Modafinil: A Review of Neurochemical Actions and Effects on Cognition

Modafinil is an FDA-approved drug with wake-promoting properties. Pre-clinical studies of suggest a complex profile of neurochemical and behavioral effects distinct from amphetamine. The cognitive disease may be a particularly important emerging treatment target for modafinil, in these and other neuropsychiatric disorders.

Modafinil exhibits strong effects on the catecholamine, 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 at subcortical sites of action. It has several neurochemical actions in the brain, which may be related to primary effects on the catecholaminergic system. These effects are in general beneficial for cognitive processes. Overall, is an excellent candidate agent for the treatment of cognitive dysfunction in neuropsychiatric disorders.

INTRODUCTION

The brand name Provigil is a novel wake-up agent in the United States) first marketed in France in the 1990s, as a feature of narcolepsy as a treatment for excessive somnolence. It is popularly classified as psychoactive because of its wake-promoting properties. However, it has shown several effects on physiology and behavior in both animal models and humans, suggesting a different mechanism of action than amphetamine (described in detail below). This includes a reduced liability for misuse and a lower risk of adverse effects on organ systems such as the cardiovascular system.

Among the various potential treatment targets for modafinil found in neurology and psychiatry, cognitive dysfunction is indeed the goal, with the most important requirement for novel pharmacotherapy, the importance of cognition for clinical outcome in these disorders, and of cognition present in the current pharmacopoeia. Given the relative lack of treatment options.

In this review, we briefly summarize the pharmacokinetic profile of modafinil in humans. We then synthesize and attempt complex literature addressing the neurochemical effects of modafinil, particularly as potential treatments for cognitive disease. Finally, we briefly present empirical studies of the clinical effects of modafinil in psychiatric disorders. To evaluate as a candidate agent for.

PHARMACOKINETICS OF MODAFINIL IN HUMANS

In vitro, modafinil is reversible inhibition of CYP2C19 (in human liver microsomes) and a small but concentration-dependent induction of CEP1A2, 2B6 and 3A4 and suppression of 2C9 activity in primary cultures of human hepatocytes (Robertson et al, 2000). ; Wong et al, 1999b). The 2C9 suppression observed in vitro is much less pronounced in vivo. Modafinil metabolite Modafinil sulfone also inhibits 2C19 with comparable Ki. Inhibition of 2C19 may be important for a minority of patients who are 2D6-deficient and are concurrently taking medications that are substrates for 2D6 with adjuvant metabolic degradation via 2C19 (eg, fluoxetine, clomipramine). Wong et al, 1998a), dextroamphetamine (Hellrigel et al, 2002; Wong et al, 1998b) or warfarin (Robertson et al, 2002a).

NEUROCHEMICAL EFFECTS OF MODAFINIL

Modafinil Effects on Catecholamine Systems

Modafinil is structurally unrelated to amphetamine and has a distinct profile of pharmacological and behavioral effects (Table 2). However, a recent positron emission tomography (PET) study of rhesus monkeys found significant binding of DAT ([11C] using CFT) to the striatum (58% occupancy at 8 mg/kg) and norepinephrine (NE) transporter. (NET) ([11C] using MeNER) in thalassemia (8 mg / kg) (et Madras, et 2006).

In addition, using in vitro human monoamine transporter preparations, binding to DAT and NET was confirmed with IC50 <10 microM (and IC50> 500 μM for the 5HT transporter). Xie and Miller, 2007; Xie et al, 2007), and it is possible that TA1 receptor activity mediates some interactions of modafinil with DA neurons.