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The serotonin theory of depression

Molecular Psychiatry volume 28, page 3157 (2023)Cite this article

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We appreciated the recent review of reviews regarding the role of serotonin abnormalities in the pathophysiology of major depressive illness [1]. While this was a review of the role of serotonin in the pathophysiology of major depression, it seems to have been interpreted by the media as addressing the effectiveness of antidepressants [2]. However, there is no question that antidepressants are effective when examined in a systematic fashion [3]. The authors actually focused on looking for biologic serotonin abnormalities. Despite the nearly universal use of serotoninergic antidepressant agents to treat depression, the authors could not identify any abnormality in the serotonin system that could underlie the onset of the illness. In fact, the major abnormalities they described were that long-term antidepressant treatment reduces serotonin levels, serotonin turnover, and may change density of serotonin-related protein expression [1]. The paper has received significant media attention questioning the use of antidepressant agents (e.g., https://thehill.com/changing-america/well-being/mental-health/3569506-depression-is-likely-not-caused-by-a-chemical-imbalance-in-the-brain-study-says/). However, it is important to remember that a great many of accepted treatments in medicine involve ‘breaking things that are not broken’ to get a desired response.

For example, there is no evidence that hypertension is caused by excessive blood volume, but diuretics are among the leading treatments for hypertension. That is, clinicians create dehydration in their patients to control their patients’ blood pressure. Similarly, we administer steroids to individuals that have no evidence of steroid deficiencies. We alter physiology to achieve desired outcomes. This is frequently necessary because we do not know the cause of the abnormality, or we do not have adequate tools to correct a known abnormality, but we are able to achieve a net improvement in health. For major depression, we increase synaptic serotonin with antidepressants because serotonin increases emotional motivation and thus increases emotional effort e.g., [4]. This helps patients deal with the condition of depression and the stressors that led to that condition. It is not reasonable to assume that medical treatments generally correct physiologic abnormalities.

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References

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Authors and Affiliations

  1. Mood Disorders Research Program, Depression Center, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Rif S. El-Mallakh, Masoud Doroodgar, Omar H. Elsayed & Neil Kidambi

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  1. Rif S. El-Mallakh
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RSE did most of the writing, but the ideas originated from all the authors during discussions about the mechanisms of treatment options.

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Correspondence to Rif S. El-Mallakh.

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RSE receives grant funding from Sunovion, and is a speaker for Axsome, Intracellular, Janssen, Lundbeck, Noven, Otsuka, and Teva. The other authors declare no competing interests.

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El-Mallakh, R.S., Doroodgar, M., Elsayed, O.H. et al. The serotonin theory of depression. Mol Psychiatry 28, 3157 (2023). https://doi.org/10.1038/s41380-023-02091-2

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