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PubMed2005

Modafinil elicits sympathomedullary activation.

The autonomic effects of modafinil (Provigil), a psychostimulant widely used to attenuate fatigue and promote wakefulness, are currently unexplored. We assessed the effect of modafinil on autonomic nervous system. We compared oral modafinil (400 mgx1) versus placebo in 12 healthy hospitalized normal subjects in a randomized double-blind, placebo-controlled cross-over study for 3 days each with subjects in 150 mEq sodium, 70 mEq potassium balance at the Vanderbilt General Clinical Research Center. Modafinil increased resting heart rate (9.2+/-2.0 bpm; mean [+/-SE]; 95% confidence interval [CI], 4.7 to 13.6; P=0.001), resting systolic blood pressure (7.3+/-3.2 mm Hg; 95% CI, 0.2 to 14.4; P=0.044), and resting diastolic blood pressure (5.3+/-1.7 mm Hg; 95% CI, 1.4 to 9.1 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8+/-0.3 nmol/L; 95% CI, 0.2 to 1.3; P=0.01), and caused a 33% increase in urine norepinephrine (5.1+/-1.1 nmol/L creatinine per day; 95% CI, 2.7 to 7.4, P=0.001), and an 81% increase in urine epinephrine (1.3+/-0.2 nmol/L creatinine per day; 95% CI, 1 to 2; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). alpha1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Autonomic changes of this magnitude encourage caution in use of modafinil in patients with cardiovascular disease.

Adrenal Medulla↗
PubMed2001

Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea.

Patients with obstructive sleep apnea/hypopnea syndrome can experience residual daytime sleepiness despite regular use of nasal continuous positive airway pressure therapy. This randomized, double-blind, placebo-controlled, parallel group study assessed the efficacy and safety of modafinil for the treatment of residual daytime sleepiness in such patients. Patients received modafinil (n = 77) (200 mg/d, Week 1; 400 mg/d, Weeks 2 to 4) or matching placebo (n = 80) once daily for 4 wk. Modafinil significantly improved daytime sleepiness, with significantly greater mean changes from baseline in Epworth Sleepiness Scale scores at Weeks 1 and 4 (p < 0.001) and in multiple sleep latency times (MSLT) at Week 4 (p < 0.05). The percentage of patients with normalized daytime sleepiness (Epworth score < 10) was significantly higher with modafinil (51%) than with placebo (27%) (p < 0.01), but not for MSLT (> 10 min; 29% versus 25%). Headache (modafinil, 23%; placebo, 11%; p = 0.044) and nervousness (modafinil, 12%; placebo, 3%; p = 0.024) were the most common adverse events. During modafinil or placebo treatment, the mean duration of nCPAP use was 6.2 h/night, with no significant change from baseline observed between groups. Modafinil may be a useful adjunct treatment for the management of residual daytime sleepiness in patients with obstructive sleep apnea/hypopnea syndrome who are regular users of nasal continuous positive airway pressure therapy.

Adult↗
PubMed2006

Walking with modafinil and its use in diplegic cerebral palsy: retrospective review.

A retrospective review of pediatric patients with spastic cerebral palsy was undertaken at Texas Tech University Health Sciences Center covering a period from January 1, 2000, until December 31, 2003. One hundred twenty pediatric patients were identified in the Texas Tech University Health Sciences Center child neurology clinic with spastic cerebral palsy. Fifty-nine patients of this group received modafinil treatment for cerebral palsy. Twenty-nine of the 59 patients were noted to have an improving gait on modafinil. Six of these modafinil-treated patients improved from no ambulation or only assisted ambulation to unassisted ambulation. This varied from taking a few steps without holding on to walking down the hall without assistance. Two patients with spastic diplegia secondary to prematurity have had a dramatic improvement in gait during the first 6 months after starting modafinil. Two other patients with spastic diplegia not included in this group of six patients taught themselves to stand up and walk while in water unassisted. During this same time period, only three non-modafinil-treated patients with mild cerebral palsy were noted with gait improvements, but not to the dramatic extent of the modafinil-treated group. A nonambulatory 5-year-old child, who presented for a requested wheelchair prescription because the mother had given up all hope of her child ever walking, is now taking independent steps unassisted after starting modafinil. Modafinil, a central nervous system stimulant, appears to improve tone and ambulation in spastic diplegic cerebral palsy.

Adolescent↗
PubMed2006

Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study.

OBJECTIVES: Modafinil has recently been approved for the treatment of shift work sleep disorder, making it potentially available for shift-working emergency physicians. The authors' objectives were to determine whether modafinil improved cognitive performance of emergency physicians following overnight shifts and to record symptoms and subjective evaluations of the effect of modafinil on the participants. METHODS: This was a randomized, double-blind, placebo-controlled crossover study that followed CONSORT guidelines. Participants were assigned to one of two study groups, with study sessions occurring at least seven weeks apart, and received either modafinil or placebo depending on their random allocation. Testing after night shifts included a coding task and an AX version of the Continuous Performance Task, both of which test cognitive function. Participants also completed visual analog scales for three subjective outcomes, and symptoms were elicited. RESULTS: Modafinil facilitated performance on long interstimulus-interval AX trials (F [1, 23] = 6.65, p = 0.1) and marginally reduced errors on AY trials in the Continuous Performance Task (F [1, 23] = 3.59, p = 0.07), suggesting facilitation of sustained attention, cognitive control, and working memory. Additionally, modafinil, compared with placebo, facilitated performance on the coding task at the first session. Subjective data from visual analog scales confirmed that modafinil increased perceived alertness during the simulated patient care sessions but worsened sleep onset when opportunities for sleep arose. CONCLUSIONS: Modafinil increased certain aspects of cognitive function and subjectively improved participants' ability to attend post-night-shift didactic sessions but made it more difficult for participants to fall asleep when opportunities for sleep arose.

Adult↗
PubMed2003

Clinical pharmacokinetic profile of modafinil.

Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain. After single or multiple oral doses, modafinil is readily absorbed, reaching maximum plasma concentrations at 2-4 hours after administration and pharmacokinetic steady state within 2-4 days. Its pharmacokinetics are dose-independent between 200 and 600 mg/day. The elimination half-life is approximately 12-15 hours, which is largely reflective of the pharmacokinetics of the longer-lived l-enantiomer. Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging. Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that modafinil has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes. Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil. In summary, the results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised.

Aged↗
PubMed2004

An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy.

OBJECTIVE: In patients with major depressive disorder (MDD), excessive sleepiness and fatigue not only are major components of the disorder, but also may occur as side effects of antidepressant therapy. In addition, sedation may be a consequence of antidepressant regimens. The novel wake-promoting agent modafinil improves wakefulness and reduces fatigue across a variety of clinical disorders. This study assessed the use of modafinil as an adjunctive treatment in patients with MDD who reported sedation related to serotonergic antidepressant therapy. METHOD: Data were collected between September 2001 and December 2003. Twenty men and women with DSM-IV-defined MDD were enrolled in this 3-week, open-label, single-center study. In addition to ongoing and stable treatment with selective serotonin reuptake inhibitors (SSRIs), clinic patients received modafinil once daily. Efficacy assessments were conducted at 1-week intervals. RESULTS: Sixteen patients (80%) completed the study. Modafinil plus SSRIs significantly improved overall depressive symptoms, as shown by reductions in mean Hamilton Rating Scale for Depression total scores (p <.001 vs. baseline). Adjunctive modafinil significantly improved subjective estimates of wakefulness on the Epworth Sleepiness Scale (p <.001, all weeks) and reduced fatigue on the Fatigue Severity Scale (p =.009). At the final visit, modafinil had improved overall health status and health-related quality of life, as shown by significant improvements in mean Medical Outcomes Study Short-Form 12-Item Health Survey total scores (p =.007) and in physical health (p =.04) and mental health (p =.006) subscores. CONCLUSION: In patients with MDD who experience sedation as a side effect of antidepressant therapy, adjunctive modafinil improved wakefulness and reduced fatigue. Modafinil plus SSRIs also improved mood and quality of life.

Adult↗
PubMed2005

A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness.

BACKGROUND: Up to one half of depressed patients have partial or no response to antidepressant monotherapy. This multicenter, placebo-controlled study evaluated the efficacy of modafinil augmentation in major depressive disorder (MDD) patients with fatigue and excessive sleepiness despite selective serotonin reuptake inhibitor (SSRI) monotherapy. METHOD: Patients (18-65 years) with a DSM-IV diagnosis of MDD and partial response to SSRI monotherapy (> or = 8 weeks) at a stable dose for > or = 4 weeks were eligible. Patients had screening/baseline 31-item Hamilton Rating Scale for Depression (HAM-D) scores of 14 to 26, Epworth Sleepiness Scale (ESS) scores > or = 10, and Fatigue Severity Scale (FSS) scores > or = 4. Patients were randomly assigned to augmentation therapy with modafinil 200 mg/day or placebo for 8 weeks. Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Of 311 enrolled patients who received > or = 1 dose of study drug, 158 were randomly assigned to modafinil (70% women) and 153 to placebo (72% women); 85% of each treatment group completed the study. At final visit, modafinil significantly improved patients' overall clinical condition compared with placebo on the basis of CGI-I scores (p = .02), and there were trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores versus placebo. Modafinil significantly reduced BFI scores for worst fatigue at final visit (p < .05 vs. placebo). There were no significant differences between modafinil and placebo at final visit in FSS or BFI total scores. Adverse events significantly more common during modafinil compared with placebo treatment were nausea (9% vs. 2%; p = .01) and feeling jittery (4% vs. 1%; p = .03). CONCLUSION: These findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness.

Adolescent↗
PubMed2002

Circadian rhythm of rectal temperature during sleep deprivation with modafinil.

BACKGROUND: Sleep deprivation (SD) induces many adverse psychological and physiological effects, particularly on vigilance and the thermoregulatory system. The drug modafinil appears to suppress or diminish the harmful effects on vigilance. However, the effects of modafinil combined with SD on the circadian rhythm of core temperature are not well established. HYPOTHESIS: We studied the circadian rhythm of rectal temperature (CRTre) during 62 h of SD alone or with three dosage levels of modafinil. METHODS: Six men underwent repeated SD experiments lasting 7 d each, including a 24-h control period, 62 h of SD, and a 24-h recovery period. Experiments were repeated four times in mixed order for placebo and three levels of modafinil (50, 150, or 300 mg x 24 h(-1)). The Tre was recorded each minute throughout the experiment and the CRTre was studied by the single cosinor method. RESULTS: Independent of modafinil, SD increased the mesor (p < 0.05) and reduced the amplitude (p < 0.01) of the CRTre without changing the acrophase. During the recovery period, a rebound increase was seen in the amplitude of the CRTre (p < 0.01). The 50 mg x 24 h(-1) dose of modafinil, but not the higher doses, induced a lower mesor (p < 0.01) independent of SD. CONCLUSIONS: The observed changes may reflect a threshold for the central action of modafinil on core temperature. The hyperthermic effect reported in the literature for SD with modafinil may actually result from the sleep deprivation alone.

Adult↗
PubMed2002

Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial.

OBJECTIVES: To assess the therapeutic efficacy of modafinil in the treatment of increased daytime sleepiness in patients with Parkinson's disease (PD). DESIGN: Double-blind, randomized, placebo-controlled crossover study with two 2-week treatment blocks, separated by a 2-week washout phase. SETTING: Tertiary Parkinson's disease care center and sleep laboratory at university hospital neurology department. PATIENTS: Fifteen patients with idiopathic PD and daytime sleepiness (Epworth sleepiness score (ESS) 10 or more). INTERVENTIONS: Administration of placebo or modafinil as a single morning dose in a randomized crossover order. The modafinil dose was 100 mg in the first, and 200 mg in the second treatment week. MEASUREMENTS AND RESULTS: At baseline and at the end of each treatment block, sleepiness was evaluated using subjective (perceived sleepiness with the ESS) and objective measures (maintenance of wakefulness test). Twelve patients completed the study (9 male, 3 female; mean age 65.0 +/- 7.6 years, mean disease duration 6.8 +/- 4.1 years). Epworth scores were significantly improved with modafinil (3.42 +/- 3.90) compared to placebo (0.83 +/- 1.99; p = 0.011). Latency to sleep in the maintenance of wakefulness test was not significantly altered by modafinil treatment: 10.9 (3-40)/15.1 (2.5-40) minutes before/after placebo and 12 (2.6-40)/17.8 (4.2-40) minutes before/after modafinil (p = 0.139) [data given as mean +/- standard deviation or median (range)]. CONCLUSIONS: The results of this study suggest that modafinil improves daytime sleepiness in PD patients, at least on a subjective or behavioral level. Modafinil treatment may be considered for EDS in PD patients, in whom otherwise treatable causes of Excessive Daytime Sleepiness (EDS) are absent.

Aged↗
PubMed1994

Effect of modafinil on heat production and regulation of body temperatures in cold-exposed humans.

Military personnel often undergo sustained operations that affect vigilance and alertness. Pharmacological agents may be used to enhance vigilance. Most such agents also have thermogenic properties. Whether a new promising stimulant, modafinil (Lyons and French, Aviat. Space Environ. Med. 1991; 62:432-435), has a beneficial effect on cold tolerance in the military context, is not known. The goal of this study was, therefore, to evaluate the effect of this new drug on thermal balance and the regulation of body temperatures in neutral conditions and when challenged by a cold exposure. Nine subjects underwent three trials each: two in the cold (3 h at rest, 10 degrees C) 0.5 h after the ingestion of either placebo or modafinil (200 mg), and one in thermal neutrality with modafinil (same conditions except Tdb = 29.3 degrees C). As expected, cold produced a drop in Tre and Tsk and an increase in Vo2. Although non-significant, there was a tendency for a slightly greater drop in Tre with modafinil (0.65 degrees C vs. 0.57 degrees C with placebo). A similar tendency was found for the heat debt (S) which was greater with modafinil than with placebo (16.1 +/- 0.7 vs. 14.7 +/- 0.6 kJ.kg-1, respectively, +9.5%, p = 0.11). This tendency appears to be the combined result of a slightly lower mean heat production during the test and a slightly greater mean dry heat loss. When tested at thermal neutrality, the drug had no effect on any thermal or metabolic parameters. The results demonstrate that the ingestion of a single dose of modafinil has no significant acute effect on thermal balance in neutral conditions and on thermoregulation in normal subjects exposed to cold. However, a tendency for slightly greater cooling was noted with modafinil. It is not known whether the use of modafinil in conjunction with sleep deprivation (a likely scenario) could magnify this effect.

Adult↗
PubMed2000

A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy.

Objective: To assess the continued efficacy of modafinil in the treatment of excessive daytime somnolence (EDS) of narcolepsy.Background: Modafinil has been shown to be a safe and effective treatment for the EDS presented by patients with narcolepsy. However, the duration of treatment has been relatively brief, particularly considering the chronic nature of the disease.Methods: Sixty-nine patients with narcolepsy, who completed a 6-week crossover study of modafinil continued on modafinil for 16 weeks of open-label treatment (300+/-100 mg). This was followed by 2 weeks during which patients were randomly and blindly allocated to continue modafinil (M) at the same dose (n=30), or placebo (P; n=33).Results: A mean dose of 330 mg of modafinil continued to produce a significant decrease in EDS as measured by the Maintenance of Wakefulness Test (9.7+/-7.9 for P; 16.4+/-13.7 for M; P=0.009), the Epworth Sleepiness Scale (15.4+/-5.8 for P; 13.2+/-5.7 for M; P=0.023), and the number of episodes of severe somnolence and sleep reported in patient diaries (8.2+/-7.2 for P; 4.2+/-5.2 for M; P=0.017). Modafinil had no significant effects on nocturnal sleep, blood pressure, heart rate, the electrocardiogram (ECG), weight, or mood.Conclusion: Modafinil continues to be an effective and well-tolerated drug after 16 weeks of treatment.

Journal Article↗
PubMed1999

Modafinil: a second look. Confirmed efficacy in narcolepsy.

(1) Modafinil, a psychostimulant, has been available in France for the treatment of narcolepsy and idiopathic hypersomnia since 1994. (2) The initial clinical file was inadequate to judge its possible clinical value. (3) In narcolepsy three new short-term clinical trials have compared modafinil with a placebo (nearly 500 patients treated with modafinil). (4) These trials show that the effects of modafinil on daytime drowsiness are only moderate (average reduction of one unwanted sleep episode a day) but are subjectively better than those of a placebo. In all, 84% of patients preferred the modafinil period to the placebo period during a cross-over trial. In contrast, modafinil does not improve cataplexy. (5) No new trials have been done in idiopathic hypersomnia. (6) The effects of modafinil persist for at least four months according to a double-blind placebo-controlled trial. (7) The safety profile of modafinil appears to be similar to that of non amphetamine psychostimulants. (8) There is currently no evidence of dependence leading to withdrawal symptoms after abrupt treatment cessation, or of a risk of abuse.

Benzhydryl Compounds↗
PubMed2005

Modafinil for excessive sleepiness associated with shift-work sleep disorder.

BACKGROUND: Patients with shift-work sleep disorder chronically have excessive sleepiness during night work and insomnia when attempting to sleep during the day. We evaluated the use of modafinil for treating sleepiness in patients with this disorder. METHODS: In a three-month, double-blind trial, we randomly assigned 209 patients with shift-work sleep disorder to receive either 200 mg of modafinil or placebo before the start of each shift. Assessments were performed with the use of the nighttime Multiple Sleep Latency Test, the Clinical Global Impression of Change, the Psychomotor Vigilance Test, diaries of patients, and daytime polysomnography. After randomization, we conducted monthly assessments. RESULTS: Treatment with modafinil, as compared with placebo, resulted in a modest improvement from baseline in mean (+/-SEM) nighttime sleep latency (the interval between the time a person attempts to fall asleep and the onset of sleep) (1.7+/-0.4 vs. 0.3+/-0.3 minutes, respectively; P=0.002), and more patients had improvement in their clinical symptoms (74 percent vs. 36 percent, respectively; P<0.001). Patients who were receiving modafinil also had a reduction in the frequency and duration of lapses of attention during nighttime testing of their performance on the Psychomotor Vigilance Test (change from baseline, a reduction in lapse frequency of 2.6 vs. an increase of 3.8, respectively; P<0.001), and proportionally fewer patients reported having had accidents or near accidents while commuting home (29 percent vs. 54 percent, respectively; P<0.001). Despite these benefits, patients treated with modafinil continued to have excessive sleepiness and impaired performance at night. Modafinil did not adversely affect daytime sleep as compared with placebo. Headache was the most common adverse event. CONCLUSIONS: Treatment with 200 mg of modafinil reduced the extreme sleepiness that we observed in patients with shift-work sleep disorder and resulted in a small but significant improvement in performance as compared with placebo. However, the residual sleepiness that was observed in the treated patients underscores the need for the development of interventions that are even more effective.

Adult↗
PubMed2003

Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease.

We assessed the safety and efficacy of modafinil for the treatment of excessive daytime sleepiness in patients with Parkinson's disease (PD). This was a single-site, randomized, double-blind, placebo-controlled crossover study of 21 PD patients having an Epworth Sleepiness Scale (ESS) score > or =10. They received either placebo or modafinil 200 mg/day for 3 weeks, followed by a washout week, then the alternate treatment for 3 weeks. The ESS data demonstrated a carryover effect, so the changes from baseline ESS scores were compared between the two treatments for period 1 only. The ESS scores for the placebo group went from 16.0 +/- 4.2 (mean +/- SD) to 17.0 +/- 5.1 and for the modafinil group went from 17.8 +/- 4.2 to 14.4 +/- 5.7 (P = 0.039). There was no significant carryover effect for any other measure. The patient Clinical Global Impression of Change (+3 to -3) improved by 0.75 on modafinil compared with 0.15 for placebo (P = 0.07). A total of 7 of 20 (35%) of the patients reported some improvement on modafinil but not placebo. There was no significant improvement or worsening of the UPDRS subscores I-III, Timed Tap test, or time on. Vital signs, electrocardiograms, and lab tests were unchanged. Modafinil was very well tolerated. Our data demonstrate that, in a small sample size, administration of 200 mg/day of modafinil was associated with few side effects and was modestly effective for the treatment of excessive daytime sleepiness in patients with PD.

Adult↗
PubMed2005

Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat.

In view of a postulated role of the vigilance-promoting drug modafinil in depression, the interaction of modafinil and two classical antidepressant drugs, fluoxetine and imipramine, were studied in 5-HT levels in the dorsal raphe-cortical system using dual-probe microdialysis. Fluoxetine (1-10 mg/kg) dose-dependently increased dorsal raphe-cortical 5-HT levels. Modafinil at a very low dose (3 mg/kg), by itself ineffective, enhanced the fluoxetine (5 mg/kg)-induced increases of 5-HT levels in both brain areas. A synergistic interaction was observed in the prefrontal cortex with fluoxetine (1 mg/kg) in terms of 5-HT release, but not in the dorsal raphe. Imipramine (1.3 mg/kg) increased 5-HT levels in the dorsal raphe, but not in the prefrontal cortex, while the higher doses (10.9-21.8 mg/kg) caused substantial increases in both brain areas. Modafinil (3 mg/kg), injected before imipramine (1.3 mg/kg), which by itself was ineffective on cortical 5-HT levels, increased cortical 5-HT levels. On other hand, modafinil failed to affect the high-dose imipramine (10.9 mg/kg)-induced increase of 5-HT levels in the prefrontal cortex and the imipramine (1.3; 10.9 mg/kg)-induced increase of 5-HT levels in the dorsal raphe nucleus. These results demonstrate that modafinil in low doses enhances the acute effects of fluoxetine and imipramine on 5-HT levels in the dorsal raphe nucleus (fluoxetine only) and especially in the prefrontal cortex of the awake rat. These findings suggest a therapeutic potential of low doses of modafinil in the treatment of depression when combined with low doses of classical antidepressants, especially by increasing 5-HT transmission in cortical regions.

Animals↗
PubMed2003

Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG.

RATIONALE: Modafinil is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance. Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in EEG slow-wave activity. These diachronic effects suggest an action of modafinil on a homeostatic sleep regulatory process. OBJECTIVES: The aim of this study was to determine whether modafinil, in comparison to the d-amphetamine reference psychostimulant and to placebo, interferes with the vigilance regulatory processes reflected in the EEG during waking. METHODS: Thirty-three healthy subjects were investigated during 60 h of sustained wakefulness in a double-blind placebo-controlled parallel-design study. A 4-min maintenance-of-wakefulness test administered hourly allowed the concomitant assessment of alertness and waking EEG activity. The effects of equipotent psychostimulant dosages (modafinil 300 mg and d-amphetamine 20 mg) were evaluated at the beginning of the first sleep deprivation night, at the end of the second sleep deprivation night and in the afternoon preceding the first recovery night. RESULTS: One hour following ingestion, both psychostimulants increased alertness during 10-12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5-7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the alpha(1) (8.5-11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night. CONCLUSIONS: These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory processes. While d-amphetamine inhibits the expression of a sleep-related process, probably through a direct cortical activation masking EEG circadian rhythms, modafinil, through a synchronic effect, preferentially disrupts the homeostatic down-regulation of a waking drive.

Adolescent↗
PubMed2003

Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy.

INTRODUCTION: In addition to excessive sleepiness, patients with narcolepsy often have significant fatigue, depressed mood, and decreased quality of life. OBJECTIVE: To determine whether treatment with modafinil for excessive sleepiness improves fatigue, mood, and health-related quality of life (HRQOL) in patients with narcolepsy. MATERIALS AND METHODS: Outpatients with narcolepsy underwent a 14-day washout of psychostimulants and then were enrolled in this 6-week, open-label, multicenter study. Patients received modafinil starting at 200 mg once daily for week 1, and then 200 or 400 mg daily for weeks 2 through 6. Efficacy was evaluated using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Profile of Mood States (POMS). Safety was assessed by monitoring adverse events (AE). RESULTS: At baseline, 151 patients had moderate to severe excessive sleepiness (mean Epworth Sleepiness Scale score=17.8+/-4.4). Most patients (> or =70% of 123 who completed the study) received 400 mg modafinil once daily during weeks 2 through 6. Modafinil significantly improved HRQOL, based on SF-36 measures of mental and physical component summary scores and subdomain scores of role-physical, social functioning, and vitality (each P<0.001). Modafinil treatment was also associated with significantly reduced fatigue and significantly improved vigor and cognition as assessed by the POMS (each P<0.001) from weeks 1 through 6. The most frequent AE with modafinil treatment were headache, nausea, and insomnia; most AE were mild or moderate in nature. Only seven patients (5%) withdrew from the study because of AE. CONCLUSION: In narcolepsy patients who were switched from psychostimulants, modafinil therapy improved HRQOL and subjective feelings of vigor and cognitive functioning and reduced fatigue.

Adolescent↗
PubMed2004

Effects of modafinil on working memory processes in humans.

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, understanding 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 standardized 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 studying the noradrenergic modulation of the prefrontal cortex.

Adult↗