Part 1
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.
The Chemical Imbalance Story We Were All Told
You’ve probably heard the analogy before, maybe from a doctor, maybe from a friend explaining why they take their medication.
Some people’s pancreas doesn’t make enough insulin. Some people’s brain doesn’t make enough serotonin. Either way, you’re just replacing what your body’s missing.
It’s a tidy comparison. It’s also part of why so many people feel at peace with taking an antidepressant — it’s not a mood-altering drug, it’s medicine, correcting a deficiency, same as insulin for diabetes.
Here’s the thing about that story: it isn’t backed by the evidence.
That’s not a fringe opinion. It’s the conclusion of one of the most cited papers in modern psychiatry, a 2022 systematic review in Molecular Psychiatry, led by UCL psychiatrist Dr. Joanna Moncrieff. She and her team pulled together decades of research on serotonin and depression, and found no consistent evidence that depressed people have abnormally low serotonin. Not in one area. Not in any of them.
And she’d know. Moncrieff has spent more than 30 years researching antidepressants and psychiatric diagnosis, and just released a book on exactly this subject: Chemically Imbalanced: The Making and Unmaking of the Serotonin Myth. She recently sat down with Dr. Bruce Wampold on the Making Therapy Better podcast to walk through what her research actually found, and what it means for the millions of people taking these drugs.
The Search for a Deficiency That Isn’t There
For decades, the working theory went like this: depression happens because your brain doesn’t have enough serotonin. SSRIs — selective serotonin reuptake inhibitors — fix that by increasing serotonin levels. Problem identified, problem solved.
Moncrieff’s team set out to test that theory properly. They gathered every major strand of research that had been repeated enough times to have a real evidence base, and pulled together the existing systematic reviews on each one.
The finding: no area showed consistent evidence of a serotonin abnormality in people with depression, let alone one that caused it.
That distinction matters more than it might seem. Depression clearly shows up in our biology somehow, of course it does, our emotions are reflected in our bodies. But correlation isn’t causation. To show serotonin causes depression, you’d need evidence that a serotonin change comes before the depression starts.
Almost none of the research even tried to test that.
A few things that surprised even Moncrieff herself:
- Some studies suggested people taking antidepressants had lower serotonin levels than people who weren’t. The opposite of what the drugs are supposed to do.
- The research connecting serotonin to mood, cognition, or emotion in general is inconsistent. The one exception is sexual behavior, where the evidence is actually fairly solid.
- SSRIs may not reliably raise serotonin at all, at least not with long-term use
“When I started to delve into the research on serotonin, I realized how very little we know about it,” Moncrieff said on the podcast. The press, she notes, is full of confident claims about what serotonin does. The actual research isn’t nearly that certain.
Okay, But the Drugs Still Work — Don’t They?
This is usually where the conversation goes next. Maybe the chemistry story isn’t right, but people take antidepressants and feel better. Isn’t that what matters?
Antidepressant efficacy claims rest on placebo-controlled trials. And when you pool the available data — published and unpublished — there is a difference between antidepressants and placebo.
It’s just small. Small enough that it falls short of what most researchers would call a clinically meaningful difference.
And there’s a deeper problem: that small gap might not even be a real drug effect.
Here’s why:
Most antidepressant trials are supposed to be double-blind (neither the patient nor the researcher knows who’s getting the real drug). In practice, that’s harder to pull off than it sounds. Side effects like dry mouth, nausea, or just feeling “off” give it away. Research shows patients in these trials can often guess, at rates better than chance, whether they got the drug or the placebo.
Guess what happens next. People who know they got the real drug tend to show a bigger response, an amplified placebo effect, driven by the belief that they’re getting real medicine. People who suspect they got the placebo may respond worse.
One study split participants by whether they’d taken antidepressants before. The people with prior experience — who knew what the drug felt like — showed a real gap between drug and placebo. The people with no prior experience, who had nothing to compare it to, showed no difference at all.
“The claims that antidepressants work are based on studies that show a very small difference between a drug and placebo that is very likely not even to be a real pharmacological difference,” Moncrieff explained, “but to be an amplified placebo effect.”
There’s a way to test this more rigorously: an active placebo, something that mimics the drug’s side effects without the actual antidepressant mechanism, so patients can’t guess their group from symptoms alone. Researchers tried this back in the 1960s. Most of those trials showed no difference between the antidepressant and the active placebo.
The last one was run around 1975. Since then? Nothing. Very few trials even ask participants whether they can guess which group they’re in, and Moncrieff’s read is straightforward: most trials are run by drug companies who have little incentive to find out if their drug’s edge is real.
What’s Actually Happening in Your Brain
To be clear: Moncrieff isn’t saying antidepressants do nothing. They’re active drugs. They cross into the brain. They change things.
The question is what, and whether that’s actually helpful.
One property that shows up across many antidepressants: they numb emotion, to varying degrees. Some produce it more than others — a foggy, flat, dialed-down feeling.
And a drug that blunts emotional intensity will, unsurprisingly, lower your score on a depression rating scale. That’s a very different mechanism than “correcting a chemical imbalance,” and it’s the kind of distinction Moncrieff thinks patients deserve to know before they decide whether to take something.
“Taking a drug that numbs you a bit is a very different kettle of fish from taking something that is supposed to reverse an underlying chemical imbalance in your brain,” she said. “I think most people are likely to make different decisions about whether or not to take antidepressants, given those two different sorts of explanations.”
One more thing worth sitting with: most antidepressant trials run about eight weeks. Few go past twelve. People in the real world often take these medications for months, years even, and there’s remarkably little solid data on what that actually does to a person over time.
So Where Does That Leave Us?
Not with “antidepressants are fake,” that’s not what the evidence says. It leaves us somewhere more uncomfortable: a widely prescribed class of drugs, taken by tens of millions of people, whose benefit over placebo is small, whose mechanism is murkier than the story we’ve been told, and whose long-term effects are barely studied.
The insulin comparison was never really true. So how did it become the story everyone knows anyway?
That’s not a scientific question anymore. That’s next.
