Abstract

Background. Psychopharmacology emerged in the 1950s from a run of serendipitous discoveries — chlorpromazine, iproniazid, imipramine, lithium — drugs found before any theory could account for them. The biochemical hypotheses on the origin of mental disorders, and the monoamine hypothesis of depression above all, were framed only afterwards, reasoned backwards from the effects of the drugs themselves. From those provisional conjectures descended the “chemical imbalance” narrative, which hardened into the dominant public account and the commercial frame of an industry.

Objectives. To reconstruct the true chronological order — chance, drug, theory, market — that the received account inverts; to weigh critically the evidentiary standing of the monoamine hypothesis; and to trace its epistemic, clinical, and ethical consequences.

Methods. Critical narrative review. The sources are primary — the founding papers, the court filings, the recent systematic reviews — traced and verified at first hand. This is not a systematic review and lays no claim to exhaustiveness or to procedural replicability.

Results. The monoamine theory was built to justify drugs already in use; its own author declared it, as early as 1965, neither confirmable nor refutable. The “chemical imbalance,” never demonstrated, endured by virtue of its explanatory convenience and its commercial utility: it underwrote the spread of the SSRIs and promotional practices later sanctioned by the American courts (the GlaxoSmithKline and Johnson & Johnson settlements). The recent umbrella review of the serotonin evidence found no consistent link between serotonin and depression, reviving — not without dispute — a doubt half a century old.

Conclusions. The clinical usefulness of many psychotropic drugs is a thing apart from the truth of the theories summoned to explain them: the first may stand while the second give way. To grant this distinction is not to abandon pharmacology but to free it from its founding myth and from capture by the market, and to restore to the patient an honest account of what a drug does and does not do.

Keywords. psychopharmacology, monoamine hypothesis, chemical imbalance, serotonin, history of psychiatry, pharmaceutical industry, reification.

A Note from the Editors

This article reconstructs how, in the history of psychopharmacology, a provisional hypothesis — the “chemical imbalance” — became a public narrative and an instrument of the market. It is a critique of the narrative, not of the treatment. That distinction is everything, and it is worth stating without ambiguity before a single page is turned, because it is the key to reading what follows without misreading it.

The efficacy of a drug is a thing apart from the truth of the theory invoked to explain it. That the most widespread explanation does not hold does not mean the drugs do not work: it means we have told their story badly. For many patients psychotropic medicines are, today, a real and at times indispensable help; to claim the contrary — that they are so much water, that suffering yields to willpower alone — is as dishonest as the fable these pages take apart. No reader following a course of treatment should draw from this article any reason to alter or discontinue it: that is a clinical decision, to be made with one’s physician, never on the strength of a headline.

A word, finally, for anyone tempted to use this text as a weapon. To lift a single phrase from it — “the chemical imbalance is a fable,” “the difference from placebo is modest” — in order to prove that psychiatry is a fraud is to do precisely what these pages denounce: to bend a fact to a story written in advance, against the evidence. This article criticizes psychiatry from within, out of regard for its rigor and not from any wish to demolish it. Whoever cites it against psychiatry has not understood it; whoever cites it stripped of this note has understood it very well, and is counting on an audience that has not gone to read the original.

The maturity of a science is measured, in part, by its capacity to bear its own critical history without feeling threatened. It is in that spirit that we publish.

— The Editors of Psychiatry on Line Italia

Introduction — The Order Reversed

In the early 1950s, in certain tuberculosis sanatoria, something happened that no one had foreseen and that no one, at the time, could explain. Patients — many of them dying — were being given a new drug, iproniazid, a derivative of isoniazid developed to fight Koch’s bacillus. Against tuberculosis the compound proved less effective than hoped; but on the patients it produced a startling side effect. Men and women wasted by disease recovered vigor, appetite, sociability, to the point that the chroniclers of the day wrote of euphoric consumptives. The effect on mood had not been sought, nor deduced from any theory: it was simply observed. Only later would it emerge that the drug blocked an enzyme, monoamine oxidase, and so raised the concentration of certain neurotransmitters in the brain. But the effect came first; the explanation came after.

This small inaugural scene contains, in miniature, the thesis of this review. Psychiatry often tells its own pharmacological history as the orderly triumph of a method: first one understands the mechanism of the disease, then one builds the drug that corrects it. It is a reassuring story — theory, therefore cure — and it has the defect of being almost exactly the reverse of what took place. The real order, at the birth of psychopharmacology, was another: first chance, then the drug, then the theory, and finally the market. The cardinal molecules of the 1950s were found by serendipity, with no biochemical hypothesis to have predicted them; the theories on the chemical origin of mental disorders were framed afterwards, backwards, to account for drugs that already worked; and from those provisional theories descended, at last, the public narrative of the “chemical imbalance,” which became at once a widespread belief and the commercial frame of an industry.

To reconstruct that order — and to observe what happens when it is set back on its feet — is the purpose of these pages. It is worth saying plainly, and without pretense: this is a critical narrative review, not a systematic one. It claims neither exhaustiveness nor procedural replicability; it claims exactness in its facts and its sources, and a thesis worth arguing. The focus falls chiefly on depression and the monoamine hypothesis, the best known and the most instructive; the parallel history of the antipsychotics and dopamine follows a similar curve, and will be summoned where it serves.

The Decade of Chance

The drug that opened the psychopharmacological era was born not in a neuroscience laboratory but in research on antihistamines. Chlorpromazine was synthesized late in 1950 by Paul Charpentier in the laboratories of Rhône-Poulenc, within a program on phenothiazine derivatives. Its psychiatric destiny is owed to a French military surgeon, Henri Laborit, who used it in anesthesia to induce what he called “artificial hibernation”: a state of calm detachment, of serene indifference, in surgical patients. Struck by that effect, Laborit intuited that it might serve in psychiatry. In 1952, in Paris, Jean Delay and Pierre Deniker administered it to psychotic patients at the Sainte-Anne hospital and observed a reduction in agitation, in hallucination, in delusion. It went on sale in France as Largactil that same year, 1952, and in the United States as Thorazine, marketed by Smith Kline & French, in 1954: its rapid American diffusion owed no little to a vigorous promotional campaign. No one, at that moment, knew why it worked. That it acted by blocking dopamine receptors was something that would be understood much later. Here too: first the effect, then the mechanism.

The same sequence repeated itself, almost simultaneously, for the two progenitors of the antidepressants. Iproniazid, as we have seen, came from phthisiology; its effects on mood, noticed in tuberculosis patients, were studied in depressed patients by Nathan Kline’s team in 1957, and the following year the compound became the first antidepressant properly so called, the founder of the monoamine oxidase inhibitors. Imipramine, for its part, was born of a fruitful misunderstanding. The Swiss psychiatrist Roland Kuhn received from Geigy a compound, coded G22355, structurally akin to chlorpromazine, in the hope that it would share its antipsychotic effects. On schizophrenia it did nothing; but Kuhn noticed that it lifted the mood of depressed patients, and in 1957 he presented his discovery. It was the first tricyclic antidepressant. And lithium too, whose efficacy against manic excitement was reported by the Australian psychiatrist John Cade in 1949, belonged to the same family of findings: a clinical observation before any theory whatever.

Four drugs, four classes, a single pattern. Not one of them was deduced from a theory of the disease; all were found by oblique routes — an antihistamine, an antitubercular, a failed antipsychotic, a salt — and recognized for what they did before anyone knew how they did it. Modern psychopharmacology, in short, was born blind to its own cause. And it was precisely this blindness that generated, by reaction, the question that would dominate the half-century to follow: if these drugs act on the neurotransmitters and relieve suffering, might it not be that suffering consists, at bottom, in a want of neurotransmitters?

The Theory That Came After

It is a reasonable question, and at the same time a logical trap. That a drug should correct a symptom by acting on a substance does not prove that the symptom arises from a deficit of that substance: aspirin relieves a headache, but migraine is not a shortage of acetylsalicylic acid. Yet it was precisely this step — from the action of the drug to the nature of the disease — that constituted the monoamine hypothesis. The reasoning ran backwards: since the drugs that raise the monoamines improve mood, and since reserpine, which depletes them, was held to induce depression, then depression must consist in a deficit of monoamines.

The canonical formulation arrived in 1965, when the Harvard psychiatrist Joseph Schildkraut published in the American Journal of Psychiatry his “catecholamine hypothesis of affective disorders,” centered on a deficit of noradrenaline. Two years later, in 1967, the Briton Alec Coppen shifted the emphasis to serotonin. Together the two papers crystallized what would come to be called the “monoamine hypothesis of depression.” It bears noting that both grew out of the drugs: they were attempts to explain after the fact why imipramine and iproniazid worked, not independent discoveries about the biology of the disease.

And — a detail posterity would forget — their authors knew it. The very title of Schildkraut’s paper presents it as “a review of supporting evidence”; and in the text he cautioned that, with the data available, the hypothesis could be neither confirmed nor refuted. The caution was warranted, for from the outset the theory showed cracks. The first is known as the latency problem: the drugs raise the monoamines within hours, but mood, when it lifts, lifts over weeks. If the deficit were the direct cause, the correction ought to be just as swift. The second crack was reserpine: it was taken for granted that it depressed by depleting the monoamines, yet already in the 1950s there were data — long ignored thereafter — crediting it, in certain patients, with effects that were actually antidepressant. The hypothesis, in other words, was born fragile, and its fathers handed it on for what it was: a working conjecture.

From Hypothesis to Dogma

Between a working conjecture and an article of faith runs a long road, and psychiatry traveled all of it. In the decades that followed, the monoamine hypothesis, and its serotonergic version in particular, ceased to be one theory among others and became the explanation: the “chemical imbalance” of the brain. The formula enjoyed an extraordinary fortune, and not by accident. It was intelligible: anyone can grasp the idea of a fluid that is lacking and a pill that tops it up. It was reassuring: it granted depression the standing of a “real” disease, organic, like diabetes, lifting it clear of the charge of moral weakness. And it was, it must be said, often well meant: many clinicians used it to free their patients from guilt. But in becoming a popular formula it shed along the way all the cautions of its authors — the “cannot be confirmed,” the “so to speak,” the date. What had remained a hypothesis was fixed into a fact.

The gap between the specialist literature, forever prudent, and the public narrative, ever more certain, grew abyssal. According to the data gathered in the recent review by Moncrieff and colleagues, still today eighty per cent and more of the public holds it established that depression is caused by a chemical imbalance. It is a belief the more solid for being the less founded: having survived half a century of inconclusive findings, it owes its persistence not to the force of the evidence but to its usefulness — for exposition, for therapy, and, as we shall see, for commerce.

The Narrative as an Instrument of the Market

The moment when the hypothesis became a mass narrative has a date and a name: December 1987, fluoxetine. Approved by the Food and Drug Administration on the twenty-ninth of that month and launched as Prozac by Eli Lilly, it was the first selective serotonin reuptake inhibitor to be marketed in the United States. Here our sequence takes an instructive turn: fluoxetine, unlike the drugs of the 1950s, was in no way a chance discovery. It was rationally designed upon the serotonergic hypothesis itself — that is, upon the theory constructed backwards twenty years before. Chance had begotten the theory; now the theory begot, in its turn, the drug. And the planetary success of that drug — tens of millions of users, a phenomenon of custom before ever it was one of medicine — cemented in the collective imagination the very theory that had produced it. The “chemical imbalance” became, in the 1990s, not merely an explanation but a slogan: the frame within which the SSRIs were presented to physicians and, where the law allowed, directly to patients. Around the new antidepressants the diagnostic boundaries widened — from severe depression to mild, to social phobia, to anxiety — and each widening was at once a therapeutic advance claimed and a market that swelled.

That in this expansion the narrative sometimes preceded and bent the evidence is no conjecture: it is a matter of court judgments. In 2012 GlaxoSmithKline pleaded guilty and agreed to pay three billion dollars to close a proceeding of the United States Department of Justice; among the counts figured the unlawful promotion of paroxetine (Paxil), including its unapproved use in adolescents, and the circulation of a misleading scientific paper — the notorious “Study 329” — which credited the drug with an efficacy in adolescent depression that the data did not show, while minimizing its risks, the risk of suicide among them. Just how misleading that paper was would be established, in 2015, by an independent reanalysis of the original data carried out by Le Noury and colleagues under the RIAT initiative: neither paroxetine nor high-dose imipramine had proved effective in adolescents, while the harms had risen, suicidal ideation and behavior included. The year after, in 2013, Johnson & Johnson agreed to pay more than two billion dollars over the off-label promotion of risperidone (Risperdal), pushed toward demented elderly patients and children beyond the approved indications.

These cases do not prove that the psychotropic drugs fail to work: they prove that the narrative could be built, at need, against the evidence. On the more properly clinical ground — how well they work — the discussion remains open, and prudent. The celebrated meta-analysis of Irving Kirsch and colleagues (2008), conducted also on the unpublished data lodged with the FDA, found that the difference between antidepressant and placebo is modest, and reaches the threshold of clinical significance only in the most severe depressions. It is a contested and much-debated result, but it must be kept distinct from the question of theory: one may grant that a drug affords a real benefit, however contained, without for that reason believing the fable of the imbalance that accompanied its sale.

The Reckoning of the Evidence

The most recent and most resounding test of the serotonergic hypothesis is the umbrella review — a systematic review of systematic reviews — published in 2022 in Molecular Psychiatry by Joanna Moncrieff and her collaborators. Sifting the principal lines of research — concentrations of serotonin and its metabolites, receptors, the transporter, tryptophan-depletion studies, genetics — the authors concluded that there is no consistent evidence of an association between serotonin and depression, nor any in support of the hypothesis that depression is caused by reduced serotonergic activity. Downloaded more than a million times and taken up by the press the world over, the work brought back to the surface, with updated data, the very doubt that Schildkraut had confessed in 1965.

It would be dishonest, however, to present its conclusions as a settled verdict. The review provoked vigorous replies: a comment signed by thirty-six specialists, hosted by the same journal, contested its method and its reach. The objections are of two orders. The first is technical: aggregating heterogeneous lines of research into an umbrella review entails losses of information, and some critics hold that the study’s design underestimated signals that were nonetheless present. The second is subtler, and in some ways revealing: many researchers objected that they had never held the naive version of the theory — the “chemical imbalance” to be corrected — which had long been abandoned by serious science and survived only in popularization. It is a double-edged defense. If it is right, then for decades academic psychiatry allowed the public and the prescribers to be told a theory it no longer believed itself: and the responsibility for that narrative — clinical, ethical, commercial — remains wholly to be accounted for. The point of the review, in the end, is not that “antidepressants do not work” — which it does not assert — but that the most widespread explanation of how they work does not hold.

Clinical and Ethical Implications

Everything turns, in the clinic as in epistemology, on a distinction the dominant narrative has labored to erase: the usefulness of a drug is independent of the truth of the theory summoned to explain it. Chlorpromazine helped thousands of patients when no one had yet heard the name of dopamine; an SSRI may confer benefit without there being any deficit of serotonin to correct. A drug is not its explanation. To confound the two planes is the error that has left psychopharmacology more vulnerable than it needed to be: it has bound the efficacy of its instruments to the fate of fragile hypotheses, so that every crack in the theory risks being taken for a condemnation of the cure.

But if on the plane of efficacy the distinction protects the drug, on the ethical plane it obliges the clinician to a surplus of honesty. To tell a patient that he suffers from a “chemical imbalance” is to communicate something that has not been demonstrated, and that shapes nonetheless the way he understands himself: his trust in the drug, his expectations, the idea of himself as a defective organism, his willingness — or his reluctance — to suspend the treatment. Informed consent, in psychiatry, concerns not only the risks and benefits of a molecule but also the explanatory frame one gives it. To hand a patient a hypothesis as though it were a fact is no mere matter of phrasing: it is, quite literally, a defect of consent.

One must, at the same time, guard against the opposite temptation. To recognize that the imbalance theory does not hold does not authorize therapeutic nihilism, nor the restoration of stigma. To tell the sufferer that the drugs are so much water is as dishonest as to tell him they repair a chemical fault. The honest position lies not in overturning one dogma into another, but in holding together what the evidence permits: drugs often useful, mechanisms in large part unknown, theories to be handled as hypotheses. It is a position less comfortable than either absolute, and for that very reason truer.

Limits and Conclusions

This review has the limits of its form. It is narrative and not systematic: it selects, orders, argues, and makes no claim to the procedural neutrality of a meta-analysis. It has concentrated on depression and the monoamines, leaving in the background the parallel history — analogous in its structure — of the antipsychotics and dopamine. And it moves over historiographically contested ground, where so-called critical psychiatry and academic psychiatry often read the same facts through different lenses; of that contention it has tried to give an account without concealing it.

What remains is the order this review has tried to set back on its feet. Psychopharmacology proceeded not from theory to cure but from cure to theory, and from theory to market. Its cardinal drugs were found by chance; its explanations were built afterwards, to justify them; and the most fortunate of those explanations — the chemical imbalance — became the sales pitch of an industry before ever it was a discovery of science, which has in fact never confirmed it. None of this diminishes the drugs, which remain, for many patients, a real help. It diminishes only the fable. And perhaps the maturity of a discipline is measured precisely in its capacity to tell its own story in the right order: to admit that here the cure preceded the cause, and that for half a century the tale was told backwards. To tell it forwards — from chance admitted as chance, to the hypothesis declared a hypothesis, to the drug offered for what it does and not for what it is said to repair — is no act of modesty. It is the condition on which psychiatry may call itself, without pretense, a science.

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