Researchers: Depression is “a normal brain responding to stress or adversity”

Moncrieff et al. write, “There is abundant evidence that it is the context of our lives and not the balance of our chemicals that offer the most insight into depression.”

“Difficult lives explain depression better than broken brains,” according to researchers in a recent letter to the editor in Molecular Psychiatry. The authors, led by Joanna Moncrieff, argue that there is no real evidence for brain differences in depression but that there is convincing evidence of the role of social and environmental factors as a cause.

“We suggest that in the absence of convincing proof of a pathological process, it is more likely that depression is part of the range of emotional reactions to the circumstances of life that are typical of humans,” write Moncrieff et al.

“We agree that mental activity arises from brain activity, but it seems more likely that depression is the result not of a faulty brain but rather a normal brain responding to stress or adversity: in other words, a behavioural state best understood at the level of the mind (that is, the thoughts, feelings, and actions of human beings in their social context) and not of the brain,” they add.

Their article comes as a response to four other letters to the editor by proponents of the biomedical model of depression—those who consider depression to be a “brain illness” first and foremost.

The dialogue around depression’s cause and treatment has reached a fever pitch in the past two years after the current authors—Moncrieff et al.—provided the “decisive blow” to the outdated theory that low serotonin causes depression. Their comprehensive analysis revealed the complete lack of evidence for this long-debunked myth. Although some prominent psychiatrists had already claimed that no one ever actually believed the serotonin myth, others attacked Moncrieff et al. with contradictory claims. Still others tried to spin null results into positive ones regarding serotonin’s supposed causal effect.

Now, four more articles have appeared in Molecular Psychiatry to argue that depression is still a brain disease. None of them challenge the conclusions of the study debunking the low serotonin myth. Yet they attack Moncrieff and her co-authors as anti-science and write that depression is still a brain disorder.

According to one letter by Fountoulakis and Tsapakis, the argument that depression is caused by social and environmental factors (such as trauma and loss) is equivalent to a belief in the “supernatural.” In another letter, Arnone et al. write that it is a rejection of science to argue that these factors are primary because, they argue, a complex and poorly understood neurobiological process causes depression.

Yet Moncrieff et al. write that a vague statement that the biological cause is “complex”—without providing evidence for its effect or even explaining the nature of the complexity—is meaningless and certainly cannot be considered scientific evidence.

“Without specifying the nature of the relationship, this is equivalent to saying that blood is involved in depression. It surely is, but this has little bearing on the nature, origins, or causation of depression,” write Moncrieff et al.

Moncrieff et al. thoroughly address Arnone et al.’s many claims, many of which don’t even relate to depression specifically. These include inconsistent serotonin results from animal studies, contradictory results on serotonin and reward learning, and vague theories about structural connectivity in the brain that—according to Moncrieff et al.—don’t even include testable hypotheses.

Moncrieff et al. also address the critiques proposed by Smith et al. in another letter. Smith et al. argued that the original comprehensive serotonin analysis was flawed for a variety of minor reasons, including inappropriate methodological choices. Yet Moncrieff et al. write that Smith et al.’s complaints are misleading and that they used the gold-standard guidance on how to conduct systematic reviews and carefully enumerated their inclusion and exclusion criteria. Moreover, even if they changed their analysis based on all minor critiques lobbed their way by Smith et al., they write, it would not change the actual findings.

“Even if every criticism put forward by Smith et al. were true (and they are not), it would not alter the conclusion of the umbrella review,” they write.

“We suggest that this letter is an example of the logic-chopping fallacy (trivial objections),” they add. “The quibbling over minor differences of opinion with regard to methodological approaches and confected concerns over the choice of references appear to disguise our correspondents’ displeasure at the exposure of the failure of the biomedical enterprise to understand depression.”

Moncrieff et al. note that the effects of social and environmental factors like povertyisolation, and trauma have been demonstrated repeatedly while neuroimaging and genetics studies have failed to find consistent evidence of biological differences in depression.

For instance, they cite a 2022 study in JAMA Psychiatry led by Nils Winter, which included every major neuroimaging modality (structural MRI, fMRI, connectivity, DTI, and more) as well as a measure of complex genetic risk, the polygenic risk score (PRS). Winter et al. found that all the neuroimaging results and the PRS predicted depression at about the accuracy of a coin flip. But the social-environmental variables “social support” and “childhood maltreatment” were significantly linked with depression, and each predicted with greater than 70% accuracy.

After conducting a similarly failed 2023 follow-up study attempting to use machine learning to identify impactful neuroimaging variables, Winter wrote on Twitter:

“The fact that we cannot find meaningful (univariate or multivariate) neurobiological differences on the level of the individual for one of the most prevalent mental disorders should give us pause.”

Reflecting on the failure of neuroscience to explain psychiatric diagnoses, a 2022 article by influential neuroscientist Raymond Dolan argues that “psychiatry’s most fundamental characteristic is its ignorance, that it cannot successfully define the object of its attention, while its attempts to lay bare the etiology of its disorders have been a litany of failures.”

Ultimately, Moncrieff et al. write, “There is abundant evidence that it is the context of our lives and not the balance of our chemicals that offer the most insight into depression.”


Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2024). Difficult lives explain depression better than broken brains. Molecular Psychiatry. Published online February 19, 2023. (Link)

This article is a repost from our sister site Mad in America.