A Decisive Blow to the Serotonin Hypothesis of Depression

Almost as soon as it was floated in 1965 by Harvard psychiatrist Joseph Schildkraut, the serotonin hypothesis of depression—reduced and simplified by pharma marketing to the “chemical imbalance” theory of depression and anxiety—has been subject to critical research and found wanting.

The poor standing of the hypothesis in the scientific literature, however, barely dented its afterlife in textbooks, across clinical and treatment settings, and on mental health apps and websites. Nor has it dispelled the continued use of the phrase as “shorthand” between doctors and patients and in everyday settings, including for quite different mental states and conditions.

The “Chemical Imbalance” Metaphor Takes Root

Revisiting the history of this controversy raises several still-relevant details. In December 2005, as advertising for SSRI antidepressants flooded American magazines, talk shows, and network TV, the result of multibillion-dollar campaigns pitched in this case directly to consumers, Florida-based professors and researchers Jeffrey Lacasse and Jonathan Leo asked pointedly in PLoS Medicine, “Are the claims made in SSRI advertising congruent with the scientific evidence?”

The answer in “Serotonin and Depression: A Disconnect Between the Advertisements and the Scientific Literature,” their well-researched article, was a resounding no. The resulting “incongruence,” they determined, was “remarkable and possibly unparalleled.”

Lacasse and Leo found repeated evidence that the U.S. Food and Drug Administration had approved the marketing of SSRIs with two phrases still heavily in the subjunctive—that depression “may be due to a serotonin deficiency” and that SSRI efficacy, “modestly” outcompeting placebo, was “presumed to be linked to potentiation of serotonergic activity.” However, the research itself could not identify the precise mechanism.

The FDA had accepted aspirational language that the drugs “help to restore the brain’s chemical balance” and “bring serotonin levels closer to normal,” even though both claims were, and remain, scientifically meaningless.

“There is no such thing as a scientifically established correct ‘balance’ of serotonin,” Lacasse and Leo cautioned more than a decade ago, joining numerous other experts then and now. Additionally, both aspirational claims rest on a hypothesis that follow-up studies would end up contradicting repeatedly. In short, both the hypothesis and the expensive marketing that pushed it into American living rooms rested on a hedge: “Scientists believe that it could be linked with an imbalance of a chemical in the brain called serotonin.”

A Multibillion-Dollar Error

The hedge proved highly effective, even though, as David Healy explained in 2015 in “Serotonin and Depression,” in the BMJ, in practice, it entailed embracing or tacitly accepting “the marketing of a myth.” Through further oversimplification, a revised metaphor of a “chemical imbalance” took root as folk wisdom for multiple, dissimilar conditions listed in the DSM.

Returning to the controversy in “Antidepressants and the Chemical Imbalance Theory of Depression” (2015), Lacasse and Leo found that while the marketing had shifted emphasis from “correcting imbalances” to “‘adjusting’ or ‘affecting’ neurotransmitter levels,” leading psychiatrists were if anything, more wedded to the “chemical imbalance” metaphor than before.

Some had taken to the airwaves to say that it simplified communication with their patients. Daniel Carlat, the editor of The Carlat Psychiatry Report, explained on National Public Radio when asked what we know about psychiatric medication:

We don’t know how the medications actually work in the brain…. I’ll often say something like the way Zoloft works, is, it increases the level of serotonin in your brain (or synapses, neurons) and, presumably, the reason you’re depressed or anxious is that you have some sort of a deficiency. And I say that [chuckles] not because I really believe it, because I know the evidence really isn’t there for us to understand the mechanism—I think I say that because patients want to know something. And they want to know that we as physicians have some basic understanding of what we’re doing when we’re prescribing medications. They certainly don’t want to know that a psychiatrist essentially has no idea how these medications work (Qtd. in Lacasse and Leo).

The point in reproducing Carlat (who has made several such admissions on national media) was not to single him out but to stress how widespread the thinking and practice he shared so candidly. In 2007, as Lacasse and Leo pointed out, Frances, Lysaker, and Robinson found that among 237 psychology students interviewed, “46 percent had heard the chemical imbalance explanation from a physician.”

Inevitably, the problem of spreading false scientific information dovetails with that of medical ethics and the risk of enabling medically-induced harms. Because physicians swear to uphold the Hippocratic oath Primum non nocere (“First Do No Harm”), Lacasse and Leo questioned “the ethics of telling a falsehood to patients because you think it is good for them.”

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They asked more broadly of those repeating the discredited hypothesis, whether as metaphor or oversimplification: “Do you believe it is ethical to present a falsified scientific theory as a fact to a patient? What are the possible negative effects of doing so?”

A significant consequence they anticipated at the time was that patients would realistically “conclude that they have been misled.”

Cut to the Present-day

A major new review of the research—the first of its kind exhaustively reviewing the evidence, published today in the journal Molecular Psychiatry—reaches a strikingly similar conclusion. In “The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence,” University College London Psychiatry Professor Joanna Moncrieff and a team of five other top European researchers found “there is no evidence of a connection between reduced serotonin levels or activity and depression.”

The peer-reviewed umbrella review—representing one of the highest forms of evidence in scientific research—was extrapolated from meta-analyses and systematic reviews on depression and serotonin levels, receptors, and transporters involving tens of thousands of participants.

Although “the serotonin hypothesis of depression is still influential,” Moncrieff and coauthors noted, citing widely adopted textbooks published as recently as 2020 and surveys indicating that “85-90 percent of the public believes that depression is caused by low serotonin or a chemical imbalance,” the primary research indicates there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

Among other key findings:

• “Research on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconclusive evidence suggestive of higher levels of serotonin activity in people with depression.” Widespread use of antidepressants is seen as the likely cause.
• The researchers also looked at studies where serotonin levels had been “artificially lowered in hundreds of people” (by depriving their diets of the necessary amino acid that makes serotonin) and found that “lowering serotonin in this way did not produce depression in hundreds of healthy volunteers,” according to a 2007 meta-analysis and several recent studies.
• Numerous other reviews on re-examination were found to provide weak, inconsistent, or nonexistent evidence of a connection between serotonin and depression.
• The researchers also probed well-powered studies involving tens of thousands of patients that focused on gene variation, including the gene for the serotonin transporter. These found “no difference in the genes between people with depression and healthy controls.” As such, “high-quality genetic studies effectively exclude an association between genotypes related to the serotonin system and depression, including a proposed interaction with stress.”
• The researchers also looked at “the effects of stressful life events and found that these exerted a strong effect on people’s risk of becoming depressed—the more of these a person had experienced, the more likely they were to be depressed.”

Legacy Effects of a Discredited Theory

“The popularity of the chemical imbalance idea of depression has coincided with a huge increase in the use of antidepressants,” note Moncrieff and coauthor Mark A. Horowitz in the study’s press release. “Prescriptions for antidepressants have sky-rocketed since the 1990s, going from being rare to a situation now where one in six adults in England and 2 percent of teenagers are prescribed an antidepressant in a given year.”

The practical ramifications of the umbrella review are thus vast and consequential, involving millions of people across multiple countries because the findings are tied to a discredited theory that is still fueling mass prescribing on a global basis.

Moncrieff explained in the press release:

Patients should not be told that depression is caused by low serotonin or by a chemical imbalance and they should not be led to believe that antidepressants work by targeting these hypothetical and unproven abnormalities. In particular, the idea that antidepressants work in the same way as insulin for diabetes is completely misleading. We do not understand what antidepressants are doing to the brain exactly, and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.

Invited to extrapolate the review’s findings for Psychology Today, Moncrieff added:

Antidepressant use has reached epidemic proportions across the world and is still rising, especially among young people. Many people who take them suffer side effects and withdrawal problems that can be really severe and debilitating. A major driver of this situation is the false belief that depression is due to a chemical imbalance. It is high time to inform the public that this belief is not grounded in science.