Part 2
If you’re currently taking an antidepressant, please don’t stop or change your dose based on this article. Talk to your prescriber first. This piece is about the research behind the theory, not medical advice for your situation.
How a Theory With No Evidence Became Common Knowledge
Picture a therapist’s office in the 1960s. A patient describes feeling low after a divorce, or a layoff, or a loss. Back then, the working explanation was neurosis: a psychological reaction, tangled up with Freud and psychoanalysis, something you talked through over months or years on a couch.
Fast forward a few decades. That same patient walks into urgent care today, and the explanation on offer looks completely different. A chemical imbalance. Something biological. Something a pill can fix.
Neither the human brain nor human grief changed in that time. So what did?
In Part 1, we covered the science: there was never solid evidence for a serotonin deficiency in depression. Now for the harder question. If the science was this thin the whole time, how did “chemical imbalance” become something almost everyone just… knows?
A Theory in Search of a Reason to Exist
The idea that depression was fundamentally biochemical got floated, loosely, in the 1960s. And biological psychiatry grabbed onto it fast, before the evidence had a chance to catch up.
Dr. Joanna Moncrieff, the UCL psychiatrist behind the landmark 2022 review on serotonin and depression, spent years digging into how that happened for her book, Chemically Imbalanced: The Making and Unmaking of the Serotonin Myth. What she found, in her words on the Making Therapy Better podcast, was “shocking”: badly supported assumptions that barely got questioned before they hardened into consensus.
Part of the appeal, she argues, wasn’t really scientific. It was about drawing a line.
The 1960s weren’t just a decade of new pharmacology research. They were also the start of the recreational drug scene, one that grew directly out of prescribed substances like barbiturates and amphetamines getting diverted and sold on the street. By the time that scene was in full swing, psychiatrists needed a way to separate what they were handing patients from what a dealer might hand out at a party.
A drug that corrects a specific chemical imbalance sounds nothing like a drug that just alters your normal mental state. That distinction mattered enormously to a profession trying to establish itself as legitimate medicine, on equal footing with the rest of the doctors down the hall.
“It’s a medical model that enables psychiatrists to align themselves to other medical doctors,” Moncrieff said, “and to present the treatments they are offering as bona fide medical treatments.”
Enter the Pharmaceutical Industry
The theory existed quietly for a couple of decades before it became the story everyone knows. That shift happened in the late 1980s and early 1990s, and it wasn’t driven by new research. It was driven by a market opportunity.
Before SSRIs, the pharmaceutical industry had been selling benzodiazepines, drugs with effects close enough to alcohol that it was hard to market them as sophisticated or targeted. When that market collapsed, the industry needed something to replace it with. Something that sounded more precise. More medical.
The chemical imbalance narrative fit perfectly. It let a new class of drugs get sold not as sedatives, but as corrective treatments for a specific biological problem. Companies promoted the idea directly to the public in the U.S., where direct-to-consumer drug advertising is legal, and more subtly elsewhere.
That marketing didn’t just sell a drug. It sold a whole new way of understanding sadness. People who might once have described their struggles as a reaction to divorce, unemployment, or loss were converted, as Moncrieff put it, into believing they had a medical disorder that needed a pharmaceutical fix.
And it worked both ways. Psychiatrists benefited too. As Dr. Bruce Wampold noted in their conversation, the theory raised the field’s status and its profits at the same time. It’s no coincidence that the diagnostic manual shifted in that window as well. The old DSM category of “neurosis,” tied to Freud and psychoanalysis, gave way to “depression” as a distinct disorder, one now understood as something a drug could treat.
Why the Story Was So Easy to Believe
None of this would have spread the way it did if it hadn’t also offered something people wanted.
There’s real comfort in being told your depression is biological. It’s not your fault. It’s not something you failed to manage or think your way out of. It’s an illness, and illnesses have pills.
Moncrieff doesn’t dismiss that appeal. But she points to something less comfortable underneath it: research showing that believing your depression is a fixed biological condition, in the long run, tends to make people more pessimistic. Less hopeful they’ll recover. Less likely to believe they can do anything about their own situation.
The story that was supposed to relieve the burden of depression may have quietly deepened it.
What Happened When the Theory Got Tested
By the time Moncrieff’s 2022 paper came out, the chemical imbalance idea had been circulating, largely unchallenged, for roughly three decades. So when a major systematic review found no consistent evidence for it, you might expect that to be treated as significant news within psychiatry.
Instead, Moncrieff described a pattern that surprised even her.
The first wave of response, from parts of the profession, amounted to: we already knew that, it isn’t important, don’t pay attention. When that didn’t quiet the public reaction, a second wave arrived, insisting there actually was evidence for serotonin after all. When that didn’t hold up either, a third wave shifted the target entirely: maybe it isn’t serotonin exactly, but it’s probably glutamate, or noradrenaline, or inflammation, or some combination.
“It seemed to me like a desperate attempt to get the public to continue to believe that depression had some biological origins,” Moncrieff said. “Just throw out as much sort of biological-sounding, clever scientific stuff as you can, so that people were befuddled.”
A group of psychiatrists, mostly in the UK, also published formal criticisms of her paper. Moncrieff says the critiques were largely inaccurate or beside the point: claims that her team had missed studies they hadn’t, disputes over a minor methodological detail, all while conceding the actual substance of her finding. The evidence for a serotonin and depression connection really is inconsistent.
Even now, patient information leaflets from some psychiatric and medical organizations still describe depression in terms of a chemical imbalance, or an “abnormality” in serotonin or noradrenaline. Some organizations corrected their materials after Moncrieff’s paper. Many haven’t.
Why “If Not Serotonin, What Is It?” Is the Wrong Question
One response to Moncrieff’s research came up constantly in interviews after her paper published: okay, if it’s not serotonin, then what biological mechanism is it?
She sees that question itself as evidence of how deep the indoctrination runs.
Go back a few decades, she points out, and ask someone what causes depression. The answer wasn’t biological. It was divorce. Unemployment. Grief. Abuse. A recognizable human response to a hard life event.
That framing hasn’t disappeared because it stopped making sense. It disappeared because a more profitable story replaced it, one repeated so consistently, for so long, that most people now can’t picture an explanation for depression that isn’t chemical.
Depression is still, in Moncrieff’s view, best understood as an emotional reaction. Sometimes proportionate, sometimes overwhelming, always shaped by someone’s personality and history. Not a malfunction to correct. A response to make sense of.
And that reframe changes something important: it means depression isn’t a fixed state you’re stuck with. It’s something you can influence, with time, support, and often help from other people. Not a life sentence. A signal.
We’ll get into what that means for treatment, and where Moncrieff thinks the field is headed next (psychedelics included) in Part 3.
