30+ Experts Question Validity of Serotonin/Depression Study

Pauline Anderson

June 27, 2023

A group of more than 30 academics and researchers in psychiatry and psychopharmacology is challenging the conclusions of an umbrella review published last year that concluded there is no convincing evidence that serotonin deficiency is the primary cause of depression. However, the authors of the article stand by their conclusion.

"The methodology doesn't conform to a conventional umbrella review," said the commentary's lead author, Sameer Jauhar, MD, PhD, first author of the commentary criticizing the review, which was published online June 16 in Molecular Psychiatry.

In addition, preeminent psychiatrist David J. Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology, Imperial College London, United Kingdom, is calling for the review to be retracted. In an interview with The Daily Mail, he said the article is "full of flaws and it should never have been published in the first place. Yet it has been frequently cited and people believe it is true. It's essentially misinformation. That's why I'm calling on the journal to retract it." Nutt is also one of the authors of the published commentary.

"No Convincing Evidence"

Led by Joanna Moncrieff, MD, professor of clinical and social psychiatry, University College London, United Kingdom, the authors analyzed systematic reviews and meta-analyses to determine whether low serotonin levels are, in fact, associated with depression.

Of 361 potential studies, 17 were selected for the review, including meta-analyses, systematic reviews, and a genetic association study.

The review included examinations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in "body fluids," 5HT1A receptor and serotonin transporter protein (SERT) availability in imaging and postmortem studies, investigations of SERT gene polymorphisms, interactions between SERT and stress in depression, and effects of tryptophan depletion on mood.

The tryptophan hypothesis suggests depression occurs through tryptophan depletion, which lowers available serotonin. According to the review, two crossover studies of patients with depression who were currently receiving or had recently received antidepressant treatment did not show substantial effects of depletion, and data from studies involving volunteers largely showed no effect.

Ultimately, Moncrieff and colleagues concluded that "there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity."

"Unconventional, Odd" Methodology

However, Jauhar and the commentary's co-authors disagree with the study's conclusion. The researchers claim that "we don't see depression symptoms in healthy volunteers when given tryptophan depletion; everyone knows that and agrees with that; it's only in people vulnerable to depression who will have it."

Furthermore, he said, for the study's conclusion does not consider that experimental medicine studies of tryptophan depletion are difficult to conduct. "You're not going to have huge sample sizes as you would in a genetic study or big epidemiological studies.

Jauhar said he found it "unconventional" and "odd" that the review included individual tryptophan depletion studies that were not in the prespecified protocol.

For studies involving molecular imaging, Jauhar said the review's inferences were "simplistic" and the review authors are "basically shaping the argument" to fit their desired narrative.

He also noted factual errors in the review. "They make a mistake when they talk about serotonin transporter imaging; they say there are no consistent findings across studies when, in fact, there are."

With both tryptophan depletion and molecular imaging studies, the review "glosses over findings" from the original studies, said Jauhar.

For tryptophan depletion, "a more accurate, constructive conclusion would be that acute tryptophan depletion and decreased plasma tryptophan in depression indicate a role for 5-HT in those vulnerable to or suffering from depression, and that molecular imaging suggests the system is perturbed," the commentators write.

"The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position," they add.

Jauhar also took issue with criteria for certainty of finding of these and other studies used in the review. "If you're setting the criteria yourself, it's arbitrary."

No New Data

An umbrella review is supposed to be of the highest quality and should entail "taking out the studies and analysing them yourself," but here, "all they have done is put a synthesis forward of other people's reviews, so essentially there's no new data there," said Jauhar.

And sometimes the review's findings differ from the original research. "When you have people who haven't conducted original research themselves quoting someone else's work and ignoring what those people say, we're all in trouble," said Jauhar.

In an additional commentary also published in Molecular Psychiatry , Jacob Pade Ramsøe Jacobsen, Evecxia Therapeutics, Inc, Durham, North Carolina, also criticized the review by Moncrieff and colleagues.

Its authors appear unfamiliar with serotonin biology and pharmacology, Jacobsen writes.

"The review contains factual errors, makes conclusions serotonin neurobiology may not support, and quotes the cited literature in a selective manner," he adds.

"Most troubling, they misinterpret some data reviewed and intimate that serotonin reuptake inhibitor antidepressants, eg, SSRIs, may decrease, rather than increase, serotonin function."

If accepted by general practitioners and the public, the review's conclusions "could lead to reduced use of antidepressants among patients in need and increased morbidity related to depression."

Moncrieff Pushes Back

Responding to the torrent of criticism of her study, Moncrieff told Medscape Medical News via email that they stand by the review, adding that Jauhar and others "don't want to let the cat out of the bag" that there's no good evidence to support the hypothesis that low serotonin causes depression because it challenges antidepressant use.

"The idea that antidepressants work by correcting an underlying chemical imbalance or serotonin abnormality has led research up a blind alley and meant scientists have not taken the harmful effects of these drugs seriously enough."

These critics, she added, "want business as usual ― which means people will continue to be misinformed and exposed to harmful effects of drugs that have minimal and uncertain benefits."

In a letter to the editor of Molecular Psychiatry, Moncrieff and her fellow authors maintain that they used approved and well-accepted methods for the umbrella review, including preregistering the protocol and using recommended search methods and quality assessments, and that they did not miss certain studies, as has been claimed.

In her blog, Moncrieff writes that the "marginal differences between antidepressants and placebo that are apparent in clinical trials are likely to be produced by alternative, more plausible mechanisms like the emotional blunting effects of the drugs or by amplified placebo effects, rather than by targeting underlying biological mechanisms (since these have not been demonstrated)."

It also highlights "how we don't know what antidepressants do to the brain exactly, which is a cause for concern," she adds.

Jauhar has received honoraria for nonpromotional educational talks on antipsychotics from Janssen, Sunovion, and Lundbeck and on causes of schizophrenia for Boehringer-Ingelhim. He has also received honoraria for consulting on antipsychotics for LB Pharmaceuticals. He sits on Council for the British Association for Psychopharmacology and was a recent panel member for the Wellcome Trust.

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