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Although serotonin is not a major player in depression, its precursor is

Molecular Psychiatry volume 28, pages 3155–3156 (2023)Cite this article

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We read with great interest the umbrella review by Moncrieff et al. titled “The serotonin hypothesis of depression: a comprehensive umbrella review of the data” [1]. These authors conclude that serotonin plays no significant role in major depression (MDD) [1], and we completely agree, despite the fact that we [2, 3] and others [4] have repeatedly underscored the importance of low levels of its precursor in MDD.

Recent findings from a large-scale meta-analysis have shown that MDD, bipolar disorder (BD), and their severe phenotypes, including melancholia and psychotic depression, are associated with a considerable decrease in tryptophan (TRP), the precursor of serotonin [5, 6]. The availability of plasma TRP to the brain partially controls brain TRP levels and, thus, may influence serotonin transmission. Since 1993, we have repeatedly reported that a low TRP level is an immune-inflammatory biomarker in infectious, immunological, and neuropsychiatric diseases [7, 8]. The neuroimmunotoxic-neuroprotective theory of depression was developed based on findings that cytokine-based treatments of cancer patients induce depression in many individuals and stimulate indoleamine 2,3-dioxygenase (IDO), thereby lowering plasma TRP and increasing the production of neuro-active TRP catabolites (TRYCATs), which are strongly associated with the onset of depression due to cytokine treatment [9, 10]. Recent meta-analyses indicate, contrary to this previous theory [9], that there is no consistent activation of IDO in MDD/BD (not cytokine-induced), and thus that TRYCATs do not play a key role [5, 7]. Nonetheless, decreased TRP in MDD/BD is likely a consequence of the immune-inflammatory response (IRS) in MDD/BD, in part owing to the acute phase response with decreased albumin levels, which bind TRP [11].

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References

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Funding

The study was funded by the C2F program, Chulalongkorn University.

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Authors and Affiliations

  1. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Abbas F. Almulla & Michael Maes

  2. Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq

    Abbas F. Almulla

  3. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  4. Department of Psychiatry, IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia

    Michael Maes

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  1. Abbas F. Almulla
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Correspondence to Michael Maes.

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Almulla, A.F., Maes, M. Although serotonin is not a major player in depression, its precursor is. Mol Psychiatry 28, 3155–3156 (2023). https://doi.org/10.1038/s41380-023-02092-1

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