Modafinil: A Review of Neurochemical Actions and Effects on Cognition

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.

The neuropsychopharmacology of action inhibition: cross-species translation of the stop-signal and go/no-go tasks

“…In addition, the SSRT-improving specificity of noradrenergic manipulations is so similar to the pattern of effects of modafinil on this task that it would not be unreasonable to suggest that modafinil also improves SSRT via noradrenaline action. Whilst modafinil exhibits effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin and histamine systems in the brain (Minzenberg and Carter 2008), the evidence reviewed in this paper suggests that it exerts its action over SSRT via noradrenaline. However, the effects of noradrenaline and, thus, the possible effects of modafinil on action cancellation may not be modulated via the α2a-adrenergic receptor specifically because guanfacine had no effect on SSRT in healthy adults (Muller et al 2005) or in rats (Bari et al, unpublished findings; Fig.…”

The effects of modafinil treatment on neuropsychological and attentional bias performance during 7-day inpatient withdrawal from methamphetamine dependence.

“…Animal and blinded controlled trials in healthy and nonpsychiatric populations (e.g., narcolepsy) have demonstrated dose-related effects on cognition when moving from 100 mg to 200 mg (Minzenberg & Carter, 2007).…”

“…The pharmacological mechanism(s) of modafinil's action has yet to be clearly determined (see Minzenberg & Carter, 2007, for a review), with effects on multiple neurotransmitter systems including catecholamine, serotonin, glutamate, GABA, orexin, and histamine systems. The cognitive enhancing effects of modafinil have been associated with its action on the binding (or blocking) of dopamine and norepinephrine transporters (Hermant, Rambert, & Duteil, 1991;Madras et al, 2006), and resulting in increased extracellular dopamine in cortical regions critical to cognition (Volkow et al, 2009).…”

“…More recently, modafinil has been used to treat cognitive dysfunction in conditions such as attention-deficit/hyperactivity disorder (ADHD; Greenhill et al, 2006;Kahbazi et al, 2009), schizophrenia (Hunter, Ganesan, Wilkinson, & Spence, 2006;Morein-Zamir, Turner, & Sahakian, 2007;Turner, Clark, Pomarol-Clotet, et al, 2004) and where fatigue is a side effect of treating the principal condition (Minzenberg & Carter, 2007). We are not aware of any published research examining the effect of modafinil on drug-dependent groups, and the clinical trials of modafinil for cocaine and MA dependence (De La Garza, Zorick, London, & Newton Heinzerling (2010);McElhiney et al, 2009;McGregor et al, 2008;Shearer et al, 2009) have not examined cognitive performance.…”

Cognitive Remediation for Schizophrenia

“…106) Modafinil and d-amphetamine have promising pro-cognitive effects, though their clinical use for this purpose in schizophrenia patients remains to be established. 107,108) It is an intriguing, though thus far untested, possibility that while pharmacological agents in and of themselves may have modest efficacy on cognitive deficits in schizophrenia, they may prove to have synergistic effects when used in combination with psychosocial approaches to cognitive remediation.…”