{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T11:03:46Z","timestamp":1793271826209,"version":"4.5.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Fujita Health University School of Medicine Research Grant"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>In order to appraise the risk-benefit balance of the three available dual orexin receptor antagonists (DORAs; daridorexant, lemborexant, and suvorexant) for the management of adults with insomnia, we conducted a systematic review and random-effects model network meta-analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Included were all published double-blind, randomized, placebo-controlled trials of these agents. Outcomes included subjective time to sleep onset at month 1 (sTSO, primary), subjective total sleep time at month 1 (sTST, co-primary), subjective wake after sleep onset at month 1, Insomnia Severity Index scores at month 1, all-cause discontinuation, discontinuation due to adverse events, and the incidence of individual adverse events such as somnolence, dizziness, falls, headache, nasopharyngitis, and upper respiratory tract infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>This meta-analysis included eight trials (5198 adults, average age\u2009=\u200956.33 years, 67.84% female). The treatment arms included daridorexant 25\u2009mg\/day (DAR25), daridorexant 50\u2009mg\/day (DAR50), lemborexant 5\u2009mg\/day (LEM5), lemborexant 10\u2009mg\/day (LEM10), suvorexant 20\u2009mg\/day (15\u2009mg\/day for people \u226565years, SUV20\/15), and placebo. All active-treatments outperformed placebo in terms of all efficacy outcomes. The standardized mean difference (95% CI) in primary outcomes ranged from; sTSO: \u22120.430 (\u22120.568, \u22120.292) for LEM10 to \u22120.164 (\u22120.296, \u22120.031) for SUV20\/15 and sTST: \u22120.475 (\u22120.593, \u22120.357) for DRA50 to \u22120.206 (\u2009\u22120.330, \u22120.082) for LEM5. An additional sensitivity analysis suggested that DRA25, LEM10, and SUV20\/15 were associated with a higher incidence of somnolence compared to a placebo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Considering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41398-025-03439-8","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T02:03:55Z","timestamp":1750730635000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9237-2236","authenticated-orcid":false,"given":"Taro","family":"Kishi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0848-302X","authenticated-orcid":false,"given":"Toshikazu","family":"Ikuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-9266","authenticated-orcid":false,"given":"Leslie","family":"Citrome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Sakuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Hatano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Hamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasufumi","family":"Nishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3189-6076","authenticated-orcid":false,"given":"Nakao","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"3439_CR1","doi-asserted-by":"publisher","first-page":"215013272110140","DOI":"10.1177\/21501327211014084","volume":"12","author":"ML Perlis","year":"2021","unstructured":"Perlis ML, Pigeon WR, Grandner MA, Bishop TM, Riemann D, Ellis JG, et al. Why treat insomnia? J Prim Care Community Health. 2021;12:21501327211014084.","journal-title":"J Prim Care Community Health"},{"key":"3439_CR2","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/S0140-6736(22)00879-0","volume":"400","author":"ML Perlis","year":"2022","unstructured":"Perlis ML, Posner D, Riemann D, Bastien CH, Teel J, Thase M. Insomnia. Lancet. 2022;400:1047\u201360.","journal-title":"Lancet"},{"key":"3439_CR3","doi-asserted-by":"publisher","first-page":"zsae122","DOI":"10.1093\/sleep\/zsae122","volume":"47","author":"L Fang","year":"2024","unstructured":"Fang L, Lyu Z, Ai S, Du S, Zhou W, Zeng S, et al. Is cognitive behavioral therapy for insomnia more cost-effective? new-perspective on economic evaluations: a systematic review and meta-analysis. Sleep. 2024;47:zsae122.","journal-title":"Sleep"},{"key":"3439_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-024-03087-4","volume":"14","author":"T Kishi","year":"2024","unstructured":"Kishi T, Koebis M, Sugawara M, Kawatsu Y, Taninaga T, Iwata N. Orexin receptor antagonists in the treatment of insomnia associated with psychiatric disorders: a systematic review. Transl Psychiatry. 2024;14:374.","journal-title":"Transl Psychiatry"},{"key":"3439_CR5","doi-asserted-by":"publisher","unstructured":"Hillman D, Mitchell S, Streatfeild J, Burns C, Bruck D, Pezzullo L. The economic cost of inadequate sleep. Sleep 2018;41. https:\/\/doi.org\/10.1093\/sleep\/zsy083.","DOI":"10.1093\/sleep\/zsy083"},{"key":"3439_CR6","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1002\/npr2.12205","volume":"41","author":"T Kishi","year":"2021","unstructured":"Kishi T, Nishida M, Koebis M, Taninaga T, Muramoto K, Kubota N, et al. Evidence-based insomnia treatment strategy using novel orexin antagonists: a review. Neuropsychopharmacol Rep. 2021;41:450\u20138.","journal-title":"Neuropsychopharmacol Rep"},{"key":"3439_CR7","doi-asserted-by":"crossref","unstructured":"Reuben C, Elgaddal N, Black LI. Sleep medication use in adults aged 18 and over: United States, 2020. NCHS Data Brief. 2023:1\u20138. https:\/\/pubmed.ncbi.nlm.nih.gov\/36700855\/.","DOI":"10.15620\/cdc:123013"},{"key":"3439_CR8","doi-asserted-by":"publisher","first-page":"2549","DOI":"10.2147\/NDT.S297504","volume":"17","author":"R Rosenberg","year":"2021","unstructured":"Rosenberg R, Citrome L, Drake CL. Advances in the treatment of chronic insomnia: a narrative review of new nonpharmacologic and pharmacologic therapies. Neuropsychiatr Dis Treat. 2021;17:2549\u201366.","journal-title":"Neuropsychiatr Dis Treat"},{"key":"3439_CR9","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/S0140-6736(22)00878-9","volume":"400","author":"F De Crescenzo","year":"2022","unstructured":"De Crescenzo F, D\u2019Alo GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, et al. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. Lancet. 2022;400:170\u201384.","journal-title":"Lancet"},{"key":"3439_CR10","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1056\/NEJMra1611832","volume":"376","author":"M Soyka","year":"2017","unstructured":"Soyka M. Treatment of benzodiazepine dependence. N Engl J Med. 2017;376:1147\u201357.","journal-title":"N Engl J Med"},{"key":"3439_CR11","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/s00213-002-1376-8","volume":"167","author":"C de las Cuevas","year":"2003","unstructured":"de las Cuevas C, Sanz E, de la Fuente J. Benzodiazepines: more \u201cbehavioural\u201d addiction than dependence. Psychopharmacology. 2003;167:297\u2013303.","journal-title":"Psychopharmacology"},{"key":"3439_CR12","doi-asserted-by":"publisher","first-page":"152","DOI":"10.18773\/austprescr.2015.055","volume":"38","author":"J Brett","year":"2015","unstructured":"Brett J, Murnion B. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015;38:152\u20135.","journal-title":"Aust Prescr"},{"key":"3439_CR13","unstructured":"FDA. U.S. Food and Drug Administration. https:\/\/www.fda.gov\/. Accessed 21 September 2024."},{"key":"3439_CR14","unstructured":"PMDA. Pharmaceuticals and Medical Devices Agency. https:\/\/www.pmda.go.jp\/english\/. Accessed 21 September 2024."},{"key":"3439_CR15","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.1111\/jgs.18372","volume":"71","author":"By the American Geriatrics Society Beers Criteria Update Expert P.","year":"2023","unstructured":"By the American Geriatrics Society Beers Criteria Update Expert P. American Geriatrics Society 2023 updated AGS Beers Criteria(R) for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71:2052\u201381.","journal-title":"J Am Geriatr Soc"},{"key":"3439_CR16","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.jpsychires.2020.05.025","volume":"128","author":"T Kishi","year":"2020","unstructured":"Kishi T, Nomura I, Matsuda Y, Sakuma K, Okuya M, Ikuta T, et al. Lemborexant vs suvorexant for insomnia: a systematic review and network meta-analysis. J Psychiatr Res. 2020;128:68\u201374.","journal-title":"J Psychiatr Res"},{"key":"3439_CR17","doi-asserted-by":"publisher","first-page":"20m13795","DOI":"10.4088\/JCP.20m13795","volume":"82","author":"L Citrome","year":"2021","unstructured":"Citrome L, Juday T, Frech F, Atkins N Jr. Lemborexant for the treatment of insomnia: direct and indirect comparisons with other hypnotics using number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Clin Psychiatry. 2021;82:20m13795.","journal-title":"J Clin Psychiatry"},{"key":"3439_CR18","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1080\/00325481.2024.2359891","volume":"136","author":"FX Chalet","year":"2024","unstructured":"Chalet FX, Luyet PP, Rabasa C, Vaillant C, Saskin P, Ahuja A, et al. Daridorexant for patients with chronic insomnia disorder: number needed to treat, number needed to harm, and likelihood to be helped or harmed. Postgrad Med. 2024;136:396\u2013405.","journal-title":"Postgrad Med"},{"key":"3439_CR19","unstructured":"EMA. European Medicines. https:\/\/www.ema.europa.eu\/en\/homepage. Accessed 21 September 2024."},{"key":"3439_CR20","doi-asserted-by":"publisher","first-page":"777","DOI":"10.7326\/M14-2385","volume":"162","author":"B Hutton","year":"2015","unstructured":"Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162:777\u201384.","journal-title":"Ann Intern Med"},{"key":"3439_CR21","unstructured":"Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024). Cochrane, 2024. Available from https:\/\/www.training.cochrane.org\/handbook."},{"key":"3439_CR22","doi-asserted-by":"publisher","first-page":"1175372","DOI":"10.3389\/fphar.2023.1175372","volume":"14","author":"T Xue","year":"2023","unstructured":"Xue T, Wu X, Li J, Chen S, Wang Z, Tan X, et al. Different doses of dual orexin receptor antagonists in primary insomnia: a Bayesian network analysis. Front Pharmacol. 2023;14:1175372.","journal-title":"Front Pharmacol"},{"key":"3439_CR23","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1055\/s-0043-1768667","volume":"81","author":"RB Rocha","year":"2023","unstructured":"Rocha RB, Bomtempo FF, Nager GB, Cenci GI, Telles JPM. Dual orexin receptor antagonists for the treatment of insomnia: systematic review and network meta-analysis. Arq Neuropsiquiatr. 2023;81:475\u201383.","journal-title":"Arq Neuropsiquiatr"},{"key":"3439_CR24","doi-asserted-by":"publisher","first-page":"zsad293","DOI":"10.1093\/sleep\/zsad293","volume":"47","author":"HJ Na","year":"2024","unstructured":"Na HJ, Jeon N, Staatz CE, Han N, Baek IH. Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis. Sleep. 2024;47:zsad293.","journal-title":"Sleep"},{"key":"3439_CR25","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/S1389-9457(00)00065-4","volume":"2","author":"CH Bastien","year":"2001","unstructured":"Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2:297\u2013307.","journal-title":"Sleep Med"},{"key":"3439_CR26","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","volume":"7","author":"R DerSimonian","year":"1986","unstructured":"DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials. 1986;7:177\u201388.","journal-title":"Controlled Clin Trials"},{"key":"3439_CR27","unstructured":"R\u00fccker G, Schwarzer G, Krahn U, K\u00f6nig J. netmeta: network meta-analysis using frequentist methods (R package version 0.9\u20135). 2017. https:\/\/cran.r-project.org\/web\/packages\/netmeta\/index.html. Accessed 21 Sept 2024."},{"key":"3439_CR28","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1002\/sim.3767","volume":"29","author":"S Dias","year":"2010","unstructured":"Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29:932\u201344.","journal-title":"Stat Med"},{"key":"3439_CR29","doi-asserted-by":"publisher","first-page":"3639","DOI":"10.1002\/sim.6188","volume":"33","author":"D Jackson","year":"2014","unstructured":"Jackson D, Barrett JK, Rice S, White IR, Higgins JP. A design-by-treatment interaction model for network meta-analysis with random inconsistency effects. Stat Med. 2014;33:3639\u201354.","journal-title":"Stat Med"},{"key":"3439_CR30","doi-asserted-by":"publisher","first-page":"130","DOI":"10.7326\/0003-4819-159-2-201307160-00008","volume":"159","author":"A Cipriani","year":"2013","unstructured":"Cipriani A, Higgins JP, Geddes JR, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. 2013;159:130\u20137.","journal-title":"Ann Intern Med"},{"key":"3439_CR31","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/wps.20972","volume":"21","author":"G Ostuzzi","year":"2022","unstructured":"Ostuzzi G, Bertolini F, Tedeschi F, Vita G, Brambilla P, Del Fabro L, et al. Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants. World Psychiatry. 2022;21:295\u2013307.","journal-title":"World Psychiatry"},{"key":"3439_CR32","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1002\/jrsm.1054","volume":"3","author":"G van Valkenhoef","year":"2012","unstructured":"van Valkenhoef G, Lu G, de Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta-analysis. Res Synth Methods. 2012;3:285\u201399.","journal-title":"Res Synth Methods"},{"key":"3439_CR33","doi-asserted-by":"publisher","first-page":"zsaa123","DOI":"10.1093\/sleep\/zsaa123","volume":"43","author":"M Karppa","year":"2020","unstructured":"Karppa M, Yardley J, Pinner K, Filippov G, Zammit G, Moline M, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep. 2020;43:zsaa123.","journal-title":"Sleep"},{"key":"3439_CR34","doi-asserted-by":"publisher","first-page":"e99682","DOI":"10.1371\/journal.pone.0099682","volume":"9","author":"G Salanti","year":"2014","unstructured":"Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JP. Evaluating the quality of evidence from a network meta-analysis. PLoS ONE. 2014;9:e99682.","journal-title":"PLoS ONE"},{"key":"3439_CR35","doi-asserted-by":"publisher","first-page":"e1003082","DOI":"10.1371\/journal.pmed.1003082","volume":"17","author":"A Nikolakopoulou","year":"2020","unstructured":"Nikolakopoulou A, Higgins JPT, Papakonstantinou T, Chaimani A, Del Giovane C, Egger M, et al. CINeMA: an approach for assessing confidence in the results of a network meta-analysis. PLoS Med. 2020;17:e1003082.","journal-title":"PLoS Med"},{"key":"3439_CR36","doi-asserted-by":"publisher","first-page":"e1080","DOI":"10.1002\/cl2.1080","volume":"16","author":"T Papakonstantinou","year":"2020","unstructured":"Papakonstantinou T, Nikolakopoulou A, Higgins JPT, Egger M, Salanti G. CINeMA: Software for semiautomated assessment of the confidence in the results of network meta-analysis. Campbell Syst Rev. 2020;16:e1080.","journal-title":"Campbell Syst Rev"},{"key":"3439_CR37","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/ana.25680","volume":"87","author":"Y Dauvilliers","year":"2020","unstructured":"Dauvilliers Y, Zammit G, Fietze I, Mayleben D, Seboek Kinter D, Pain S, et al. Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder. Ann Neurol. 2020;87:347\u201356.","journal-title":"Ann Neurol"},{"key":"3439_CR38","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S1474-4422(21)00436-1","volume":"21","author":"E Mignot","year":"2022","unstructured":"Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CLA, et al. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022;21:125\u201339.","journal-title":"Lancet Neurol"},{"key":"3439_CR39","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.sleep.2024.07.037","volume":"122","author":"N Uchimura","year":"2024","unstructured":"Uchimura N, Taniguchi M, Ariyoshi Y, Oka Y, Togo O, Uchiyama M. Daridorexant in Japanese patients with insomnia disorder: a phase 3, randomized, double-blind, placebo-controlled study. Sleep Med. 2024;122:27\u201334.","journal-title":"Sleep Med"},{"key":"3439_CR40","doi-asserted-by":"publisher","first-page":"e1918254","DOI":"10.1001\/jamanetworkopen.2019.18254","volume":"2","author":"R Rosenberg","year":"2019","unstructured":"Rosenberg R, Murphy P, Zammit G, Mayleben D, Kumar D, Dhadda S, et al. Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial. JAMA Netw Open. 2019;2:e1918254.","journal-title":"JAMA Netw Open"},{"key":"3439_CR41","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.biopsych.2014.10.003","volume":"79","author":"WJ Herring","year":"2016","unstructured":"Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry. 2016;79:136\u201348.","journal-title":"Biol Psychiatry"},{"key":"3439_CR42","unstructured":"APA. Diagnostic and statistical manual of mental disorders, DSM-5 in 2013, DSM-IV-TR in 2000, Washington, DC: American Psychiatric Association."},{"key":"3439_CR43","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1007\/s40261-018-0650-4","volume":"38","author":"KL Yee","year":"2018","unstructured":"Yee KL, McCrea J, Panebianco D, Liu W, Lewis N, Cabalu T, et al. Safety, tolerability, and pharmacokinetics of suvorexant: a randomized rising-dose trial in healthy men. Clin Drug Investig. 2018;38:631\u20138.","journal-title":"Clin Drug Investig"},{"key":"3439_CR44","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.euroneuro.2019.05.009","volume":"29","author":"C Muehlan","year":"2019","unstructured":"Muehlan C, Brooks S, Zuiker R, van Gerven J, Dingemanse J. Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration. Eur Neuropsychopharmacol. 2019;29:847\u201357.","journal-title":"Eur Neuropsychopharmacol"},{"key":"3439_CR45","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1097\/JCP.0000000000001182","volume":"40","author":"C Muehlan","year":"2020","unstructured":"Muehlan C, Zuiker R, Peeters P, Rowles R, Dingemanse J. Pharmacokinetics and pharmacodynamics of the dual orexin receptor antagonist daridorexant in japanese and caucasian subjects. J Clin Psychopharmacol. 2020;40:157\u201366.","journal-title":"J Clin Psychopharmacol"},{"key":"3439_CR46","doi-asserted-by":"publisher","first-page":"e202300030","DOI":"10.1002\/cmdc.202300030","volume":"18","author":"A Treiber","year":"2023","unstructured":"Treiber A, Aissaoui H, Delahaye S, Glutz S, Grimont J, Muller C, et al. CYP3A4 catalyzes the rearrangement of the dual orexin receptor antagonist daridorexant to 4-hydroxypiperidinol metabolites. ChemMedChem. 2023;18:e202300030.","journal-title":"ChemMedChem"},{"key":"3439_CR47","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1517\/17425250903379546","volume":"6","author":"MA Perera","year":"2010","unstructured":"Perera MA. The missing linkage: what pharmacogenetic associations are left to find in CYP3A? Expert Opin Drug Metab Toxicol. 2010;6:17\u201328.","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"3439_CR48","doi-asserted-by":"publisher","first-page":"912618","DOI":"10.3389\/fphar.2022.912618","volume":"13","author":"Q Zhai","year":"2022","unstructured":"Zhai Q, van der Lee M, van Gelder T, Swen JJ. Why we need to take a closer look at genetic contributions to CYP3A activity. Front Pharmacol. 2022;13:912618.","journal-title":"Front Pharmacol"},{"key":"3439_CR49","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2133\/dmpk.DMPK-11-RV-111","volume":"27","author":"K Kurose","year":"2012","unstructured":"Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics\/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet. 2012;27:9\u201354.","journal-title":"Drug Metab Pharmacokinet"},{"key":"3439_CR50","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.sleep.2023.08.010","volume":"110","author":"AR Willoughby","year":"2023","unstructured":"Willoughby AR, Alikhani I, Karsikas M, Chua XY, Chee MWL. Country differences in nocturnal sleep variability: observations from a large-scale, long-term sleep wearable study. Sleep Med. 2023;110:155\u201365.","journal-title":"Sleep Med"},{"key":"3439_CR51","doi-asserted-by":"publisher","first-page":"e14302","DOI":"10.1111\/jsr.14302","volume":"34","author":"M Uchiyama","year":"2024","unstructured":"Uchiyama M, Mishima K, Yagi T, Yoshihara T, Eto T, Muehlan C, et al. Pharmacokinetics, safety, and efficacy of daridorexant in Japanese subjects: results from phase 1 and 2 studies. J Sleep Res. 2024;34:e14302.","journal-title":"J Sleep Res"},{"key":"3439_CR52","first-page":"371.e311","volume":"19","author":"LJ Seppala","year":"2018","unstructured":"Seppala LJ, Wermelink A, de Vries M, Ploegmakers KJ, van de Glind EMM, Daams JG, et al. Fall-risk-increasing drugs: a systematic review and meta-analysis: II. Psychotropics. J Am Med Dir Assoc. 2018;19:371.e311\u20137.","journal-title":"J Am Med Dir Assoc"},{"key":"3439_CR53","first-page":"225","volume":"162","author":"AM Holbrook","year":"2000","unstructured":"Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162:225\u201333.","journal-title":"CMAJ"}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03439-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03439-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03439-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T14:02:43Z","timestamp":1750773763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-025-03439-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,24]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3439"],"URL":"https:\/\/doi.org\/10.1038\/s41398-025-03439-8","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,24]]},"assertion":[{"value":"25 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All authors have no competing interests to declare concerning this study. They also declare any potential competing interests that have arisen in the last 3 years. Prof. Kishi has received speaker\u2019s honoraria from Eisai, Janssen, Boehringer Ingelheim, Meiji, Otsuka, Sumitomo, Takeda, Mitsubishi-Tanabe, Kyowa, Yoshitomi, and Viatris and research grants from Eisai, a Fujita Health University School of Medicine Research Grant, JSPS KAKENHI (19K08082 and 23K06998), Japan Agency for Medical Research and Development (JP22dk0307107, JP22wm0525024, JP23dk0307122, and 24dk0307129), and the Japanese Ministry of Health, Labour and Welfare (21GC1018). Dr. Ikuta has nothing to disclose. Prof. Citrome serves as consultant to AbbVie\/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Bristol-Myers Squibb \/Karuna, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Lundbeck, Luye, Lyndra, MapLight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo\/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals\/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie\/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Bristol-Myers Squibb, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations\/Societies; owns stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago, stock options: Reviva; and receives royalties\/publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). Dr. Sakuma has received speaker\u2019s honoraria from daiichisankyo, Eisai, Janssen, Kyowa, Meiji, Otsuka, Sumitomo, and Takeda and has received a Fujita Health University School of Medicine Research Grant for Early-Career Scientists, Grant-in-Aid for Young Scientists (B)(19K17099), Grant-in-Aid for Scientific Research (C)(23K06998), and Japan Agency for Medical Research and Development (JP22dk0307107 and JP23dk0307122). Dr. Hatano received the speaker\u2019s honoraria from Meiji and Sumitomo, and has received Grant-in-Aid for Early-Career Scientists (23K14827). Dr. Hamanaka has received speaker\u2019s honoraria from Meiji, Otsuka, and Sumitomo. Dr. Nishii has received speaker\u2019s honoraria from Meiji, Otsuka, and Sumitomo. Prof. Iwata has received speaker\u2019s honoraria from Eisai, Janssen, Meiji, Otsuka, Sumitomo, Takeda, Mitsubishi-Tanabe, and Viatris and research grants from Daiichi Sankyo, Eisai, Meiji, Otsuka, Sumitomo, Takeda, Tanabe-Mitsubishi, Grant-in-Aid for Scientific Research (B)(22H03003), and Japan Agency for Medical Research and Development (JP22wm0425008).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"211"}}