Tackling obstructive sleep apnea with pharmacotherapeutics: expert guidance

References

• Malhotra A, White DP. Obstructive sleep apnoea. Lancet. 2002 Jul 20;360(9328):237–245. doi: 10.1016/S0140-6736(02)09464-3
   PubMed Web of Science ®Google Scholar
• Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019 Aug;7(8):687–698. doi: 10.1016/S2213-2600(19)30198-5
   PubMed Web of Science ®Google Scholar
• Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA. 2004 Apr 28;291(16):2013–2016. doi: 10.1001/jama.291.16.2013
   PubMed Web of Science ®Google Scholar
• Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010 Jul 27;122(4):352–360. doi: 10.1161/CIRCULATIONAHA.109.901801
   PubMed Web of Science ®Google Scholar
• Lal C, Strange C, Bachman D. Neurocognitive impairment in obstructive sleep apnea. Chest. 2012;141(6):1601–1610. doi: 10.1378/chest.11-2214
   PubMed Web of Science ®Google Scholar
• Djonlagic IE, Guo M, Igue M, et al. Continuous positive airway pressure restores declarative memory deficit in obstructive sleep apnea. Am J Respir Crit Care Med. 2021 May 1;203(9):1188–1190. doi: 10.1164/rccm.202011-4253LE
   PubMed Web of Science ®Google Scholar
• Sterling KL, Alpert N, Cistulli PA, et al. Healthcare resource utilisation and costs in patients with treated obstructive sleep apnea. J Sleep Res. 2023 Nov;14:e14099. doi: 10.1111/jsr.14099
   Google Scholar
• Lin CM, Huang YS, Guilleminault C. Pharmacotherapy of obstructive sleep apnea. Expert Opin Pharmacother. 2012 Apr;13(6):841–857. doi: 10.1517/14656566.2012.666525
   PubMed Web of Science ®Google Scholar
• Hudgel DW. Pharmacologic treatment of obstructive sleep apnea. [Review] [66 refs]. J Lab Clin Med. 1995;126(1):13–18.
   PubMed Web of Science ®Google Scholar
• Schweitzer PK, Taranto-Montemurro L, Ojile JM, et al. The combination of aroxybutynin and atomoxetine in the treatment of obstructive sleep apnea (MARIPOSA): a randomized controlled trial. Am J Respir Crit Care Med. 2023 Oct 9;208(12):1316–1327. doi: 10.1164/rccm.202306-1036OC.
   PubMed Web of Science ®Google Scholar
• Malhotra A, Bednarik J, Chakladar S, et al. Tirzepatide for the treatment of obstructive sleep apnea: rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial. Contemp Clin Trials. 2024 Mar 26;141:107516. doi: 10.1016/j.cct.2024.107516
   PubMed Web of Science ®Google Scholar
• Perger E, Bertoli S, Lombardi C. Pharmacotherapy for obstructive sleep apnea: targeting specific pathophysiological traits. Expert Rev Respir Med. 2023 Aug 03;17(8):663–673. doi: 10.1080/17476348.2023.2241353
   PubMed Web of Science ®Google Scholar
• Nobre ML, Sarmento ACA, de Oliveira PF, et al. Pharmacological treatment for obstructive sleep apnea: a systematic review and meta-analysis. Clinics. 2024;79:79. doi: 10.1016/j.clinsp.2024.100330
   Web of Science ®Google Scholar
• Jenkinson C, Davies RJ, Mullins R, et al. Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet. 1999;353(9170):2100–2105. doi: 10.1016/S0140-6736(98)10532-9
   PubMed Web of Science ®Google Scholar
• Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet. 1981;317(8225):862–865. doi: 10.1016/S0140-6736(81)92140-1
   Google Scholar
• Patel SR, White DP, Malhotra A, et al. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med. 2003 Mar 10;163(5):565–571. doi: 10.1001/archinte.163.5.565
   PubMedGoogle Scholar
• Pachito DV, Bagattini ÂM, Drager LF, et al. Economic evaluation of CPAP therapy for obstructive sleep apnea: a scoping review and evidence map. Sleep Breathing. 2022 Mar;26(1):17–30. doi: 10.1007/s11325-021-02362-8
   PubMed Web of Science ®Google Scholar
• Ayas NT, FitzGerald JM, Fleetham JA, et al. Cost-effectiveness of continuous positive airway pressure therapy for moderate to severe obstructive sleep apnea/hypopnea. Arch Intern Med. 2006 May 8;166(9):977–984. doi: 10.1001/archinte.166.9.977
   PubMedGoogle Scholar
• Cistulli PA, Armitstead J, Pepin JL, et al. Short-term CPAP adherence in obstructive sleep apnea: a big data analysis using real world data. Sleep Med. 2019 Jul;59:114–116. doi: 10.1016/j.sleep.2019.01.004
   PubMed Web of Science ®Google Scholar
• Drager LF, Malhotra A, Yan Y, et al. Adherence with positive airway pressure therapy for obstructive sleep apnea in developing versus developed countries: a big data study. J Clin Sleep Med. 2021;17(4): 703–709. doi: 10.5664/jcsm.9008
   PubMed Web of Science ®Google Scholar
• Malhotra A, Crocker ME, Willes L, et al. Patient engagement using new technology to improve adherence to positive airway pressure therapy: a retrospective analysis. Chest. 2018 Apr;153(4):843–850. doi: 10.1016/j.chest.2017.11.005
   PubMed Web of Science ®Google Scholar
• Broström A, Nilsen P, Johansson P, et al. Putative facilitators and barriers for adherence to CPAP treatment in patients with obstructive sleep apnea syndrome: a qualitative content analysis. Sleep Med. 2010 Feb;11(2):126–130. doi: 10.1016/j.sleep.2009.04.010
   PubMed Web of Science ®Google Scholar
• Ancoli-Israel S, Klauber MR, Stepnowsky C, et al. Sleep-disordered breathing in African-American elderly. Am J Respir Crit Care Med. 1995;152(6 Pt 1):1946–1949. doi: 10.1164/ajrccm.152.6.8520760
   PubMed Web of Science ®Google Scholar
• Redline S, Young T. Epidemiology and natural history of obstructive sleep apnea. Ear Nose Throat J. 1993;72(1):20–1, 24–6. doi: 10.1177/014556139307200106
   Google Scholar
• Platt AB, Field SH, Asch DA, et al. Neighborhood of residence is associated with daily adherence to CPAP therapy. Sleep. 2009 Jun;32(6):799–806. doi: 10.1093/sleep/32.6.799
   PubMed Web of Science ®Google Scholar
• Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc. 2008 Feb;5(2):173–178. doi: 10.1513/pats.200708-119MG
   PubMedGoogle Scholar
• Engelman H, Wild MR. Improving CPAP use by patients with the sleep apnea/hypopnea syndrome (SAHS). Sleep Med Rev. 2003;7(1):81–99. doi: 10.1053/smrv.2001.0197
   PubMed Web of Science ®Google Scholar
• Lin HS, Zuliani G, Amjad EH, et al. Treatment compliance in patients lost to follow-up after polysomnography. Otolaryngol Head Neck Surg. 2007 Feb;136(2):236–240. doi: 10.1016/j.otohns.2006.08.007
   PubMed Web of Science ®Google Scholar
• Shaw R, McKenzie S, Taylor T, et al. Beliefs and attitudes toward obstructive sleep apnea evaluation and treatment among blacks. J Natl Med Assoc. 2012 Nov;104(11–12):510–519. doi: 10.1016/S0027-9684(15)30217-0
   PubMed Web of Science ®Google Scholar
• Pepin JL, Viot-Blanc V, Escourrou P, et al. Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study. Eur Respir J. 2009 May;33(5):1062–1067. doi: 10.1183/09031936.00016808
   PubMed Web of Science ®Google Scholar
• Schweitzer PK, Mayer G, Rosenberg R, et al. Randomized controlled trial of solriamfetol for excessive daytime sleepiness in OSA: an analysis of subgroups adherent or nonadherent to OSA treatment. Chest. 2021 Feb 22;160(1):307–318. doi: 10.1016/j.chest.2021.02.033
   PubMed Web of Science ®Google Scholar
• Steier JS, Bogan RK, Cano-Pumarega IM, et al. Recommendations for clinical management of excessive daytime sleepiness in obstructive sleep apnoea - a Delphi consensus study. Sleep Med. 2023 Oct 9;112:104–115. doi: 10.1016/j.sleep.2023.10.001
   PubMed Web of Science ®Google Scholar
• Pack AI, Black JE, Schwartz JRL, et al. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med. 2001;164(9):1675–1681. doi: 10.1164/ajrccm.164.9.2103032
   PubMed Web of Science ®Google Scholar
• Castrogiovanni A, Bonsignore MR. May continuous positive airway pressure (CPAP) treatment be detrimental in obstructive sleep apnea? EBioMedicine. 2024 Mar;101:105052–105052. doi: 10.1016/j.ebiom.2024.105052
   PubMed Web of Science ®Google Scholar
• Gottlieb DJ, Lederer DJ, Kim JS, et al. Effect of positive airway pressure therapy of obstructive sleep apnea on circulating Angiopoietin-2. Sleep Med. 2022 Aug;96:119–121. doi: 10.1016/j.sleep.2022.05.007
   PubMed Web of Science ®Google Scholar
• Peker Y, Celik Y, Behboudi A, et al. CPAP may promote an endothelial inflammatory milieu in sleep apnoea after coronary revascularization. EBioMedicine. 2024 Mar;101:105015–105015. doi: 10.1016/j.ebiom.2024.105015
   PubMed Web of Science ®Google Scholar
• Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–719. doi: 10.1093/sleep/30.6.711
   PubMed Web of Science ®Google Scholar
• Sánchez AI, Martínez P, Miró E, et al. CPAP and behavioral therapies in patients with obstructive sleep apnea: effects on daytime sleepiness, mood, and cognitive function. Sleep Med Rev. 2009 Jun 01;13(3):223–233. doi: 10.1016/j.smrv.2008.07.002
   PubMed Web of Science ®Google Scholar
• Bratton DJ, Gaisl T, Wons AM, et al. CPAP vs mandibular advancement devices and blood pressure in patients with obstructive sleep apnea: a systematic review and meta-analysis. JAMA. 2015;314(21):2280–2293. doi: 10.1001/jama.2015.16303
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Edwards BA, Malhotra A. Drug therapy for obstructive sleep apnea: are we there yet? Am J Respir Crit Care Med. 2022 Mar 23;205(12):1379–1381. doi: 10.1164/rccm.202202-0301ED
   PubMed Web of Science ®Google Scholar
• Welch K, Foster G, Ritter C, et al. A novel volumetric magnetic resonance imaging paradigm to study upper airway anatomy. Sleep. 2002;25(5):530–540. doi: 10.1093/sleep/25.5.530
   Web of Science ®Google Scholar
• Isono S, Remmers JE, Tanaka A, et al. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol. 1997;82(4):1319–1326. doi: 10.1152/jappl.1997.82.4.1319
   PubMed Web of Science ®Google Scholar
• Malhotra A, Huang Y, Fogel R, et al. Aging influences on pharyngeal anatomy and physiology: the predisposition to pharyngeal collapse. Am J Med. 2006 Jan;119(1):72 e9–14. doi: 10.1016/j.amjmed.2005.01.077
   PubMedGoogle Scholar
• Wang SH, Keenan BT, Wiemken A, et al. Effect of weight loss on upper airway anatomy and the apnea-hypopnea index. the importance of tongue fat. Am J Respir Crit Care Med. 2020 Mar 15;201(6):718–727. doi: 10.1164/rccm.201903-0692OC
   PubMed Web of Science ®Google Scholar
• Peppard P, Young T, Palta M, et al. Longitudinal study of moderate weight change and sleep disordered breathing. JAMA. 2000;284(23):3015–3021. doi: 10.1001/jama.284.23.3015
   PubMed Web of Science ®Google Scholar
• Schwartz AR, Gold AR, Schubert N, et al. Effect of weight loss on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis. 1991;144(3 Pt 1):494–498. doi: 10.1164/ajrccm/144.3_Pt_1.494
   PubMedGoogle Scholar
• O’Donnell C, Crilly S, O’Mahony A, et al. Continuous positive airway pressure but not GLP1-mediated weight loss improves early cardiovascular disease in obstructive sleep apnea: a randomized proof-of-concept study. Ann Am Thorac Soc. 2024 Mar;21(3):464–473. doi: 10.1513/AnnalsATS.202309-821OC
   PubMedGoogle Scholar
• Winslow DH, Bowden CH, DiDonato KP, et al. A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults. Sleep. 2012 Nov;35(11):1529–1539. doi: 10.5665/sleep.2204
   PubMed Web of Science ®Google Scholar
• Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016 Aug;40(8):1310–1319. doi: 10.1038/ijo.2016.52
   PubMed Web of Science ®Google Scholar
• Le KDR, Le K, Foo F, et al. The impact of glucagon-like peptide 1 receptor agonists on obstructive sleep apnoea: a scoping review. Pharmacy. 2024 Jan;12:11. doi: 10.3390/pharmacy12010011
   Web of Science ®Google Scholar
• Weiss T, Carr RD, Pal S, et al. Real-world adherence and discontinuation of glucagon-like peptide-1 receptor agonists therapy in type 2 diabetes mellitus patients in the United States. Patient Preference Adherence. 2020;14:2337–2345. doi: 10.2147/PPA.S277676
   PubMed Web of Science ®Google Scholar
• Weiss T, Yang L, Carr RD, et al. Real-world weight change, adherence, and discontinuation among patients with type 2 diabetes initiating glucagon-like peptide-1 receptor agonists in the UK. BMJ Open Diabetes Res Care. 2022 Jan;10(1):e002517. doi: 10.1136/bmjdrc-2021-002517
   PubMed Web of Science ®Google Scholar
• Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest. 1992;89(5):1571–1579. doi: 10.1172/JCI115751
   PubMed Web of Science ®Google Scholar
• Horner RL. The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea. Respir Res. 2001;2(5):286–294. doi: 10.1186/rr71
   PubMed Web of Science ®Google Scholar
• Horner RL. Pathophysiology of obstructive sleep apnea. J Cardiopulm Rehabil Prev. 2008 Sep;28(5):289–298. doi: 10.1097/01.HCR.0000336138.71569.a2
   PubMed Web of Science ®Google Scholar
• Horner RL, Hughes SW, Malhotra A. State-dependent and reflex drives to the upper airway: basic physiology with clinical implications. J Appl Physiol (1985). 2014 Feb 1;116(3):325–336. doi: 10.1152/japplphysiol.00531.2013
   PubMed Web of Science ®Google Scholar
• McGinley BM, Schwartz AR, Schneider H, et al. Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea. J Appl Physiol (Bethesda, Md: 1985). 2008;105(1):197–205. doi: 10.1152/japplphysiol.01214.2007
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Messineo L, Sands SA, et al. The combination of atomoxetine and oxybutynin greatly reduces obstructive sleep apnea severity. a randomized, placebo-controlled, double-blind crossover trial. Am J Respir Crit Care Med. 2019 May 15;199(10):1267–1276. doi: 10.1164/rccm.201808-1493OC
   PubMed Web of Science ®Google Scholar
• Rosenberg R, Abaluck B, Thein S. Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. J Clin Sleep Med. 2022;18(12):2837–2844. doi: 10.5664/jcsm.10250
   PubMed Web of Science ®Google Scholar
• Lee Y-C, Lu C-T, Chuang L-P, et al. Pharmacotherapy for obstructive sleep apnea - a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev. 2023 Aug 01;70:101809. doi: 10.1016/j.smrv.2023.101809
   PubMed Web of Science ®Google Scholar
• Apnimed. Parallel Arm Trial of AD109 and Placebo with Patients with OSA (LunAiro) ClinicalTrials.Gov identifier: NCT05811247. [ Updated 2024 May 1;cited 2024 May 24]. Available from: https://www.clinicaltrials.gov/study/NCT05811247?id=NCT05811247&rank=1
   Google Scholar
• Apnimed. Parallel-arm study to compare ad109 to placebo with patients with OSA (SynAirgy Study) ClinicalTrials.Gov identifier: NCT05813275. [ Updated 2024 May 2;cited 2024 May 24]. Available from: https://www.clinicaltrials.gov/search?id=NCT05813275
   Google Scholar
• Carley DW, Prasad B, Reid KJ, et al. Pharmacotherapy of apnea by cannabimimetic enhancement, the PACE clinical trial: effects of dronabinol in obstructive sleep apnea. Sleep. 2018 Jan 1;41(1). doi: 10.1093/sleep/zsx184
   PubMed Web of Science ®Google Scholar
• Taranto-Montemurro L, Sands SA, Edwards BA, et al. Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation. Eur Respir J. 2016 Nov;48(5):1340–1350. doi: 10.1183/13993003.00823-2016
   PubMed Web of Science ®Google Scholar
• Hedner J, Kraiczi H, Peker Y, et al. Reduction of sleep apnea after the orally available cholinesterase inhibitor donepezil. Sleep Med. 2005;6(2):e545–e545.
   Google Scholar
• Hedner J, Kraiczi H, Peker Y, et al. Reduction of sleep-disordered breathing after physostigmine. Am J Respir Crit Care Med. 2003 Nov;168(10):1246–1251. doi: 10.1164/rccm.200211-1344OC
   PubMed Web of Science ®Google Scholar
• Li Y, Owens RL, Sands S, et al. The effect of donepezil on arousal threshold and apnea-hypopnea index. a randomized, double-blind, cross-over study. Ann Am Thorac Soc. 2016 Nov;13(11):2012–2018. doi: 10.1513/AnnalsATS.201605-384OC
   PubMed Web of Science ®Google Scholar
• Gaisl T, Haile SR, Thiel S, et al. Efficacy of pharmacotherapy for OSA in adults: A systematic review and network meta-analysis. Sleep Med Rev. 2019 Aug;46:74–86. doi: 10.1016/j.smrv.2019.04.009
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Owens RL, Edwards BA, et al. OSA endotypes: what are they and what are their potential clinical implications? Curr Sleep Med Rep. 2018 Sep;4(3):231–242. doi: 10.1007/s40675-018-0121-8.
   Google Scholar
• Schmickl CN, Landry S, Orr JE, et al. Effects of acetazolamide on control of breathing in sleep apnea patients: mechanistic insights using meta-analyses and physiological model simulations. Physiol Rep. 2021 Oct;9(20):e15071. doi: 10.14814/phy2.15071
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Landry SA, Orr JE, et al. Acetazolamide for OSA and central sleep apnea: a comprehensive systematic review and meta-analysis. Chest. 2020 Dec;158(6):2632–2645. doi: 10.1016/j.chest.2020.06.078
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Landry SA, Orr JE, et al. Acetazolamide for OSA and central sleep apnea. Chest. 2020 Dec;158(6):2632–2645. doi: 10.1016/j.chest.2020.06.078
   PubMed Web of Science ®Google Scholar
• Eskandari D, Zou D, Grote L, et al. Acetazolamide reduces blood pressure and sleep-disordered breathing in patients with hypertension and obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med. 2018 Mar;14(3):309–317. doi: 10.5664/jcsm.6968
   PubMed Web of Science ®Google Scholar
• Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. [Review] [83 refs]. Sleep. 1997;20(8):654–675. doi: 10.1093/sleep/20.8.654
   PubMed Web of Science ®Google Scholar
• Gleeson K, Zwillich CW, WHite DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis. 1990;142(2):295–300. doi: 10.1164/ajrccm/142.2.295
   PubMed Web of Science ®Google Scholar
• Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci (Lond). 2011 Jun;120(12):505–514. doi: 10.1042/CS20100588
   PubMed Web of Science ®Google Scholar
• Edwards BA, Sands SA, Owens RL, et al. The combination of supplemental oxygen and a hypnotic markedly improves obstructive sleep apnea in patients with a mild to moderate upper airway collapsibility. Sleep. 2016 Nov 1;39(11):1973–1983. doi: 10.5665/sleep.6226
   PubMed Web of Science ®Google Scholar
• Eckert DJ, Malhotra A, Wellman A, et al. Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold. Sleep. 2014 Apr 1;37(4):811–819. doi: 10.5665/sleep.3596
   PubMed Web of Science ®Google Scholar
• Smales ET, Edwards BA, Deyoung PN, et al. Trazodone effects on obstructive sleep apnea and non-REM arousal threshold [research-article]. 2015 May 12. Available from: https://doi.org/10.1513/AnnalsATS201408-399OC
   Google Scholar
• Clarenbach CF, Kohler M, Senn O, et al. Does nasal decongestion improve obstructive sleep apnea? J Sleep Res. 2008 Dec;17(4):444–449. doi: 10.1111/j.1365-2869.2008.00667.x
   PubMed Web of Science ®Google Scholar
• Koutsourelakis I, Minaritzoglou A, Zakynthinos G, et al. The effect of nasal tramazoline with dexamethasone in obstructive sleep apnoea patients. Eur Respir J. 2013 Oct;42(4):1055–1063. doi: 10.1183/09031936.00142312
   PubMed Web of Science ®Google Scholar
• Van Der Touw T, Crawford ABH, Wheatley JR. Effects of a synthetic lung surfactant on pharyngeal patency in awake human subjects. J Appl Physiol. 1997;82(1):78–85. doi: 10.1152/jappl.1997.82.1.78
   PubMed Web of Science ®Google Scholar
• Kirkness JP, Christenson HK, Garlick SR, et al. Decreased surface tension of upper airway mucosal lining liquid increases upper airway patency in anaesthetised rabbits. J Physiol. 2003 Mar 1;547(Pt 2):603–611. doi: 10.1113/jphysiol.2002.031013
   PubMed Web of Science ®Google Scholar
• Morrell MJ, Arabi Y, Zahn BR, et al. Effect of surfactant on pharyngeal mechanics in sleeping humans: implications for sleep apnoea. Eur Respir J. 2002;20(2):451–457. doi: 10.1183/09031936.02.00273702
   PubMed Web of Science ®Google Scholar
• Weaver TE, Chasens ER, Arora S. Modafinil improves functional outcomes in patients with residual excessive sleepiness associated with CPAP treatment. J Clin Sleep Med. 2009 Dec;5(6):499–505. doi: 10.5664/jcsm.27648
   PubMed Web of Science ®Google Scholar
• Dinges DF, Weaver TE. Effects of modafinil on sustained attention performance and quality of life in OSA patients with residual sleepiness while being treated with nCPAP. Sleep Med. 2003 Sep;4(5):393–402. doi: 10.1016/S1389-9457(03)00108-4
   PubMed Web of Science ®Google Scholar
• Morgenthaler TI, Kapen S, Lee-Chiong T, et al. Practice parameters for the medical therapy of obstructive sleep apnea. Sleep. 2006 Aug;29(8):1031–1035. doi: 10.1093/sleep/29.8.1031
   PubMed Web of Science ®Google Scholar
• Damkier P, Broe A. First-trimester pregnancy exposure to modafinil and risk of congenital malformations. JAMA. 2020 Jan;323(4):374–376. doi: 10.1001/jama.2019.20008
   PubMed Web of Science ®Google Scholar
• Kaplan S, Braverman DL, Frishman I, et al. Pregnancy and fetal outcomes following exposure to modafinil and armodafinil during pregnancy. JAMA Intern Med. 2021 Feb;181(2):275–277. doi: 10.1001/jamainternmed.2020.4009
   PubMed Web of Science ®Google Scholar
• Malhotra A, Shapiro C, Pepin JL, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep Med. 2019 Nov 6;64:S241. doi: 10.1016/j.sleep.2019.11.674
   Google Scholar
• Schweitzer PK, Rosenberg R, Zammit GK, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3). A randomized controlled trial. Am J Respir Crit Care Med. 2019 Jun 1;199(11):1421–1431. doi: 10.1164/rccm.201806-1100OC
   PubMed Web of Science ®Google Scholar
• Pépin JL, Georgiev O, Tiholov R, et al. Pitolisant for residual excessive daytime sleepiness in OSA patients adhering to CPAP: A randomized trial. Chest. 2021 Apr;159(4):1598–1609. doi: 10.1016/j.chest.2020.09.281
   PubMed Web of Science ®Google Scholar
• Pépin JL, Attali V, Caussé C, et al. Long-term efficacy and safety of pitolisant for residual sleepiness due to OSA. Chest. 2024 Mar;165(3):692–703. doi: 10.1016/j.chest.2023.11.017
   PubMed Web of Science ®Google Scholar
• Engleman HM, Wild MR. Improving CPAP use by patients with the sleep apnoea/hypopnoea syndrome (SAHS). Sleep Med Rev. 2003;7(1):81–99. doi: 10.1053/smrv.2001.0197
   PubMed Web of Science ®Google Scholar
• Lettieri CJ, Shah AA, Holley AB, et al. Effects of a short course of eszopiclone on continuous positive airway pressure adherence: a randomized trial. Ann Intern Med. 2009 Nov 17;151(10):696–702. doi: 10.7326/0003-4819-151-10-200911170-00006
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Lettieri CJ, Orr JE, et al. The arousal threshold as a drug target to improve continuous positive airway pressure adherence: secondary analysis of a randomized trial. Am J Respir Crit Care Med. 2020 Dec 1;202(11):1592–1595. doi: 10.1164/rccm.202003-0502LE
   PubMed Web of Science ®Google Scholar
• Kjelsberg FN, Ruud EA, Stavem KSS, et al. Predictors of symptoms of anxiety and depression in obstructive sleep apnea. Sleep Med. 2005;6(4):341–346. doi: 10.1016/j.sleep.2005.02.004
   PubMed Web of Science ®Google Scholar
• Law M, Naughton M, Ho S, et al. Depression may reduce adherence during CPAP titration trial. J Clin Sleep Med. 2014;10(2):163–163. doi: 10.5664/jcsm.3444
   PubMed Web of Science ®Google Scholar
• Wickwire EM, Cole KV, Dexter RB, et al. Depression and comorbid obstructive sleep apnea: association between positive airway pressure adherence, occurrence of self-harm events, healthcare resource utilization, and costs. J Affect Disord. 2024 Mar;349:254–261. doi: 10.1016/j.jad.2023.12.055
   PubMed Web of Science ®Google Scholar
• Shah R, Patel N, Emin M, et al. Statins restore endothelial protection against complement activity in obstructive sleep apnea: a randomized clinical trial. Ann Am Thorac Soc. 2023 Jul;20(7):1029–1037. doi: 10.1513/AnnalsATS.202209-761OC
   PubMed Web of Science ®Google Scholar
• Wellman A, Eckert DJ, Jordan AS, et al. A method for measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol. 2011 Jun;110(6):1627–1637. doi: 10.1152/japplphysiol.00972.2010
   PubMed Web of Science ®Google Scholar
• Wellman A, Edwards BA, Sands SA, et al. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol. 2013 Apr;114(7):911–922. doi: 10.1152/japplphysiol.00747.2012
   PubMed Web of Science ®Google Scholar
• Jen R, Grandner MA, Malhotra A. Future of sleep-disordered breathing therapy using a mechanistic approach. Can J Cardiol. 2015 Jul;31(7):880–888. doi: 10.1016/j.cjca.2015.02.007
   PubMed Web of Science ®Google Scholar
• Malhotra A, Mesarwi O, Pepin JL, et al. Endotypes and phenotypes in obstructive sleep apnea. Curr Opin Pulm Med. 2020 Nov;26(6):609–614. doi: 10.1097/MCP.0000000000000724
   PubMed Web of Science ®Google Scholar
• Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet. 2014 Feb 22;383(9918):736–747. doi: 10.1016/S0140-6736(13)60734-5
   PubMed Web of Science ®Google Scholar
• Keenan BT, Kim J, Singh B, et al. Recognizable clinical subtypes of obstructive sleep apnea across international sleep centers: a cluster analysis. Sleep. 2018 Mar 1;41(3). doi: 10.1093/sleep/zsx214
   Web of Science ®Google Scholar
• Mazzotti DR, Keenan BT, Lim DC, et al. Symptom subtypes of obstructive sleep apnea predict incidence of cardiovascular outcomes. Am J Respir Crit Care Med. 2019 Aug 15;200(4):493–506. doi: 10.1164/rccm.201808-1509OC
   PubMed Web of Science ®Google Scholar
• Mazzotti DR, Lim DC, Sutherland K, et al. Opportunities for utilizing polysomnography signals to characterize obstructive sleep apnea subtypes and severity. Physiol Meas. 2018 Sep 13;39(9):09TR01. doi: 10.1088/1361-6579/aad5fe
   PubMed Web of Science ®Google Scholar
• Ye L, Pien GW, Ratcliffe SJ, et al. The different clinical faces of obstructive sleep apnoea: a cluster analysis. Eur Respir J. 2014 Dec;44(6):1600–1607. doi: 10.1183/09031936.00032314
   PubMed Web of Science ®Google Scholar
• Schmickl CN, Orr JE, Sands SA, et al. Loop gain as a predictor of blood pressure response in patients treated for obstructive sleep apnea: secondary analysis of a clinical trial. Ann ATS. 2024 Feb;21(2):296–307. doi: 10.1513/AnnalsATS.202305-437OC
   Google Scholar
• Sternson SM, Bleakman D. Chemogenetics: drug-controlled gene therapies for neural circuit disorders. Cell Gene Ther Insights. 2020 Aug;6(7):1079–1094. doi: 10.18609/cgti.2020.112
   PubMedGoogle Scholar
• Horton GA, Fraigne JJ, Torontali ZA, et al. Activation of the hypoglossal to tongue musculature motor pathway by remote control. Sci Rep. 2017 Apr;7(1). doi: 10.1038/srep45860
   Google Scholar
• Herlihy R, Frasson Dos Reis L, Gvritishvili A, et al. Chronic intermittent hypoxia attenuates noradrenergic innervation of hypoglossal motor nucleus. Respir Physiol Neurobiol. 2023 Dec 21;321:104206. doi: 10.1016/j.resp.2023.104206
   PubMed Web of Science ®Google Scholar
• Mueller JS, Tescarollo FC, Sun H. DREADDs in epilepsy research: network-based review. Front Mol Neurosci. 2022;15:863003. doi: 10.3389/fnmol.2022.863003
   PubMed Web of Science ®Google Scholar
• Pun FW, Ozerov IV, Zhavoronkov A. AI-powered therapeutic target discovery. Trends Pharmacol Sci. 2023 Sep;44(9):561–572. doi: 10.1016/j.tips.2023.06.010
   PubMed Web of Science ®Google Scholar
• Redline S, Tishler PV. The genetics of sleep apnea. Sleep Med Rev. 2000 Dec;4(6):583–602. doi: 10.1053/smrv.2000.0120
   PubMed Web of Science ®Google Scholar