Adrafinil: A novel vigilance promoting agent

Abstract

Adrafinil is a novel drug that is not well known outside of France, where it is used primarily as a vigilance-enhancing agent. Clinical studies strongly indicate that adrafinil has efficacy in improving attention, memory, as well as other deficits resulting from decreased vigilance. Adrafinil has two metabolites, modafinil and CRL 40476. Little is known about CRL 40476. Modafinil, on the other hand, has been much more extensively studied, and the production of modafinil is likely to account for at least part of the effects of adrafinil. Thus, adrafinil has very similar pharmacological effects to modafinil. Moreover, the behavioral effects of adrafinil are more closely tied to the pharmacokinetics of its metabolite modafinil. Most researchers assume that adrafinil works as a selective α1-adrenergic receptor agonist. This belief, however, is challenged by evidence that adrafinil does not produce peripheral adrenergic effects, instances where the actions of adrafinil are not blocked by α1 blockers, and by instances where adrafinil is unable to counteract the effect of α1 blockers. Recent evidence indicates that adrafinil affects amino acid release, generally causing increased release of glutamate and decreased release of GABA. Given the effectiveness of adrafinil in improving performance on psychometric tests and motor function in people with mild cognitive impairment, it is surprising that neither adrafinil nor modafinil have been used in trials with demented patients. In fact, two possible applications deserve careful consideration. One possible application is the treatment of age-associated memory impairment (AAMI). This term was introduced to describe 'medically, neurologically, and psychiatrically healthy persons over 50 years of age who have experienced a gradual decline in the ability to perform certain tasks of daily life dependent on memory' (14,15). A second possible application for adrafinil would be in the treatment of subjects with dementing disorders, such as Alzheimer's disease. This application is not directly suggested from the studies performed thus far, which have precluded examination of severely demented patients because of the subject selection criterion used. In fact, research with canines provides limited support for this possibility. Adrafinil improved discrimination learning in a group of aged dogs; the dogs that showed the greatest improvement in cognitive functioning were those that showed the greatest overall impairment (42). The evidence that modafinil can have neuroprotective effects provides another compelling reason for testing adrafinil in patients with dementing disorders. This study raises at least the possibility that long-term treatment with adrafinil can arrest or even reverse neurodegenerative processes that contribute to dementia. Clearly, however, further preclinical studies are needed before this potential application can be evaluated. Three other therapeutic applications of adrafinil warrant further study. The first application is as a potential therapeutic drug in treatment of Parkinson's (see ref. 30) and another is as a potential treatment for deficits associated with movement disorders (8). Finally, further investigations of the antidepressive effects of adrafinil are warranted. In summary, adrafinil is a novel stimulant that lacks the adverse effects associated with other psychostimulants. It directly affects CNS function, but its mechanism of action is not completely understood. Clinical studies have demonstrated that adrafinil has efficacy as a vigilance-promoting agent. It has also cognitive enhancing potential, and trials on patients with dementing disorders appear warranted.