Dummies Guide to “The British Professor Leading the Controversial Backlash Against Antidepressants”
British journalists and editors, this is for you
It has been two and a half years since the publication of Joanna Moncrieff and colleagues’s umbrella review about the “serotonin theory” of depression, and one would imagine that journalists, especially for prominent outlets such as the Times, would’ve figured out by now how to ask the right questions and how to appropriately contextualize the findings. Apparently not, as illustrated by a cover story published on Jan 12, 2025, by the Sunday Times magazine. The piece is a fawning profile of Moncrieff, that uses the umbrella review as its starting point and serves as a promotional advertisement of her upcoming book, “Chemically Imbalanced.” What is frequently being presented in the article are basically one contrarian psychiatrist’s controversial opinions that are well outside the clinical and scientific consensus. It is this casual conflation of empirical evidence and personal opinion that I find deeply irresponsible. Not only that, the whole debate around chemical imbalance and antidepressants is a messy conflation of distinct issues that should be apparent to anyone paying attention.
For the benefit of journalists and editors who may be interested in covering these issues in the future and in getting the conceptual and scientific details right, I am making yet another effort to show how these issues can be approached in a better manner.
First things first, what the umbrella review doesn’t examine
The umbrella review looks at a subset of available scientific evidence pertaining to one neurotransmitter system (serotonin) and its alterations in clinical depression. It does not look at all at other neurotransmitter systems or other aspects of brain functioning. It does not look at the general role of serotonin in regulation of mood and behavior or in clinical conditions such as neuroticism. It does not look at antidepressant efficacy or mechanisms of antidepressant response.
Yet the media talks to Moncrieff as if the publication of the umbrella review gives her the scientific legitimacy to confidently assert whether depression is a medical condition, whether it is a brain disorder, whether antidepressants work, and how antidepressants produce apparent benefit, etc., as if these were simple corollaries of the conclusion that there is no robust evidence of an abnormality of the serotonin system in depression.
The reason Moncrieff gets away with it is partly because of journalistic laziness and partly because of the popular misconceived narrative that antidepressants work by “correcting a chemical imbalance.” Give that up, and you will be left wondering how any of these assertions follow from the umbrella review.
Methodological issues with the umbrella review
Responses to the umbrella review have focused on issues around the selection and interpretation of results. The most prominent of these by Jauhar et al. makes the case that a more accurate conclusion is that tryptophan depletion studies and molecular imaging studies suggest that the serotonin system is playing some role, especially in those vulnerable to or suffering from depression.
Is this conclusively established? Not at all. I am myself uncertain about the robustness of these findings. But it does illustrate that available evidence is suggestive and that a different team of authors could have reviewed the same studies and come to a different conclusion.
What exactly is the “serotonin hypothesis”? What is being refuted?
Discussions on the serotonin hypothesis become confusing quickly because there is no precise articulation of what the serotonin hypothesis of depression is or what the nature of the relationship between various aspects of the serotonergic system and various aspects of depression is supposed to be. As a result, it is not evident that disproving some versions of the serotonin hypothesis means that “serotonin has nothing to do with depression.”
Here is an incomplete list of the ways in which we might understand the relationship between depression and serotonin:
Depression is caused by low levels of serotonin in the brain or low serotonergic activity
Depression, generally or in some subset of patients, involves alterations of the serotonin signaling system (e.g. in the distribution or sensitivity of certain sorts of serotonin receptors)
The serotonergic system mechanistically links depressive symptoms and neurobiological dysfunctions in other aspects of brain functioning (e.g. neurogenesis or neuroplasticity)
The serotonin system is generally involved in the regulation of mood and temperament, and there may be no specific abnormality in the serotonin system in depression, by and large, but it still provides us a target for intervention with serotonergic antidepressants.
In addition, we can also talk about whether this involvement of serotonin is considered the central or primary cause of depression or whether it exists as one causal element in a more complex causal web.
We’ve known for decades that the crude version of this hypothesis referring to synaptic serotonin levels is not supported by evidence. Many researchers have believed that some alterations exist in the serotonin system, and some preliminary research findings did suggest that, but nothing conclusive has emerged that commands a strong consensus.
The significance of monoamine depletion remains to be dispelled. In 2007, a meta-analysis in Molecular Psychiatry reported that monoamine depletion produces depressed mood in individuals with a family history of depression and in drug-free patients with depression in remission. A 2015 meta-analysis showed that serotonin transporter availability in depressed patients is reduced in key regions of the limbic system. And in October 2022, after the Moncrieff paper, the first direct assessment of serotonin release capacity in people with depression reported a reduction in serotonin release capacity in patients experiencing a major depressive episode (it’s a small study and the difference between the groups is not that striking; I consider the findings to be weak and preliminary).
I am not making a particularly strong claim here, merely saying that the presence and nature of alteration of the serotonergic system in depression are open scientific problems.
Aside from the question of serotonin alteration or dysfunction, the involvement of the serotonin system in the general regulation of mood and emotions is backed by a large body of literature from animals as well as humans (e.g., see this comprehensive review). Even if there is no dysfunction of serotonin in depression, the link between serotonergic mechanisms and aspects of mood/behavior allows for the possibility of effective intervention. There is nothing wrong with kidneys in chronic heart failure, but we can use diuresis as a treatment; there is nothing wrong with prostaglandin pathways in infections, but we can act on them to treat fever; etc. Serotonergic pathways appear to be mechanistically involved in regulation of mood and emotions. There may not necessarily be anything “wrong,” “dysfunctional,” or “imbalanced” in these pathways (except in an indirect sense) — they may be working just fine — but if they are involved in how mood/emotions are regulated, they can be intervened on to produce desired effects.
The Moncrieff Playbook
Moncrieff and colleagues defend their methodology and the interpretation of results, but to my mind, they fail to acknowledge all the different ways in which the serotonin system may be related to mood and antidepressant actions, and the implications this has for their arguments.
But what is particularly annoying is that they use the umbrella review as an excuse to promote skepticism about antidepressant efficacy and push speculative ideas about antidepressant benefits being accounted for by effects such as emotional blunting. Their narrative only works in the broader context of critical beliefs that lack widespread scientific support, beliefs including a general dismissal of the neurobiology of depression, skepticism about antidepressant efficacy, and adoption of the “drug-centered model.” Challenge any of them, and the story falls apart. Since these questions are not directly answered by the umbrella review, journalists cannot simply rely on Moncrieff’s opinion. You have to look at the actual evidence.
None of this justifies the traditional “chemical imbalance” narrative
The legitimacy of the “chemical imbalance” narrative has had little to do with what science says about the serotonin system. None of the discussion above justifies characterizing depression primarily as a “chemical imbalance” (which is misleading at best, outright false at worst) or as fundamentally a problem of serotonin. Serotonergic system or even serotonergic alterations may or may not be involved in depression in some complex manner, but depression is a highly heterogenous and multifactorial condition, and involves a range of neurophysiological, psychological, and sociopolitical factors. Given the heterogeneity of depression, it is unlikely that abnormalities of serotonin, even if they exist, will be present in most individuals with depression. The chemical imbalance story as it has existed in the public imagination has little scientific legitimacy.
The emphasis on serotonin and other monoamines in depression literature stems from the fact that, for a long time, monoaminergic pharmaceuticals produced some of the most reliable effects on depressed mood among the options available. There is a good reason why one pharmaceutical company after another developed me-too serotonergic antidepressants.
Does “chemical imbalance” really have a precise meaning?
In the 1990s and 2000s, a substantial proportion of the psychiatric communication directed at patients and the general public, in awareness and anti-stigma campaigns as well as in individual clinical encounters, centered around a few ambiguous and vague buzzwords such as “chemical imbalances” and “brain disorders.” A convergence of factors was responsible for this, including the pop neuro-reductionism of “the decade of the brain,” a belief that combating moralistic social attitudes towards mental illness requires emphasizing their brain origins, pharmaceutical advertising that sought to benefit from it, a series of preliminary research findings implicating neurotransmitters that received disproportionate media attention, and the exhausting conceptual difficulties of explaining the complex, multi-level constitution and etiology of mental illness in simple words to a confused public. The narrative congealed around the skeleton of “mental illnesses are chemical imbalances, and psychiatric medications correct these imbalances.” This narrative was most pronounced in the case of depression, but it wasn’t specific to it; it was a more generalized narrative about mental illness.
The end result is that the public wasn’t learning any well-defined “chemical imbalance theory of depression.” They were learning a mishmash of buzzwords, with little to no sense of how all this connects with the complex scientific literature. For many people, “chemical imbalance” came to stand for the most concrete interpretation, that depression is caused by low serotonin, and for others, it became merely a way to acknowledge the complex neurobiology of depression or that it is a condition that can be medically treated, and for others, everything in between.
We find numerous examples of the use of the phrase “chemical imbalance” in patient brochures and patient education materials. Such use was quite common, even until recently. Many psychiatric and medical associations around the world use the language for public communication. But we also find no clearly articulated “chemical imbalance theory” in these materials. It’s all vague, leaving it up to the patients and the public to make of it what they want. The scientific literature, at the same time, continued to tell a complex story.
Questions journalists should be asking about Moncrieff’s views on efficacy of antidepressants
What does an umbrella review of the serotonin hypothesis have to say about the clinical efficacy of antidepressants? [Nothing]
What does clinical literature say about the efficacy of antidepressants? What is the medical consensus in the form of international prescribing guidelines from organizations such as NICE, RANZAP, and CANMAT?
How does the efficacy of antidepressants compare to psychotherapy and lifestyle interventions such as exercise?
What are clinical indications for antidepressant medications? Is the efficacy of antidepressants in doubt for all psychiatric indications? [In addition to major depression, they are used for other depressive disorders such as dysthmia and post-stroke depression, as well as a wide range of conditions, such as anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder.]
When Moncrieff says, “I’m not convinced antidepressants have any use” [her statement to the Times], is the medical community supposed to convince her, or is she supposed to convince the medical community? And if the international medical community has examined the evidence carefully and remains unconvinced, what does that tell us? What is the responsibility of a competent journalist in a situation such as this?
When Moncrieff says, “I’m not convinced antidepressants have any use,” is the medical community supposed to convince her, or is she supposed to convince the medical community?
Questions journalists should be asking about Moncrieff’s views on depression as a medical disorder and the neurobiology of depression
What does it mean to characterize something as a medical disorder or a medical condition? What would we call severe, disabling, or persistent behavioral states over which an individual has limited to no voluntary control, that are associated with a wide range of negative health outcomes including increased risk of death, that are associated with adversity but also with temperament (neuroticism) and a range of physiological processes such as endocrine and inflammatory processes, and for which medications, psychotherapy, and neurostimulation have been shown to be effective options?
If depression is not a medical condition, is any psychiatric disorder a medical condition? What principled distinction is there?
Does the term “brain disorder” have a precise meaning in psychiatry? How has this term been interpreted by various commentators?
What does the efficacy of transcranial magnetic stimulation and electroconvulsive therapy tell us about the involvement of brain mechanisms in depression?
If clinical depression is “a normal reaction to adverse circumstances,” as Moncrieff maintains, then what does an abnormal reaction to adverse circumstances look like? How do we distinguish? In what sense is the inability to experience pleasure, severe slowing down of thoughts and bodily actions, inability to care for self, and suicidality “normal”? Why do so many people around the world seek professional help for “normal reactions” to life? If depression were an expected reaction, like physical injuries are to physical trauma, would that make medical treatment of depression automatically inappropriate?
Is the dichotomy between “circumstances make us depressed” and “chemistry makes us depressed” a valid one in light of our best understanding of the brain-behavior relationship and multi-level causality of psychiatric conditions? Is there a rich body of philosophical and scientific literature on the topic, and if so, what does that tell us?
Examples of good journalistic coverage of the umbrella review and subsequent discussion
Shayla Love, VICE. The New Study on Serotonin and Depression Isn’t About Antidepressants.
Laura Sanders, Science News. A chemical imbalance doesn’t explain depression. So what does?
Joanna Thompson, Quanta Magazine. The Cause of Depression Is Probably Not What You Think.
Criticizing Moncrieff (and similar people) is complicated ... So many laypeople still believe in an extremely simplified chemical imbalance theory (need not be for depression only, but for everything psychiatric). Like some slightly updated version of the medieval humour theory - the four humours of serotonin, dopamin, and ... maybe adrenalin and oxytocin, must be balanced! The doctors job is to balance them.
This can be somewhat helpful for people who try to defend themselves from a constant barrage of "you wouldn't need those pills if you just exercised more or learnt to pull yourself together like the adult you are or ... (insert more blamey stuff)". I gather this is much more common among those on anti-depressants or ADHD-stimulants than if you're on anti-psychotics like I was, and I get that it sucks.
Also, if you ARE a schizo-something-psychosis patient, there's this constant message of "you're basically brain damaged already and if you have a relapse you're gonna get much more brain damage so you GOTTA TAKE YOUR PILLS" and then reading some Moncrieff stuff that questions this narrative really was like a breath of fresh air.
In general, this whole narrow biomedical framework is often pushed on people from clinicians, and it's great to find someone who questions that. (I think people who do research in addition to clinical work, like you do Awais, and who know many other smart people in the field, sometimes underestimate how common all kinds of simplified and/or uninformed bullshit is among both GPs and non-research psychiatrists.)
HOWEVER. Moncrieff is, as far as I know, not Mad herself. Just like traditional psychiatrists, she's got this favourite narrative that she pushes on those concerned. (And even if she were Mad, she shouldn't make sweeping generalizations based on her own case alone, and speak over those who can't make themselves heard in the same way).
She says, for instance, that anti-psychotics only numb people down, and don't actually have an anti-psychotic effect. I think this is intended to be a liberating message, and it might be for those psych patients who have this experience, but their doctors insist that the meds do much more than that and won't listen to what they say. But I did NOT have that experience with Haldol, and telling me that I can't understand my own experiences, but SHE does, is pretty damn disrespectful.
Actually testing this claim would be pretty hard, but it would probably involve something like gradually replacing the anti-psychotics with benzos for one group and not doing it with another, and then it should be double-blind. If people like me, who said they experienced an anti-psychotic effect, couldn't tell the difference between being on Haldol and being on Xanax in a blinded study, that would provide some evidence. But in the absence of evidence, the default position should be to take people's self-reports seriously (thus, taking seriously that the effects of those meds vary a lot between individuals). It should NOT be to assume that Moncrieff is right and everyone else is wrong.
This is a problem not just with Moncrieff, but with lots of critical psychiatrists or anti-psychiatrists. At the end of the day, it's more voices from up high who wants to push THEIR narrative on all the Madpeople, service users, patients, survivors (you do you re terminology) down there, regardless of whether they agree or not.
Wow what an excellent rebuttal of Dr Moncrieff, and of the unfortunate article that disseminates her misleading views! I echo Dr. Pies comment: You have taken on a Sisyphean task. It is Sisyphean, and it also reminds me of never-ending battles against zombies in horror movies. Denying the material basis of experience is a zombie idea that should be have been dead long ago - It is in fact dead - but it keeps getting up off the ground and lumbering towards us again and again. .I suspect that the temptation to deny materiality somehow motivates Dr Moncrieff and the journalist who interviewed her - a journalist who mindlessly got the ball and ran with it. Thanks for the detailed reasoning and evidence!