Modafinil improves attentional performance in healthy, non-sleep deprived humans at doses not inducing hyperarousal across species

Abstract

The wake-promoting drug modafinil is frequently used off-label to improve cognition in psychiatric and academic populations alike. The domain-specific attentional benefits of modafinil have yet to be quantified objectively in healthy human volunteers using tasks validated for comparison across species. Further, given that modafinil is a low-affinity inhibitor for the dopamine and norepinephrine transporters (DAT/NET respectively) it is unclear if any effects are attributable to a non-specific increase in arousal, a feature of many catecholamine reuptake inhibitors (e.g., cocaine, amphetamine). These experiments were designed to test for domain-specific enhancement of attention and cognitive control by modafinil (200 and 400 mg) in healthy volunteers using the 5-choice continuous performance task (5C-CPT) and Wisconsin Card Sort Task (WCST). An additional cross-species assessment of arousal and hyperactivity was performed in this group and in mice (3.2, 10, or 32 mg/kg) using species-specific versions of the behavioral pattern monitor (BPM). Modafinil significantly enhanced attention (d prime) in humans performing the 5C-CPT at doses that did not affect WCST performance or induce hyperactivity in the BPM. In mice, only the highest dose elicited increased activity in the BPM. These results indicate that modafinil produces domain-specific enhancement of attention in humans not driven by hyperarousal, unlike other drugs in this class, and higher equivalent doses were required for hyperarousal in mice. Further, these data support the utility of using the 5C-CPT across species to more precisely determine the mechanism(s) underlying the pro-cognitive effects of modafinil and potentially other pharmacological treatments.

Paying attention to attention in depression

“…106 ). It can improve both sustained and selective attention in healthy subjects 116,117 , enhance sustained attention in ADHD patients 118 , and increase feature-based selective attention and clinical symptoms in depressed patients 119 . Finally, the D3 agonist pramipexole has recently been shown to improve sustained attention, particularly in baseline low performers 120 .…”

Efficacy of THN102 (a combination of modafinil and flecainide) on vigilance and cognition during 40‐hour total sleep deprivation in healthy subjects: Glial connexins as a therapeutic target

“…In healthy young non–sleep‐deprived subjects modafinil (100 and 200 mg) significantly enhances performance on planning, accuracy and inhibition tasks, mostly without dose‐dependent effect . The executive processes assessed using the WCST task were improved during sleep deprivation with 400 mg of modafinil while no effect was observed in non–sleep‐deprived subjects with 200 mg and 400 mg . Go errors are typically considered as an indicator of lack of attention, while noGo errors responses are considered as indicators of impulsivity .…”

Amphetamine improves mouse and human attention in the 5-choice continuous performance test

“…Critically, consistency of performance across humans and mice enable research with model organisms for molecular, cellular, and circuit level analyses, which can be used to delineate the neural substrates of attention and potential pathological processes (such as in ADHD or schizophrenia). In mice, 5C-CPT performance was impaired by scopolamine, a non-specific mAChR antagonist (Young et al, 2013), and improved in both mouse and human by D-amp (present data) and by modafinil in humans, a dopamine transporter (DAT) and norepinephrine transporter (NET) inhibitor (Cope et al, 2017). These data corroborate the importance of DAT/NET inhibition in improving attentional functioning.…”