Pharmaceutical CEO, others attempt contradictory critiques of serotonin debunking study

Last summer, an in-depth analysis hit what Psychology today called a decisive blow to the myth of the chemical imbalance 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 That outdated theory that a lack of serotonin causes depression has been debunked many times over the past few decades, but it clings to the public consciousness, perhaps in large part due to pharmaceutical industry propaganda and media oversimplification. In fact, prominent psychiatrists have even claimed that the serotonin theory is promoted by a antipsychiatry conspiracy.

Given this stance, one would think that psychiatry would welcome a major review of the evidence on the subject, the largest and most comprehensive ever conducted, silencing the alleged anti-psychiatry propaganda. Instead, the reaction of psychiatry has been vitriolic against the perpetrators.

Now, researchers who have bet their financial future on the serotonin theory have teamed up to attempt to debunk that study. The only problem? Their concerns are highly technical, contradictory and, in some cases, outright false, according to the authors of the original study. None of them provide solid or consistent evidence for serotonin’s role in depression.

Indeed, minor and paradoxical complaints from several critics, including a pharmaceutical CEO, illuminate a picture of industry-funded researchers clinging to a poorly supported, controversial and outdated theory that is nonetheless likely to aid their commercialization of new drugs.

In response to the criticisms, the authors of the original study write of the serotonin theory: No one believes it, but no one wants to let it go either.

Critics and a response from the original authors of the serotonin study were published in Molecular psychiatry.

The authors of the original article were Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner, Martin Plderl, and Mark A. Horowitz.

Battle of the brain and war of wits concept as two opposing open symbols of the human brain fighting as a debate or dispute metaphor and an icon for creative competition in a 3D illustration style.Summarizing the criticisms, Horowitz tweeted:

It was confusing to respond to critics of our article because some argued that the serotonin hypothesis of depression was dismissed a long time ago, some argued it was still supported, and others argued both.

Critics include Jacob Jacobsen, the founder and CEO of Evecxia Therapeutics, a company he founded to commercialize his own serotonin-targeting drug, and a large group of authors led by Sameer Jauhar, who has a list of financial conflicts of interest with the l industry which includes several pages of small print. These critics have argued that serotonin should still be considered the root cause of depression, despite being unable to provide any valid or consistent evidence of such.

Other critics include Abbas F. Almulla and Michael Maes, who argue that serotonin Yes it has nothing to do with depression but that serotonin precursor it’s the cause; and Lucie Bartov et al., who argue that a complex and poorly understood system involving every part of the brain is involved in depression, necessarily including the serotonin system.

A final critical paper comes from Rif S. El-Mallakh et al., who admits that the serotonin theory of depression has long been debunked, but argues that Moncrieff et al. they are wrong to call attention to how this weakens the evidence base for antidepressant drugs.

Thus, some critics write that low serotonin is still clearly the cause of depression, despite being unable to provide any evidence for it; some write that a complex system that we don’t understand, but definitely involving serotonin, is clearly the cause of depression, although they are unable to provide any evidence for it; and some write it even though We Know serotonin is not involvedwe should certainly never question the effectiveness of drugs based on this system.

Indeed, the advocacy of SSRI antidepressants appears to be the predominant concern of critics. For example, Jauhar et al. write, The proven efficacy of SSRIs in a percentage of people with depression lends credence [to the serotonin imbalance theory].

In response, Moncrieff et al. write that the effectiveness of SSRIs is hotly debated, far from proven, as they often fail to beat placebo for the treatment of depression. Even when they beat the placebo, it’s by a small margin that it’s considered clinically undetectable. This could be due to an enhanced placebo effect or effects, such as emotional numbing, that are not true effects targeting depression.

Furthermore, 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 issues, but that doesn’t make it a successful medical treatment for an alcohol deficiency.

From the perspective of the public, taking a drug that is thought to reverse an underlying chemical imbalance or other brain abnormality is quite a different perspective from taking a drug that disrupts brain chemistry in ways that are incompletely understood and potentially unpredictable, with poorly studied effects on mood. and behavior, with emotional numbing emerging as a clear effect. However, this approach to marketing drugs by drawing on unproven and implausible single neurotransmitter hypotheses to provide biological justifications for their use continues rapidly, write Moncrieff et al.

Perhaps the most unscientific criticism, according to Moncrieff et al., is the idea that serotonin is a vital link in a complex interconnected brain pattern that we are only just beginning 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:

Although they appear scientific, the hypotheses put forward are so vague and too inclusive as to be completely untestable, Moncrieff et al. write.

Other criticisms included controversy over the inclusion and exclusion criteria for studies in the original review by Moncrieff et al. and objections to the type of ratings used to assess study quality. However, Moncrieff et al. they respond that their criteria were clearly stated in the original piece and that they followed validated guidance on how to use these ratings and, indeed, that Jauhar’s critique in this regard is actually a blatant falsehood:

Not true, as Jauhar et al. suggest, that we have not used validated processes to evaluate our results. We used the AMSTAR to assess the quality of the included systematic reviews and the STREGA for the genetic study, and we used the GRADE to assess the certainty of the results, all of which are validated and widely used measures. In fact, the review of risk factors cited by Jauhar et al. as an example of an exemplary umbrella review it uses the same quality assessment measure, the AMSTAR, and a GRADE-like credibility rating that includes criteria for sample size and the presence of bias.

Finally, many of the critics cited tiny, biased, and unreplicated studies of serotonin-related biological processes to claim that Moncrieff et al. carefully selected results that furthered their vision. However, again, the inclusion and exclusion criteria used by Moncrieff et al. have been well described and validated, and they write that these additional studies do not provide convincing evidence for a link between low serotonin and depression. Indeed, this is an example of the critics failing to conduct a systematic review of selected supporting studies They discussion.

Like Moncrief explained on Twitter:

Jauhar’s points (although mostly false) make no difference to our findings and conclusions. There is no evidence of low serotonin levels and some weak evidence of increased serotonin, plausibly explained by previous medication use.

she added,

Jauhar & co can’t make a compelling case, but they are desperate to discredit our research so they can continue to perpetuate the myth that the biological underpinnings of depression have been established.

In conclusion, Moncrieff et al. again summarize the need for their research:

The reason our paper is important is that the pharmaceutical industry, along with many physicians and academics, have been telling the public for decades that depression is caused by a neurochemical abnormality to justify the use of antidepressants and to overcome the reluctance of some people to use mood-altering drugs. Our newspaper exposed this claim as false. Major areas of research provide no support for the best-known neurochemical hypothesis, the serotonergic theory of depression, the idea that depression is caused by low levels or low activity of serotonin.

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Moncrieff, J., Cooper, RE, Stockmann, T., Amendola, S., Hengartner, MP, Plderl, M., & Horowitz, MA (2023). The Serotonergic 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)


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