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PubMed2006

Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome.

OBJECTIVE: Armodafinil is the R-enantiomer of racemic modafinil and has a significantly longer half-life than the S-enantiomer. This study evaluated armodafinil 150 mg/day as an adjunct treatment for residual excessive sleepiness in patients with obstructive sleep apnea/hypopnea syndrome (OSA/HS) who were otherwise well controlled with nasal continuous positive airway pressure (nCPAP). We assessed the ability of armodafinil to improve wakefulness and cognition and reduce fatigue in this population. METHODS: In this 12-week, randomized, double-blind study, patients (n=259) received armodafinil (150 mg) or placebo once daily. Efficacy assessments at baseline and weeks 4, 8, and 12 included the Maintenance of Wakefulness Test (MWT), Clinical Global Impression of Change (CGI-C), Cognitive Drug Research battery, Epworth Sleepiness Scale, and Brief Fatigue Inventory. RESULTS: At final visit, mean (SD) MWT sleep latency increased from baseline by 2.3 (7.8) min with armodafinil and decreased by 1.3 (7.1) min in the placebo group (P=0.0003). Armodafinil improved clinical condition (CGI-C, 71% vs. 53% for armodafinil and placebo, respectively; P=0.0069). Armodafinil significantly improved episodic secondary memory (P=0.0102) and patient-estimated wakefulness (P<0.01) and reduced fatigue (P<0.05) compared with placebo. Armodafinil did not adversely affect nCPAP use. The most common adverse event associated with armodafinil was headache. Sleep macroarchitecture was not altered by armodafinil. CONCLUSION: Adjunct treatment with armodafinil significantly improved alertness, overall clinical condition, and long-term memory. Armodafinil also reduced fatigue and the impact of sleepiness on daily activities in patients with OSA/HS who have residual excessive sleepiness notwithstanding regular use of nCPAP. Armodafinil was well tolerated.

Adjuvants, Pharmaceutic↗
PubMed1999

Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.

Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation. Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons. We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.

Age of Onset↗
PubMed2003

Temporal pattern of hippocampal high-frequency oscillations during sleep after stimulant-evoked waking.

Hippocampal ripple oscillations (140-200 Hz) are believed to be critically involved in the consolidation of memory traces during slow-wave sleep (SWS). We investigated the temporal pattern of ripple occurrence in relation to sleep phases following different types of waking. Amphetamine, the atypical wakening drug modafinil or non-pharmacological sleep deprivation lead to an increased ripple occurrence ("rebound") during the subsequent SWS episode. Waking of the same duration evoked by amphetamine or sleep deprivation led to a ripple rebound of similar extent (approximately 200%). The mean intraripple frequency was also elevated by up to 20 Hz during SWS following all treatments. Ripple amplitude was significantly increased only in experiments with amphetamine. Ripple occurrence but not intraripple frequency clearly correlated with the antecedent waking duration independent of treatment. Recovery of ripple occurrence and frequency to the pretreatment level during SWS depended on SWS duration. At the end of the recovery period paradoxical sleep (PS) acted like waking, elevating ripple occurrence during subsequent SWS episodes. On the other hand, PS decreased ripple occurrence if recovery from the rebound was not yet complete. Thus occurrence and structure of ripple oscillations are regulated by the timing and duration of previous SWS, PS and waking episodes.

Amphetamine↗
PubMed2006

[Augmentation strategies for therapy resistant depression - a review].

OBJECTIVE: Various pharmacological strategies have been developed to treat such refractory depression, of which augmentation therapies are one of the most important. This article reviews both benefits and risks of all known augmentation therapies. METHODS: The relevant literature was identified by means of a computerized MEDLINE research on the years 1990 - 2004 and scanning of review articles. RESULTS: The efficacy of lithium augmentation is very well documented by a large number of controlled studies - lithium augmentation can therefore be recommended in depression refractory to antidepressant treatment. T3 augmentation is - in contrast to lithium augmentation - only a second-line strategy. There is an increasing number of augmentation therapies with atypical antipsychotics - its efficacy already supported by some well designed placebo controlled studies. Augmentation strategies with buspirone, modafinil and dopaminergic agents show good results in some case series and open studies, but there is a lack of doubleblind placebo controlled studies till now. Other augmentation therapies with stimulants, reserpine, pindolol, SAME and Yohimbine are very interesting clinical research strategies with rather little impact on clinical practice at the moment. CONCLUSIONS: The distinct knowledge of available augmentation strategies may help to increase response - as well as remission rates in therapy resistant depression.

Antidepressive Agents↗
PubMed2006

Molecular genetics and treatment of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Animals↗
PubMed2005

Management of cancer-related fatigue.

Fatigue is among the most commonly reported symptoms of patients with cancer, with prevalence exceeding 60% in many studies. It is among the most distressing symptoms associated with cancer and cancer treatments because it substantially disturbs patients' quality of life and ability to function optimally on a daily basis. Although the development of this condition has been associated with a number of factors, its etiology remains poorly understood. Important elements to include in any definition of cancer-related fatigue include its pervasiveness, persistence, detrimental effect on quality of life, and its inability to be relieved by rest or sleep. Several validated questionnaires can be used to measure fatigue in patients with cancer, and research efforts are currently focused on ways to distinguish it from depression with which it shares many symptoms. All patients with cancer should be evaluated for fatigue, and treatment options should be considered for those who are experiencing excessive levels of fatigue. Treatment should be individualized according to the underlying pathology when a specific cause has been identified (e.g., anemia, sleep disorder, depression, or metabolic disorder). Nonspecific therapies may be useful in short- and long-term cancer-related fatigue management in many patients. In addition to older therapies, such as hematopoietics, antidepressants, corticosteroids, and psychostimulants, the effectiveness of the new wake-promoting agent modafinil is currently being studied. A more thorough evaluation of the various therapeutic options is required to better define their efficacy and safety profiles in this patient population.

Antidepressive Agents↗
PubMed1991

Relative efficacy of drugs for the treatment of sleepiness in narcolepsy.

A survey was conducted on 10 polysomnographic studies on the pharmacologic treatment of the sleepiness of narcolepsy. Three studies employed the MSLT and 7 employed the MWT as their polygraphic measure of sleep tendency. Statistically and clinically significant therapeutic changes were apparent for pemoline, modafinil, dextroamphetamine and methylphenidate. Codeine, ritanserin and protriptyline did show statistically significant effects. The common feature among the drugs that did produce clinically significant improvements seems to be facilitatory action on central catecholaminergic transmission. Within this group of drugs, only methylphenidate and dextroamphetamine brought MWT sleep latencies to approximately 70% of normal levels.

Adult↗
PubMed2004

What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications.

Numerous studies dissecting the basic mechanisms that control sleep regulation have led to considerable improvement in our knowledge of sleep disorders. It is now well accepted that transitions between sleep and wakefulness are regulated by complex neurobiologic mechanisms, which, ultimately, can be delineated as oscillations between two opponent processes, one promoting sleep and the other promoting wakefulness. The role of several neurotransmitter or neuromodulator systems, including noradrenergic, serotonergic, cholinergic, adenosinergic, and histaminergic systems and, more recently, the hypocretin/orexin and dopamine systems, has been clearly established. Amphetamine-like stimulants are known to increase wakefulness by blocking dopamine reuptake, by stimulating dopamine release, or by both mechanisms. Modafinil may increase wakefulness through activation of noradrenergic and dopaminergic systems, possibly through interaction with the hypocretin/orexin system. Caffeine inhibits adenosinergic receptors, which in turn can produce activation via interaction with GABAergic and dopaminergic neurotransmission. Nicotine enhances acetylcholine neurotransmission in the basal forebrain and dopamine release. Understanding the exact role of the hypocretin/orexin and dopamine systems in the physiology and pharmacology of sleep-wake regulation may reveal new insights into current and future wakefulness-promoting drugs.

Amphetamine↗
PubMed2004

The month-of-birth pattern in narcolepsy is moderated by cataplexy severity and may be independent of HLA-DQB1*0602.

OBJECTIVES: A March peak and a September trough in the birth pattern of narcolepsy patients with clear-cut cataplexy was recently reported. The objectives of the present study were to determine whether the month-of-birth pattern would (a) vary with the presence and severity of cataplexy and (b) differ for patients positive and negative for HLA-DQB1*0602. DESIGN: Cross-sectional survey with data obtained from the clinical trials assessing the safety and efficacy of modafinil in the treatment of narcolepsy. SETTING: Sleep clinics throughout the United States. PATIENTS: A group of 530 narcolepsy patients diagnosed based on the International Classification of Sleep Disorders using clinical histories, nocturnal polysomnography, and Multiple Sleep Latency Tests. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: A surplus of March births and a fall-off in September births was found in narcolepsy relative to the general population. This finding was only observed when cataplexy was moderate or severe. The month-of-birth pattern was similar for HLA-DQB1*0602 positive and negative patients. A March birth and HLA-DQB1*0602 positivity were independent risk factors in a logistic regression analysis. CONCLUSIONS: Environmental events during development may influence narcolepsy severity or the likelihood of developing the disease.

Adult↗
PubMed2006

The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy.

OBJECTIVE: This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy. RESEARCH DESIGN AND METHODS: This was a multicenter double-blind study with 196 patients (aged 18-65 years) randomized to receive armodafinil 150 mg (n = 65), armodafinil 250 mg (n = 67), or placebo (n = 64) once daily for 12 weeks. MAIN OUTCOME MEASURES: Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20-min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory). RESULTS: Armodafinil significantly increased MWT mean sleep latency (at 0900-1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9 min in the 150-mg, 250-mg, and combined groups, respectively, compared with a decrease of 1.9 min for placebo (p < 0.01 for all three comparisons). Mean late-day MWT latency (1500-1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8 min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGIC rating from baseline to final visit in the armodafinil 150-mg, 250-mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness. CONCLUSIONS: Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.

Adolescent↗
PubMed2003

Glutamatergic agents for cocaine dependence.

Effective medications for cocaine dependence are needed to improve outcome in this chronic, relapsing disorder. Medications affecting glutamate function are reasonable candidates for investigation, given the involvement of glutamate circuits in reward-related brain regions and evidence of cocaine-induced glutamatergic dysregulation. In addition, it is increasingly apparent that glutamatergic mechanisms underlie several clinical aspects of cocaine dependence, including euphoria, withdrawal, craving, and hedonic dysfunction. Even denial, traditionally viewed as purely psychological, may result, in part, from dysfunctional glutamate-rich cortical regions. We review the involvement of glutamate in reward-related circuits, the acute and chronic effects of cocaine on these pathways, and glutamatergic mechanisms that contribute to the neurobiology of cocaine dependence. We also present preliminary data from our research of modafinil, a glutamate-enhancing agent with promise in the treatment of cocaine-addicted individuals.

Animals↗
PubMed2006

Emerging pharmacological strategies in the fight against cocaine addiction.

Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a beta-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials.

Adrenergic beta-Antagonists↗
PubMed2004

Pharmacologic management of daytime sleepiness.

Excessive daytime sleepiness and abnormal sleep-wake patterns are becoming increasingly pervasive in modern society. The major causes of excessive daytime sleepiness include pathologic abnormalities of the central nervous system, such as narcolepsy and idiopathic hypersomnia; deficiencies in quality or quantity of sleep, such as those caused by sleep apnea and poor sleep hygiene; disturbances to the body's natural circadian rhythm, such as those caused by shift work or jet lag; and drugs, which can increase sleepiness either therapeutically or as a side effect. Determining the cause of daytime sleepiness is the first step in treating it. Setting appropriate and realistic treatment goals with the patient and initiating treatment are the next steps. Although the medications available to improve daytime wakefulness (e.g., amphetamines, methylphenidate, pemoline, and modafinil) are effective, they are not a substitute for sleep. Finally, timely follow-up is necessary to monitor treatment adherence, response, and side effects.

Amphetamines↗
PubMed2005

Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures.

Uncomfortable working and sleeping environments, high operational tempos, sustained operations, and insufficient staffing make fatigue a growing concern. In aviation, where a single mistake can cost millions of dollars, it is essential to optimize operator alertness. Although behavioral and administrative fatigue countermeasures should comprise the "first line" approach for sustaining aircrew performance, pharmacological fatigue countermeasures are often required. Various components of the U.S. military have authorized the use of specific compounds for this purpose. Hypnotics such as temazepam, zolpidem, or zaleplon can mitigate the fatigue associated with insufficient or disturbed sleep. Alertness-enhancing compounds such as caffeine, modafinil, or dextroamphetamine can temporarily bridge the gap between widely spaced sleep periods. Each of these medications has a role in sustaining the safety and effectiveness of military aircrews. The present paper provides a short overview of these compounds as well as factors to be considered before choosing one or more to help manage fatigue.

Acetamides↗
PubMed2005

Nonstimulant therapies for attention-deficit hyperactivity disorder (ADHD) in children and adults.

While stimulant medications are the primary pharmacological treatment for ADHD across the lifespan, a subset of patients with ADHD do not experience significant symptom relief from stimulants or can not tolerate effective stimulant doses. Psychosocial therapies, particularly behavioral modification techniques, should be considered for children with ADHD and oppositional behaviors, while Cognitive Behavioral Therapy (CBT) may be a helpful adjunct for adolescents and adults with ADHD. Among the nonstimulant medications, atomoxetine (Strattera) is the only the FDA approved option. It has been found to be efficacious for the entire spectrum of ADHD symptoms in both children and adults. However, daily compliance is essential, and it may take several weeks to achieve full therapeutic effect. Other nonstimulants that have been used to treat ADHD include bupropion (Wellbutrin), the alpha-2 agonists guanfacine (Tenex) and clonidine (Catapres) as well as the tricylic antidepressants. Modafinil (Provigil) is actively being studied for the treatment of pediatric ADHD, and there has been some preliminary studies assessing the efficacy of cholinergic agents for ADHD. Recently, there has been increasing interest in combining nonstimulant therapies with stimulants to further enhance treatment effects. However, more controlled data on the safety and efficacy of combining pharmacological therapies are needed.

Adrenergic Uptake Inhibitors↗
PubMed1993

Fibrositis syndrome and narcolepsy.

Fibrositis is often associated with sleep disturbances and with an alpha nREM abnormality on sleep electroencephalogram. We describe a case occurring during the course of a typical longstanding narcolepsy-cataplexy. Modafinil, that is an effective treatment of hypersomnia, did not alleviate the symptoms of fibrositis in the short term.

Aged↗
PubMed1997

HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.

Narcolepsy is a sleep disorder associated with HLA DR15 (DR2) and DQB1*0602. We HLA typed 509 patients enrolled in a clinical trial for the drug modafinil and analyzed the results in relation to cataplexy, a symptom of narcolepsy characterized by muscle weakness triggered by emotions. The patients were either subjects with cataplexy who had a mean sleep latency (SL) of less than 8 minutes and two or more sleep onset rapid eye movement (REM) periods (SOREMPs) during a multiple sleep latency test, or narcoleptic patients without cataplexy but with a mean SL shorter than 5 minutes and two or more SOREMPs. The respective values of DRB1*15 (DR2) and DQB1*0602 as markers for narcolepsy were first compared in different ethnic groups and in patients with and without cataplexy. DQB1*0602 was found to be a more sensitive marker for narcolepsy than DRB1*15 across all ethnic groups. DQB1*0602 frequency was strikingly higher in patients with cataplexy versus patients without cataplexy (76.1% in 421 patients versus 40.9% in 88 patients). Positivity was highest in patients with severe cataplexy (94.8%) and progressively decreased to 54.2% in patients with the mildest cataplexy. A voluntary 50-item questionnaire focusing on cataplexy was also analyzed in 212 of the 509 HLA-typed patients. Subjects with definite cataplexy as observed by an experienced clinician were more frequently HLA DQB1*0602-positive than those with doubtful cataplexy, and the manifestations of cataplexy were clinically more typical in DQB1*0602-positive patients. These results show that the HLA association is as tight as previously reported (85-95%) when cataplexy is clinically typical or severe. We also found that patients with mild, atypical, or no cataplexy have a significantly increased DQB1*0602 frequency (40-60%) in comparison with ethnically matched controls (24%). These results could be explained by increased disease heterogeneity in the noncataplexy group or by a direct effect of the HLA DQB1*0602 genotype on the clinical expression of narcolepsy.

Adolescent↗
PubMedDate not supplied

Narcolepsy. Signs, symptoms, differential diagnosis, and management.

Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness and cataplexy and less often by hypnagogic hallucinations and sleep paralysis. While patients report excessive daytime sleepiness and cataplexy as the more frequent symptoms of this condition, excessive daytime sleepiness is generally believed to be the most debilitating. Narcolepsy often is undiagnosed or misdiagnosed for a variety of reasons. Although confirmation of an initial diagnosis requires monitoring of physiologic variables conducted at a sleep center by specialists, the primary care physician has a critical role in the identification and management of this incurable affliction. This article provides recommendations for the diagnosis and management of narcolepsy. The cataplexy associated with narcolepsy can be managed with tricyclic antidepressants. The excessive sleepiness is managed with stimulants but newer agents, such as modafinil, which will be marketed as Provigil, and selegiline hydrochloride, with fewer adverse effects and less abuse potential, may offer means of promoting daytime wakefulness. Groups such as the National Sleep Foundation, Washington, DC, and the Narcolepsy Network, Cincinnati, Ohio, can provide patients with needed support and information.

Diagnosis, Differential↗