From the Journals

More than 30 experts question validity of serotonin/depression study


 

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. The authors of the article, however, 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 in Molecular Psychiatry.

In addition, preeminent psychiatrist David J. Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology, Imperial College London, 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.” Dr. Nutt is 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, 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, Dr. 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, Dr. Jauhar and the commentary’s coauthors 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, 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.

Dr. 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, Dr. 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 Dr. 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 wrote.

“The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position,” they added.

Dr. 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.”

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