The search for additional indications for modafinil naturally focused on diseases associated with wake deficits and somnolence. The effects of the drug in an animal model of sleep-disordered breathing suggested that modafinil might be effective in reducing sleepiness associated with sleep apnea,50 and this was subsequently demonstrated in the clinic.51-53 Other disorders where somnolence or sedation was concomitant with the disease, e.g., Parkinson's disease,54-56 myotonic dystrophy,57-60 fibromyalgia,61 amyotrophic lateral sclerosis,62 multiple sclerosis,63 cerebral lymphoma,64 or resulting from the side-effects of other medications such as antidepressants,65 antipsychotics,66 dopaminergic D2 agonists,67,68 opioids,69 or valproic acid,70 have also proven to be amenable to treatment with modafinil.
Likewise modafinil has been applied with equal success to treating the fatigue coexisting with other serious diseases, including multiple sclerosis,71,72 pain,73 and acquired immunodeficiency syndrome (AIDS).74
Because wake and vigilance are essential requirements for attention, learning, and cognition, research on these topics has also been undertaken in animals. Modafinil was found to induce a faster learning rate in a serial spatial discrimination task, demonstrating an improvement of learning processes following acute75,76 and chronic administration in mice77 and facilitating performance on a delayed nonmatching to position swim task in rats.78 In healthy human volunteers without sleep deprivation, modafinil had subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks, especially in lower-performing subjects.79 In addition, in healthy volunteers, modafinil produced a selective improvement of neuropsychological task performance, attributable to an enhanced ability to inhibit prepotent responses, leading to a reduction of impulsive responding, that appears to be beneficial in the treatment of ADHD.80 Based on this result, it was then obvious to try modafinil in ADHD, without any animal prerequisites but by analogy with the established uses of stimulants, even though its mechanism of action was unknown but unquestionably was dissimilar from amphetamine and methylphenidate. Modafinil was found to be effective in ADHD in children81,82 and in adults83,84 and has been approved as Sparlon.
Beyond this application, research focused on diseases in which symptoms could be related to cognition deficits. In the five-choice serial reaction time task of attentional function in rats, modafinil had attention-enhancing effects that may be relevant to the treatment of cognitive deficits in schizophrenia.85 Likewise, in patients with schizophrenia, modafinil produced a significant improvement in attentional set shifting (despite no effect of modafinil on this task being seen in healthy volunteers), that led to the assumption that the compound may have potential as an important therapy for cognitive impairment.86 The results of a preliminary open study suggested that modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition in patients with schizophrenia or schizoaffective disorder.87 Other applications resulted from case observations such as spastic cerebral palsy.88
Based on the activity of modafinil in the forced swim test in animals, considered as predictive of some antidepressant activity in humans, several preliminary clinical studies demonstrated that modafinil was able to enhance the effects of antidepressant drugs, especially in patients with residual tiredness or fatigue.89 It was recently confirmed that modafinil was potentially effective as adjunctive therapy in depressed patients, particularly in those with problematic fatigue and sleepiness.90'91 Adjunct therapy of modafinil at initiation of treatment with a selective serotonin reuptake inhibitor (SSRI) improved the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue.92 These beneficial effects may result from an enhancement by modafinil of the increase of extracellular serotonin levels induced by antidepressant drugs, such as fluoxetine and imipramine, in awake rat93 and a differential enhancement of serotonin efflux in distinct brain regions of the awake rat by modafinil, that could be possibly relevant for wakefulness and depression.94 Modafinil regulated cortical serotonergic transmission, suggesting that the drug could preferentially act by amplifying the electroneurosecretory coupling via mechanisms that do not involve the reuptake processes.95 Such puzzling results are not fully elucidated yet, as modafinil does not affect serotonergic transmission from cortical synaptosomes. Also, the serotonin-releasing effects of modafinil are different from those of either DL-fenfluramine or fluoxetine.96
Despite its stimulant activity, modafinil did not produce reinforcing or rewarding effects and did not modify the effects of cocaine in rats.97 Evaluation for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration demonstrated that the reinforcing and discriminative stimulus effects of modafinil required very high doses.98 The low abuse potential was confirmed via an extensive data set in healthy human volunteers23,99 and in volunteers with a recent history of cocaine abuse where cocaine and methylphenidate, but not modafinil, produced cocaine-like discriminative stimulus, subject-rated, and cardiovascular effects.100
Based on the low potential of addiction and dependence, a preliminary study provided evidence that modafinil improved clinical outcome when combined with psychosocial treatment for cocaine dependence.101 An anecdotal story in a woman outpatient with social phobia and comorbid amphetamine dependence reported that her craving for amphetamines diminished and her anxiety and depression improved without the same 'high' with modafinil that she experienced with amphetamines.102
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