Serotonin strikes back
A series of commentaries by prominent researchers challenges the validity of the 2022 "serotonin hypothesis" umbrella review
A series of responses published in Molecular Psychiatry offers a sharp critique of the “serotonin hypothesis” umbrella review published last year by Joanna Moncrieff, et al. in the same journal. The most important among them is a commentary by Sameer Jauhar et al. in Molecular Psychiatry, authored by 35 distinguished scientists, a who’s who of psychiatric and psychopharmacological research, aptly titled “A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.” Moncrieff and colleagues had concluded in their review last year, “The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.” As many readers will remember, the article generated provocative headlines all over the world and was weaponized to promote skepticism about the use of antidepressants.
Jauhar and colleagues point out serious issues with the methodology of the umbrella review, identify compromising errors in the interpretation of data, and dispute the validity of the conclusions. I’ll summarize some of the main points of their critique below.
SJ et al. argue that multiple methodological choices (such as choosing not to synthesize the results of individual meta-analyses because they included overlapping studies, exclusion of important primary studies relevant to the serotonin-depression link, assessing quality of evidence using a “modified” version of GRADE introduced in a post-hoc protocol amendment, etc.) biased the conclusions of the review.
The confounding effects of antidepressants were only considered if the results were positive. SJ et al. counter: “It is unclear why confounding of effects of antidepressants would not apply to all studies, i.e. not just where positive outcomes were seen: antidepressants are as likely to confound studies with negative results...”
Aside from noting the exclusion of an important clinical and molecular imaging study of tryptophan depletion, SJ et al. also dispute JM et al.’s interpretation of a meta-analysis of tryptophan depletion. The meta-analysis actually showed a large effect size of tryptophan depletion on mood in depressed people not taking antidepressants. “A more accurate interpretation is that tryptophan depletion studies suggest a role for 5-HT in people vulnerable to depression and in those remitted on SSRI treatment. In contrast, by citing a series of individual negative studies in healthy participants, the authors give the impression tryptophan depletion has no effect.”
Several studies of circulating tryptophan concentrations were excluded from the umbrella review. L-tryptophan plasma concentrations have been shown to be decreased in major depression in small studies, including in unmedicated individuals.
Important molecular imaging evidence was misinterpreted. JM et al. stated that reduced binding of serotonin 1A receptors suggests increased levels of synaptic serotonin, but reduced binding can also be because of decreased receptor density or affinity. JM et al. appear to have mistakenly assumed that serotonin 1A receptors are exclusively pre-synaptic autoreceptors, but most serotonin 1A receptors are post-synaptic heteroreceptors. Diminished availability of serotonin 1A receptors in unmedicated depression is consistent with lowered serotonin transmission, and SJ et al. say that this is a replicated finding in people who were not on antidepressants.
JM et al. stated that there is a lack of consistency in the brain areas in which serotonin transporter binding has been reported. SJ et al. argue that in serotonin transporter binding studies, a number of brain regions have actually been consistently implicated.
JM et al. attributed the results of serotonin transporter binding studies in meta-analyses to prior antidepressant treatment, but this ignores the fact that reduced serotonin transporter findings have also been reported in drug-naive populations, and they missed the fact that 149 out of 364 people in an included meta-analysis were drug naive.
A small study published late last year employing a relatively direct assessment of serotonin release capacity, the first study of its kind, provided preliminary evidence of reduced serotonin release capacity in individuals with depression, which shows that this is still an active area of scientific inquiry and any closure is premature.
The serotonergic system continues to be an important mechanism implicated in the effects of traditional antidepressants as well as psychedelics.
SJ et al. conclude: “To summarise, the methodology is inconsistent with an umbrella review, with substantial bias created by the authors’ chosen quality criteria, selective reporting, and interpretation of results. There is an underappreciation of the complexities of neuroscience and neuropsychopharmacology, and it is therefore impossible for the reader to draw valid or reliable conclusions. 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 proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position.”