerve in a way that facilitates gut-brain serotonin signaling.

The authors (McVey Neufeld et al., 2019) describe the context and significance of their findings:

"The vagus nerve is the tenth cranial nerve and is the main afferent pathway connecting the gut to the brain. The vagus nerve can transmit signals to the brain resulting in a reduction in depressive behavior as evidenced by the long-term beneficial effects of electrical stimulation of the vagus in patients with intractable depression. The vagus is the major neural connection between gut and brain, and we have previously shown that ingestion of beneficial bacteria modulates behaviour and brain neurochemistry via this pathway. Given the high levels of serotonin in the gut, we considered if gut-brain signaling, and specifically the vagal pathway, might contribute to the therapeutic effect of oral selective serotonin reuptake inhibitors (SSRI)."

In a recent interview with Canadian Press published on October 4, 2019, first author Karen-Anne McVey Neufeld said, "This [research] opens the door for examining the gut and the continuous communication that happens between the gut and the brain." She also said that her team's findings "suggest the gut may play a larger role in depression than previously believed and the latest research hints at new treatment possibilities in the future."

Interestingly, McVey Neufeld also told the Canadian Press reporter that another class of antidepressants called "noradrenaline reuptake inhibitors (NRIs)" did not appear to have the same activating effect on the vagus nerve as SSRIs.

"Our results lend weight to the possibility that the vagal pathway connecting gut to brain may provide a novel opportunity for treatment of some psychiatric disorders," the authors write in the paper's conclusion. "While further study is both necessary and ongoing, we believe that these findings may point towards a newly invigorated approach in the continuing search for new drugs, dietary supplements or bacteria to beneficially modulate these conditions through their effects on vagal afferent communication."

The next step for McVey Neufeld and colleagues at McMaster's Brain-Body Institute is to identify specific gut microbiome factors that may play into mental health and psychological well-being using vagus nerve gut-to-brain signaling.

Why Is the Vagus Nerve Also Called the Wandering Nerve?

If a picture is worth a thousand words, this early anatomical drawing of the vagus nerve (below) speaks volumes. As you scroll down this narrow-and-long image, try visualizing how your vagus nerve facilitates communication along your gut-brain axis as part of a bidirectional feedback loop.