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The Serotonin Hypothesis and the Gut-Brain Axis

The serotonin hypothesis is too simplistic, but the drugs still work for many.

Key points

  • The serotonin hypothesis of depression is under fire because it is too simplistic.
  • Nevertheless, serotonin drugs still work for many.
  • Antidepressants affect the gut-brain axis, complicating the issue.
Antidepressants can be lifesavers, even if we don’t know how they work.
Source: Prostock-Studio/iStock

A recent review of the literature has spooked a lot of people because it purports to show that the “serotonin hypothesis” of depression is wrong. The researchers concluded that there is no significant association between serotonin levels and depression. Does that invalidate SSRIs and close the book on chemical treatments of depression?


SSRIs undeniably help some people, although psychiatrists don’t know exactly how. The serotonin hypothesis stipulates that raising serotonin levels can improve depression. That may fit a bumper sticker, but the reality is far more convoluted.

It wasn’t that long ago that depression was treated by exorcism to expel demons. The serotonin hypothesis sounds sciencey, but it has about the same explanatory power as demonic possession. But that’s true of a lot of medicine. We’ve used aspirin for over a hundred years, but only recently have we learned how it works.

Biology is complex

First off, the brain is ridiculously complicated, with dozens of different neurotransmitters in dozens of different regions. Worse yet, some of these neurotransmitters act differently depending on which region they’re in. The idea that you just need to top off a low level of neurotransmitters is naïve; you can’t measure the brain with a dipstick. This appealing yet simple notion was created by advertisers, not scientists. No one really knows why SSRIs sometimes work—and sometimes don’t.

Part of the mystery lies in the gut. Surprisingly, 95 percent of the serotonin in your body is active in your gut, not your brain. Your gut has an impressive network of nerves, and serotonin helps to control peristalsis (the wavelike muscle contractions that move food along the digestive system). SSRIs, because they affect serotonin levels, therefore have a direct impact on gut nerves.

To add to the complexity, gut microbes are involved. Amazingly, the first antidepressant was actually an antibiotic. Here’s an excerpt from my book, The Psychobiotic Revolution, describing the interesting backstory that took place in a tuberculosis ward:

The first antidepressant was discovered accidentally in 1951 when a new antibiotic, iproniazid, was trialed to treat tuberculosis. Iproniazid helped TB patients, but it also caused some of them to become quite happy and even rambunctious. Instead of lethargic moping, there was suddenly laughter and dancing in the halls. It was an astonishing turnaround.

Researchers discovered that drugs like iproniazid seemed to increase levels of the neurotransmitter serotonin in the brain. Due to this unexpected success, scientists started to look for more drugs that could boost serotonin levels. In quick succession, Prozac, Paxil, and Zoloft hit the market. Other drugs, including monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), also worked to affect levels of serotonin and another neurotransmitter called norepinephrine.

It turns out that most neurotransmitters can't cross the blood-brain barrier (BBB): Simply eating these drugs won't work. The solution was to find chemicals that could pass through the BBB that could either enhance the production or reduce the absorption of any given neurotransmitter.

That’s how SSRIs work: The drugs aren’t serotonin, per se, but a chemical that prevents the recycling of serotonin, thereby increasing its levels. This accidental breakthrough revolutionized psychiatry. It showed that depression involved a chemical change in the brain, no demons necessary. Lost in the excitement was the singular fact that iproniazid was invented to fight bacteria, not lift moods. How are microbes entwined with antidepressants?

Experimental evidence

A marvelously simple experiment is to add psychoactive meds to a petri dish full of bacteria and watch what happens. One particular antidepressant, desipramine, which works to amplify norepinephrine in the brain, acts as a fairly potent antibiotic, killing or inhibiting two important beneficial bacterial genera: Bifidobacteria and Akkermansia.

In mice, antidepressants, including SSRIs, were found to reduce the richness of the microbiota. One bacterial genus in particular, Ruminococcus, was reduced with antidepressant treatment. Intriguingly, when extra Ruminococcus species were added along with duloxetine (Cymbalta), it negated its antidepressant effect. In essence, part of the action of duloxetine may be attributable to its antibiotic effect on Ruminococcus.

Many antidepressants are ineffective in some patients, and that variability may be due to differences in gut microbes. Even side effects may be explained by gut microbes. With gut microbes taking on such a large role, it only makes sense that some researchers are looking at them as a way to protect against antidepressant-induced dysbiosis. Researchers at Monash University report that “Probiotics, prebiotics, and fecal microbiota transplantation are promising strategies to ameliorate antidepressant-associated dysbiosis.”

Microbes play a major role

The antibiotic effect of antidepressants can, in turn, affect mood via the gut-brain axis. Among the astonishing revelations of recent microbiome research is that microbes can secrete neurotransmitters on their own, including dopamine, GABA, and, importantly, serotonin.

At least some of the impact of antidepressants is to kill specific microbes and, along with that, the neurotransmitters they produce. This domino effect is fantastically complicated and varies from person to person.

Microbes that produce neurotransmitters and substances like butyrate that can improve your mood are called psychobiotics, and they may confound the effects of other psychoactive medicines. With a better understanding of their action, we may someday find these microbes to be adjuncts—or even replacements—to today’s psychoactive drugs.

So much for a simple explanation.

In sum, simply correlating depression to serotonin doesn’t capture the full impact of antidepressants on the whole body. The real answer is multifaceted and doesn’t fit on a bumper sticker.


Moncrieff, Joanna, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner, and Mark A. Horowitz. “The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence.” Molecular Psychiatry, July 20, 2022, 1–14.

Lukić, Iva, Dmitriy Getselter, Oren Ziv, Oded Oron, Eli Reuveni, Omry Koren, and Evan Elliott. “Antidepressants Affect Gut Microbiota and Ruminococcus Flavefaciens Is Able to Abolish Their Effects on Depressive-like Behavior.” Translational Psychiatry 9, no. 1 (April 9, 2019): 1–16.

Sjöstedt, Peter, Jesper Enander, and Josef Isung. “Serotonin Reuptake Inhibitors and the Gut Microbiome: Significance of the Gut Microbiome in Relation to Mechanism of Action, Treatment Response, Side Effects, and Tachyphylaxis.” Frontiers in Psychiatry 12 (May 26, 2021): 682868.

Macedo, Danielle, Adriano José Maia Chaves Filho, Caren Nádia Soares de Sousa, João Quevedo, Tatiana Barichello, Hélio Vitoriano Nobre Júnior, and David Freitas de Lucena. “Antidepressants, Antimicrobials or Both? Gut Microbiota Dysbiosis in Depression and Possible Implications of the Antimicrobial Effects of Antidepressant Drugs for Antidepressant Effectiveness.” Journal of Affective Disorders 208 (January 15, 2017): 22–32.