Chemical imbalance: the serotonin story that science outgrew

“Depression is a chemical imbalance in the brain.” That sentence is one of the most successful in the history of health communication. Almost everyone has heard it, many heard it from a doctor, and for decades it passed as a summary of what the field knew.

The trouble is that the field would not write it that way today. Not because biology is unimportant — it matters a great deal — but because the account of a serotonin shortage was always a simplification that outlived its welcome.

In this piece I try to do something harder than debunking: to say where the story came from, what was true in it, what caused a large upheaval in 2022, and — most importantly — what it means for someone taking antidepressants or considering them. Up front: this is not an argument against medication.

Where the story came from

The 1950s, and as so often in medicine, by accident.

A tuberculosis drug noticeably lifted mood in some patients. A blood pressure drug lowered it in others. Both compounds affected monoamines — the group of neurotransmitters that includes serotonin, noradrenaline and dopamine.

From this came the monoamine hypothesis: if a substance that lowers monoamines causes low mood, and one that raises them relieves it, then depression is probably caused by their shortage.

The logic is understandable and, as a starting point, entirely legitimate in science. But the inference ran the wrong way — from a drug’s effect to a disease’s cause. By the same logic, a headache is caused by a shortage of aspirin.

What unsettled the hypothesis

The following decades produced findings that did not fit the simple version.

The time lag. Antidepressants raise serotonin in the synapse within hours. Mood improves in two to four weeks. If this were the direct filling of a deficit, the effect should arrive quickly.

Depletion experiments. Researchers artificially lowered tryptophan, serotonin’s precursor, in healthy volunteers. Most did not become depressed. In people with a history of depression, mood did worsen — which points to vulnerability, not cause.

Measurements. Comparisons of serotonin levels and its metabolites in people with and without depression have not produced consistent differences.

In 2022 an extensive umbrella review gathered this evidence and concluded that there is no convincing evidence of a link between depression and low serotonin levels or activity. The public reaction was large and in places misread as “antidepressants don’t work”. That does not follow and the study did not claim it — a point stressed by its critics too, who noted that the field had not defended the monoamine hypothesis in this simple form for at least two decades.

So why do the drugs work

This question matters more than debunking the old account.

Meta-analyses show antidepressants are more effective than placebo in moderate and severe depression. The effect in mild depression is small and often not clinically meaningful; in more severe forms it is clear. So they do something — the explanation is simply not the refilling of an empty tank.

Contemporary accounts run in a different direction. One of the most promising concerns neuroplasticity: the medication is thought to increase the brain’s capacity to change its connections, opening a window in which a person responds more readily to new experience. That would explain the time lag, and also why a combination of medication and therapy works better for many people than either alone.

A second account concerns a change in how emotional information is processed. Research shows that in people on antidepressants, perceptual bias shifts relatively quickly — negative faces and words stop standing out so sharply — while subjective mood follows later, once this different processing works its way into everyday experience.

Neither account is settled. The honest current picture is: we know they work for a proportion of people, and we do not know precisely how. That is not unusual in medicine; the same holds for many established drugs.

Why the story matters at all

One could argue the explanation is irrelevant as long as the drug helps. It is not, and for good reasons.

It shapes expectations. Someone who believes in a chemical imbalance often expects the tablet to sort things out on its own. When that does not happen, they conclude something is even more wrong with them.

It shapes the sense of agency. Research on biological explanations of mental disorders consistently shows the same thing: they reduce blame and simultaneously increase pessimism about recovery. If the cause is broken chemistry, everything a person does themselves seems less relevant.

It shapes the decision about therapy. If the problem is chemical, conversation seems like ointment on a broken leg. That is the most expensive conclusion of all — in depression specifically, psychotherapy and the combination of both approaches have solid evidence.

It was never the field’s official account. Curiously, the simple version was more widespread in advertising and popular writing than in the professional literature. For many people it was an understandable way of saying “this is not your fault” — a good intention with a side effect.

So what causes depression

The most honest answer: not one thing.

The prevailing understanding is multifactorial. Susceptibility — genetic, temperamental, developmental — meets experience, circumstances and patterns of responding. None of these factors is sufficient alone and none is irrelevant.

This is less appealing than a single explanation and considerably more useful. It means there are several entry points: medication that lowers intensity; therapy that addresses patterns and relationships; a change of circumstances where possible; sleep and movement as support. And it means the question is not “what is the cause” but “where is it easiest for you to start”.

This is precisely why combination works well in depression. On when to use what, I have written in why antidepressants and therapy are not rivals.

What this means if you take medication

First, what needs saying plainly: do not read this piece as a reason to stop medication. Abruptly stopping antidepressants can cause unpleasant withdrawal symptoms and increase the risk of relapse. Changes are decided with the doctor who prescribed them.

What does change with the newer understanding is expectation. The medication is not repairing a deficit — it is support that often lowers intensity enough to make everything else feasible. Getting up, moving, talking, working on patterns.

For many people that is better news than the old account. If it were broken chemistry, a person would depend on the tablet. If it is several factors, they have several levers — including their own.

What to remember

Depression is not a demonstrated serotonin shortage, and that account was always a simplification. Antidepressants do work in moderate and severe depression, although we do not know the mechanism precisely; most likely through neuroplasticity and altered processing of emotional information.

The practical consequence is simple. If someone told you that you have a chemical imbalance, they were not lying — they passed on an account that had long been in circulation. But they did not tell you that you have more options than that account suggests.