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The involvement of serotonin in major depression: nescience in disguise?

Molecular Psychiatry (2024)Cite this article

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Moncrieff and colleagues’ umbrella review [1] offers an opportunity to reflect on the ‘Serotonin hypothesis’ of depression serendipitously developed 50 years ago. The notion that a simplistic serotonin model of depression, suggesting that a reduction in serotonergic activity fully explains the complex nature of this heterogeneous condition, has been discarded by experts in the field for some time [2]. However, the involvement of serotonin in the pathophysiology of depression in a more complex manner is very likely, especially when the limitations of current experimental techniques are taken into account.

Serotonin (5-HT) is a complex and versatile neurotransmitter with 7 families of receptors (5-HT 1 to 5-HT 7) which include 14 subtypes with presynaptic and postsynaptic functions and a transporter. The technology to directly measure serotoninergic function in humans requires the use of advanced neuroimaging techniques, such as Positron Emission Tomography (PET), and has not yet allowed for a complete understanding of the architecture of this system in humans, let alone in conditions such as major depression [3]. Therefore, until recently, our knowledge of the role of serotonin in depression has been largely based almost entirely on indirect evidence. Highlighting the value and importance of direct measurement, a recent research paper demonstrated a reduction in serotonin release (measured with PET radioligand displacement) in response to a d-amphetamine challenge in individuals with depression compared to healthy controls [4]. These findings provide the first direct evidence that reduced serotonin availability may be a contributing factor in depression.

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Acknowledgements

CJH is supported by the Oxford Health NIHR Biomedical Research Centre. In the last 3 years PBF is supported by a National Health and Medical Research Council of Australia Investigator grant (1193596). The other authors report no source of funding or financial support to declare.

Funding

CJH has received consultancy payments from P1vital, Lundbeck, Zogenix, J&J, Medscape and Compass Pathways. She holds current grants from UCB, J&J and Pfizer. PBF has received equipment for research from Neurosoft, Nexstim and Brainsway Ltd. He has served on scientific advisory boards for Magstim and LivaNova and received speaker fees from Otsuka. He has also acted as a founder and board member for TMS Clinics Australia and Resonance Therapeutics. The other authors have no financial disclosures or conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Psychiatry, University of Ottawa, Ottawa, Canada

    Danilo Arnone

  2. Centre for Affective Disorders, Psychological Medicine, Institute of Psychiatry, Psychology and Neurosciences, King’s College London, London, UK

    Danilo Arnone

  3. Department of Mental Health, The Ottawa Hospital, Ottawa, Canada

    Danilo Arnone

  4. Department of Neuroimaging, Institute of Psychiatry, Psychology and Neurosciences, King’s College London, London, UK

    Toby Wise

  5. School of Medicine and Psychology, College of Health and Medicine, The Australian National University, Canberra, Australia

    Paul B. Fitzgerald

  6. Department of Psychiatry, University of Oxford, Oxford, UK

    Catherine J. Harmer

  7. Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK

    Catherine J. Harmer

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  1. Danilo Arnone
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  2. Toby Wise
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  4. Catherine J. Harmer
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DA developed the idea and wrote the first draft. TW, PBF, CJH contributed to the conceptualisation of the article and the writing of the subsequent versions of the manuscript. All authors approved the final version.

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Correspondence to Danilo Arnone.

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Arnone, D., Wise, T., Fitzgerald, P.B. et al. The involvement of serotonin in major depression: nescience in disguise?. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02459-y

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