{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:42:24Z","timestamp":1788838944587,"version":"build-2803163510"},"reference-count":54,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:00Z","timestamp":1760140800000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain and Behavior"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Narcolepsy Type 1 (NT1) is a chronic neurological disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and REM intrusions, caused by a deficiency of orexin (hypocretin), a hypothalamic neuropeptide essential for arousal, REM sleep regulation, metabolism, and emotional stability. This review synthesizes and critically analyzes the pathophysiological, clinical, and therapeutic dimensions of orexin deficiency in narcolepsy, with particular emphasis on recent advances from 2023 to 2025.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This narrative analytical review analyzed 50 peer\u2010reviewed publications covering the neurobiology of the orexin system, diagnostic evolution of NT1, comparative symptomatology of central hypersomnia disorders, and recent therapeutic innovations. Out of which 16 studies were selected based on relevance, recency, and translational impact.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Recent research confirms that over 90% of NT1 patients exhibit cerebrospinal fluid (CSF) orexin\u2010A levels below 110 pg\/mL and carry the HLA\u2010DQB1*06:02 allele, indicating a strong genetic and immunological association. Postmortem analyses have revealed a loss of up to 95% of orexin\u2010producing neurons in the lateral hypothalamus. In a 2024 multicenter trial, danavorexton (a selective orexin receptor\u20102 [OX2R] agonist) was associated with a mean improvement of 11.1 points on the Maintenance of Wakefulness Test, outperforming modafinil and suggesting the feasibility of receptor\u2010level restoration. In addition, intermediate orexin levels (110\u2013200 pg\/mL) have been documented in a subset of patients with narcolepsy Type 2 (NT2) and idiopathic hypersomnia (IH), challenging the binary diagnostic threshold and prompting reevaluation of orexin's diagnostic role. Orexin dysfunction has also been correlated with high psychiatric comorbidity rates, including major depressive disorder in 40% and anxiety disorders in nearly 30% of NT1 patients. These manifestations reflect orexin's broader role in regulating REM sleep, metabolic processes, and autonomic stability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Orexin deficiency remains the central mechanism underlying NT1, with far\u2010reaching implications in psychiatric and neurodegenerative disease. While emerging orexin\u2010targeted therapies offer promising disease\u2010modifying potential, critical challenges persist in standardizing biomarkers, resolving NT2 classification ambiguities, and ensuring global access to therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/brb3.70984","type":"journal-article","created":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:13:06Z","timestamp":1760242386000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Orexin Deficiency in Narcolepsy: Molecular Mechanisms, Clinical Phenotypes, and Emerging Therapeutic Frontiers"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1007-7182","authenticated-orcid":false,"given":"Rameesha","family":"Rauf","sequence":"first","affiliation":[{"name":"Tbilisi State Medical University  Tbilisi 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Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3970-0914","authenticated-orcid":false,"given":"Maryam Muhammad","family":"Nadeem","sequence":"additional","affiliation":[{"name":"Nantong Medical University  Nantong City China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1502-1714","authenticated-orcid":false,"given":"Zohra Kamran","family":"Rao","sequence":"additional","affiliation":[{"name":"Tbilisi State University  Tbilisi Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4724-3810","authenticated-orcid":false,"given":"Aliya Shaju Shahul","family":"Hameed","sequence":"additional","affiliation":[{"name":"East European University  Tbilisi Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7091-1268","authenticated-orcid":false,"given":"Karthik","family":"Chintharala","sequence":"additional","affiliation":[{"name":"NRI Academy of Medical Sciences  Guntur India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9250-4001","authenticated-orcid":false,"given":"Muhammad Faheem","family":"Anwar","sequence":"additional","affiliation":[{"name":"Tbilisi State Medical University  Tbilisi Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4664-591X","authenticated-orcid":false,"given":"Asad Ali Ahmed","family":"Cheema","sequence":"additional","affiliation":[{"name":"International School of Medicine International University of Kyrgyzstan  Bishkek 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Neurobiological Basis of Narcolepsy","volume":"48","author":"Mahoney C. 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