Last summer, a thorough analysis struck what Psychology Today called “a decisive blow” to the chemical imbalance myth of depression. That outdated theory—that a lack of serotonin causes depression—has been debunked many times over the past few decades, but it clings to the public consciousness, perhaps largely due to pharmaceutical industry propaganda and media oversimplification. Indeed, prominent psychiatrists have even claimed that the serotonin theory is promoted by an anti-psychiatry conspiracy.
Given that position, one might think that psychiatry would welcome a large review of the evidence on the topic—the largest and most comprehensive ever conducted—putting the supposed anti-psychiatry propaganda to rest. Instead, the reaction from psychiatry has been vitriolic against the authors.
Now, researchers who have staked their financial future on the serotonin theory have joined together to attempt a debunking of that study. The only problem? Their concerns are extremely technical, contradictory, and in some cases, outright false, according to the original study authors. None of them provide solid or consistent evidence for serotonin’s role in depression.
Indeed, the minor, paradoxical gripes by various critics, including a pharma CEO, illuminate a picture of industry-funded researchers clinging to a poorly supported, controversial, and outdated theory that is nevertheless likely to help their marketing of new drugs.
Responding to the criticism, the authors of the original study write of the serotonin theory, “No one believes it, but no one wants to let it go, either.”
The critics, and a response by the original authors of the serotonin-debunking study, were published in Molecular Psychiatry.
The authors of the original paper were Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner, Martin Plöderl, and Mark A. Horowitz.
Summarizing the criticism, Horowitz Tweeted:
It was confusing replying to critics of our paper because some argued the serotonin hypothesis of depression was long ago discarded, some argued it was still supported – and some argued both. @joannamoncrieff @HengartnerMP @PloederlM https://t.co/kfd88bqbxw
— Mark Horowitz (@markhoro) June 16, 2023
“It was confusing replying to critics of our paper because some argued the serotonin hypothesis of depression was long ago discarded, some argued it was still supported—and some argued both.”
The critics include Jacob Jacobsen, the founder and CEO of Evecxia Therapeutics, a company he started in order to market his own serotonin-targeting drug, and a large group of authors led by Sameer Jauhar, who have a list of financial conflicts of interest with the pharma industry comprising several pages of small print. These critics argued that serotonin should still be considered the main cause of depression, despite not being able to provide any valid or consistent evidence of such.
Other critics include Abbas F. Almulla and Michael Maes, who argue that serotonin itself has nothing to do with depression but that a serotonin precursor is the cause; and Lucie Bartov et al., who argue that a complex and poorly understood system including every part of the brain is involved in depression, which necessarily includes the serotonin system.
A final critical paper comes from Rif S. El-Mallakh et al., who admit that the serotonin theory of depression has long been debunked but argues that Moncrieff et al. are wrong for calling attention to how this undermines the evidence base for antidepressant drugs.
Thus, some critics write that low serotonin is still clearly the cause of depression, despite not being able to provide any evidence for it; some write that a complex system we don’t understand—but certainly involving serotonin—is clearly the cause of depression, despite not being able to provide any evidence for it; and some write that even though we know serotonin isn’t involved, we should certainly never question the efficacy of the drugs based on this system.
Indeed, the defense of SSRI antidepressants seems to be the predominant concern of the critics. For instance, Jauhar et al. write, “The proven efficacy of SSRIs in a proportion of people with depression lends credibility [to the serotonin imbalance theory].”
In response, Moncrieff et al. write that the efficacy of SSRIs is quite hotly debated—far from “proven”—as they often fail to beat placebo for depression treatment. Even when they do beat placebo, it is by a tiny margin that is considered to be clinically undetectable. This could be due to an enhanced placebo effect or to effects, like emotional numbing, that are not true depression-targeting effects.
Moreover, just because a drug treats a condition does not mean that the condition is caused by a lack of that drug: As Moncrieff et al. write, people “self-medicate” with alcohol to dull their mood and anxiety problems, but that doesn’t make it a successful medical treatment for an alcohol deficiency.
“From the public’s point of view, taking a drug that is believed to reverse an underlying chemical imbalance or other brain abnormality is quite a different prospect from taking a drug that perturbs brain chemistry in incompletely known and potentially unpredictable ways, with poorly researched effects on mood and behavior, with emotional numbing emerging as a clear effect. Yet, this approach to marketing drugs by drawing on unproven, implausible single neurotransmitter hypotheses to provide biological justiﬁcations for their use continues apace,” write Moncrieff et al.
Perhaps the most unscientific criticism, according to Moncrieff et al., is the notion that serotonin is a vital link in a complex interlocking brain pattern that we have barely even begun to understand. Saying something must be true because it is too complex for us to understand does not constitute a valid or testable scientific theory:
“Whilst appearing scientific, the hypotheses proffered are so vague and overinclusive as to be completely untestable,” Moncrieff et al. write.
Other criticisms included disputes about the inclusion and exclusion criteria for studies in Moncrieff et al.’s original review and objections to the type of assessments used to evaluate the quality of studies. However, Moncrieff et al. respond that their criteria were clearly stated in the original piece and that they followed validated guidance on how to use these assessments—and indeed, that Jauhar’s critique in this respect is actually a blatant falsehood:
“It is not true, as Jauhar et al. suggest, that we did not use validated processes to evaluate our findings. We used the AMSTAR to evaluate the quality of included systematic reviews, and the STREGA for the genetic study, and we used the GRADE to assess the certainty of findings, all of which are validated and widely used measures. Indeed the review of risk factors cited by Jauhar et al. as an example of an exemplary umbrella review uses the same quality assessment measure, the AMSTAR, and a similar classification of credibility to the GRADE that includes criteria related to sample size and presence of bias.”
Finally, many of the critics cited tiny, biased, and unreplicated studies of serotonin-related biological processes in order to claim that Moncrieff et al. cherry-picked results that favored their view. However, again, the inclusion and exclusion criteria used by Moncrieff et al. were well-described and validated, and they write that these additional studies provide no convincing evidence of a link between low serotonin and depression. Indeed, this is an example of the critics—who did not conduct a systematic review—cherry-picking studies to support their argument.
As Moncrieff explained on Twitter:
To conclude, Jauhar’s points (though mostly false) make no difference to our findings and conclusions. There is no evidence for low serotonin and some weak evidence of increased serotonin, plausibly explained by prior medication use. 26/28
— Dr Joanna Moncrieff (@joannamoncrieff) June 26, 2023
“Jauhar’s points (though mostly false) make no difference to our findings and conclusions. There is no evidence for low serotonin and some weak evidence of increased serotonin, plausibly explained by prior medication use.”
“Jauhar & co cannot make a convincing case but are desperate to discredit our research so they can continue to perpetuate the myth that the biological basis of depression has been established.”
In conclusion, Moncrieff et al. summarize again the necessity for their research:
“The reason our paper is important is that the pharmaceutical industry, along with many doctors and academics, have been telling the public for decades that depression is caused by a neurochemical abnormality in order to justify the use of antidepressants, and to overcome some people’s reluctance to use mood-modifying medicines. Our paper exposed this claim as untrue. The main areas of research do not provide support for the most well-known neurochemical hypothesis, the serotonin theory of depression—the idea that depression is caused by low levels or low activity of serotonin.”
Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., Plöderl, M., & Horowitz, M. A. (2023). The serotonin hypothesis of depression: both long discarded and still supported? Molecular Psychiatry. Published online June 16, 2023. https://doi.org/10.1038/s41380-023-02094-z (Link)