Article

Modafinil: a review of neurochemical actions and effects on cognition.

Imaging Research Center, Davis School of Medicine, UC-Davis Health System, University of California, Sacramento, CA 95817, USA.
Neuropsychopharmacology (Impact Factor: 7.83). 07/2008; 33(7):1477-502. DOI: 10.1038/sj.npp.1301534
Source: PubMed

ABSTRACT Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term 'modafinil' and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. 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. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.

0 Bookmarks
 · 
132 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric illness often accompanied of cognitive dysfunction which may persist even when patients achieve clinical remission. Currently, cognitive deficits emerge as a potential target because they compromise the functional outcome of depressed patients. The aim of this study was to review data for several potential pharmacological treatments targeting cognition in MDD, resulting from monotherapy or adjunctive treatment. An extensive and systematic Pubmed/Medline search of the published literature until March 2014 was conducted using a variety of search term to find relevant articles. Bibliographies of retrieved papers were further examined for publications of interest. Searches were limited to articles available in English language. We describe studies using modafinil, lisdexamfetamine, ketamine, lanicemine, memantine, galantamine, donepezil, vortioxetine, intranasal oxytocin, omega-3, s-adenosyl-methionine, scopolamine and erythropoietin. From these articles, we determined that there are a number of promising new therapies, pharmacological agents or complementary medicines, but data are just emerging. Drugs and therapies targeting cognitive dysfunction in MDD should prove effective in improving specific cognitive domains and functioning, while ruling out pseudospecificity. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 01/2015; DOI:10.1016/j.euroneuro.2014.12.004 · 3.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The present experiment examined the influence of modafinil on working memory in rats. Control and experimental rats were placed in cages equipped with a running wheel. The study was divided into three periods: 1) habituation, 2) experimental - in which modafinil was orally administered to experimental animals, and 3) withdrawal. Spatial working memory was tested utilizing the Morris Water Maze. Animals were given two trials in each session: 1) a sample trial in which they discovered the location of the platform and 2) a test trial in which they recalled the location of the platform. Platform placement and starting place location of the rats were changed every session. Performance of control animals during sample trials and test trials showed no difference in time to reach the platform; whereas, experimental animals demonstrated faster attainment of the goal during the test trial. In withdrawal, there was no difference in time between the two trials for experimental animals. Wheel running activity of the experimental group was lower than the control group during the experimental period. This study supports the hypothesis that modafinil has a positive effect on working memory in rats. It is suggested that benefits of modafinil can extend beyond its prescribed usage; however, these advantages of modafinil use should be addressed in discussions related to ethical concerns associated with neuroenhancers. Copyright © 2015. Published by Elsevier Inc.
    Physiology & Behavior 02/2015; 142. DOI:10.1016/j.physbeh.2015.02.003 · 3.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies. This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal-chemical perspective. Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of Drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters. Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Drug and Alcohol Dependence 12/2014; 147. DOI:10.1016/j.drugalcdep.2014.12.005 · 3.28 Impact Factor

Full-text (2 Sources)

Download
75 Downloads
Available from
Jun 1, 2014