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Introduction Solanezumab is an anti-amyloid monoclonal antibody in clinical testing for treatment of Alzheimer's disease (AD). Its mechanism suggests the possibility of slowing the progression of AD. Methods A possible disease-modifying effect of solanezumab was assessed using a new statistical method including noninferiority testing. Performance differences were compared during the placebo-controlled period with performance differences after the placebo patients crossed over to solanezumab in the delayed-start period. Results Noninferiority of the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14 ) and Alzheimer's Disease Cooperative Study Activities of Daily Living inventory instrumental items (ADCS-iADL) differences was met through 132 weeks, indicating that treatment differences observed in the placebo-controlled period remained, within a predefined margin, after the placebo group initiated solanezumab. Solanezumab was well tolerated, and no new safety concerns were identified. Discussion The results of this secondary analysis show that the mild subgroup of solanezumab-treated patients who initiated treatment early, at the start of the placebo-controlled period, retained an advantage at most time points in the delayed-start period.

Modafinil is a first-line wake-promoting medication and a useful therapeutic alternative to psychostimulant medications for excessive daytime sleepiness.This 5-week, randomized, open-label study evaluated three strategies for switching patients from methylphenidate, a commonly used psychostimulant, to modafinil.Patients ( n=40) with excessive daytime sleepiness related to narcolepsy, who had received previous treatment with methylphenidate, were switched from methylphenidate to modafinil (200 mg/day followed by 400 mg/day) without a washout period between treatments, with a 2-day washout period between treatments, or by using a taper-down/titrate-up protocol. Adverse events were recorded throughout the study, and Epworth Sleepiness Scale scores were determined at the end of the study.The majority of patients (95%) were successfully switched to modafinil. At the study end point, mean Epworth Sleepiness Scale scores were12 for each treatment group. All three switching strategies were well tolerated, with adverse events mild or moderate in nature. Adverse events most frequently reported during modafinil treatment were among those seen previously in large-scale, placebo-controlled studies. There were no meaningful differences among the treatment groups in the frequency or severity of adverse events or in their relationship to modafinil treatment. Only one patient discontinued modafinil treatment because of a treatment-related adverse event (i.e. moderate headache); another patient discontinued due to insufficient efficacy.Switching from methylphenidate to modafinil was well tolerated with or without a washout period or when the methylphenidate dose is gradually tapered during initiation of modafinil therapy. Daytime wakefulness was maintained in patients who have switched from methylphenidate to modafinil. These data suggest that patients with narcolepsy may be switched from methylphenidate to modafinil with few complications and inconveniences.

Shift work and jet lag can disrupt circadian rhythms, with detrimental effects on alertness, performance and sleep. This study examined the effects of two interventions to adapt circadian rhythms, sleep and performance to a 10-h phase delay of the work–rest cycle. Bright light was administered from 2200 to 0200 each night to promote phase delay of circadian rhythms. Low energy emission therapy (LEET) was administered for 20 min prior to daytime sleep periods to promote sleep. Twelve subjects received bright light, 12 subjects received LEET, 11 received both interventions and 10 control subjects received only placebo treatments. Bright light accelerated phase delay of the circadian melatonin rhythm after the work–rest schedule shift. Further, subjects who received bright light had greater total sleep time (TST) and improved sleep continuity. LEET treatment produced a trend (p=0.16) for increased TST, but LEET did not affect the melatonin circadian rhythm. After the schedule shift, cognitive performance measures showed few significant differences. Some minor improvements in cognitive performance were produced by light treatments but not by LEET. © 1997 John Wiley & Sons, Ltd.

The treatment of chronic psychophysiological insomnia presents a challenge that has not been met using currently available pharmacotherapy. Low energy emission therapy (LEET) has been developed as a potential alternative therapy for this disorder. LEET consists of amplitude-modulated electromagnetic fields delivered intrabuccally by means of an electrically conducting mouthpiece in direct contact with the oral mucosa. The effect of LEET on chronic psychophysiological insomnia was assessed with polysomnography (PSG) and sleep rating forms on a total of 106 patients at two different centers. Active or inactive LEET was administered for 20 minutes in late afternoon three times a week for a total of 12 treatments. Primary efficacy endpoints evaluating the results were changes from baseline in PSG-assessed total sleep time (TST) and sleep latency (SL). Secondary endpoints were changes in sleep efficiency (SE), sleep stages, and reports by the subjects of SL and TST. There was a significant increase in TST as assessed by PSG between baseline and post-treatment values for the active treatment group (76.0 +/- 11.1 minutes, p = 0.0001). The increase for the inactive treatment group was not statistically significant. The TST improvement was significantly greater for the active group when compared to the inactive group (adjusted for baseline TST; p = 0.020. R1 = 0.20). There was a significant decrease in SL as assessed by PSG between baseline and post-treatment values for the active treatment group (-21.6 +/- 5.9 minutes, p = 0.0006), whereas the decrease noted for the inactive treatment group was not statistically significant. The difference in SL decrease between the two treatment groups was marginally significant (adjusted for baseline SL and center, p = 0.068, R2 = 0.60). The number of sleep cycles per night increased by 30% after active treatment (p = 0.0001) but was unchanged following inactive treatment. Subjects did not experience rebound insomnia, and there were no significant side effects. The data presented in this report indicate that LEET administered for 20 minutes three times a week increased TST and reduced SL in chronic psychophysiological insomnia. LEET is safe and well tolerated and it effectively improved the sleep of chronic insomniacs given 12 treatments over a 4-week period by increasing the number of sleep cycles without altering the percentage of the various sleep stages during the night. The therapeutic action of LEET differs from that of currently available drug therapies in that the sleep pattern noted in insomniacs following LEET treatment more closely resembles nocturnal physiological sleep. This novel treatment may offer an attractive alternative therapy for chronic insomnia.

Objective : To repeat and extend findings suggesting that sleep disturbance, excessive daytime sleepiness, and degraded cognitive-motor abilities may be early markers of central nervous system (CNS) involvement in HIV infection. Design : A controlled, cross-sectional, prospective analysis. Setting : Clinical research center at a teaching hospital and a military health research center. Subjects : Twenty-three HIV-positive (mean CD4+ count, 387±162x10 6 /l) and 13 seronegative men who were Naval personnel or participants of the University of California, San Diego HIV Neurobehavioral Research Center. Main outcome measures : Nocturnal and daytime sleep electroencephalogram, electromyogram, and electrocardiogram. Simple and complex cognitive-motor performance assessed via computerized tasks. Results : Comparison of sleep parameters based on HIV status, length of time infected, zidovudine use, and CD4+ count indicated that CD4+ T cells >400x10 6 /l were associated with a distortion in nocturnal sleep characterized by increased stages 3 and 4 non-rapid eye movement (i.e., slow-wave) sleep in the latter portion of the night and reduced nocturnal awakenings. HIV-positive patients were no sleepier in the daytime than controls. Cognitive-motor performance revealed deficits in both accuracy and efficiency for HIV-positive patients. Conclusion : Asymptomatic HIV-positive patients with CD4+ counts >400x10 6 /l demonstrate a statistically significant increase in slow-wave sleep during the latter portion of the night and less arousability. CD4+ lymphocyte count in the early phases of HIV infection appears to differentiate between various levels of HIV disease progression with respect to certain CNS measurements of nocturnal sleep and cognitive-motor performance. Sleep structure distortion remains one of the earliest and most consistently replicable physiological signs of HIV infection. This distortion may provide a link to immune function, disease progression, and cognitive-motor disability in HIV infection.

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.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.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).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 (p0.01 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 (p0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness.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.

Background: Narcolepsy, a neurological disorder characterized by excessive daytime sleepiness and abnormal REM sleep, is known to be tightly associated with the human leukocyte antigen (HLA) DQB1*0602.Methods: In this study, baseline data collected for a large clinical trial involving 504 narcolepsy patients were used to compare clinical and polysomnographic features of narcolepsy patients with and without HLA-DQB1*0602. Comparisons were adjusted for possible confounding factors and linear regression modeling was used to extract the best predictors for DQB1*0602 positivity.Results: As previously reported, cataplexy was the best clinical predictor for DQB1*0602 positivity. At the polysomnographic level, subjects with DQB1*0602 were found to have a significantly more disrupted nocturnal sleep, a much shorter nocturnal rapid eye movement (REM) sleep latency and more multiple sleep latency test abnormalities (increased number of sleep onset REM periods and decreased mean sleep latency). We also found that subjects with DQB1*0602 had a much higher incidence of periodic limb movements during sleep, confirming the notion that this symptom is genuinely associated with the narcolepsy phenotype.Conclusions: These results support the notion that HLA-DQB1*0602-positive narcolepsy patients are more etiologically homogenous than HLA-DQB1*0602-negative 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.

Introduction Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD). Methods Patients (n = 2042) with mild and moderate AD were randomized 1:1 to 400-mg solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open-label extension. Magnetic resonance imaging scans monitored for amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemorrhage/hemosiderin deposition. Results Sixteen patients (solanezumab, n = 11; placebo, n = 5) developed ARIA-E during the double-blind phase, and 7 patients developed ARIA-E during the open-label extension as of July 31, 2014. Unique cases are discussed including solanezumab patients who were given solanezumab, while ARIA-E was present and a patient who developed ARIA-E during placebo treatment and again during solanezumab treatment. Discussion Asymptomatic ARIA-E was detected in solanezumab-treated and placebo-treated AD patients. ARIA-E occurs infrequently during solanezumab and placebo treatments but may occur repeatedly in some patients.