Modafinil improves attentional performance in healthy, non-sleep deprived humans at doses not inducing hyperarousal across species
Introduction
Cognitive deficits, particularly in the domains of attention and cognitive control, are key features of multiple psychiatric illnesses, e.g., schizophrenia (SCZ), bipolar disorder (BD), and attention deficit hyperactivity disorder (ADHD). Traditional treatments such as methylphenidate have been considered as therapeutic agents in the treatment of impaired attention and cognitive control. There has been longstanding reticence to use these drugs for individuals with SCZ and BD however, since they can exacerbate many of their symptoms (Chiarello and Cole, 1987). Further, given the mechanism of action of stimulants in potently blocking or reversing the dopamine transporter (DAT), these drugs carry a high potential for abuse (Volkow and Swanson, 2003). The lack of pro-cognitive pharmacotherapies with low abuse potential stands as a critical treatment gap for individuals suffering from these illnesses (Fusar-Poli et al., 2015, Geddes and Miklowitz, 2013, Lindenmayer et al., 2013).
Modafinil, a low potency inhibitor of the DAT and norepinephrine transporter (NET), is a Federal Drug Administration-approved compound that was developed to increase wakefulness in the treatment of narcolepsy (Madras et al., 2006, Volkow et al., 2009). This drug however, is increasingly used off-label to remediate deficient attention and cognitive control in psychiatric patients (Minzenberg and Carter, 2008), as well as a cognition-enhancing aid in academic institutions (Sahakian and Morein-Zamir, 2015). Certainly, there are myriad findings reporting modafinil-induced improved working memory, cognitive control, and sustained attention in healthy sleep-deprived volunteers, psychiatric populations, and rodents (Sahakian and Morein-Zamir, 2015). Improved cognition in non-sleep deprived healthy adults has been rarely observed however (Baranski et al., 2004, Battleday and Brem, 2015, Muller et al., 2004), except at the highest levels of difficulty in working memory, or in higher order planning and decision-making tasks (Battleday and Brem, 2015, Muller et al., 2013, Turner et al., 2003). Modafinil-induced improvements in the attentional domain have yet to be observed in healthy adults, which contrasts with what has been seen with high-potency DAT inhibitors such as amphetamine (Linssen et al., 2014, Smith and Farah, 2011).
In addition to improving attention, high-potency DAT inhibitors such as amphetamine also increase arousal (Bensadoun et al., 2004, Berridge, 2006, Kalivas and Volkow, 2005), an effect linked to its abuse potential (Sahakian and Morein-Zamir, 2015). In both healthy human volunteers and mice, d-amphetamine increases activity in the behavioral pattern monitor (BPM) at clinically relevant doses (Minassian et al., 2016). Similarly, modafinil increases activity in the mouse BPM (Young et al., 2011a) and increases motivation in mice as measured by progressive ratio breakpoint (Young and Geyer, 2010) at similar doses (32 mg/kg). It would therefore be important to separate the potential effect of modafinil on attention from its effects on arousal. In terms of feedback-related decision-making, amphetamine increased safe lever choice preference (preference for low risk, low reward option), while the more selective DAT inhibitor GBR12909 worsened performance, and modafinil had no effect in a mouse consolidation-dependent Gambling Task (van Enkhuizen et al., 2013b). This suggests a separation of the effect of modafinil from other DAT inhibitors in a risk-based decision-making task. The effect of modafinil on various psychiatric-related behaviors, however, remains unclear. The use of cross-species tasks would enable future studies to investigate mechanism-related effects of modafinil in rodents using neuroscience tools not available for testing in humans.
In an attempt to parse these potential domains of effect, we assessed the effects of clinically relevant doses of modafinil in healthy, non-sleep deprived human volunteers in the five-choice continuous performance task (5C-CPT), Wisconsin Card Sort Task (WCST), and the human BPM. These tests are validated for the assessment of attention and cognitive control (Cope et al., 2016, Lustig et al., 2013), and arousal and exploration (Minassian et al., 2011, Perry et al., 2009, van Enkhuizen et al., 2013a), respectively. We also determined the effects of modafinil on the arousal and exploratory behavior of male and female mice at doses that are directly comparable to those used in human testing. Given the separation of effects for more selective DAT inhibitors, we hypothesized that modafinil would improve attention without inducing hyperarousal.
Section snippets
Volunteer recruitment
Procedures were approved by The University of California San Diego (UCSD) School of Medicine's institutional review board. Using online advertisements and flyers posted throughout the community, 61 male and female participants were recruited according to the following inclusion criteria: 1) Ages 18–35; 2) In good general health; 3) No lifetime history of an axis I or axis II disorder; 4) No first-degree relative with a history of psychotic or mood disorder; and 5) No specific contraindications
Demographics and treatment randomization
Demographic information and treatment group sample sizes are reported in Table 2. Although a greater number of female participants participated in this study, the gender difference did not reach statistical significance (Pearson χ2(1,62) = 1.61, p = 0.20). There were more females than males in the modafinil groups; this difference approached statistical significance (Fisher's Exact Test (2,62) = 4.43, p = 0.11). Participants did not differ significantly in terms of age (F(2,61) = 1.32, n.s.) or
Discussion
Here, we report that modafinil improved 5C-CPT performance. Further, enhancement of attention/cognitive control was achieved at doses that did not induce hyperarousal in either healthy volunteers or mice. Therefore, it appears that the pro-cognitive effects of modafinil may be domain-specific, occurring independently from the levels of arousal induced by similar drugs, supporting its use as a pro-cognitive pharmacotherapy with a likely limited abuse potential.
Modafinil significantly improved
Conclusions
In summary, it is clear that modafinil effectively enhances cognitive ability within the domain of attention and cognitive control in healthy adult volunteers. Further, this pro-cognitive effect is domain-specific insofar as it is achieved at doses that did not result in hyperactivity. Although the precise mechanism underlying this effect remains to be determined, the availability of rat and mouse 5C-CPTs (Barnes et al., 2012a, Barnes et al., 2012b, Young et al., 2015, Young et al., 2011b)
Disclosure of biomedical financial interests and potential conflicts of interest
Dr. Geyer has received consulting compensation from Lundbeck, Omeros, Otsuka, and Sunovion, and holds an equity interest in San Diego Instruments. Dr. Young has received funding from Cerca Insights and Lundbeck Ltd, and has received consulting compensation for Amgen, and honoraria from Arena Pharmaceuticals and Sunovion. Drs. Cope, Perry, Minassian, and MacQueen, plus Ms. Kreitner and Milienne-Petiot report no biomedical financial interests or potential conflict of interest.
Acknowledgements
We thank all of the participants who volunteered for these studies, which were made possible by funding from NIMH grants R01MH104344-03, UH2MH109168–01, R01 MH071916, and T32MH018399-30, as well as by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center. They have full control of all primary data. The authors thank Dr. Harriet De Wit for her assistance in designing this study, and Mahalah Buell, Elise Winbrock, and Karen Kloezeman for their contributions
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