Modafinil, (RS)-2-(diphenylmethylsulfinyl)acetamide derivative (Modiodal, Provigil), is a vigilance-promoting
agent which reduces sleep episodes by improving wakefulness. It is approved by the USA FDA for narcolepsy, shiftwork
sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive
airway pressure. Unlike classical psychostimulants such as amphetamine and amphetamine-like compounds, the awaking
effect of modafinil is not associated with a disturbance of nighttime sleep, tolerance, and sensitization. Its precise
mechanism of action is still unclear. In animal studies, modafinil and its analogues have been shown to modify
dopaminergic, noradrenergic, glutamatergic, GABAergic, serotoninergic, orexinergic, and histaminergic pathways.
Besides the approved use in sleep disorders, modafinil has been investigated for the treatment of fatigue, impaired
cognition and some symptoms in a number of other disorders. In particular, clinical studies seem to indicate that the drug
could be particularly successful in the treatment of depression and its use in major depressive and bipolar disorders, has
been suggested. However, the molecular mechanisms underlying this possible effect are still unknown. The present
review firstly summarizes the structure-activity relationship studies and the mechanism of action of modafinil and its
related compounds. Then, it focuses on data demonstrating that modafinil interacts with serotonin neuronal activity in rat
frontal cortex and dorsal raphe nucleus, two brain areas linked together and involved in depression. Preclinical and
clinical evidence of a positive interaction between modafinil and classical antidepressant drugs, is also summarized.