Mg Of Modafinil Research Articles

Effects of modafinil on nocturnal sleep patterns in patients with narcolepsy: A cohort study

BackgroundPatients with narcolepsy often experience disturbed nighttime sleep. Modafinil is commonly prescribed for hypersomnolence, but its impacts on nocturnal sleep remain unclear. This study uses actigraphy to examine the effect of modafinil on both hypersomnolence and nocturnal sleep patterns in patients with narcolepsy. MethodsPrior to treatment, 87 patients with narcolepsy wore an actigraphy for 7–14 days to assess their nighttime sleep. After evaluation, they received a daily dose of 200–400 mg of modafinil in the morning and wore an actigraphy again six months after initiating treatment. Questionnaires, including the Epworth-Sleepiness-Scale (ESS), the Visual-Analogue-for-Hypersomnolence (VAS), and the Short-Form-36-Health-Survey (SF-36), were used to evaluate hypersomnolence and quality of life both before and after treatment. Paired t-tests and independent samples t-tests were used for pre- and post-treatment comparisons and subgroup analysis. We used the Pearson's correlation test to measure the correlations between the sleep parameters of the actigraphy and data of the questionnaires. ResultsImprovements in hypersomnolence were noted following modafinil treatment, and we observed no significant deterioration in nocturnal sleep parameters by the actigraphy. The total number of awakenings by actigraphy significantly decreased (p = 0.005), especially in females (p = 0.008), while sleep onset latency significantly increased in children/adolescents (p = 0.014). Correlations were found between the sleep parameters of the actigraphy and ESS, VAS, and SF-36 scores. ConclusionModafinil treatment may not worsen nighttime sleep in patients with narcolepsy. However, it should be administered with care in children and adolescents.

The Effectiveness of Augmenting Modafinil to Risperidone or Olanzapine for Treating Negative Symptoms in Schizophrenic Patients: A Randomized Controlled Trail

Background: Recent evidence suggests the potential efficacy of modafinil in addressing specific symptom domains associated with schizophrenia, particularly negative and cognitive symptoms. However, it's important to note that findings in this area have been inconsistent. Objectives: This study was done to assess the impact of modafinil on improving negative symptoms in schizophrenia patients. Methods: In this clinical trial, 40 individuals diagnosed with schizophrenia and referred to Golestan Hospital were selected. Patients received a daily dose of 100 to 200 mg of modafinil in addition to their ongoing antipsychotic treatment with either Risperidone or Olanzapine. In the control group, patients received a placebo along with their prescribed antipsychotic therapy. The duration of the follow-up was 4 weeks. Both the evaluator and the patients were blinded to the administered medication. The Scale for the Assessment of Negative Symptoms (SANS) was utilized to measure negative symptoms before the intervention, and at 2 and 4 weeks following the intervention. Results: The mean age of participants in the intervention and control groups was 34.00 ± 6.60 and 36.90 ± 6.88 years, respectively. Two weeks after the intervention, the average SANS score was lower in the intervention group compared to the placebo group (99.70 ± 10.24 vs. 111.24 ± 7.08, P = 0.04). At 4 weeks post-intervention, the average SANS score in the intervention group was significantly reduced compared to the placebo group (84.39 ± 3.54 vs. 113.79 ± 3.75, P = 0.002). Conclusions: This study suggests that modafinil may be an effective adjunctive therapy for schizophrenia, particularly for treating anhedonia symptoms.

1020 Modafinil Induced Psychosis

Abstract Introduction Modafinil has been used for the treatment of numerous different conditions, including daytime somnolence (EDS). Modafinil is a non-amphetamine central nervous system (CNS) stimulant with wakefulness-promoting properties. There have been few reported cases of psychosis associated with modafinil use, however a large majority of those were seen in patients with a history of primary psychiatric disturbances. Report of case(s) We present a case of a 48 year old female coming for evaluation of excessive daytime somnolence. She completed polysomnography and a multi sleep latency test (MSLT) which revealed mildly elevated AHI, but no sleep onset rapid eye movements (SOREMPs). A diagnosis of idiopathic hypersomnia was subsequently made and 200mg of modafinil up to twice daily was prescribed for her. Patient initially tolerated the modafinil well, however she began having delusions and she subsequently required psychiatric evaluation. These delusions primarily consisted of her believing she was under surveillance and had conspiracy theories against her. She also described having auditory hallucinations as well, especially voices telling her about these conspiracy theories. She also demonstrated poor insight into her medical condition as she refused to discontinue modafinil. Upon evaluation, routine labs including complete blood count, chemistry profile and urine drug screens were completed to rule out any secondary causes of psychosis. It was therefore recommended by psychiatry to discontinue modafinil as there was concern that the delusions were occurring secondary to medication use. The patient's psychotic delusions seemed to dissipate after this. A multidisciplinary meeting was held regarding management of patients' excessive daytime sleepiness (EDS) and a decision was made to begin the patient on pitolisant, a histamine receptor antagonist. The patient was able to achieve great benefit with this medication. Conclusion The presented case illustrates a patient who began having psychosis after beginning modafinil 200mg twice daily. Psychosis is a much more rare side of modafinil and providers should become aware of it. Therefore, patients who are prescribed modafinil should be carefully followed for psychosis development, even when they are previously healthy and have no history of any primary psychiatric conditions. Support (if any)

A multi-pronged investigation of option generation using depression, PET and modafinil.

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.

Evaluation of the Effect of Modafinil on Respiratory and Cerebral Outcomes after Coronary Artery Bypass Graft Surgery

BACKGROUNDPulmonary complications following cardiopulmonary bypass (CPB) pump during coronary artery bypass grafting (CABG) are relatively common and the incidence of cognitive dysfunction is reported as ranging in rate from 30% to 80% in the early postoperative period. The purpose of this study was to assess the effect of modafinil administration on the prevention of pulmonary and cerebral complications and shortening the hospital stay after CABG surgery.METHODSThis randomized double-blind intervention-controlled clinical trial was performed on 74 patients (37 in the intervention group and 37 in the control group) undertaking CABG surgery. The intervention group was orally treated with doses of 200 mg of modafinil on the day of surgery, and on the morning of the day after surgery, the second dose of modafinil 200 mg was given to patients. The control group underwent a placebo with the same intervals.RESULTSAdministration of modafinil in intervention group significantly decreased the time to reach consciousness (P = 0.001), ventilator time in intensive care unit (ICU) (P < 0.001), length of stay in ICU (P = 0.009), duration of hospitalization (P = 0.008), and arterial blood carbon dioxide pressure (PaCO2) (P = 0.047). In the intervention group, no patients with delirium, agitation, respiratory depression, non-invasive respiratory ventilation, and endotracheal re-intubation were observed.CONCLUSIONModafinil tablet as a respiratory and brain stimulant through the central nervous system (CNS) can improve the quality of breathing and arterial blood gases (ABGs) and also can increase the level of consciousness and shorten the recovery time.

A double blind randomized placebo controlled pilot study of single-dose preoperative modafinil for functional recovery after general anesthesia in patients with obstructive sleep apnea.

Background:We theorized that modafinil, an atypical psychomotor stimulant, utilized to improve daytime somnolence in patients with obstructive sleep apnea, would improve functional recovery after general anesthesia by improving time to extubation, post-anesthesia care unit (PACU) length of stay and subjective recovery after general anesthesia.Methods:A double blind, randomized, placebo-controlled pilot study was performed. 102 patients with the diagnosis of obstructive sleep apnea (OSA) were randomized to receive either 200 mg of modafinil or placebo before general anesthesia. The trial was terminated for futility. The primary outcome was PACU length of stay between groups. Secondary functional metrics of improved post-anesthesia recovery were compared between groups.Results:No difference between groups was found on the primary outcome of PACU length of stay (PACULOS). Emergence from general anesthesia was not significantly different when assessed by the time period between termination of volatile anesthetic and extubation. Similarly, no difference between groups was found in intraoperative bispectral index (BIS) values, postoperative pain scores or narcotic consumption (morphine equivalent units). In the post-anesthesia care unit, respiratory rate was increased and mean arterial pressure was lower in the modafinil group.Conclusions:Our results suggest that the use of single-dose preoperative modafinil may not improve functional recovery after general anesthesia in patients with the diagnosis of OSA. Further research is needed before use of atypical psychomotor stimulants in this surgical population.

Effect of Modafinil Administration on the Level of Consciousness in Patients with Brain Injuries of Moderate Severity

Background: With regards to the importance of traumatic brain injury (TBI) and its high incidence rate in Iran as well as its severe consequences, it is important to determine the safety and efficiency of modafinil to increase the level of consciousness in hospitalized TBI patients. Methods: This double-blind randomized controlled trial was done during 2016. Sixty patients with TBI and moderate GCS score between 9 and 13 had the inclusion criteria and entered the study and were divided into two groups. Patients in the treatment group received 200 mg of modafinil once a day and the control group received the placebo. Overall, 24 hours after admission, defined as base day, modafinil was prescribed for 196 hours after admission and GCS scores were recorded: this period was defined as the last day. Level of consciousness in both treatment and control groups was assessed by the GCS score. Data were analyzed by SPSS version 21 software using the independent t-test with intention-to-treat approach. Results: Among 60 patients, there were 34 (56.66%) males and 26 (43%) females; 45 (75%) survived. The ITT analysis was employed to assess changes in the level of consciousness (LOC) after prescribing modafinil and placebo. Based on the findings, modafinil prescription was not associated with significant differences in LoC in the first time period (24 hours after) and the last day (196 hours) (P > 0.05). Conclusions: Prescribing modafinil was not associated with significant changes in LoC in comparison with the placebo.

Cognitive effects of modafinil in patients with multiple sclerosis: A clinical trial.

To assess the efficacy of modafinil for the treatment of new learning and memory deficits and fatigue in multiple sclerosis. Only 1 previous study in the literature, to our knowledge, examined the effect of modafinil on cognition specifically in persons with multiple sclerosis. Sixteen patients with a diagnosis of multiple sclerosis (MS) and documented new learning impairment completed the study. In a 5-week randomized, double-blinded, crossover design, participants received either a single daily oral dose of modafinil (200 mg) or placebo for 2 weeks. A 1-week washout period was included between study arms. No effect of modafinil was noted on learning and memory performance. Participants taking 200 mg of modafinil showed improvement in 1 of the 2 working memory measures administered, the Wechsler Adult Intelligence Scale-III (WAIS-III) Letter-Number Sequencing task, as compared with those on placebo. Treatment with modafinil did not have a beneficial effect in reducing self-reported fatigue. No changes were noted on the Modified Fatigue Impact Scale or the Fatigue Severity Scale with the treatment of modafinil, as compared with placebo. Findings indicate that 200 mg of modafinil has the potential to improve working memory in persons with MS. These findings suggest that modafinil may enhance aspects of cognition in persons with MS and may be an effective adjunct to clinical rehabilitation interventions.

A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence

BackgroundModafinil is a medication approved for narcolepsy and shift work sleep disorder. It has both dopaminergic and glutamatergic activity that could be useful for the treatment of cocaine dependence. Modafinil has reduced cocaine subjective effects and cocaine self-administration in human laboratory trials and has reduced cocaine use in cocaine dependent patients in some clinical trials. MethodsThis was an 8-week, double blind, placebo controlled clinical trial involving 94 cocaine dependent subjects. Subjects received 300mg of modafinil or identical placebo daily along with weekly individual therapy. The primary outcome measure was cocaine use measured by self-report, and confirmed by twice weekly urine benzoylecgonine tests (UBT). Additional outcome measures included cocaine craving measured by the Brief Substance Craving Scale and global improvement measured by the Clinical Global Impression Scale (CGI). ResultsThe odds ratio (OR) in favor of abstinence for modafinil vs. placebo was 2.54 (p=. 03) and modafinil-treated subjects were significantly more likely than placebo-treated subjects to be abstinent from cocaine during the last 3 weeks of the trial, 23% vs. 9%, χ2=3.9, p<.05. Modafinil treated subjects were more likely to report very low levels of cocaine craving intensity and duration on the Brief Substance Craving Scale (OR=2.04, p=.03 and OR 1.06, p=.03 respectively). Modafinil-treated subjects were also more likely than placebo-treated subjects to rate themselves as “very much improved” on the CGI (OR=2.69, p=.03). ConclusionModafinil may be an efficacious treatment for cocaine dependence.

New Onset of Compulsive Gambling Associated With Modafinil: A Case Report.

To the Editor: We describe a case of compulsive gambling associated with the use of modafinil in a patient with idiopathic hypersomnia. Modafinil is a wakefulness-promoting agent that is approved by the US Food and Drug Administration for hypersomnolence associated with narcolepsy, obstructive sleep apnea, shift work sleep disorder, and fatigue associated with multiple sclerosis.1 Modafinil prescribing information reports psychiatric adverse experiences including mania, delusions, hallucinations, suicidal ideation, and depression.1 Tarrant and colleagues2 have described a case of a patient with minor gambling, who reported a 10-fold increase in his slot-machine use after taking modafinil. However, new-onset impairment of impulse control has been more commonly described in patients receiving dopamine agonist therapy for restless legs syndrome and Parkinson’s disease.3 Case report. A 46-year-old white woman with history of idiopathic hypersomnia diagnosed in 2005 at another sleep center presented to our sleep clinic as a transfer of care in 2010. She had history of excessive daytime sleepiness dating back to early school years. She had also experienced hypnogogic hallucinations and occasional sleep paralysis. There was no clear history of cataplexy. In 2005, her primary complaint included excessive sleepiness and snoring. She underwent diagnostic polysomnography (PSG) and a multiple sleep latency test (MSLT with 4 naps). Review of these records indicated an unremarkable PSG. Results from a MSLT performed after 8 hours of PSG-documented sleep showed a sleep latency of 4 minutes 45 seconds with no sleep-onset rapid-eye-movement periods. She was diagnosed with narcolepsy without cataplexy (based on International Classification of Sleep Disorders, second edition4), and modafinil was started at a dose of 200 mg in the morning and a 100-mg additional dose if needed for residual daytime sleepiness. She had a good response to the medication and no longer required daily naps. The patient’s hypersomnolence symptom remained stable on a dose of 200 mg of modafinil for a year when she developed impulsive gambling. She was not taking any other medications at that time. She tried to curtail her gambling, but could not, and would go to casinos and lose significant amounts of money until she was seen in our sleep center in 2010. She described losing up to $1,000 each time and reported losing $20,000 in the past 5 years prior to the visit to our clinic. She has tried behavior modifications such as talking to her husband when there was an urge to gamble, but had little success. In the year 2010, she was switched from modafinil to methylphenidate, which helped resolve gambling severity within a month. She was never restarted on modafinil after this as she did not want to risk having another episode of gambling again. On a follow-up visit the next year, she reported improvement in the compulsive gambling. She still had urges, but was able to exercise control over the impulses. In regard to her hypersomnolence symptoms, however, she had better results with modafinil. A more divided dose of methylphenidate was recommended during the visit. The patient has continued to take methylphenidate since 2010 and has had no reported side effects. She was taking a sustained dose of methylphenidate with good response. Impulse-control disorders (ICD) are characterized by excessive rumination and/or unwanted behaviors that lead to dysfunction or interference with work or social functioning.5 In a group of patients treated with dopaminergic agents, up to 17% of patients developed ICDs, of which 5% was pathological gambling. Mean time to onset of symptoms was 9.5 months.6 Modafinil is a non-amphetamine stimulant medication, and the exact mechanism of action is unknown.7 The wakefulness-promoting action useful in narcolepsy treatment could be due to activation of orexin neurons in the hypothalamus.6 In addition, modafinil has been shown to inhibit dopamine transporter and increase cortical and caudate dopamine concentrations.8 The effects of modafinil on impulse control are poorly studied. Zack and Poulos9 found that modafinil can have bidirectional effects on pathological gambling patients, ie, it can increase desire to gamble, disinhibition, and risky decision-making in low-impulsivity subjects, while decreasing these indexes in high-impulsivity subjects. In our patient, a previous history of gambling was not associated with disruption in her life. Moreover, there was no previous psychiatric comorbidity. She did not describe episodic hypersomnia, suggestive of Kleine-Levin syndrome, which commonly is associated with behavioral disturbances. However, the patient developed a new-onset pathological gambling and an inability to stop despite financial and social repercussions. Symptoms began after the use of modafinil, with significant improvement in gambling preoccupation and urges once the medication was stopped. While the majority of patients who develop ICDs while using dopaminergic agents for Parkinson’s disorder will have remission of symptoms, ICDs, particularly pathological gambling, can persist.10

Effectiveness of Modafinil on Fatigue in Chronic Hepatitis C

Introduction: Objective: To assess the efficacy of modafinil on fatigue in patients with Chronic Hepatitis C. Background: Hepatitis C Virus (HCV) is present in about 8% of the veteran population. Fatigue accompanies HCV infection in 53%-67% of patients and is sufficiently severe enough to impair activity in 17%. Modafinil is a unique wake-promoting agent that has been found to be effective in the treatment of fatigue in patients with multiple sclerosis. Methods: Patients aged 18-65 years with a diagnosis of HCV and mean score >27 on the fatigue severity scale (FSS) were eligible for the randomized double-blind placebo controlled trial. Exclusion criteria included hemoglobin <12, total bilirubin >2, uncontrolled diabetes with HBA1c >8, congestive heart failure with EF <35%, malignancy, or pregnancy. Patients received either placebo or 100 mg of modafinil for 2 weeks. Efficacy was evaluated with self-rating scales: fatigue severity scale (FSS) [score= 9-63], Epworth sleep scale (ESS) [score=0-24], and CES-D depression scale [score=0-60]. Change scores were calculated as pre-score minus post-score. Adverse events were also recorded. The independent samples t-test was used to compare groups on change scores. Results: Of the 25 patients enrolled, 4 were lost to follow-up. Eleven patients received modafinil and 10 received placebo. Ten patients in each group completed all outcome measures. No significant improvement in fatigue, sleep, or depression was demonstrated. FSS decreased 7.4 for the modafinil group (pre=50.2, post=42.8) vs. 6.4 for the placebo group (pre=48.9, post 42.5) [p=0.87]. ESS decreased 2.5 for the modafinil group (pre=12.3, post=9.8) vs. 0.8 for the placebo group (pre=10.9, post 10.1) [p=0.38]. CES-D decreased 5.35 for the modafinil group (pre=24.0, post=18.65) vs. 1.9 for the placebo group (pre=25.4, post 23.5) [p=0.36]. Serious adverse events were not found. The most common adverse events were headache and nausea. Conclusion: While 100 mg modafinil daily did not improve fatigue, sleep, or depression compared to placebo, our study was an exploratory study with limited power (n=10 for each group). We showed the feasibility of such a study (i.e., low dropout rate and no serious adverse events) and recommend a future investigation with a larger sample to determine the effectiveness of modafinil to reduce fatigue in HCV patients. The lack of improvement in fatigue in the modafinil group may have also been due to lower dose of modafinil used.

Neural substrates of impulsive decision making modulated by modafinil in alcohol-dependent patients.

Impulsive decision making is a hallmark of frequently occurring addiction disorders including alcohol dependence (AD). Therefore, ameliorating impulsive decision making is a promising target for the treatment of AD. Previous studies have shown that modafinil enhances cognitive control functions in various psychiatric disorders. However, the effects of modafinil on delay discounting and its underlying neural correlates have not been investigated as yet. The aim of the current study was to investigate the effects of modafinil on neural correlates of impulsive decision making in abstinent AD patients and healthy control (HC) subjects. A randomized, double-blind, placebo-controlled, within-subjects cross-over study using functional magnetic resonance imaging (fMRI) was conducted in 14 AD patients and 16 HC subjects. All subjects participated in two fMRI sessions in which they either received a single dose of placebo or 200mg of modafinil 2h before the session. During fMRI, subjects completed a delay-discounting task to measure impulsive decision making. Modafinil improved impulsive decision making in AD pateints, which was accompanied by enhanced recruitment of frontoparietal regions and reduced activation of the ventromedial prefrontal cortex. Moreover, modafinil-induced enhancement of functional connectivity between the superior frontal gyrus and ventral striatum was specifically associated with improvement in impulsive decision making. These findings indicate that modafinil can improve impulsive decision making in AD patients through an enhanced coupling of prefrontal control regions and brain regions coding the subjective value of rewards. Therefore, the current study supports the implementation of modafinil in future clinical trials for AD.

Use of modafinil to moderate the relationship between cancer-related fatigue and depression in 541 patients receiving chemotherapy: A URCC CCOP study.

9572 Background: Over 50% patients with cancer report symptoms of depression; 15% meet diagnostic criteria for Major Depressive Disorder. Depression is associated with increased insomnia, fatigue and reduced quality of life. We previously found that modafinil is effective for reducing high levels of fatigue among patients undergoing chemotherapy. This study aims to test whether modafinil can alleviate symptoms of depression by reducing fatigue. Methods: This study is a secondary analysis of 541 cancer patients receiving chemotherapy and experiencing fatigue (Brief Fatigue Inventory (BFI) &gt;=3) that were randomized to receive either 200 mg of modafinil (N=260) or placebo (N=281) daily from baseline (Cycle 2) until post-test (Cycle 4). Depression was measured by the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and post-test. The CES-D total score and its subscales (Positive Affect, Negative Affect, Somatic Symptoms, and Interpersonal Symptoms) were analyzed. A linear model with CES-D post (outcome) and BFI baseline, Arm, and BFI*Arm interaction term (independent variables) was used to address the hypothesis; p&lt;0.05 indicates significance. Results: We found no overall effect of modafinil on depression; however, the model demonstrated a significant moderating effect of modafinil on the relationship between baseline fatigue and CES-D total scores (p = 0.04). For subjects with severe fatigue (BFI ≥ 7), the drug reduced CES-D scores by 3-4. Modafinil also significantly moderated the relationship between baseline fatigue and Positive Affect subscale scores (p = 0.003), but not the relationship between baseline fatigue and Somatic, Negative Affect, or Interpersonal subscales. Conclusions: Modafinil differentially impacts depression based on a patient’s level of fatigue; reduced depressive symptoms occurred in those with extreme fatigue. This effect is driven by increases in positive affective symptoms. These results have significant implications for intervention; in patients with high levels of fatigue, modafinil might also reduce depression. Future RCTs are needed to confirm these results. Funding: U10CA37420, K07CA120025, K07CA132916.

Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China

To describe the population pharmacokinetic profile of modafinil acid and to compare the extent of metabolism of modafinil into modafinil acid in 5 major ethnic groups (Han, Mongolian, Korean, Uygur, and Hui) of China. In a multi-center, open-label, single dose clinical trial, 49 healthy volunteers from the 5 ethnic groups received 200 mg of modafinil orally. Blood samples for pharmacokinetic evaluation of modafinil and modafinil acid were drawn before and at different time after the administration. Systematic population pharmacokinetic (PopPK) modeling for modafinil acid was conducted, integrating with our previous PopPK model for modafinil. The influence of ethnicity, gender, height, body weight and body mass index (BMI) was estimated. The extent of metabolism of modafinil into modafinil acid, expressed as the relative conversion fraction, was estimated and compared among the 5 ethnic groups. When combined with the PopPK model of modafinil, the concentration of modafinil acid versus time profile was best described with a one-compartment model. The typical clearance and volume of distribution for modafinil acid were 4.94 (l/h) and 2.73 (l), respectively. The Korean group had 25% higher clearance, and the Uygur and Hui groups had 12% higher clearance than the Han group. The median for the relative conversion fraction was 0.53 for Koreans, and 0.24 for the other 4 ethnicities. Ethnicity has significant influence on the clearance of modafinil acid. When patients in the 5 ethnic groups are administered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered.

Dependence on Supratherapeutic Doses of Modafinil

To the Editor: Modafinil is a wakefulness-promoting agent used for the treatment of various sleep disorders like narcolepsy, obstructive sleep apnea, and shift work sleep disorder. Over the years it has gained popularity among prescribers due to its wakefulness-promoting efficacy and presumably lower abuse potential and has been used in the treatment of various fatigue syndromes, treatment-resistant depression, and attention-deficit/hyperactivity disorder.1,2 There is a controversy with regard to the abuse potential of modafinil, with some authors suggesting that it has low abuse potential and others suggesting that it has psychoactive and euphoric effects and leads to alterations in mood, perception, thinking, and feelings, all of which are seen with other central nervous system stimulants.1,2 The data with regard to its use in toxic doses are also limited.3–6 In our search, we could find no report of modafinil abuse or dependence in the literature. We report a case of a patient who used modafinil in supratherapeutic doses in a pattern that conformed with drug dependence. Case report. Mr A, a 53-year-old man diagnosed with schizoaffective disorder (DSM-IV criteria) for the last 33 years along with tobacco and benzodiazepine dependence syndrome (currently abstaining), presented with a history of excessive use of modafinil. Exploration of his history revealed that, 3 years prior, he consulted a psychiatrist for symptoms of fluctuating sadness of mood, lethargy, and sedation and was started on tablet modafinil, 50 mg/d, which was later increased to 100 mg/d along with tablet sertraline, 50–100 mg/d, and tablet amisulpride, 100 mg/d. The addition of modafinil made the patient feel fresh and active, and after 4–5 months modafinil was increased to 200 mg/d at the request of the patient. Over the next year, he started self-medicating with modafinil, taking 1 or 2 tablets (100–200 mg) in the afternoon or evening to overcome his boredom and fatigue, having felt a strong desire to take the same. On days when he would not take modafinil, he had strong craving and urge to do so, felt that something was missing in his life, and became irritable, felt weak, and had difficulty in concentrating on the work at hand. Over the next year, his intake of modafinil increased to 1,500–2,000 mg/d in order to experience the desired effect; he consumed 100–200 mg every 1–4 hours. Later, due to heavy doses of modafinil, he would have slurring of speech and poor attention and concentration. He continued to take modafinil against the advice of family and treating psychiatrists and would indulge in doctor shopping if he had difficulty in getting a prescription for modafinil or procuring it. With the available information, an additional diagnosis of modafinil dependence syndrome (per DSM-IV criteria for substance dependence disorder) was considered. He was counseled to taper off the dose of modafinil and was given benzodiazepines to manage the symptoms of withdrawal. The usual recommended dosage of modafinil is 200 mg/d. The previous reports of the use of modafinil in supratherapeutic or toxic doses did not describe continuous intake of the higher doses over the period.3–6 In the case reported here, the patient took 1,500–2,000 mg of modafinil per day for about 1 year. The intake of modafinil followed the typical pattern of drug dependence, which indicates its abuse potential. To conclude, our case suggests that modafinil has abuse potential and hence it should be prescribed cautiously and clinicians should be aware of its abuse potential. There is a need for further systematic studies to evaluate its abuse and dependence potential.

P5. Diagnosis and management of hypersomnia in bilateral thalamic lesions

Introduction The rare bilateral thalamic lesions (BTL) are usually accompanied by hypersomnia and apathy. The temporal course and prognosis of hypersomnia in BTL is still unclear. No specific treatment is available for this condition. Methods Case-report of a 44-year-old Caucasian male with MRI-confirmed bilateral paramedian thalamic lesions due to streptococcus pneumoniae meningo-encephalitis and sleep–wake behavior documented with repeated actigraphy over a period of 1.5 years. Results During the acute phase (1st month) the actigraphic pattern showed an irregular sleep/wake cycle with prolonged phases of assumed inactivity during the daytime ( Fig. 1 A). In the (sub-) chronic phase (3rd month) a regular hypersomnic pattern ( Fig. 1 B) with average assumed 24-h sleep time of 14 h, with 5.6 of them occurring during the daytime. Administration of 100 mg and 50 mg of modafinil (single morning dose) led to a prominent circadian rhythm disruption ( Fig. 1 C and E). Although the average 24-h-sleep time decreased to 9.5–10.4 h, mean daytime sleep length exceeded the nocturnal one. Withdrawal of modafinil resulted in a complete re-establishment of the previous hypersomnic pattern ( Fig. 1 D). A further attempt with an even lower dose of modafinil (25 mg/day) reduced the average 24-h sleep time to 10.9 h, daytime sleep to 3.5 h and nocturnal sleep to 7.4 h, without disrupting the circadian sleep/wake pattern ( Fig. 1 F). Clinical follow up after 2 months confirmed good efficacy of this low dose of modafinil. Conclusions To our knowledge, this is the first long-term actigraphic documentation of sleep–wake behavior and response to modafinil in BTL. Treatment with modafinil was associated with the emergence of dose-dependend circadian disruption, recommending the use of very low dosages in treating hypersomnia in BTL.

Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers

BackgroundModafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions. The aim of this study was to investigate the effects of modafinil on non-verbal cognitive functions in healthy volunteers, with a particular focus on variations of cognitive load, measures of motivational factors and the effects on creative problem-solving. MethodsA double-blind placebo-controlled parallel design study evaluated the effect of 200 mg of modafinil (N = 32) or placebo (N = 32) in non-sleep deprived healthy volunteers. Non-verbal tests of divergent and convergent thinking were used to measure creativity. A new measure of task motivation was used, together with more levels of difficulty on neuropsychological tests from the CANTAB battery. ResultsImprovements under modafinil were seen on spatial working memory, planning and decision making at the most difficult levels, as well as visual pattern recognition memory following delay. Subjective ratings of enjoyment of task performance were significantly greater under modafinil compared with placebo, but mood ratings overall were not affected. The effects of modafinil on creativity were inconsistent and did not reach statistical significance. ConclusionsModafinil reliably enhanced task enjoyment and performance on several cognitive tests of planning and working memory, but did not improve paired associates learning. The findings confirm that modafinil can enhance aspects of highly demanding cognitive performance in non-sleep deprived individuals.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Population Pharmacokinetics of Modafinil and Its Acid and Sulfone Metabolites in Chinese Males

Modafinil is a psychostimulant used to treat excessive sleepiness. The aim of this study was to develop a population pharmacokinetic model of modafinil and its major metabolites in Chinese male adults and to identify covariates that predict variability in disposition. Eighty healthy volunteer subjects were randomized to 4 oral dose groups: 3 doses of 50 mg of modafinil, 3 doses of 100 mg of modafinil, 2 doses of 200 mg of modafinil plus 1 dose of placebo, or 3 doses of placebo (each dose given 8 hourly). Blood samples were collected up to 58 hours post-first dose for plasma concentrations of modafinil and its metabolites. Pharmacokinetic data analyses were performed using noncompartmental and compartmental approaches. The population pharmacokinetic study was conducted using the nonlinear mixed-effects model software, NONMEM, and validated using the bootstrap, crossvalidation and visual predictive check approaches. Data were best described by a 5-compartment model: 2 compartments for modafinil (first-order absorption from gut compartment) and 1 each for modafinil acid and modafinil sulfone. A covariate analysis identified body weight as influencing volumes of the central and peripheral compartments for modafinil. All the parameters were estimated with good precision (relative standard error < 39%). The visual predictive check found that the final pharmacokinetic model adequately predicted observed concentrations of all 3 molecular species. The authors developed dosing schedules to achieve minimum trough plasma modafinil concentrations of 3 mcg/mL. A robust population pharmacokinetic model for modafinil and its metabolites was developed for the first time. Based on this model, individualized dosing based on weight is now possible.

Uso de modafinilo en astenia por cáncer avanzado

Modafinil is a psychostimulant with a different mechanism of action to other similar drugs. It is approved for the treatment of excessive daytime sleepiness in relation with several causes. It has also been used in neurology illness- related fatigue with positive results. There is an increasing interest in modafinil as a potentially effective drug to improve fatigue. Following the trend to use other psychostimulants (e.g.,methylphenidate) to improve symptomatic problems in Palliative Care, we performed a review with the aim of exploring the use of modafinil to alleviate cancer - related fatigue. We analysed modafinil articles published in the last ten years, with particular attention to the practical aspects of its use (type of patient, dose, secondary effects, etc.), as well as prospective studies and randomised trials on cancer-related fatigue. The pharmacological profile of Modafinil is appropiate for advanced cancer patients. Four prospective studies and three randomised trials have examined its use since 2005. Between 46-90% of the 157 patients treated with 200 mg of modafinil had a significant improvement in fatigue. There were significant improvements in fatigue in two of the three randomised trials. Modafinil had a good tolerance in all of them. These results justify further research into the treatment of cancer-related fatigue, and meanwhile modafinil could be considered as an alternative for cancer - related fatigue.

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Histamine and dopamine contribute to the maintenance of wakefulness. This study aims to conduct an exploratory analysis of the effects of 10 and 50mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep. A total of 25 healthy men were recruited to a double-blind, placebo-controlled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at two-hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness. After placebo, sleep deprivation was associated with enhancements in delta and theta and reductions in alpha and beta activity. Following dosing at 02:00 h, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00h, latency to sleep onset and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1% was increased and total sleep time, SWS% and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249, the 50-mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep. After modafinil, no changes were observed for power spectra during sleep. Both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.