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Serotonin Blues

It’s Good When Science Confirms That Depression Is Complicated

A major paper debunking the “serotonin hypothesis” has a lot of people agitated. But leaving more room for nuance in our discussions about mental health is the right idea.

Pink pills spill out of an overturned bottle.
Joe Raedle/Getty Images
A bottle of antidepressant pills, photographed in 2004.

Can you really blame your sadness on your serotonin levels? Recent research says “probably not.” While the public has been led to believe that depression is due to an “imbalance” of one or more chemicals in the brain, a paper in the journal Molecular Psychology says the evidence for serotonin just isn’t there. Of course, an absence of evidence is not evidence of absence, but neuroscientists have been testing the serotonin hypothesis—which proposes that a deficiency of serotonin is a cause of depression—for almost 60 years, apparently with little to show for it. Worse yet, critics say the serotonin hypothesis has pulled funding away from other, perhaps more useful, avenues of research.

The paper has been a lightning rod for professional and public discourse. While it said nothing truly new about the serotonin hypothesis (which has been under attack for decades), it said it loudly. Within days, it was one of the top 400 research articles shared on any topic ever. To many, the researchers—a team of six spread across the UK, Italy, and Switzerland—were challenging essential dogma: “In many ways, serotonin gave birth to the field of neuroscience,” as Patricia M. Whitaker-Azmitia, a neuropharmacologist at Stony Brook University, wrote in 1999. To others, they were making dangerous and unsupported inferences: Though the paper did nothing to evaluate the still-unresolved question of antidepressant efficacy, “the danger is, it’s now being used to answer that question,” Lucy Foulkes, an academic psychologist and author of Losing Our Minds, told Shayla Love at Vice.

But perhaps the biggest problem posed by this review is the necessary, if unwelcome, acknowledgement that no one really knows what causes depression, let alone how to explain it in an accessible yet accurate way. “It’s so much more complex than being down to one chemical,” Eileen Daly, a developmental neuroscientist at King’s College London who co-edited the book on the serotonin system, told me over Zoom. “It’s many chemicals, it’s biology, it’s psychology, it’s your social factors.” And how these factors come together to create what we call “depression” is not remotely clear.

Building a more complex, subtle, and accurate model of depression will doubtlessly require further research. But exactly how to do that research—despite technical limitations, the dominance of the biochemical model of the mind, and the interference of the pharmaceutical industry—remains to be seen.

Serotonin was first discovered in the 1930s, as Whitaker-Azmitia has documented. Early researchers thought it might be used to improve the vascular system. But in the 1950s, biologist Betty Twarog showed that serotonin played an even more important role: It was a neurotransmitter, a molecule that helps to move messages across the hills and valleys of nerve cells and synapses.

Building on Twarog’s work, the influential biochemist Dilworth Wayne Woolley suggested that serotonin might play an important role in mental illness. In 1974, researchers developed the first serotonin reuptake inhibitor, or SSRI, intended to treat depression. It was called fluoxetine, better known by the brand name Prozac.

Today, millions of Americans are on antidepressants—not just SSRIs, but other serotonin, dopamine, and norepinephrine modulators. These prescriptions are informed by the biological theories of the last century. But the drugs themselves have been evaluated in clinical trials that document their effect on patients in the real world. The results have been mixed: In adults with moderate to severe depression, between 40 and 60 percent improved with antidepressants, compared to 20 to 40 percent who took a placebo. But the response varies widely between individuals; antidepressants don’t appear to improve health-related quality of life overall, and the side effects can be severe. To make the whole thing more dubious, numerous other studies on antidepressant efficacy, many with even worse outcomes, have been systematically suppressed by manufacturers.

It’s important to say that no one should discontinue any medication without consulting with their doctor. If someone feels they are being helped by their antidepressants, they probably are. In the future, alternative mechanisms for why antidepressants work may help researchers to understand why. Unfortunately, the public flame out of the serotonin hypothesis leaves the average depressed person to either muddle through life with an oversimplified, or even falsified, understanding of depression, or to fall into what philosophers call an epistemological gap—“the disparity between what is and what is believed,” writes César Augusto Fontanillo López. In a piece on the problems posed by “neuro-realism,” López argues that the “uncritical validation” of any data derived from brain research has only set us up for failure, as new evidence undermines old explanations. Fortunately, it doesn’t have to be this way.

While there’s still a lot to learn about depression, it’s possible to talk more openly and honestly about what we know and what we don’t. The serotonin hypothesis was, at best, a metaphor for the way we understand the complex mental experiences we call depression.” It just no longer serves its purpose. We may have arrived at a perfectly natural point on what cognitive psychologist and linguist Steven Pinker has termed the euphemism treadmill,” a process whereby we must continually reexplain the world to ourselves, in response to the latest data.

Brain science has relied on metaphors for centuries, from hydraulic pumps to phrenology to the brain as a computer, as scientist-historian Matthew Cobb argued in his 2020 book, The Idea of the Brain. But academics, clinicians, and journalists have so far failed to grapple with the implications of this reliance, and continued to use metaphors to illuminate some evidence—and obscure the rest. This poses a problem for the future of research: “Metaphors change how science is done,” historian Stephen Casper wrote in his review of Cobb’s book, “by licensing new interpretations or inspiring new experiments.”

Unfortunately, the pharmaceutical industry has been able to buy, sell, and trade euphemisms, often with the result they stay in circulation long after they’ve been rendered useless. This appears to be the case with the serotonin theory of depression. While researchers have been pushing back against this “myth” for decades, many members of the general public were shocked to find the explanations offered by their friends, and even doctors, lacked a strong evidence base.

The fall of the serotonin hypothesis could be seen as a breath of fresh air—an opportunity for new, better, more accurate ideas to grow. In the coming years, researchers have the opportunity to step away from the dominant biological model of the mind, and invest in better understanding psychological, social, evolutionary, and other underpinnings of depression. They might find that “depression” isn’t one thing at all, but rather an umbrella for a dozen other experiences, each with their own origin (some distinctly biological, and others less so).

Until we can metaphorize depression more responsibly, we could do well to take melancholy, sleep disruption, difficulty concentrating, and other symptoms for what they are: an expression of distress, complicated in its origins, and demanding a personalized kind of care.