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Serotonin and depression—an alternative interpretation of the data in Moncrieff et al.

Molecular Psychiatry volume 28, pages 3158–3159 (2023)Cite this article

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Moncrieff et al. [1] report in a review of reviews that depression is not generally linked with serotonin deficiency. This is hardly news to neuropharmacologists, which Moncrieff et al. tacitly admits, as they justify their review by citing examples of laity and general practitioners believing depression is caused by a “chemical imbalance”, i.e., in serotonin. For instance, already in 1986 did Depue and Spoont point out that serotonin deficiency may not be a general cause of depression or other psychiatric illness [2]. Further, that increasing extracellular serotonin—e.g., with selective serotonin reuptake inhibitors (SSRIs)—treats depression does not mean decreased serotonin causes depression.

Of course, none of the parameters reviewed by Moncrieff are validated biomarkers of chronic state-levels of extracellular brain serotonin, the biologically active serotonin pool. Measuring state-levels of brain extracellular serotonin can at current only be done by intracerebral microdialysis, which is invasive, and hence feasible only in animals.

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References

  1. Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022. Online ahead of press.

  2. Depue RA, Spoont MR. Conceptualizing a serotonin trait. A behavioral dimension of constraint. Ann NY Acad Sci. 1986;487:47–62.

    Article  CAS  PubMed  Google Scholar 

  3. Kaufman J, DeLorenzo C, Choudhury S, Parsey RV. The 5-HT1A receptor in major depressive disorder. Eur Neuropsychopharmacol. 2016;26:397–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hensler JG. Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration. Life Sci. 2003;72:1665–82.

    Article  CAS  PubMed  Google Scholar 

  5. Jacobsen JP, Siesser WB, Sachs BD, Peterson S, Cools MJ, Setola V, et al. Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice. Mol Psychiatry. 2012;17:694–704.

    Article  CAS  PubMed  Google Scholar 

  6. Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12:331–59.

    Article  CAS  PubMed  Google Scholar 

  7. Bel N, Artigas F. Reduction of serotonergic function in rat brain by tryptophan depletion: effects in control and fluvoxamine-treated rats. J Neurochem. 1996;67:669–76.

    Article  CAS  PubMed  Google Scholar 

  8. van der Plasse G, Meerkerk DT, Lieben CK, Blokland A, Feenstra MG. Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion. Psychopharmacology. 2007;195:377–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stancampiano R, Melis F, Sarais L, Cocco S, Cugusi C, Fadda F. Acute administration of a tryptophan-free amino acid mixture decreases 5-HT release in rat hippocampus in vivo. Am J Physiol. 1997;272:R991–994.

    CAS  PubMed  Google Scholar 

  10. Brand T, Anderson GM. The measurement of platelet-poor plasma serotonin: a systematic review of prior reports and recommendations for improved analysis. Clin Chem. 2011;57:1376–86.

    Article  CAS  PubMed  Google Scholar 

  11. Borup C, Petersen IM, le Fevre Honore P, Wetterberg L. Reduction of whole blood serotonin in depressed patients treated with a new, selective serotonin-uptake inhibitor, femoxetine. Psychopharmacology. 1979;63:241–3.

    Article  CAS  PubMed  Google Scholar 

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  1. Evecxia Therapeutics, Inc. 2 Davis Drive, Research Triangle Park, Durham, NC, 27709, USA

    Jacob Pade Ramsøe Jacobsen

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The article was fully authored by JPRJ.

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Correspondence to Jacob Pade Ramsøe Jacobsen.

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The author is a full-time employee of Evecxia Therapeutics, a company developing drugs for depression and other psychiatric diseases, and owns stock in the company.

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Jacobsen, J.P.R. Serotonin and depression—an alternative interpretation of the data in Moncrieff et al.. Mol Psychiatry 28, 3158–3159 (2023). https://doi.org/10.1038/s41380-023-02090-3

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