Effects Of Modafinil Research Articles

Depression-like deficits in rats improved by subchronic modafinil

Attentional and sensorimotor gating deficits in human depression are observed as residual symptoms irrespective of antidepressant treatment. Clinical studies point to a benefit of modafinil in depression. No data are available on modafinil effects in depression-like animal models. We investigated effects of modafinil on attention and sensorimotor gating after subchronic treatment during a restraint stress protocol inducing depression-like changes in rats. Effects of modafinil were investigated (a) acutely in the forced swim test (FST) 1 h after administration of drug or placebo and (b) in a further experiment on cognition-related behaviour in rats after induction of depression-like changes using a restraint stress protocol for 15 days. Beginning from day 10, one restrained (R) and one non-restrained (NR) group were treated with modafinil (R-M and NR-M groups) and two groups with placebo (R-P and NR-P groups). At the end of protocol, behavioural testing was performed under conditions of nearly drug-free plasma. Depression-like behaviour was examined in the FST. Selective attention and sensorimotor gating were investigated as social novelty discrimination (SND) and prepulse inhibition (PPI) of acoustic startle response. Restraint led to reduced body weight, decreased mobility in the FST and impaired cognitive capabilities in the SND and the PPI. Subchronic modafinil treatment reversed restraint-induced deficits in the FST, the SND and PPI, whereas it was without effect on body weight. The improvement of impaired attentional and information-processing functions under depression-like conditions suggests a benefit of modafinil in treatment of cognitive residual symptoms in affective disorders.

P.3.17 The effects of modafinil on cognitive and emotional functions in the first episode of psychosis

P.3.17 The effects of modafinil on cognitive and emotional functions in the first episode of psychosis

Effects of Psychostimulants on Alertness and Spatial Bias in Healthy Participants

Converging evidence from neuropsychological and neuroimaging studies suggests that the ability to maintain an alert, ready-to-respond state is mediated by a network of right-hemisphere frontal and parietal cortical areas. This right lateralization may help to explain why visuospatial hemineglect, a cluster of deficits in detecting and responding to contralesional stimuli, is more common and persistent after right-hemisphere lesions. Indeed, it has been hypothesized that this asymmetry reflects a direct, functional link between alertness and spatial attention. In the present study, we investigated whether a pharmacologically induced increase in alertness would influence lateral bias in healthy people. Eighteen healthy participants were each given placebo or the psychostimulant drugs methylphenidate 40 mg or modafinil 400 mg on separate days and completed an hour-long version of the spatially sensitive landmark task. For those participants who demonstrated the expected alerting effect of modafinil, there was a significant Condition by Time interaction, consistent with the effects of the drug resisting time-on-task rightward drifts in spatial bias in the placebo condition. In contrast, no effect of methylphenidate on spatial bias was observed. These results suggest that spatial bias may be modulated by a psychostimulant-induced increase in alertness, supporting the hypothesis of a direct, functional link between right-hemisphere systems controlling alertness and visuospatial attention.

Evidence for the Involvement of Dopamine Transporters in Behavioral Stimulant Effects of Modafinil

Modafinil is prescribed for numerous medical conditions, but the drug's mechanism of action is unclear. Here, we examined the interaction of modafinil with receptors and transporters in vitro and compared pharmacological effects of the drug with those produced by indirect dopamine (DA) agonists 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) and (+)-methamphetamine (METH). Modafinil was screened at various receptors and transporters using binding assays. Transporter-mediated uptake and release were examined in rat brain synaptosomes. Effects of modafinil on motor activity and neurochemistry were determined in rats undergoing in vivo microdialysis in nucleus accumbens. Of the receptors and transporters assayed, modafinil displayed measurable potency only at DA transporters (DAT), inhibiting [(3)H]DA uptake, with an IC(50) value of 4.0 microM. Accordingly, modafinil pretreatment (10 microM) antagonized METH-induced release of the DAT substrate [(3)H]1-methyl-4-phenylpyridinium. Intravenous modafinil (20 and 60 mg/kg) produced dose-dependent increases in motor activity and extracellular DA, without affecting serotonin (5-HT). Analogous results were observed for GBR12909 (1 and 3 mg/kg), whereas METH (0.3 and 1 mg/kg) increased DA and 5-HT. Locomotor effects of all drugs were positively correlated with dialysate DA (P < 0.001). Interestingly, modafinil pretreatment reduced METH-induced ambulation and DA release. Our data show that modafinil interacts with DAT sites in rat brain, a property shared with agonist medications under investigation for treating cocaine dependence. Nondopaminergic mechanisms may also contribute to the pharmacology of modafinil. Finally, the results suggest that modafinil should be tested as an adjunct for treating METH addiction.

Commentary] THE LONG ROAD TO PHARMACOTHERAPIES FOR STIMULANT DEPENDENCE

Many marketed antidepressants, dopamine agonists and γ-aminobutyric acid compounds have been trialled and discarded on the long road towards a pharmacotherapy for psychostimulant dependence. Illicit methylamphetamine (MA) can create a particularly debilitating disorder and James Shearer and his colleagues are to be congratulated for their timely trial of modafinil among this population [1]. The headline finding is that modafinil was not associated with adverse events or medication misuse, and that medication compliant participants gave more MA and illicit psychostimulant negative urine tests during treatment. Modafinil is a novel wake-promoting agent and the front-line treatment for narcolepsy idiopathic hypersomnia. It also improves some aspects of neuropsychological test performance in normal volunteers [2] and, in part, this trial can be seen as a means of ameliorating neurocognitive dysfunction among patients and thereby enhancing their acceptance of clinic recovery services in these critical early weeks of recovery. Along with several other stimulant medications, there are now encouraging signs that modafinil may be an effective pharmacotherapy for cocaine and synthetic stimulant dependence [3]. This ‘off label’ application makes sense from a neurobiological perspective although much remains to be understood about the precise mechanisms of action and, of course, larger more powerful trials are needed to firm the evidence base. Good implementation features of the present trial included monitoring of self-administration of trial medication, regular medical assessment of side effects, tolerable patient study attrition and good primary outcome measurement in the form of weekly urinalysis for target substance use (specifying for MA, cocaine and MDMA). There were also challenging aspects for the analysis: up to one third of participants completed their treatment, and the modafinil effect appears to have been moderated by concurrent polydrug use and the over-representation of HIV positive patients in the experimental group. More powerful studies are needed to investigate the pattern of outcome and the characteristics of non-response. Also, the assessment of neuropsychological problems and response during treatment may prove to be a useful avenue on the search for mediation of outcome and patient non-response. Many medication trials in our field rest on a platform of structured psychosocial intervention (four sessions of cognitive behavioural therapy in this instance) as a standard treatment. The Shearer group suggest that modafinil may emerge as a combination therapy alongside a behavioural intervention: this makes good sense and offers real-world generalizability to clinic programmes. It will also be important for future triallists to ensure a high fidelity of their studied behavioural interventions, with their rationale, procedures and monitoring arrangements clearly set out in an accessible protocol or manual. This will facilitate replication of efforts and the translation of results into practice [4]. Making these materials available to the scientific community is now Addiction policy. Dr Marsden holds a research grant from the Medical Research Council to evaluate the feasibility of a multicentre controlled trial of modafinil for cocaine dependence in specialist NHS treatment clinics in England.

An Exploration of the Effect of Modafinil on Olanzapine Associated Weight Gain in Normal Human Subjects

Weight gain has been associated with many second generation antipsychotics (SGAs). A variety of theories have been put forward as to the etiology of SGA-associated weight gain. Modafinil possesses pharmacologic effects that could influence the weight gain associated with SGAs. The objective of this trial was to determine the effect of modafinil on olanzapine-associated weight gain. This study was a 3-week, randomized, double-blind, placebo-controlled trial. All subjects received olanzapine titrated to 10 mg/day. Concurrently, subjects were randomized to receive modafinil titrated to 200 mg/day or placebo. Weight and feeding lab assessments were conducted at baseline and endpoint. Fifty subjects were enrolled in the study with 20 subjects per group completing the trial. The primary outcome variable was change in the body mass index (BMI) over the 3 weeks of the trial. Increases in BMI were observed in both groups. However, analysis of covariance, controlled for baseline BMI, revealed that the olanzapine/placebo group had a greater increase in BMI at end point compared with the olanzapine/modafinil group (.89 +/- .59 vs. .47 +/- .50 kg/m(2), p < .05). When controlled for gender, the comparison showed a significant difference between groups at week 1 but not at weeks 2 or 3. The results of this trial should not be extrapolated to clinical practice at this time. These data do serve to support further evaluation in a patient population to determine if the weight modifying effect of modafinil can be demonstrated over a longer period of time.

Modafinil normalized hyperreflexia after spinal transection in adult rats

Study DesignHyperreflexia occurs after spinal cord injury and can be assessed by measuring low frequency-dependent depression of the H-reflex in the anesthetized animal.ObjectiveTo determine the effects of Modafinil (MOD), given orally, following a complete SCI compared with animals receiving MBET and transected untreated animals and examine if changes exist in Connexin 36 (Cx-36) protein levels in the lumbar enlargement of animals for the groups described.SettingCTN, Little Rock, AR, USA.MethodsAdult female rats underwent complete transection (Tx) at T10 level. H-reflex testing was performed 30 days following Tx in one group, and after initiation of treatment with MOD in another group, and after MBET training in the third group. The Lumbar enlargement tissue was harvested and western blots were performed after immunoprecipitation techniques to compare Cx-36 protein levels.ResultsStatistically significant decreases in low frequency-dependent depression of the H-reflex were observed in animals that received MOD and those that were treated with MBET compared with the Tx, untreated group. Statistically significant changes in Cx-36 protein levels were not observed in animals treated with MOD compared with Tx, untreated animals.ConclusionNormalization of the loss of low frequency -dependent depression of the H-reflex was demonstrated in the group receiving MOD and the group receiving MBET compared with the Tx, untreated group. Further work is needed to examine if Cx-36 protein changes occur in specific subregions of the spinal cord.

Gaps That Wake You Up

ALTHOUGH MODAFINIL HAS BECOME ONE OF THE MOST WIDELY PRESCRIBED STIMULANTS AND IS AN APPROVED TREATMENT FOR NARCOLEPSY, SHIFT work disorder, and the residual sleepiness in treated sleep apnea, its mode of action is poorly understood. It has been suggested that it acts by binding to the dopamine transporter thus inhibiting dopamine reuptake, thereby activating dopamine receptors.1 Modafinil is effective in hypocretin (orexin) knockout animals, demonstrating that, contrary to a prior claim, hypocretin is not needed to mediate its effects.2 One study showed that modafinil selectively activates a localized cell group in the anterior hypothalamus,3 however another showed that it produces a widespread activation of many brain regions.4 Now Beck et al.5 present new data suggesting that modafinil acts by opening “gap junctions” between neurons. The classical view of neuronal communication is that neurons interact by transmitter release acting through receptors which either open ion channels or activate proteins within the neuronal soma of postsynaptic cells to produce membrane polarization changes. However, it is now known that some groups of neurons are electrically coupled, such that changes in membrane potential are rapidly communicated through pores linking adjacent cells, allowing bidirectional ion currents. Gap junctions are thought to exist between GABAergic cells of the pedunculopontine nucleus, a nucleus also containing cholinergic cells.6 These cholinergic cells are involved in regulating REM sleep through brainstem connections as well as the cortical EEG through thalamic projections.7 Gap junctions are also present in the coeruleus and subcoeruleus nuclei, cortical cells, and nucleus reticularis of the thalamus, which has a critical role in generating the EEG. It has been demonstrated that the number or size of gap junctions can be increased by neurotransmitter action.8,9 One way of assessing arousal is to measure the amplitude of an auditory evoked positive response peaking approximately 13 msec after the initiation of the stimulus, the P13 wave. Prior work by this group5 and others has suggested that this wave is generated by the pedunculopontine nucleus, a brainstem nucleus containing cholinergic cells. Beck et al.5 showed that microinjection of modafinil into this nucleus in rats increased the amplitude of this wave. They also showed that this effect was blocked by gap junction antagonists (carbenoxolone or mefloquine). An earlier study had shown that modafinil also increased the electrical coupling of cortical interneurons.10 Gap junctions allow more rapid spread of membrane polarization changes between neurons. This synchronizes the membrane potential of such neurons but also makes it more difficult to trigger action potentials, since by lowering the electrical resistance of the network relative to that of a single cell, a larger current is needed to reach a voltage sufficient to trigger action potentials, according to Ohm's law. It is this effect that is now hypothesized to be responsible for the arousing effect of modafinil. Because of the increased coupling of GABA cells in the pedunculopontine nucleus caused by modafinil, these cells become less active, releasing adjacent cholinergic cells from GABAergic inhibition. However, once an action potential is triggered in cells connected by gap junctions it will tend to occur in all cells in the network because of the rapid flow of sodium currents between cells. This will produce an explosive and synchronous output of the network. This effect is seen in fish, which use gap junctions to generate synchronized action potentials in cells mediating the tail flip and in snails, which use synchronized action potentials to release a protective cloud of ink. Beck et al.'s finding does not exclude the possibility that some of modafinil's action is mediated by chemical synapses including those affecting monoaminergic transport or receptor systems, amino acid or cholinergic mechanisms. Indeed Beck et al.'s study suggests the need for further work to determine the extent to which systemic administration of modafinil acts through gap junction mechanisms as opposed to more conventional chemical synaptic mechanisms. It also raises the possibility that the effects of other alertness controlling drugs may be mediated by their effects on gap junctions rather than by acting exclusively through chemical synapses.

Effects of modafinil on simulator driving and self‐assessment of driving following sleep deprivation

While it has been suggested that the novel wake promoting drug modafinil may have some utility with respect to drowsy driving in healthy adults, this has not been investigated until now. The present study was designed to assess the effects of modafinil on objective and self-assessed driving simulator performance during an overnight period of sleep loss. Sixteen healthy participants (eight males and eight females) remained awake overnight on two separate occasions during which they ingested either a single 300 mg dose of modafinil or a placebo capsule at either 0230 or 0330 h. Two hours post-treatment, participants were evaluated using measures of driving simulator performance, self-assessed driving performance and subjective alertness. Modafinil treatment reduced lane deviation but had less effect on speed deviation, off-road incidents and reaction time to a concurrent task. Modafinil also improved subjective appraisals of driving performance, although its use may have resulted in overconfidence in driving ability during short trips. Modafinil offers some benefits with respect to objective driving performance under conditions of sleep loss. However it may induce overconfidence, suggesting that its use as a countermeasure to drowsiness when driving requires further examination.

Pharmacogenetics of Modafinil After Sleep Loss: Catechol-O-Methyltransferase Genotype Modulates Waking Functions But Not Recovery Sleep

Sleep loss impairs waking functions and is homeostatically compensated in recovery sleep. The mechanisms underlying the consequences of prolonged wakefulness are unknown. The stimulant modafinil may promote primarily dopaminergic neurotransmission. Catechol-O-methyltransferase (COMT) catalyzes the breakdown of cerebral dopamine. A functional Val158Met polymorphism reduces COMT activity, and Val/Val homozygous individuals presumably have lower dopaminergic signaling in the prefrontal cortex than do Met/Met homozygotes. We quantified the contribution of this polymorphism to the effects of sleep deprivation and modafinil on subjective state, cognitive performance, and recovery sleep in healthy volunteers. Two-time 100 mg modafinil potently improved vigor and well-being, and maintained baseline performance with respect to executive functioning and vigilant attention throughout sleep deprivation in Val/Val genotype subjects but was hardly effective in subjects with the Met/Met genotype. Neither modafinil nor the Val158Met polymorphism affected distinct markers of sleep homeostasis in recovery sleep. In conclusion, dopaminergic mechanisms contribute to impaired waking functions after sleep loss.

Modafinil improves rapid shifts of attention

The majority of studies investigating the cognitive effects of modafinil, a wake-promoting compound, demonstrate some improvements in attention. The potential of the drug to selectively benefit distinct components of attention has yet to be fully explored in healthy adults. The present study was conducted to investigate modafinil's effect on specific cognitive tasks that tax components of attention switching. One required the rapid switching of attention between stimuli, and another contained an embedded working memory component on top of the attentional shift requirements. Additionally, prospective memory was examined, which requires the interruption of an ongoing activity to retrieve and act upon a previously formed intention. Healthy non-smoking volunteers, matched on age, intelligence, and baseline cognitive ability, received either a capsule that contained 200 mg modafinil or placebo. Subjective measures of mood and physiological response were taken throughout the experimental session, and the tasks were completed between 2 and 3 h post-dosing. Two hundred milligrams modafinil improved accuracy without a reaction time trade-off, in both conditions of the attention-shifting task, but only when resources were most challenged. In contrast, the drug afforded no improvement in prospective remembering or in the ongoing task that was interrupted. Modafinil appears to promote rapid switching of attention in conditions that are most demanding, whilst it offers no benefits in a task that requires unpredictable and infrequent disengagement of attention from an ongoing task in order to act upon an alternative task.

Modafinil as an Adjunctive Treatment of Sedation, Negative Symptoms, and Cognition in Schizophrenia

Given recent reports about the off-label use of modafinil as an adjuvant for the treatment of antipsychotic-associated sedation in schizophrenia patients and the recent interest in its putative cognitive-enhancing effects in this population, we present a systematic review of available data on trials of modafinil as an adjuvant in the treatment of cognitive deficits, negative symptoms, and antipsychotic-induced fatigue, and its tolerability. PubMed was searched for trials published in English up to January 2008 evaluating modafinil's effects on fatigue, negative symptoms, and cognition in schizophrenia with combinations of the following terms: schizophrenia, modafinil, cognition, negative symptoms, and fatigue. Six trials were identified: 2 randomized, prospective, double-blind placebo-controlled trials; 3 randomized, prospective, double-blind placebo-controlled crossover trials; and 1 open-label pilot study. Case series and case reports were excluded in the data analysis, except to identify potential adverse reactions to modafinil. Studies were examined for number of subjects, trial duration, design, dosing, and outcomes with respect to sedation, negative symptoms, cognitive function, and tolerability. One of 4 reviewed studies found a significant effect of modafinil as an alerting agent for antipsychotic-induced fatigue and sedation. Neither of 2 reviewed studies found modafinil to improve negative symptoms of schizophrenia. Three of 6 reviewed studies showed that modafinil may improve short-term memory, attention, and the ability to shift mental sets. Two neuroimaging studies identified functional correlates in areas associated with working memory functions. The main adverse effect was found to be a small risk of psychosis exacerbation, which was seen in 5 of 83 patients (6.0%) in the active treatment groups as compared to 2 of 70 patients (2.9%) in the placebo groups. While the available data suggest that modafinil is generally well tolerated and may have some efficacy in the treatment of antipsychotic-induced sedation and cognitive domains, the small sample sizes, contradictory results, and methodological differences between trials, especially with respect to cognitive testing, make it difficult to draw firm conclusions about the overall effectiveness of modafinil as an adjunct in the treatment of schizophrenia. Well-powered, prospective, randomized placebo-controlled trials using the MATRICS battery concomitantly with functional outcome measures are necessary to elucidate modafinil's efficacy and effectiveness as an adjunctive treatment for sedation, negative symptoms, and cognitive deficits in schizophrenia. Hence, before prescribing modafinil to a schizophrenia patient, the possible risks and benefits of each particular case should be evaluated.

Regulation of Synaptic Efficacy in Hypocretin/Orexin-Containing Neurons by Melanin Concentrating Hormone in the Lateral Hypothalamus

The lateral hypothalamus (LH) is a central hub that integrates inputs from, and sends outputs to, many other brain areas. Two groups of neurons in the LH, expressing hypocretin/orexin or melanin concentrating hormone (MCH), have been shown to participate in sleep regulation, energy homeostasis, drug addiction, motor regulation, stress response, and social behaviors. The elucidation of crosstalk between these two systems is essential to understand these behaviors and functions because there is evidence that there are reciprocal innervations between hypocretin/orexin and MCH neurons. In this study, we used MCH receptor-1 knock-out (MCHR1 KO) and wild-type (WT) mice expressing green fluorescent protein in hypocretin/orexin-containing neurons to examine the hypothesis that MCH modulates hypocretin/orexin-mediated effects on behavioral state and synaptic transmission in the LH. In MCHR1 KO mice, the efficacy of glutamatergic synapses on hypocretin/orexin neurons is potentiated and hypocretin-1-induced action potential firing is facilitated, potentially explaining an increased effect of modafinil observed in MCHR1 KO mice. In wild-type mice with intact MCHR1 signaling, MCH significantly attenuated the hypocretin-1-induced enhancement of spike frequency in hypocretin/orexin neurons. The MCH effect was dose dependent, pertussis toxin sensitive, and was abolished in MCHR1 KO mice. Consistent with this effect, MCH attenuated hypocretin-1-induced enhancement of the frequency of miniature EPSCs in hypocretin/orexin neurons. These data from MCHR1 KO and WT mice demonstrate a novel interaction between these two systems, implying that MCH may exert a unique inhibitory influence on hypocretin/orexin signaling as a way to fine-tune the output of the LH.

Effects of dextroamphetamine, caffeine and modafinil on psychomotor vigilance test performance after 44 h of continuous wakefulness

Prolonged sleep loss impairs alertness, vigilance and some higher-order cognitive and affective capacities. Some deficits can be temporarily reversed by stimulant medications including caffeine, dextroamphetamine, and modafinil. To date, only one study has directly compared the effectiveness of these three compounds and specified the doses at which all were equally effective in restoring alertness and vigilance following 64 h of wakefulness. The present study compared the effectiveness of these same three stimulants/doses following a less extreme period of sleep loss (i.e., 44 h). Fifty-three healthy adults received a single dose of modafinil 400 mg (n = 11), dextroamphetamine 20 mg (n = 16), caffeine 600 mg (n = 12), or placebo (n = 14) after 44 h of continuous wakefulness. After 61 h of being awake, participants obtained 12 h of recovery sleep. Psychomotor vigilance was assessed bi-hourly during waking and following recovery sleep. Relative to placebo, all three stimulants were equally effective in restoring psychomotor vigilance test speed and reducing lapses, although the duration of action was shortest for caffeine and longest for dextroamphetamine. At these doses, caffeine was associated with the highest percentage of subjectively reported side-effects while modafinil did not differ significantly from placebo. Subsequent recovery sleep was adversely affected in the dextroamphetamine group, but none of the stimulants had deleterious effects on postrecovery performance. Decisions regarding stimulant selection should be made with consideration of how factors such as duration of action, potential side-effects, and subsequent disruption of recovery sleep may interact with the demands of a particular operational environment.

Dopaminergic D1and D2Receptors Are Essential for the Arousal Effect of Modafinil

Modafinil is a wake-promoting compound with low abuse potential used in the treatment of narcolepsy. Although the compound is reported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine, however, the molecular mechanism by which modafinil increases wakefulness is debated. Herein we used dopamine (DA) D(2) receptor (D(2)R)-deficient mice combined with D(1)R- and D(2)R-specific antagonists to clarify the role of DA receptors in the arousal effects of modafinil. In wild-type mice, intraperitoneal modafinil induced wakefulness in a dose-dependent manner. Pretreatment with either D(1)R antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] at 30 microg/kg or D(2)R antagonist raclopride at 2 mg/kg blocked the arousal effects of low-dose modafinil at 22.5 and 45 mg/kg. When modafinil was given at 90 and 180 mg/kg, pretreatment of D(1)R antagonist did not affect the wakefulness at all, whereas D(2)R antagonist significantly attenuated the wakefulness to the half level compared with vehicle control. Similarly, D(2)R knock-out (KO) mice exhibited attenuated modafinil-induced wakefulness. However, pretreatment of D(2)R KO mice with D(1)R antagonist completely abolished arousal effects of modafinil. These findings strongly indicate that dopaminergic D(1)R and D(2)R are essential for the wakefulness induced by modafinil.

Behavioral responses of dopamine β-hydroxylase knockout mice to modafinil suggest a dual noradrenergic–dopaminergic mechanism of action

Modafinil is approved for use in the treatment of excessive daytime sleepiness. The precise mechanism of modafinil action has not been elucidated, although both dopamine (DA) and norepinephrine (NE) systems have been implicated. To explore the roles of DA and NE in the mechanism of modafinil-induced arousal, dopamine β-hydroxylase knockout ( Dbh −/−) mice were examined in behavioral paradigms of arousal (photobeam breaks and behavioral scoring of sleep latency). Dbh −/− mice completely lack NE but have hypersensitive DA signaling. It was hypothesized that Dbh −/− mice would be unresponsive to modafinil if the compound acts primarily via NE, but would be hypersensitive to modafinil if it acts primarily via DA. Dbh −/− mice had increased sensitivity to the locomotor-activating and wake-promoting effects of modafinil. Paradoxically, the α1-adrenergic receptor antagonist, prazosin, attenuated the effects of modafinil in control mice, but not in Dbh −/− mice. Blockade of DA receptors with flupenthixol decreased modafinil-induced locomotion and wake in both control and Dbh −/− mice. These results suggest that both NE and DA are involved in the behavioral effects of modafinil in control mice, but the requirement for NE can be bypassed by hypersensitive DA signaling.

Impact of modafinil on spasticity reduction and quality of life in children with CP

This randomized double blind AB/BA cross-over trial evaluates the effect of oral modafinil versus placebo on spasticity, function, and quality of life in children with cerebral palsy (CP). Outcomes were measured at the start and end of both 8-week treatment periods (modafinil and placebo). The order of the treatment periods was randomly assigned. There was a 4-week wash-out period between treatments. Primary outcomes include the Modified Ashworth Score (MAS), and the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD), a disorder-specific quality of life measure. Ten children were randomized and eight children completed the study. The mean age of participants was 11 years 5 months (SD 1 y 5 mo, range 8 y 8 mo-12 y 11 mo). Five of the participants were male and three female. Seven children had a diagnosis of spastic quadriplegic CP and one child had spastic diplegia with overflow tone to the upper extremities. The Gross Motor Function Classification System ranged from Level III to V with one child at Level III, six children at Level IV, and one at Level V. The CPCHILD pre- to post-total scores showed a slight improvement in quality of life during the placebo period and a slight deterioration in the modafinil period (overall mean change of 7.1, SD 7.6). A t-test between post differences was statistically significant (t=2.65, p=0.03) in favor of the placebo period. The MAS for elbow flexors, ankle flexors, and hip adductors did not show any significant reduction post-modafinil or post-placebo (p values ranged from 0.41-0.79). This study did not find evidence that modafinil reduces spasticity or has a positive impact on quality of life in children with spastic CP.

Modafinil decreases food intake in humans subjected to simulated shift work

In a limited number of studies modafinil has been shown to decrease food intake by laboratory animals and humans. The present study represents a secondary data analysis, in which the effects of modafinil on several measures of food intake were determined in humans living in a residential laboratory during simulated shift work. During this 23-day study, a wide selection of food items and beverages were freely available. During this double-blind, within-participant study, volunteers ( N = 11) received oral modafinil dose (0, 200, or 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. Modafinil (200, 400 mg) dose-dependently decreased total caloric intake by ~ 18% and ~ 38%, respectively, regardless of shift condition, without selectively altering the proportion of total calories derived from carbohydrate, fat and protein. Ratings of “Hungry” were also significantly decreased by both active doses, but only immediately before the lunch break period. In addition, tolerance to the anorexic effects of modafinil was not apparent, as these effects remained stable across the three days of modafinil dosing. These findings show that modafinil produced clear reductions in food intake and suggest that future prospective studies should examine the drug in obese participants.

The effects of modafinil on mood and cognition in Huntington’s disease

The wake-promoting agent modafinil selectively improves neuropsychological task performance in healthy volunteers, in adults with attention deficit hyperactivity disorder (ADHD) and in schizophrenia. We examined whether modafinil induced similar effects in individuals with Huntington's disease (HD). Twenty patients with genetically proven, mild HD participated in a double-blind, randomised, placebo-controlled cross-over study using a single 200 mg dose of modafinil. Patients undertook a battery of neuropsychological tests including measures of cognition and mood. Modafinil increased alertness as indexed by visual analogue scales. Modafinil did not elicit any significant improvements in cognitive function or mood. Modafinil had a deleterious effect on visual recognition and working memory. Two hundred milligrams acute modafinil administration did improve alertness but did not improve cognition or mood in patients with mild HD. A multiple dose, chronic administration study is needed before the potential clinical utility of modafinil in HD is discounted.

Effect of modafinil on cerebral blood flow in narcolepsy patients.

To investigate the effects of modafinil on regional cerebral blood flow (rCBF) in narcolepsy, we performed 99mTc-ethylcysteinate dimer single photon emission computed tomography (SPECT) before and after modafinil or placebo medication. Brain SPECT was performed twice during the awake state before and after modafinil or placebo administration for 4 weeks in 43 drug-naive narcoleptics with cataplexy (M/F = 23/20, 29.5 +/- 5.8 years). For SPM analysis, all SPECT images were spatially normalized to the standard 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- and post-modafinil or placebo SPECT images. The mean modafinil dose used was 207.8 +/- 62.3 mg/day. Modafinil significantly reduced Epworth Sleepiness Scale scores from 20.3 +/- 2.1 to 5.2 +/- 3.1 (P < 0.01), while placebo did not. Compared to the off-modafinil condition, the on-modafinil condition showed significantly increased rCBF in the right dorsolateral and bilateral medial prefrontal cortices. Conversely, after modafinil administration, rCBF was decreased in bilateral precentral gyri, left hippocampus, left fusiform gyrus, bilateral lingual gyri, and cerebellum. There was no significant rCBF change after placebo administration. By a chronic administration of modafinil in narcoleptic patients, rCBF increased in the bilateral prefrontal cortices, whereas it decreased in left mesio/basal, temporal, bilateral occipital areas, and cerebellum.