In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. Devoto P, Flore G, Vacca G, Pira L, Arca A, Casu MA et al (2003). IR formulations provide a short duration of action and are therefore generally dosed three times per day. Gill M, Haerich P, Westcott K, Godenick KL, Tucker JA (2006). The two doses were not directly compared for cognitive effects in this study. The role of post-synaptic 2 receptor-mediated transient increases in PFC delay-related activity (Li et al, 1999; Sawaguchi, 1998), and associated mitigation of interference in task performance (Arnsten and Contant, 1992), suggest a point of convergence of the Arnsten model of adrenergic function with the Aston-Jones and Cohen (Aston-Jones and Cohen, 2005) model of phasic LC activity in optimizing task performance (see below). This includes an open-label study in 11 children with ADHD, with an average dose of 195mg/day for an average 4.6 weeks (Rugino and Copley, 2001); a follow-up study of 22 children with ADHD, using a randomized, placebo-controlled design with an average dose of 264mg/day for an average of 6 weeks (Rugino and Samsock, 2003); and in a recent, much larger study of childhood ADHD, which included 100 completers in the modafinil-treated group and 41 completers in the placebo group, an average dose of 361mg for an average of 31.5 days (Greenhill et al, 2006). Low-resolution brain electromagnetic tomography (LORETA) identifies brain regions linked to psychometric performance under modafinil in narcolepsy. In these two latter studies, overall TOVA performance improved in the modafinil-treated group, whereas it declined from pre-treatment baseline in the placebo group. CAS ISSN 0893-133X (print), Modafinil: A Review of Neurochemical Actions and Effects on Cognition, Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine, Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis, Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia, Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders, Dj-vu? Modafinil also activates Fos in the tuberomammillary nucleus (TMN), which contains wake-promoting histaminergic (HA) neurons (Scammell et al, 2000), and both i.p. Whereas patients with ADHD are at an increased risk for seizure activity compared to the general population, a retrospective study using drug claims data showed that the use of stimulant medications was associated with a lower risk (Cortese 2013; Wiggs 2018). However, this group has studied university students who appear to have a high IQ (average of 115 in one study), with likely general ceiling effects on performance (Randall et al, 2003, 2005a). Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P (2004). Known hypersensitivity to modafinil, armodafinil, or any component of the formulation. Xie Z, Westmoreland S, Bahn ME, Chen GL, Yang H, Vallender E et al (2007). Schwertner HA, Kong SB (2005). Dr Minzenberg and Dr Carter have received research funding from Cephalon, a manufacturer of modafinil and armodafinil. Ferraro L, Fuxe K, Tanganelli S, Fernandez M, Rambert FA, Antonelli T (2000). This group has also reported that after a single modafinil dose of 100mg, schizophrenia patients exhibited a significantly greater amount of behavioral activity than placebo-treated patients, measured with wrist-worn actigraphy over a 20-h period on an inpatient research unit (Farrow et al, 2006). J Psychopharmacol 20: 756770. One study of adults with 85h of sleep deprivation found single-dose modafinil 400mg to reduce errors on the Wisconsin Card Sort Test (WCST) and interference on the Stroop (compared to placebo), and comparable to 600mg caffeine and 20mg amphetamine (Wesensten et al, 2005). Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task, Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders, (R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency, Receptor and circuit mechanisms underlying differential procognitive actions of psychostimulants, US Modfinil in Narcolepsy Multicenter Study Group (1998, Pharmacologic Management of Cognitive Disengagement Syndrome (CDS) and Implications for Attention-Deficit/Hyperactivity Disorder (ADHD) Treatment: Emerging Treatments and Recommendations for Future Research, Comparison of Solriamfetol and Modafinil on Arousal and Anxiety-Related Behaviors in Narcoleptic Mice, How to Tackle Mental Fatigue: A Systematic Review of Potential Countermeasures and Their Underlying Mechanisms, Effects of modafinil on electroencephalographic microstates in healthy adults, Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix Cohort. It is used to treat a lot of sleepiness that may happen with sleep apnea, narcolepsy, or shift work problems. Clin Neurophysiol 110: 10411047. Modafinil also appears to have a relatively low potential for abuse, which may be a function of its pharmacodynamic profile and/or its physical properties, being insoluble in water and unstable at high temperatures, which minimizes its bioavailability upon smoking or intravenous use (Jasinski, 2000; Myrick et al, 2004). Neurosci Lett 259: 181185. However, modafinil lacks the capacity to reduce cataplexy in dogs or humans with narcolepsy (Billiard et al, 1994; Shelton et al, 1995), a feature which is similar to other DAT inhibitors, and in contrast to 1B agonists and NET inhibitors (Mignot et al, 1993; Nishino et al, 1993). Wong YN, Simcoe D, Hartman LN, Laughton WB, King SP, McCormick GC et al (1999b). Management: Dose modifications of erdafitinib may be required. Modafinil facilitates performance on a delayed nonmatching to position swim task in rats. Heterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: a laminar analysis using the silver-enhanced diaminobenzidine sulfide (SEDS) immunolabeling technique. Modafinil-induced wakefulness can be attenuated by the . Article Dinges DF, Arora S, Darwish M, Niebler GE (2006). J Neurochem 92: 368374. Ellis CM, Monk C, Simmons A, Lemmens G, Williams SC, Brammer M et al (1999). Consider therapy modification, Esketamine: May enhance the hypertensive effect of CNS Stimulants. For the treatment of shift work sleep disorder, administer dose ~1 hour prior to start of work shift. Consider therapy modification, Lemborexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lemborexant. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Modafinil in treatment of fatigue in multiple sclerosis. Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide; brand name Provigil in the United States) is a novel wake-promoting agent first marketed in France in the early 1990s, as a treatment for the excessive somnolence as a feature of narcolepsy. Monitor therapy, Clarithromycin: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Modafinil, an atypical wakefulness-promoting agent with an unknown mechanism of action, is used to treat hypersomnolence in these patients. Alpha- and beta-adrenoceptors: from the gene to the clinic. Pharmacol Biochem Behav 82: 133139. In the clinical setting, modafinil shows efficacy in a number of neurological and psychiatric illnesses, with a significantly improved side-effect profile compared to amphetamine, including a relatively low liability to abuse. Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. In contrast, a 2-week study of 22 adult ADHD patients, where the modafinil-treated group was titrated over 47 days to an average dose of 206.8mg/day, and another group received amphetamine at an average dose of 21.8mg/day, verbal (letter) fluency was improved relative to the placebo group, but no treatment effects were observed on the Stroop or Digit Span tests (Taylor and Russo, 2000). Wong YN, King SP, Simcoe D, Gorman S, Laughton W, McCormick GC et al (1999a). Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers. Psychopharmacology 174: 316. Another double-blind, placebo-controlled study of healthy adults undergoing simulated day- and night-shift conditions found a 3-day course of modafinil 200 or 400mg to improve performance on divided attention, immediate recall, and a version of the digit-symbol task, relative to placebo (Hart et al, 2006). In a 7-week study with 190 ADHD patients (aged 617 years) enrolled, the modafinil-treated groups (receiving either 340mg (n=44) or 425mg (n=82), based on body weight) showed significantly greater improvement on the ADHD-RS-IV School and Home versions and on the CGI (Swanson et al, 2006). We then outline and attempt to synthesize the complex literature addressing the neurochemical effects of modafinil, particularly as a potential treatment for cognitive dysfunction. Some evidence suggests that the magnitude of modafinil effects in healthy adults may depend on underlying cognitive abilities. Monitor therapy, Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Consider therapy modification, Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Meunier M, Jaffard R, Destrade C (1991). Long-term efficacy and safety of modafinil (PROVIGIL(R)) for the treatment of excessive daytime sleepiness associated with narcolepsy. Cognition and control in schizophrenia: a computational model of dopamine and prefrontal function. However, the drug does not suppress cataplexy. Sleep 26: 801806. Nature 380: 6972. Neuropharmacology 52: 626633. Pierard C, Satabin P, Lagarde D, Barrere B, Guezennec CY, Menu JP et al (1995). Touret M, Sallanon-Moulin M, Fages C, Roudier V, Didier-Bazes M, Roussel B et al (1994). Among child and adolescent psychiatric disorders, modafinil has only been studied to date in ADHD. 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