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The Serotonin 1A (5-HT1A) Receptor as a Pharmacological Target in Depression

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Abstract

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT1A) receptor in the pathophysiology of depression. Stimulation of the 5-HT1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT1A ‘biased agonism’, using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT1A biased agonists.

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Authors and Affiliations

  1. Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK

    Alexander L. W. Smith, Catherine J. Harmer, Philip J. Cowen & Susannah E. Murphy

  2. Oxford Health NHS Foundation Trust, Oxford, UK

    Alexander L. W. Smith, Catherine J. Harmer, Philip J. Cowen & Susannah E. Murphy

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Correspondence to Susannah E. Murphy.

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Funding

AS is funded by a Wellcome Trust Clinical Doctoral Fellowship, grant reference 102176/B/13/Z. This research was supported the NIHR Oxford Health Biomedical Research Centre and an Oxford University John Fell Fund grant. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. 

Conflicts of Interest

CJH has received consultancy fees from P1vital Ltd., Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways and Lundbeck. SEM has received consultancy fees from Zogenix, Sumitomo Dainippon Pharma, P1vital Ltd. and Janssen Pharmaceuticals. CJH and SEM hold grant income from Zogenix, UCB Pharma, Syndesi and Janssen Pharmaceuticals. CJH and PJC hold grant income from a collaborative research project with Pfizer and the MRC. The authors are currently conducting an experimental medicine study using NLX-101, which has been gifted by Neurolixis.

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ALWS, CJH, PJC and SEM were all involved in drafting and revising the manuscript. All authors have read and approved the final article.

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Smith, A.L.W., Harmer, C.J., Cowen, P.J. et al. The Serotonin 1A (5-HT1A) Receptor as a Pharmacological Target in Depression. CNS Drugs 37, 571–585 (2023). https://doi.org/10.1007/s40263-023-01014-7

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