Modafinil modulates anterior cingulate function in chronic schizophrenia. The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia Modafinil activates cortical and subcortical sites in the sleep-deprived state. Modafinil Improves Cognition and Attentional Set Shifting in Patients with Chronic Schizophrenia Modafinil improves alertness, vigilance, and executive function during simulated night shifts. Modafinil Alters Intrinsic Functional Connectivity of the Right Posterior Insula: A Pharmacological Resting State fMRI Study Effects of Modafinil on Emotional Processing in First Episode Psychosis Modafinil Attenuates Disruptions in Cognitive Performance During Simulated Night-Shift Work Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition Modafinil affects mood, but not cognitive function, in healthy young volunteers. Effects of Modafinil on Wakefulness and Executive Function in Patients With Narcolepsy Experiencing Late-Day Sleepiness Cognitive enhancing effects of modafinil in healthy volunteers Effects of modafinil on working memory processes in humans Cerebral blood flow changes in man by wake-promoting drug, modafinil: a randomized double blind study. Effect of Modafinil on Learning and Task-Related Brain Activity in Methamphetamine-Dependent and Healthy Individuals Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial
BACKGROUND Schizophrenia is associated with widespread cognitive deficits that have an impact on social function . Modafinil promotes wakefulness and is reported to enhance cognition . AIMS To study the acute effects of modafinil administration upon brain activity and cognitive performance in people with chronic schizophrenia . METHOD In a r and omised double-blind placebo-controlled crossover design , 19 patients received either modafinil ( 100 mg ) or placebo prior to undertaking a working memory task with functional magnetic resonance imaging . RESULTS Seventeen patients completed the study and another underwent acute relapse 4 days post-drug . Modafinil administration was associated with significantly greater activation in the anterior cingulate cortex during the working memory task . The anterior cingulate cortex signal correlated with cognitive performance , although only a subset of patients exhibited ' enhancement ' . CONCLUSIONS Modafinil modulates anterior cingulate cortex function in chronic schizophrenia but its beneficial cognitive effects may be restricted to a subset of patients requiring further characterisation Modafinil is a selective wakefulness-promoting agent that has been shown to enhance cognitive performance under conditions of sleep deprivation but which has equivocal effects in normal young volunteers . In a double-blind parallel group design study , 45 non-sleep-deprived middle-aged volunteers ( 20 men and 25 women , aged 50 - 67 years ) were r and omly allocated to receive two capsules containing placebo , 100 or 200 mg modafinil , and 3 h later they completed  100 mm visual analogue scales of mood and bodily symptoms  , before and after an extensive battery of cognitive tests [ pen and paper and the Cambridge Neuropsychological Test Automated Battery ( CANTAB ) ] . There were no significant treatment-associated changes in ratings of mood or bodily symptoms and no significant effects on most of the cognitive tests used in this study . The group treated with modafinil ( 200 mg ) was significantly faster in a simple colour naming of dots and also significantly better in a test of constructional ability ( Clock Drawing Test ) compared with the placebo group . However , subjects in the 200-mg group also made significantly more total errors in the Intra/Extradimensional Set Shift ( ID/ED ) task than both the other groups . Thus , this study found limited evidence of cognitive-enhancing properties of modafinil in healthy middle-aged volunteers Patients with schizophrenia experience cognitive impairments associated with hypofunctioning of the frontal cortex . Modafinil , a novel wake-promoting agent , works through the sleep – wake centers of the brain to activate the cortex . This 4-week , open-label , pilot study evaluated adjunct modafinil in patients with schizophrenia or schizoaffective disorder . Eleven patients received once-daily oral doses of modafinil ( 100 mg/day , days 1–14 ; 100 or 200 mg/day , days 15–28 ) in addition to antipsychotic therapy . Modafinil significantly improved patients ' global functioning as assessed by a blinded clinician ( week 2 , P = 0.026 ; week 4 , P = 0.012 ) and the investigator ( week 3 , P = 0.035 ) . Modafinil significantly improved overall clinical condition , with 64 % and 82 % of patients rated as clinical ly improved at week 4 by a blinded clinician and the investigator respectively . Eighty-nine percent of patients considered themselves to be clinical ly improved . Modafinil significantly improved fatigue ( P = 0.025 , week 3 ) and tended to improve cognitive functioning scores . Control of positive symptoms was well maintained . Treatment-emergent adverse events included dry mouth ( n = 2 ) and hallucinations ( n = 2 ) . One patient discontinued the study because of hallucinations that were considered to be possibly related to inadequate antipsychotic therapy . Although preliminary , these results suggest modafinil may be an effective and well-tolerated adjunct treatment that improves global functioning and clinical condition , and reduces fatigue in patients with schizophrenia or schizoaffective disorder . Additional controlled studies are warranted UNLABELLED SUBJECT OBJECTIVES : To assess the effect of the wake-promoting drug modafinil on working memory and brain activation in the executive network , following a single night of sleep deprivation . DESIGN R and omized , placebo-controlled , 4-arm , double-blind evaluation of a single 200-mg dose of modafinil on working memory ( 1- , 2- , and 3-back)-related functional brain activation and performance following overnight sleep deprivation . SETTING General Clinical Research Center , Biomedical Imaging Center . SUBJECTS Eight medication-free men , aged 21 to 35 years . INTERVENTIONS Overnight sleep deprivation , single-dose 200-mg modafinil , functional magnetic resonance imaging MEASUREMENTS AND RESULTS Brain activation patterns and regional signal intensity based on the blood-oxygen level-dependent signal were assessed . The following reaction times were used as measures of performance : ( 1 ) attention in the scanner before functional scanning , ( 2 ) " back " responses during the active-task block , and ( 3 ) attention during the baseline task block . Contrast of activation maps among conditions revealed sleep-deprivation and drug effects , and their interactions . Performance in the deprived state was enhanced by modafinil only at an intermediate ( 2-back ) level of task difficulty and was associated with the recruitment of increased cortical activation volumes . Strong and consistent individual differences in performance were noted on the working memory tasks . CONCLUSIONS Modafinil effectively counters the adverse effects of overnight sleep deprivation on working memory but only when task difficulty is moderate , recruiting extensive areas in the executive network to do so . Interindividual differences in working-memory performance are stable trait characteristics Modafinil , a novel cognitive enhancer , selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder ( ADHD ) . It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission . The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia . Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind , r and omized , placebo-controlled crossover study using a 200 mg dose of modafinil . Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD . Improvement was seen on short-term verbal memory span , with trends towards improved visual memory and spatial planning . This was accompanied by slowed response latency on the spatial planning task . No effect on stop-signal performance was seen . Importantly , significant improvement in attentional set shifting was seen , despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients . Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia , particularly because of its beneficial effects on attentional set shifting STUDY OBJECTIVES To assess the effect of 200 mg of modafinil compared to placebo on alertness , neurobehavioral performance , and executive function during 4 consecutive simulated night shifts . DESIGN Double-blind , r and omized , parallel groups . SETTING Sleep research facility . PARTICIPANTS 32 male and female volunteers between the ages of 18 and 55 years . INTERVENTIONS 200 mg of modafinil or placebo given nightly on the 4 consecutive simulated night shifts . MEASUREMENTS AND RESULTS Subjects were r and omly assigned to 1 of the 2 treatment conditions , following medical , psychiatric , and polysomnographic screening . On 4 consecutive nights , subjects took study drug at 2200 , and then from about 2300 to 0730 participated in a simulated night shift that included the Maintenance of Wakefulness Test , Psychomotor Vigilance Test , Digit Symbol Substitution Test , measures of subjective alertness , and multiple executive-function measures . At 0800 , daytime sleep periods were recorded polysomnographically for 6 to 8 hours . Alertness -- as measured by the MWT , vigilance and reaction time as indexed by Psychomotor Vigilance Test lapses , and slowest 10 % of reaction times-- and 3 executive-function tasks showed significant enhancement with modafinil versus placebo .  Subjective sleepiness at night and some performance measures did not show consistent treatment differences . Daytime sleep showed minimal differences between conditions . CONCLUSIONS The physiologic sleepiness and neurobehavioral deficits that occurred during the hours of a typical night shift were clearly attenuated by modafinil . Modafinil also had beneficial effects on some measures of executive function Background Modafinil is employed for the treatment of narcolepsy and has also been , off-label , used to treat cognitive dysfunction in neuropsychiatric disorders . In a previous study , we have reported that single dose administration of modafinil in healthy young subjects enhances fluid reasoning and affects resting state activity in the Fronto Parietal Control ( FPC ) and Dorsal Attention ( DAN ) networks . No changes were found in the Salience Network ( SN ) , a surprising result as the network is involved in the modulation of emotional and fluid reasoning . The insula is crucial hub of the SN and functionally divided in anterior and posterior subregions . Methodology Using a seed-based approach , we have now analyzed effects of modafinil on the functional connectivity ( FC ) of insular subregions . Principal Findings Analysis of FC with resting state fMRI ( rs-FMRI ) revealed increased FC between the right posterior insula and the putamen , the superior frontal gyrus and the anterior cingulate cortex in the modafinil-treated group . Conclusions Modafinil is considered a putative cognitive enhancer . The rs-fMRI modifications that we have found are consistent with the drug cognitive enhancing properties and indicate subregional targets of action . Trial Registration Clinical Trials.gov BACKGROUND Emotional impairments are important determinants of functional outcome in psychosis , and current treatments are not particularly effective . Modafinil is a wake-promoting drug that has been shown to improve emotion discrimination in healthy individuals and attention and executive function in schizophrenia . We aim ed to establish whether modafinil might have a role in the adjuvant treatment of emotional impairments in the first episode of psychosis , when therapeutic endeavor is arguably most vital . METHODS Forty patients with a first episode of psychosis participated in a r and omized , double-blind , placebo-controlled crossover design study testing the effects of a single dose of 200 mg modafinil on neuropsychological performance . Emotional functions were evaluated with the  emotional face recognition test  , the  affective go-no go task  , and the  reward and punishment learning test . Visual analogue scales were used throughout the study to assess subjective mood changes . RESULTS Modafinil significantly improved the recognition of sad facial expressions ( z = 2.98 , p = .003 ) . In contrast , there was no effect of modafinil on subjective mood ratings , on tasks measuring emotional sensitivity to reward or punishment , or on interference of emotional valence on cognitive function , as measured by the affective go-no go task . CONCLUSIONS Modafinil improves the analysis of emotional face expressions . This might enhance social function in people with a first episode of psychosis Common complaints among shift workers are sleep disruptions and increased sleepiness while working , which may contribute to shift workers being more susceptible to diminished performance and work-related accidents . The purpose of this double-blind , within-participant study was to examine the effects of the alerting agent modafinil on cognitive/psychomotor performance , mood , and measures of sleep during simulated shift work . In all , 11 participants completed this 23-day residential laboratory study . They received a single oral modafinil dose ( 0 , 200 , 400 mg ) 1 h after waking for three consecutive days under two shift conditions : day shift and night shift . Shifts alternated three times during the study , and shift conditions were separated by an ‘ off ’ day . When participants received placebo , cognitive performance and subjective ratings of mood were disrupted during the night shift , relative to the day shift . Objective and subjective measures of sleep were also disrupted , but to a lesser extent . Modafinil reversed disruptions in cognitive performance and mood during the night shift . While modafinil produced few effects on sleep measures during the night shift , the largest dose produced several sleep alterations during the day shift . These data demonstrate that abrupt shift changes produced cognitive performance impairments and mood disruptions during night shift work . Therapeutic doses of modafinil attenuated night-shift-associated disruptions , but the larger dose produced some sleep impairments when administered during day-shift work Modafinil differs from other arousal-enhancing agents in chemical structure , neurochemical profile , and behavioral effects . Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition , but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior , too . We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions . Healthy volunteers were enrolled in this double-blinded placebo-controlled trial ( 100 mg/day for 7 days ) . They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks — a working memory ( WM ) task and a variable attentional control ( VAC ) task . A clinical assessment that included measurement of blood pressure , heart rate , the Hamilton anxiety scale , and the profile of mood state ( POMS ) question naire was also performed on each test day . BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition . During executive cognition tasks , a WM task and a VAC task , modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate . Although not statistically significant , there were trends for reduced anxiety , for decreased fatigue-inertia and increased vigor-activity , as well as decreased anger-hostility on modafinil . Modafinil in low doses has a unique physiologic profile compared with stimulant drugs : it enhances the efficiency of prefrontal cortical cognitive information processing , while dampening reactivity to threatening stimuli in the amygdala , a brain region implicated in anxiety Modafinil is a selective wakefulness-promoting agent with beneficial effects in narcolepsy and conditions of sleep deprivation . In a double-blind study we examined its effects in 30 healthy , non sleep-deprived students ( 19 men and 11 women , aged 19 - 23 years ) , who were r and omly allocated to placebo , 100 or 200 mg modafinil and 3 h later completed 100 mm visual analogue scales relating to mood and bodily symptoms , before and after an extensive battery of cognitive tests ( pen and paper and CANTAB ) . There were no significant differences between the three treatment groups on any of the cognitive tests used in this study . There was a significant post-treatment change in the factor measuring ' somatic anxiety ' and in individual ratings of ' shaking ' , ' palpitations ' , ' dizziness ' , ' restlessness ' , ' muscular tension ' , ' physical tiredness ' and ' irritability ' , which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups . Further changes in mood were revealed after the stress of cognitive testing , with the 100 mg group showing greater increases in the ' psychological anxiety ' and the ' aggressive mood ' factors ( as measured from the Bond and Lader scales ) Objectives : A modafinil daily dosing strategy promotes wakefulness in narcolepsy patients experiencing excessive daytime sleepiness ; however , some patients may continue to experience late-day sleepiness . Excessive sleepiness in narcolepsy is associated with cognitive impairment . Modafinil has improved executive function in other models of excessive sleepiness . This study evaluated the effects of once-daily vs. split doses of modafinil on wakefulness and of combined doses on executive function in narcolepsy patients experiencing late-day sleepiness despite satisfactory modafinil treatment earlier in the day . Methods : After a 2-week washout , 24 patients received 3 weeks of double-blind treatment with modafinil 400-mg once daily ( 7 AM ) plus placebo ( noon ) or modafinil 600-mg split dose ( 400 mg , 7 AM ; 200 mg , noon ) . Assessment s included a Maintenance of Wakefulness Test ( MWT ) for individual regimens and the Wisconsin Card Sort Test ( WCST ) for treatments combined . Results : Modafinil 600-mg split dose was significantly more effective than modafinil 400-mg once daily in improving late-day MWT scores ( 5 PM–7 PM ; P < 0.05 ) . Significant mean ( ± SEM ) reductions from baseline of 8.2 ± 2.7 in the total number of errors and 5.9 ± 1.9 in total percent of errors ( P < 0.05 , both ) were demonstrated for modafinil on the WCST . Modafinil was well tolerated ; adverse events included headache ( n = 1 ) , emotional lability ( n = 1 ) , bronchitis ( n = 1 ) , and accidental injury ( n = 2 ) , with no reports of insomnia . Conclusions : For patients with residual late-day sleepiness associated with narcolepsy , an additional 200-mg dose of modafinil taken at midday was effective in sustaining wakefulness throughout the entire waking day . Treatment with modafinil also significantly improved executive function Abstract Rationale . Modafinil , a novel wake-promoting agent , has been shown to have a similar clinical profile to that of conventional stimulants such as methylpheni date . We were therefore interested in assessing whether modafinil , with its unique pharmacological mode of action , might offer similar potential as a cognitive enhancer , without the side effects commonly experienced with amphetamine-like drugs . Objectives . The main aim of this study was to evaluate the cognitive enhancing potential of this novel agent using a comprehensive battery of neuropsychological tests . Methods . Sixty healthy young adult male volunteers received either a single oral dose of placebo , or 100 mg or 200 mg modafinil prior to performing a variety of tasks design ed to test memory and attention . A r and omised double-blind , between-subjects design was used . Results . Modafinil significantly enhanced performance on tests of digit span , visual pattern recognition memory , spatial planning and stop-signal reaction time . These performance improvements were complemented by a slowing in latency on three tests : delayed matching to sample , a decision-making task and the spatial planning task . Subjects reported feeling more alert , attentive and energetic on drug . The effects were not clearly dose dependent , except for those seen with the stop-signal paradigm . In contrast to previous findings with methylpheni date , there were no significant effects of drug on spatial memory span , spatial working memory , rapid visual information processing or attentional set-shifting . Additionally , no effects on paired associates learning were identified . Conclusions . These data indicate that modafinil selectively improves neuropsychological task performance . This improvement may be attributable to an enhanced ability to inhibit pre-potent responses . This effect appears to reduce impulsive responding , suggesting that modafinil may be of benefit in the treatment of attention deficit hyperactivity disorder Rationale Modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy or attention deficit disorders and to enhance vigilance in sleep-deprived military personal . So far , underst and ing of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete . Objectives The aim of this study was to investigate the effects of modafinil on working memory processes in humans and how they are related to noradrenergic stimulation of the prefrontal cortex . Methods Sixteen healthy volunteers ( aged 20–29 years ) received either modafinil 200 mg or placebo using a double blind crossover design . Two computerized working memory tasks were administered , a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths . The battery was supplemented by st and ardized paper pencil tasks of attentional functions . Results Modafinil significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions , but not in the maintenance condition of the numeric task . Analyses of reaction times showed no speed-accuracy trade-off . Attentional control tasks ( letter cancellation , trail-making , catch trials ) were not affected by modafinil . Conclusions In healthy volunteers without sleep deprivation modafinil has subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks , especially in lower performing subjects . Overlapping attentional and working memory processes have to be considered when study ing the noradrenergic modulation of the prefrontal cortex To investigate the effects of a wake-promoting drug , modafinil on regional cerebral blood flow ( rCBF ) in healthy volunteers , we performed (99m)Tc-ethylcysteinate dimer single photon emission computed tomography ( SPECT ) before and after modafinil or placebo administration . Twenty-one healthy subjects received single doses of 400 mg modafinil or placebo in a double blind r and omized crossover study design . Administrations of modafinil or placebo in a subject were separated by a 2-week washout . Brain SPECT was performed twice before and 3 h after modafinil or placebo administration . For statistical parametric mapping analysis , all SPECT images were spatially normalized to the st and ard SPECT template and then smoothed using a 12-mm full width at half-maximum Gaussian kernel . The paired t-test was used to compare pre- versus post-modafinil and pre- versus post-placebo SPECT images . Differences in rCBF between post-modafinil and post-placebo conditions were also tested . Modafinil decreased Epworth and Stanford sleepiness scales whereas placebo did not . The post-modafinil condition was associated with increased rCBF in bilateral thalami and dorsal pons , whereas the post-placebo condition showed increased rCBF in a smaller area of the dorsal pons when compared with the drug naïve baseline condition . Compared with the post-placebo condition , the post-modafinil condition showed higher rCBF in bilateral frontopolar , orbitofrontal , superior frontal , middle frontal gyri , short insular gyri , left cingulate gyrus , left middle/inferior temporal gyri , left parahippocampal gyrus , and left pons . In healthy volunteers , modafinil increased wakefulness and rCBF in the arousal-related systems and in brain areas related to emotion and executive function Methamphetamine (MA)-dependent individuals exhibit deficits in cognition and prefrontal cortical function . Therefore , medications that improve cognition in these subjects may improve the success of therapy for their addiction , especially when cognitive behavioral therapies are used . Modafinil has been shown to improve cognitive performance in neuropsychiatric patients and healthy volunteers . We therefore conducted a r and omized , double-blind , placebo-controlled , cross-over study , using functional magnetic resonance imaging , to examine the effects of modafinil on learning and neural activity related to cognitive function in abstinent , MA-dependent , and healthy control participants .  Modafinil ( 200 mg ) and placebo were administered orally ( one single dose each ) , in counterbalanced fashion , 2 h before each of two testing sessions . Under placebo conditions , MA-dependent participants showed worse learning performance than control participants . Modafinil boosted learning in MA-dependent participants , bringing them to the same performance level as control subjects ; the control group did not show changes in performance with modafinil . After controlling for performance differences , MA-dependent participants showed a greater effect of modafinil on brain activation in bilateral insula/ventrolateral prefrontal cortex and anterior cingulate cortices than control participants . The findings suggest that modafinil improves learning in MA-dependent participants , possibly by enhancing neural function in regions important for learning and cognitive control . These results suggest that modafinil may be a suitable pharmacological adjunct for enhancing the efficiency of cognitive-based therapies for MA dependence Cognitive impairment seems to be highly prevalent in patients with advanced cancer .  Modafinil , a novel vigilance and wake-promoting agent , may be an alternative treatment . We wanted to investigate this treatment on attentional and psychomotor dysfunction in cancer patients . 28 cancer patients with a tiredness score of 50 mm or more on a scale of 0 to 10 ( 0=no tiredness , 10=worst possible tiredness ) and Karnofsky Performance Status 40—70 were included . All medications were kept stable during the trial despite short acting opioids for breakthrough pain . On day 1 the patients were r and omly assigned to receive 200 mg Modafinil orally or placebo and on day 4 they crossed-over to the alternative treatment .  Finger Tapping Test ( FTT ) , Trail Making Test ( TMT ) and Edmonton Symptom Assessment System ( ESAS ) were evaluated before tablet intake and again 4 , 5 hours after . FTT for the dominant h and as well as TMT were statistically significantly improved on modafinil ( p-values=0.006 and 0.042 , respectively ) . On ESAS , depression and drowsiness also improved statistically significantly ( p-values=<0.001 and 0.038 , respectively ) . Modafinil in a single dose regimen was significantly superior to placebo regarding two cognitive tests of psychomotor speed and attention . Furthermore subjective scores of depression and drowsiness were significantly improved by modafinil
A review of its effects in schizophrenia suggests that modafinil facilitates cognitive functions , with pro-mnemonic effects and problem solving improvements .
The systematic review on the neurochemical modulation of the modafinil suggests that its mnemonic enhancing properties might be the result of glutamatergic and dopaminergic increased neuronal activation in the hippocampus and in the prefrontal cortex respectively .
Other neurotransmitters were also activated by modafinil in various limbic brain areas , suggesting that the drug acts on these brain regions to influence emotional responses .
Modafinil is a central nervous system wake promoting agent used for the treatment of excessive daytime sleeping .
Its vigilance promoting properties and low abuse potential has intrigued the scientific community and has led to use it as a cognitive enhancer , before its neural functions were understood .
Here , we review the effects of modafinil in human cognition and emotion and its specific actions on symptoms in patients with schizophrenia and whether these are consistently effective throughout the literature .
We also performed a systematic review on the effects of modafinil on neurotransmitter signalling in different areas of the brain in order to better underst and the neuromechanisms of its cognitive and emotional enhancing properties .