The present study confirmed the beneficial effect of modafinil on excessive sleepiness in MD, but did not detect a concomitant effect on spontaneous activity as measured by a structured interview of the patients and their partners. This interview, not formally validated, was designed to reflect a clinically relevant and observable increase in daily activity by asking for specific actions. Examples might be that patients went to the theatre after a busy day, when they would otherwise have postponed such a visit, or cleaning up the shed. By asking for specific actions we hoped to distinguish actions from the mere feeling of being active or the intention to become so.
The study was small, leaving open the possibility that minor changes have been missed. The study was also focused on short-term effects and thus it is not able to detect changes of behaviour that take more time to become manifest, but we believe that a fortnight is long enough to detect relevant improvements in activity as defined above. A further consideration is the unblinding we have observed, which was most probably due to a correct perception of an effect on somnolence. This might have confounding effects on the interpretation of intended double-blind studies of modafinil on symptoms other than hypersomnolence. In the present study this does not seem to have happened, as the effect on hypersomnolence was neither related to perceived improved activity, nor to perceived aspects of general health. That many patients and partners reported more activity in addition to less sleepiness when asked why they thought that modafinil or placebo had been used, might be the result of the expectations implied in the aim of the study as discussed with the participants. The structured interview did not detect this increased activity, which we feel speaks in favour of its validity.
In a previous study of 11 patients modafinil improved excessive daytime sleepiness in MD, measured with the Multiple Sleep Latency Test and the Epworth Sleepiness Scale [2
]. Possible effects on spontaneous activity were not considered. MacDonald et al. [3
], in a double-blind cross-over placebo-controlled study of 40 patients with a time-scale identical to ours confirmed the reduction of somnolence as measured by Epworth and Stanford Sleepiness Scales. They also found modafinil-induced decreased fatigue-inertia, and increased vigor-activity, as measured by the Profile of Mood States. The latter findings might predict improved observed activity, but the study did not include this issue and our study did not demonstrate such effect. Using the RAND-36 they also observed enhanced measures of energy and perception of health, but no changes in the other items of the test; the former effects were not confirmed in our study. Talbot et al. [4
] performed a similar double-blind cross-over study of 19 patients selected for hypersomnolence (ESS 10 or more points), using the ESS, a Modified Maintenance of Wakefulness test (MWT), a steering simulator, the Short Form 36 and an “activity diary” as measures. They found a reduction of sleepiness, especially in the MWT, less convincingly in the ESS. The other tests did not show significant changes. Data from the activity diaries are not given.
It is apparent that the symptoms referred to as inertia, reduced initiative, inactivity or apathy are hard to define and even harder to measure. Recently, van der Werf et al. inferred that the lack of correlation between fatigue scores and sleepiness in MD suggests that different pathophysiological mechanisms underlie these clinical manifestations [7
]). We believe that our findings point in the same direction.