Mechanism of action of serotonin selective reuptake inhibitors
Abstract
Serotonin selective reuptake inhibitors (SSRIs) are currently among the most frequently prescribed therapeutic agents in all of medicine. Their therapeutic actions are diverse, ranging from efficacy in depression to obsessive-compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are mostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A leading hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Desensitization of post-synaptic receptors in these same discrete brain regions may explain the development of tolerance to these same side effects. The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders. Understanding the topography of serotonin receptor subtypes in discrete anatomical pathways may enhance our understanding of both the therapeutic actions and side effects of these important pharmaceutical agents.
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Higher SSRI plasma levels before cessation and just after cessation predict increased withdrawal symptoms.
“Higher SSRI plasma levels before cessation 58 and just after cessation 59 predict increased withdrawal symptoms.”
From Tapering of SSRI treatment to mitigate withdrawal symptoms (2019) · cites this paper as [59]
Many antidepressant users experience side effects such as restlessness, nausea, vomiting, anxiety, insomnia, sexual dysfunction, gastrointestinal cramps and diarrhea, and headaches.
“Further, many antidepressant users also experience side effects such as restlessness, nausea, vomiting, anxiety, insomnia, sexual dysfunction, gastrointestinal cramps and diarrhea, and headaches that can make the arduous process of searching for effective treatments even harder [62].”
From Effect of fecal microbiota transplant on symptoms of psychiatric disorders: a systematic review (2020) · cites this paper as [62]
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“…of antidepressants are present only after weeks of daily dosing, involvement of several mechanisms has been posited, such as effects on downstream gene transcription, synaptogenesis , inflammation, and the hypothalamic-pituitary-adrenal axis (Malberg and Schechter 2005; Stahl 1998; Walker 2013).”
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- Authors
- Stahl, S. M.
- Corresponding author
- Stahl, Stephen M.
- ORCID
- Stahl, Stephen M.
- Venue
- Journal of Affective Disorders
- Publisher
- Elsevier BV
- Published
- 1998-12
- Volume
- 51
- Issue
- 3
- Pages
- 215-235
- ISSN
- 0165-0327 (ISSN-L)
- OpenAlex
- W2019939591
- Cited by
- 540
- References
- 97
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 26 · 2023: 20 · 2022: 25 · 2021: 27 · 2020: 21 · 2019: 33 · 2018: 27 · 2017: 30 · 2016: 28 · 2015: 15 · 2014: 22 · 2013: 22 · 2012: 19
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Affective Disorders (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01mh045787-02)
- National Institute of Mental Health (5 RO1 MH45787-02, MH30914)
- National Center for Research Resources (MO1 RR00827, M01RR000827)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- selective serotonin reuptake inhibitors, serotonin transporter, negative allosteric modulation, serotonin receptor subtypes, 5-HT1A autoreceptors, receptor desensitization, adverse drug reactions, antidepressant mechanism, depression, obsessive-compulsive disorder, panic disorder, bulimia nervosa, midbrain raphe
- MeSH terms
- Mental Disorders, Bulimia, Depressive Disorder, Humans, Mesencephalon, Neural Pathways, Obsessive-Compulsive Disorder, Raphe Nuclei, Receptors, Serotonin, Serotonin, Down-Regulation, Panic Disorder, Selective Serotonin Reuptake Inhibitors, Autoreceptors
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