A Decisive Blow to the Serotonin Hypothesis of Depression
An exhaustive new review debunks the “chemical imbalance” theory of depression.
Christopher Lane Ph.D. | PSYCHOLOGY TODAY
KEY POINTS
• Surveys indicate that 85-90 percent of the public believes low serotonin or a chemical imbalance causes depression.
• Among 237 psychology students interviewed, 46 percent had heard the chemical imbalance explanation from a physician.
• The serotonin hypothesis has been challenged repeatedly and found wanting, even as it remains popular and influential.
• A comprehensive, well-powered, high-quality umbrella review now determines that the theory is “not empirically substantiated.”
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.”
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.
References
Frances CM, Lysaker PH, and Robinson RP. (2007) The “Chemical Imbalance” Explanation for Depression: Origins, Lay Endorsement, and Clinical Implications.” Professional Psychology: Research and Practice 38(4), 411-20. [Link]
Healy, D. (2015) Serotonin and Depression. BMJ 350, h1771 [Link]
Lacasse JR and Leo J. (2005) Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature. PLoS Medicine 2.12 e392. [Link]
Lacasse JR and Leo J. (2015) Antidepressants and the Chemical Imbalance Theory of Depression: A Reflection and Update on the Discourse (with Responses from Ronald Pies and Daniel Carlat). Behavior Therapist 38: 206-13 & 260-66. [Link]
Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, and Horowitz, MA. (7.20.2022). “The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence.” Molecular Psychiatry. DOI 10.1038/s41380-022-01661-0 [Link]
READ FULL STUDY:
Depression Is Not a Serotonin Deficiency
Why the narrative of a chemical imbalance persists.
KEY POINTS
• The story of depression being a chemical imbalance has grown over 70 years despite a lack of evidence that low serotonin levels cause depression.
• The chemical imbalance story for mood disorders persists for many reasons, several of which may help, but also harm us.
• While medications are useful at times, the public should be informed of drug risks and other effective treatments that have lower relapse rates.
More than 13 percent of adults used antidepressant medications within the past 30 days for depression or anxiety in the United States, between 2015 and 2018. That's more than 40 million people (CDC).
Depression is commonly explained in the doctor’s office, in popular books, and many medical and therapy websites, to be due to a chemical imbalance in the brain.
If you take an antidepressant, such as an SSRI (selective serotonin reuptake inhibitor) and symptoms improve, then it is reasonable to conclude that your brain lacked accessible serotonin to feel better and now the balance should be restored.
Although depression is commonly explained this way, research has not supported this theory, or that “correcting” the alleged imbalance resolves depression. I am curious about the narrative of the chemical imbalance and why, as a society, we still believe it. Here are three reasons we may stay hooked to this explanation.
1. It Reduces Stigma and Blame
To start, there may be advantages to believing the brain imbalance story. For some, it reduces the stigma of depression, perhaps by immediately relieving the shame or blame that depression is a weakness, or something to just "get over." The chemical imbalance story helps us not blame the victim; however, it might place blame onto unsuspecting neurochemicals that are just doing the best they can under the circumstances.
While reducing stigma around depression is good, the chemical imbalance story is a limited view, unsupported by research, that may lead us astray and prevent a real understanding of the intricacies of depression. It simplifies what is complex—a digestible explanation, although so far shown to be inaccurate.
2. It’s Convenient
We like tidy, simple, cause-and-effect explanations for problems, especially when we are not feeling well. The chemical imbalance narrative does this for us: it’s convenient. Just right the wrong, fix the broken, balance the unbalanced. It suggests that depression should fall in line with the medical model of illness (which many other illnesses also do not fit neatly into) and concludes that a mechanical solution outside of me will fix me or I’ll stay broken.
Much less convenient would be addressing a life issue such as a family conflict, a difficult or meaningless work situation, marriage, geographical move, or past trauma. These are more complex, confusing, and time-consuming (and potentially more blame-y, see number 1). Getting professional help has not historically been valued as highly as prescriptions, and not as affordable or available, either.
Even larger and more complex are the systems in society that contribute to suicide and addictions, the largest contributors to rising despair and deaths of despair in the U.S. (NAS). Researchers Peter Sterling and Michael Platt examined the reasons behind these rising rates in the U.S. compared to a 16-country control group that has declining rates of deaths of despair. The differences found included many protective communal supports that humans need across a lifespan that the control group countries have and the U.S. does not, including the ease of job changes, affordable childcare, living wages, healthcare, and free time to pursue creative endeavors (JAMA Psychiatry, 2022).
To get to the heart of mood disorders, while inconvenient, we may need to address social disconnection issues woven into a society built around freeways, pills, accumulation of wealth, an ideology of independence, and social media reputations.
3. Advertising
Heavy advertising campaigns and a global market that reached over $26 billion dollars for antidepressants in 2020 have sold the chemical imbalance story for decades. It’s not that medications have been shown ineffective as much as they just haven’t shown to be more effective than placebo in a meaningful way. The public needs to be well-informed about how effective placebo treatment is compared with active-ingredient drugs; which for antidepressants has been found consistently comparable across hundreds of studies and hundreds of thousands of patients (Kirsch, 2019; Stone, et al., 2018).
This information should be just as heavily promoted and available to the public as the ads for medications, along with other beneficial treatments that improve mood without the risks of antidepressants. Psychotherapy and exercise have been found similar in effectiveness and also to have lower relapse rates (Shea, 1992; Babyak, 2000).
While many people heroically pursue treatment for depression via multiple routes, it is still important to be aware of the dominant collective narrative behind what depression is, what helps alleviate it, and why. To move toward healing-informed care, we may want to address our own internal strengths and struggles, and how they relate to our interdependence within a worldwide network. Finally, we can approach the data regarding depression with humility and awe, allowing a more accurate story to unfold.
References
Brody & Gu, (2020). Centers for Disease Control, National Center for Health Statistics, Antidepressant Use Among Adults, United State 2015-2018 https://www.cdc.gov/nchs/products/databriefs/db377.htm
National Academies of Science, Engineering, and Medicine. (2021). High and Rising Mortality Rates Among Working-Age Adults. The National Academies Press. doi:10.17226/25976
Sterling, P. & Platt M. Why Deaths of Despair Are Increasing in the US and Not Other Industrial Nations—Insights From Neuroscience and Anthropology. JAMA Psychiatry. 2022;79(4):368–374. doi:10.1001/jamapsychiatry.2021.4209
Kirsch, I. (2019) Placebo Effect in the Treatment of Depression and Anxiety. Front. Psychiatry, 13 https://doi.org/10.3389/fpsyt.2019.00407
Stone M, Kalaria S, Richardville K, Miller B. (2018) Components and trends in treatment effects in randomized placebo-controlled trials in major depressive disorder from 1979 to 2016. Paper presented at the American Society of Clinical Psychopharmacology, Miami.
Shea MT, Elkin I, Imber SD, Sotsky SM, Watkins JT, Collins JF, et al. (1992) Course of depressive symptoms over follow-up: findings from the National Institute of Mental Health Treatment of Depression Collaborative Research Program. Arch Gen Psychiatry, 49(10):782–7. doi: 10.1001/archpsyc.1992.01820100026006
Babyak MA, Blumenthal JA, Herman S, Khatri P, Doraiswamy PM, Moore KA, et al. (2000) Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosomatic Med, 62:633–8. doi: 10.1097/00006842-200009000-00006
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UPDATE • TAKE NOTE -- at the time of this writing, after 4 days since this story has dropped -- in the U.S., EVEN THE ABC, NBC, CBS, CNN, FOX, & MSNBC WEBSITES (not to even mention illiterate TV channels) are ALL still TOTALLY ignoring it -- despite it getting massive press in the UK, EU and around the world -- SHAMEFUL...
PREVIOUSLY ON AFROPERSPECTIVES:
And again -- in the US, I wouldn't expect any paid-off politicians or the mind control corporate media to speak very much on this -- they prefer you remain ignorant...
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