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dc.contributor.authorBrowning, Michael
dc.date.accessioned2023-08-10T11:26:34Z
dc.date.available2023-08-10T11:26:34Z
dc.date.issued2023-07
dc.identifier.citationCharacterization of the central nervous system penetrant and selective purine P2X7 receptor antagonist JNJ-54175446 in patients with major depressive disorder Kasper Recourt, Peter de Boer, Peter van der Ark, Heike Benes, Joop M. A. van Gerven, Marc Ceusters, Luc van Nueten, Wayne C. Drevets, Anindya Bhatacharya, Michael Browning & Gabriel E. Jacobs Translational Psychiatry volume 13, Article number: 266 (2023)en
dc.identifier.urihttps://oxfordhealth-nhs.archive.knowledgearc.net/handle/123456789/1294
dc.descriptionOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en
dc.description.abstractJNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1β/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1β release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1–3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).en
dc.description.urihttps://doi.org/10.1038/s41398-023-02557-5en
dc.language.isoenen
dc.subjectDepressive Disordersen
dc.titleCharacterization of the central nervous system penetrant and selective purine P2X7 receptor antagonist JNJ-54175446 in patients with major depressive disorderen
dc.typeArticleen


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