Wake-Promoting Agents (WPAs) such as amphetamine-like stimulants or modafinil, armodafinil, methyl phenidate, caffeine and nicotine reinforce the level of vigilance through an stimulated release of neurotransmitters implicated in the arousal threshold maintenance, hence shift the drive from the sleep-promoting to wake-promoting system. The modulatory effects of WPAs on cortical activation pathways give rise to enhanced vigilance. For example, cholinergic neurons of the basal forebrain and the adenosine receptors on these neurons are agonized and antagonized by nicotine and caffeine, respectively. Caffeine similarly antagonizes adenosine receptors on the GABAergic neurons and intensifies the inhibitory drive in preoptic/anterior hypothalamus which involve in sleep induction. Modafinil however exerts its wake-promoting effects through stimulating the tuberomammillary nucleus and the hypocretinergic neurons which activate the ascending reticular activating system. Although many neutransmitter systems such as dopamine are thought to be involved upon the effects of WPAs, the empirical evidence to explain the exact mechanisms need to gain strength.
Shimizu T. [Excessive daytime sleepiness (EDS)]. Nihon rinsho Japanese journal of clinical medicine. 2015;73(6):937-41.
Kara B, Kilic O. Predictors of poor sleep quality and excessive daytime sleepiness in Turkish adults with type 2 diabetes. Journal of clinical nursing. 2015;24(9-10):1436-9.
Begley KJ, Castillo S, Steinshouer CR, Malesker MA. Role of pharmacists in the treatment of excessive daytime sleepiness. The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists. 2014;29(11):741-52.
Fong SY, Ho CK, Wing YK. Comparing MSLT and ESS in the measurement of excessive daytime sleepiness in obstructive sleep apnoea syndrome. Journal of psychosomatic research. 2005;58(1):55-60.
Schreier DR, Roth C, Mathis J. Subjective perception of sleepiness in a driving simulator is different from that in the Maintenance of Wakefulness Test. Sleep medicine. 2015;16(8):994-8.
Tanaka H. [Multiple sleep latency test, maintenance of wakefulness test and suggestive immobilization test]. Nihon rinsho Japanese journal of clinical medicine. 2015;73(6):971-9.
van der Heide A, van Schie MK, Lammers GJ, Dauvilliers Y, Arnulf I, Mayer G, et al. Comparing Treatment Effect Measurements in Narcolepsy: The Sustained Attention to Response Task, Epworth Sleepiness Scale and Maintenance of Wakefulness Test. Sleep. 2015;38(7):1051-8.
Bioulac S, Chaufton C, Taillard J, Claret A, Sagaspe P, Fabrigoule C, et al. Excessive daytime sleepiness in adult patients with ADHD as measured by the Maintenance of Wakefulness Test, an electrophysiologic measure. The Journal of clinical psychiatry. 2015;76(7):943-8.
Chen Z, Wu C, Zhong M, Lyu N, Huang Z. Identification of common features of vehicle motion under drowsy/distracted driving: A case study in Wuhan, China. Accident; analysis and prevention. 2015;81:251-9.
Sadeghniiat-Haghighi K, Moller HJ, Saraei M, Aminian O, Khajeh-Mehrizi A. The Epworth Sleepiness Scale for screening of the drowsy driving: comparison with the maintenance of wakefulness test in an Iranian sample of commercial drivers. Acta medica Iranica. 2014;52(2):125-9.
Anderson C, Horne JA. Driving drowsy also worsens driver distraction. Sleep medicine. 2013;14(5):466-8.
Dawson J. Putting the brakes on drowsy driving. The American nurse. 2012;44(2):9.
Rosenberg RP. Clinical assessment of excessive daytime sleepiness in the diagnosis of sleep disorders. The Journal of clinical psychiatry. 2015;76(12):e1602.
Rose D, Gelaye B, Sanchez S, Castaneda B, Sanchez E, Yanez ND, et al. Morningness/eveningness chronotype, poor sleep quality, and daytime sleepiness in relation to common mental disorders among Peruvian college students. Psychology, health & medicine. 2015;20(3):345-52.
Haregu A, Gelaye B, Pensuksan WC, Lohsoonthorn V, Lertmaharit S, Rattananupong T, et al. Circadian rhythm characteristics, poor sleep quality, daytime sleepiness and common psychiatric disorders among Thai college students. Asia-Pacific psychiatry : official journal of the Pacific Rim College of Psychiatrists. 2015;7(2):182-9.
Suzuki K, Miyamoto M, Miyamoto T, Inoue Y, Matsui K, Nishida S, et al. The Prevalence and Characteristics of Primary Headache and Dream-Enacting Behaviour in Japanese Patients with Narcolepsy or Idiopathic Hypersomnia: A Multi-Centre Cross-Sectional Study. PloS one. 2015;10(9):e0139229.
Pereira D, Lopes E, da Silva Behrens NS, de Almeida Fonseca H, Sguillar DA, de Araujo Lima TF, et al. Prevalence of periodical leg movements in patients with narcolepsy in an outpatient facility in Sao Paulo. Sleep Science. 2014;7(1):69-71.
Heier MS, Evsiukova T, Wilson J, Abdelnoor M, Hublin C, Ervik S. Prevalence of narcolepsy with cataplexy in Norway. Acta neurologica Scandinavica. 2009;120(4):276-80.
Bjorvatn B, Lehmann S, Gulati S, Aurlien H, Pallesen S, Saxvig IW. Prevalence of excessive sleepiness is higher whereas insomnia is lower with greater severity of obstructive sleep apnea. Sleep & breathing = Schlaf & Atmung. 2015;19(4):1387-93.
Signal TL, Paine SJ, Sweeney B, Priston M, Muller D, Smith A, et al. Prevalence of abnormal sleep duration and excessive daytime sleepiness in pregnancy and the role of socio-demographic factors: comparing pregnant women with women in the general population. Sleep medicine. 2014;15(12):1477-83.
Liviya Ng W, Freak-Poli R, Peeters A. The prevalence and characteristics associated with excessive daytime sleepiness among Australian workers. Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine. 2014;56(9):935-45.
Bjorvatn B, Pallesen S, Gronli J, Sivertsen B, Lehmann S. Prevalence and correlates of insomnia and excessive sleepiness in adults with obstructive sleep apnea symptoms. Perceptual and motor skills. 2014;118(2):571-86.
Hayley AC, Williams LJ, Kennedy GA, Berk M, Brennan SL, Pasco JA. Prevalence of excessive daytime sleepiness in a sample of the Australian adult population. Sleep medicine. 2014;15(3):348-54.
Verbruggen AE, Dieltjens M, Wouters K, De Volder I, Van de Heyning PH, Braem MJ, et al. Prevalence of residual excessive sleepiness during effective oral appliance therapy for sleep-disordered breathing. Sleep medicine. 2014;15(2):269-72.
Vashum KP, McEvoy MA, Hancock SJ, Islam MR, Peel R, Attia JR, et al. Prevalence of and associations with excessive daytime sleepiness in an Australian older population. Asia-Pacific journal of public health / Asia-Pacific Academic Consortium for Public Health. 2015;27(2):NP2275-84.
Risco J, Ruiz P, Marinos A, Juarez A, Ramos M, Salmavides F, et al. Excessive sleepiness prevalence in public transportation drivers of a developing country. Traffic injury prevention. 2013;14(2):145-9.
Gunes Z, Sahbaz M, Tugrul E, Gunes H. Prevalence and risk factors for excessive daytime of sleepiness in rural western Anotolia (Turkey): the role of obesity and metabolic syndrome. The Southeast Asian journal of tropical medicine and public health. 2012;43(3):747-55.
Dunn D, Hostetler G, Iqbal M, Messina-McLaughlin P, Reiboldt A, Lin YG, et al. Wake-promoting agents: search for next generation modafinil: part I. Bioorganic & medicinal chemistry letters. 2012;22(6):2312-4.
Lesur B, Lin YG, Marcy VR, Aimone LD, Gruner J, Bacon ER, et al. Aryl-heteroaryl derivatives as novel wake-promoting agents. Chemical biology & drug design. 2013;81(3):429-32.
Louvet P, Schweizer D, Gourdel ME, Riguet E, Yue C, Marcy VR, et al. Wake-promoting agents: search for next generation modafinil: part IV. European journal of medicinal chemistry. 2012;54:949-51.
Dunn D, Hostetler G, Iqbal M, Marcy VR, Lin YG, Jones B, et al. Wake promoting agents: search for next generation modafinil, lessons learned: part III. Bioorganic & medicinal chemistry letters. 2012;22(11):3751-3.
Dunn D, Hostetler G, Iqbal M, Messina-McLaughlin P, Reiboldt A, Lin YG, et al. Wake-promoting agents: search for next generation modafinil: part II. Bioorganic & medicinal chemistry letters. 2012;22(6):2315-7.
Lynch J, Jr., Regan C, Stump G, Tannenbaum P, Stevens J, Bone A, et al. Hemodynamic and cardiac neurotransmitter-releasing effects in conscious dogs of attention- and wake-promoting agents: a comparison of d-amphetamine, atomoxetine, modafinil, and a novel quinazolinone H3 inverse agonist. Journal of cardiovascular pharmacology. 2009;53(1):52-9.
Stocking EM, Letavic MA. Histamine H3 antagonists as wake-promoting and pro-cognitive agents. Current topics in medicinal chemistry. 2008;8(11):988-1002.
Makris AP, Rush CR, Frederich RC, Kelly TH. Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity. Appetite. 2004;42(2):185-95.
Oken BS, Salinsky MC, Elsas SM. Vigilance, alertness, or sustained attention: physiological basis and measurement. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2006;117(9):1885-901.
Ebrahim IO, Howard RS, Kopelman MD, Sharief MK, Williams AJ. The hypocretin/orexin system. Journal of the Royal Society of Medicine. 2002;95(5):227-30.
McWhirter D, Bae C, Budur K. The Assessment, Diagnosis, and Treatment of Excessive Sleepiness: Practical Considerations for the Psychiatrist. Psychiatry (Edgmont). 2007;4(9):26-35.
Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM. Dopaminergic role in stimulant-induced wakefulness. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001;21(5):1787-94.
Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K. The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism. European journal of pharmacology. 1996;306(1-3):33-9.
Gerrard P, Malcolm R. Mechanisms of modafinil: A review of current research. Neuropsychiatric disease and treatment. 2007;3(3):349-64.
Saper CB, Scammell TE. Modafinil: a drug in search of a mechanism. Sleep. 2004;27(1):11-2.
Ishizuka T, Murotani T, Yamatodani A. Modanifil activates the histaminergic system through the orexinergic neurons. Neuroscience letters. 2010;483(3):193-6.
Broughton RJ, Fleming JA, George CF, Hill JD, Kryger MH, Moldofsky H, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology. 1997;49(2):444-51.
Kumar R. Approved and investigational uses of modafinil : an evidence-based review. Drugs. 2008;68(13):1803-39.
Dauvilliers Y, Neidhart E, Billiard M, Tafti M. Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. The pharmacogenomics journal. 2002;2(1):65-8.
Saper CB, Scammell TE. Emerging therapeutics in sleep. Annals of neurology. 2013;74(3):435-40.
Zaharna M, Dimitriu A, Guilleminault C. Expert opinion on pharmacotherapy of narcolepsy. Expert opinion on pharmacotherapy. 2010;11(10):1633-45.
Golicki D, Bala MM, Niewada M, Wierzbicka A. Modafinil for narcolepsy: systematic review and meta-analysis. Medical science monitor : international medical journal of experimental and clinical research. 2010;16(8):RA177-86.
Schwartz JR, Roth T. Shift work sleep disorder: burden of illness and approaches to management. Drugs. 2006;66(18):2357-70.
Schwartz JRL. Modafinil in the treatment of excessive sleepiness. Drug design, development and therapy. 2008;2:71-85.
Nishino S, Okuro M. Armodafinil for excessive daytime sleepiness. Drugs of today. 2008;44(6):395-414.
Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Annals of neurology. 1998;43(1):88-97.
Edgar CJ, Pace-Schott EF, Wesnes KA. Approaches to measuring the effects of wake-promoting drugs: a focus on cognitive function. Human psychopharmacology. 2009;24(5):371-89.
Berman SM, Kuczenski R, McCracken JT, London ED. Potential adverse effects of amphetamine treatment on brain and behavior: a review. Molecular psychiatry. 2009;14(2):123-42.
Banerjee D, Vitiello MV, Grunstein RR. Pharmacotherapy for excessive daytime sleepiness. Sleep medicine reviews. 2004;8(5):339-54.
Billiard M. Narcolepsy: current treatment options and future approaches. Neuropsychiatric disease and treatment. 2008;4(3):557-66.
Akintomide GS, Rickards H. Narcolepsy: a review. Neuropsychiatric disease and treatment. 2011;7:507-18.
Cochen De Cock V, Dauvilliers Y. Current and future therapeutic approaches in narcolepsy. Future Neurology. 2011;6(6):771-82.
Guilleminault C, Carskadon M, Dement WC. On the treatment of rapid eye movement narcolepsy. Archives of neurology. 1974;30(1):90-3.
Tunnicliff G. Sites of Action of Gamma-Hydroxybutyrate (GHB)âA Neuroactive Drug with Abuse Potential. Journal of Toxicology: Clinical Toxicology. 1997;35(6):581-90.
Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacological reviews. 2009;61(2):162-76.
Cao M, Guilleminault C. Hypocretin and its emerging role as a target for treatment of sleep disorders. Current neurology and neuroscience reports. 2011;11(2):227-34.
Equihua AC, De La Herran-Arita AK, Drucker-Colin R. Orexin receptor antagonists as therapeutic agents for insomnia. Frontiers in pharmacology. 2013;4:163.
Huang Z-L, Qu W-M, Eguchi N, Chen J-F, Schwarzschild MA, Fredholm BB, et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature neuroscience. 2005;8(7):858-9.
Rihel J, Schier AF. Sites of action of sleep and wake drugs: insights from model organisms. Current opinion in neurobiology. 2013;23(5):831-40.
Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. The Lancet Neurology. 2013;12(11):1068-75.
Hasan S, Pradervand S, Ahnaou A, Drinkenburg W, Tafti M, Franken P. How to keep the brain awake? The complex molecular pharmacogenetics of wake promotion. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2009;34(7):1625-40.
Abbott A. Neuroscience: the molecular wake-up call. Nature. 2007;447(7143):368-70.
In Y, Tomoo K, Ishida T, Sakamoto Y. Crystal and molecular structure of an (S)-(+)-enantiomer of modafinil, a novel wake-promoting agent. Chemical & pharmaceutical bulletin. 2004;52(10):1186-9.
Choi S, Kim MY, Joo KY, Park S, Kim JA, Jung JC, et al. Modafinil inhibits K(Ca)3.1 currents and muscle contraction via a cAMP-dependent mechanism. Pharmacological research. 2012;66(1):51-9.
Tahsili-Fahadan P, Carr GV, Harris GC, Aston-Jones G. Modafinil blocks reinstatement of extinguished opiate-seeking in rats: mediation by a glutamate mechanism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2010;35(11):2203-10.
Mitchell HA, Bogenpohl JW, Liles LC, Epstein MP, Bozyczko-Coyne D, Williams M, et al. Behavioral responses of dopamine beta-hydroxylase knockout mice to modafinil suggest a dual noradrenergic-dopaminergic mechanism of action. Pharmacology, biochemistry, and behavior. 2008;91(2):217-22.
Wisor JP, Eriksson KS. Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil. Neuroscience. 2005;132(4):1027-34.
Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, et al. Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Acta pharmacologica Sinica. 2004;25(3):301-5.
Lee H, Kim KC, Cho MS, Suh SH, Hong YM. Modafinil improves monocrotaline-induced pulmonary hypertension rat model. Pediatric research. 2016.
Kuan YC, Wu D, Huang KW, Chi NF, Hu CJ, Chung CC, et al. Effects of Modafinil and Armodafinil in Patients With Obstructive Sleep Apnea: A Meta-Analysis of Randomized Controlled Trials. Clinical therapeutics. 2016.
Ramachandra B. A Critical Review of Properties of Modafinil and Analytical, Bio Analytical Methods for Its Determination. Critical reviews in analytical chemistry / CRC. 2016:0.
Karila L, Leroy C, Dubol M, Trichard C, Mabondo A, Marill C, et al. Dopamine Transporter Correlates and Occupancy by Modafinil in Cocaine-Dependent Patients: A Controlled Study with High-Resolution PET and [C]-PE2I. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2016.
De Ron P, Dremier S, Winlow P, Jenkins A, Hanon E, Nogueira da Costa A. Correlating behaviour and gene expression endpoints in the dopaminergic system after modafinil administration in mouse. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2016.
Chapman JL, Vakulin A, Hedner J, Yee BJ, Marshall NS. Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis. The European respiratory journal. 2016.
Andrade C. A method for deciding about the possible safety of modafinil and armodafinil in patients with seizure disorder. The Journal of clinical psychiatry. 2016;77(1):e25-8.
Battleday RM, Brem AK. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2016;26(2):391.
Hosak L, Horacek J, Beranek M, Cermakova E. Molecular heterosis in metamphetamine abusers. International journal of psychiatry in clinical practice. 2007;11(3):250-2.
Cadet JL, Krasnova IN, Jayanthi S, Lyles J. Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neurotoxicity research. 2007;11(3-4):183-202.
Abdou MM. A molecular approach to the study of structure-activity correlation for some amphetamines. Journal of psychoactive drugs. 2001;33(3):295-300.
Ganjavi H, Shapiro CM. Hypocretin/Orexin: a molecular link between sleep, energy regulation, and pleasure. The Journal of neuropsychiatry and clinical neurosciences. 2007;19(4):413-9.
Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron. 2003;38(5):715-30.
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437-51.
Zare, B., Moosavi, B., & Torabi-Nami, M. (2016). Wake-Promoting Agents; Insights into Clinical Use and Molecular Perspectives. Journal of Advanced Medical Sciences and Applied Technologies, 2(1), 129-140. doi: 10.18869/nrip.jamsat.2.1.129
Bijan Zare; Behrooz Moosavi; Mohammad Torabi-Nami. "Wake-Promoting Agents; Insights into Clinical Use and Molecular Perspectives". Journal of Advanced Medical Sciences and Applied Technologies, 2, 1, 2016, 129-140. doi: 10.18869/nrip.jamsat.2.1.129
Zare, B., Moosavi, B., Torabi-Nami, M. (2016). 'Wake-Promoting Agents; Insights into Clinical Use and Molecular Perspectives', Journal of Advanced Medical Sciences and Applied Technologies, 2(1), pp. 129-140. doi: 10.18869/nrip.jamsat.2.1.129
Zare, B., Moosavi, B., Torabi-Nami, M. Wake-Promoting Agents; Insights into Clinical Use and Molecular Perspectives. Journal of Advanced Medical Sciences and Applied Technologies, 2016; 2(1): 129-140. doi: 10.18869/nrip.jamsat.2.1.129