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Reply to: “The serotonin theory of depression: a systematic umbrella review of the evidence” published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0)

Molecular Psychiatry volume 28, pages 3153–3154 (2023)Cite this article

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The serotonin theory of depression focusing primarily on the serotonergic neurotransmission, that was originally introduced by the English psychiatrist Alec Coppen in 1967 [1], has been increasingly amplified by groundbreaking insights on neurobiological mechanisms involving further crucial monoaminergic, glutamatergic, GABAergic and other systems [2, 3]. According to the current state of evidence-based knowledge, depression represents a dysbalanced dynamic system involving genetic, epigenetic, environmental and stress vulnerabilities initiating a cascade of neurobiological alterations in and beyond the serotonergic functioning [4,5,6,7]. These alterations are reflected by impaired neurotransmission, attenuated neuroplasticity and neurogenesis, dysfunctional neural circuitries, hypothalamic pituitary axis (HPA) abnormalities, increased inflammation and vascular changes, whereby monoamines including serotonin, norepinephrine and dopamine, as well as glutamate, GABA, glucocorticoids, inflammatory cytokines and neurotrophic factors including the brain-derived neurotrophic factor seem to be essential mediators [8]. It is noteworthy that all these pathways have been shown to be integrally related and are thought to interact multi-directionally throughout different phases of depression [9, 10]. Interacting as nodes in a matrix they are crucial in the development of depressive symptoms, in the heterogenous clinical manifestation of depression as well as its course and, importantly, antidepressant treatment, and must be hence included in the etiopathological and therapeutic considerations of this frequent and burdensome disease [4, 7, 11, 12].

The systematic umbrella review of the evidence on the serotonin theory of depression, that was published by Moncrieff et al. very recently, focused on studies investigating serotonergic mechanisms [13]. Accordingly, the authors concluded that there is no consistent international evidence of an association between serotonin and depression, and consequently no convincing evidence of a biochemical basis of depression [13]. Since this deduction is based on selected literature covering serotonin exclusively, and hence, addressing only a part of the complex understanding of depression [4], we argue that the authors’ conclusion, that the serotonin theory cannot be empirically substantiated, cannot be derived from the present work. A meta-analysis revealing spatial-temporal dynamics of the serotonergic neurotransmission in depression underlines the fact that serotonin represents a crucial but dynamic neurobiological underpinning of depression [10], and that the methods applied in some previous studies may have not been sensitive enough to measure fluctuations in neuronal activity to be able to answer the question.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria

    Lucie Bartova, Rupert Lanzenberger, Dan Rujescu & Siegfried Kasper

  2. Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria

    Lucie Bartova, Rupert Lanzenberger, Dan Rujescu & Siegfried Kasper

  3. Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Siegfried Kasper

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Contributions

LB wrote the first draft of the manuscript that was further elaborated and critically revised by RL, DR, and SK.

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Correspondence to Siegfried Kasper.

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Competing interests

Within the last 3 years, LB has received travel grants and consultant/speaker honoraria from Alpine Market Research, Angelini, Biogen, Diagnosia, Dialectica, Janssen, Lundbeck, Market Access Transformation, Medizin Medien Austria, Novartis, Schwabe and Universimed. RL received travel grants and/or conference speaker honoraria from Bruker BioSpin within the last three years and investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. Within the last three years, DR has received grant/research support from Janssen and Lundbeck; he has served as a consultant or on advisory boards for Janssen and Rovi and he has served on speakers bureaus of Janssen and Pharmagenetix. Within the last three years, SK has received grant/research support from Lundbeck; he has served as a consultant or on advisory boards for Angelini, Biogen, Esai, Janssen, IQVIA, Lundbeck, Mylan, Recordati, Sage and Schwabe; and he has served on speakers bureaus for Aspen Farmaceutica S.A., Angelini, Biogen, Janssen, Lundbeck, Neuraxpharma, Recordati, Sage, Sanofi, Schwabe, Servier and Sun Pharma.

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Bartova, L., Lanzenberger, R., Rujescu, D. et al. Reply to: “The serotonin theory of depression: a systematic umbrella review of the evidence” published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0). Mol Psychiatry 28, 3153–3154 (2023). https://doi.org/10.1038/s41380-023-02093-0

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