Orexin receptor antagonists in the treatment of depression: A leading article summarising pre-clinical and clinical studies
Orexin receptor antagonists in the treatment of depression: A leading article summarising pre-clinical and clinical studies
The orexin (hypocretin) system comprises two neuropeptides (orexin-A and orexin-B) and two G-protein coupled receptors (the orexin type 1 and the orexin type 2 receptor). The system regulates several biological functions including appetite, the sleep–wake cycle, the stress response, and motivation and reward processing. Dysfunction of the orexin system has been implicated in the pathophysiology of depression in human and animal studies, although the exact nature of this dysfunction remains unclear. Orexin receptor antagonists (ORAs) are a class of compounds developed for the treatment of insomnia and have demonstrated efficacy in this area. Three dual orexin receptor antagonists (DORAs) have received licences for treatment of primary insomnia and some ORAs have since been investigated as potential treatments for major depressive disorder (MDD). In this leading article, we summarise the existing literature on use of ORAs in depression, in pre-clinical and clinical studies. In rodent models of depression, investigated ORAs have included the DORA almorexant and TCS1102, the selective orexin 1 receptor antagonists SB334867 and SB674042 and the selective orexin 2 receptor antagonists LSN2424100, MK-1064 and TCS-OX2-29. These pre-clinical studies suggest a possible antidepressant effect of systemic DORA treatment, however the evidence from selective ORAs is conflicting. To date, four published RCTs (one with the DORA filorexant and three with the selective orexin 2 receptor antagonist seltorexant), have compared an ORA with placebo in the treatment of MDD. Only one of these demonstrated a statistically significant difference relative to placebo.
1-12
Fagan, Harry
b1cc5180-6929-4e27-8cae-1d123fdd0b6a
Jones, Edward
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Baldwin, David S.
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27 November 2022
Fagan, Harry
b1cc5180-6929-4e27-8cae-1d123fdd0b6a
Jones, Edward
26d679ea-0235-4bf6-b7e9-dc46ce972fdb
Baldwin, David S.
1beaa192-0ef1-4914-897a-3a49fc2ed15e
Fagan, Harry, Jones, Edward and Baldwin, David S.
(2022)
Orexin receptor antagonists in the treatment of depression: A leading article summarising pre-clinical and clinical studies.
CNS drugs, 37 (1), .
(doi:10.1007/s40263-022-00974-6).
Abstract
The orexin (hypocretin) system comprises two neuropeptides (orexin-A and orexin-B) and two G-protein coupled receptors (the orexin type 1 and the orexin type 2 receptor). The system regulates several biological functions including appetite, the sleep–wake cycle, the stress response, and motivation and reward processing. Dysfunction of the orexin system has been implicated in the pathophysiology of depression in human and animal studies, although the exact nature of this dysfunction remains unclear. Orexin receptor antagonists (ORAs) are a class of compounds developed for the treatment of insomnia and have demonstrated efficacy in this area. Three dual orexin receptor antagonists (DORAs) have received licences for treatment of primary insomnia and some ORAs have since been investigated as potential treatments for major depressive disorder (MDD). In this leading article, we summarise the existing literature on use of ORAs in depression, in pre-clinical and clinical studies. In rodent models of depression, investigated ORAs have included the DORA almorexant and TCS1102, the selective orexin 1 receptor antagonists SB334867 and SB674042 and the selective orexin 2 receptor antagonists LSN2424100, MK-1064 and TCS-OX2-29. These pre-clinical studies suggest a possible antidepressant effect of systemic DORA treatment, however the evidence from selective ORAs is conflicting. To date, four published RCTs (one with the DORA filorexant and three with the selective orexin 2 receptor antagonist seltorexant), have compared an ORA with placebo in the treatment of MDD. Only one of these demonstrated a statistically significant difference relative to placebo.
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Final manuscript CNS Drugs Oct 2022 re-submission fresh manuscript
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Fagan Jones Baldwin (2023) CNS Drugs
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Accepted/In Press date: 2 November 2022
Published date: 27 November 2022
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Funding Information:
No specific funding was provided for the publication of this article. HF was supported in this work by the University of Southampton National Institute of Health Research Academic Foundation Programme (August 2019–August 2021).
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© 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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Local EPrints ID: 475257
URI: http://eprints.soton.ac.uk/id/eprint/475257
ISSN: 1172-7047
PURE UUID: ccc1cc1c-8202-426f-9cfb-0a79a606c539
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Date deposited: 14 Mar 2023 17:53
Last modified: 18 Mar 2024 05:30
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Harry Fagan
Author:
Edward Jones
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