Efficacy and tolerability of indiplon in older adults with primary insomnia

OBJECTIVE: To evaluate the efficacy and safety of indiplon in elderly patients with primary insomnia. PATIENTS AND METHODS: Elderly patients, 65-80 years (N=358; 55% female; mean age, 71 years) who met the criteria for primary insomnia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) for three months were randomized to two weeks of double-blind nightly treatment with 5 mg or 10 mg indiplon or placebo. Daily self-assessments by the patients included latency to sleep onset (LSO), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and sleep quality. Data were collected between July, 2002, and October, 2003, at 52 clinical research sites in North America. RESULTS: Treatment with indiplon was associated with significant reduction in LSO at Week 1 for the 5 mg (34.6+/-1.8 min) and 10 mg doses (30.4+/-1.6 min) relative to placebo (47.4+/-2.5 min; p<0.0001 for both comparisons). During Week 2, LSO remained shorter on both indiplon doses compared to placebo (5 mg, p=0.016; and 10 mg, p=0.0028). During both study weeks, treatment with indiplon was also associated with significant improvement, relative to placebo, in TST, NAW, WASO, and sleep quality. The frequency of adverse events was similar in the indiplon 5 mg and placebo groups; somnolence, nausea, depression and decreased appetite were slightly more common in the indiplon 10 mg group. CONCLUSION: In elderly patients with primary insomnia, indiplon 5 mg and 10 mg were efficacious in inducing and maintaining sleep and improving sleep quality during the two weeks of treatment. Indiplon 5mg was well-tolerated, with no serious adverse events and no significant changes in electrocardiogram (ECG) or routine clinical laboratory evaluations; the 10mg dose produced slightly greater efficacy as well as somewhat increased adverse events.     

SEX DIFFERENCES IN TAIL-FLICK LATENCY OF NON-STRESSED AND STRESSED RATS

The present study was conducted to assess whether there are sex differences between male and female subjects in their response to noxious stimuli under non-stressed and stressed conditions. Tail-flick latency assay was used as an experimental tool on 12 adult male and 12 adult female Sprague-Dawley rats before immobilization (i.e., non-stressed condition) and after 30, 120, 240, and 360 min of continuous immobilization (i.e., stressed conditions). It was found that the non-stressed female rats exhibited significantly longer response latency to noxious thermal stimuli than the non-stressed male rats. Stressed conditions caused by immobilization of the animal inside a ventilated restrainer significantly prolonged the tail-flick latency thresholds of both sexes. Female and male rats did not develop any adaptation after 120, 240, and 360 min of immobilization compared to their 30 min of immobilization, as demonstrated by the tail-flick assay. Moreover, the difference in the tail-flick latency between male and female rats was reduced as the duration of immobilization in the restrainer lengthened. At 30 min of immobilization, the significant difference between the sexes reduced to p < .05 compared to p < .01 before immobilization, and to statistically non-significant differences after 120, 240, and 360 min of immobilization. Results from this study suggested that female rats had longer tail-flick latency than male rats in non-stressed environment, and the difference in tail-flick latency after immobilization between the sexes became less significant with time. In addition, 360 min of immobilization was not enough to adapt to the restrainer, as shown by the tail-flick assay.     

CD8 T cells and latent herpes simplex virus type 1: keeping the peace in sensory ganglia

Herpes simplex virus type 1 (HSV-1) infections represent a significant worldwide heath problem. The lack of an effective therapy to curtail reactivation of HSV-1 from a state of neuronal latency has lead to significant morbidity and mortality. Effective therapies to prevent reactivation must likely elicit a protective CD8 T-cell response that could act to prevent reactivation from sensory neurons prior to release of infectious virus at the periphery. This review focuses on the present understanding of how CD8 T cells maintain HSV-1 latency and how this knowledge could facilitate the generation of more effective therapeutic modalities.     

Evaluation of the effect of JZP-110 in patients with narcolepsy assessed using the Maintenance of Wakefulness Test censored to 20 minutes

ObjectiveTo evaluate the effects of JZP-110 on the Maintenance of Wakefulness Test (MWT) with data censored to include only the first 20 min of a 40-min MWT.MethodsIn a 4-week, placebo-controlled crossover design (Study 201; N = 33) and a 12-week parallel-group design (Study 202; N = 93), JZP-110 was evaluated in narcolepsy patients using changes from baseline in the 40-min MWT as the primary endpoint. Effect sizes based on the change from baseline in mean MWT sleep latency were calculated using 20-min censored MWT data and compared to 40-min MWT data.ResultsIn Study 201, mean (standard deviation) changes in MWT sleep latency were 12.7 (10.6) min with JZP-110 versus 0.9 (6.0) min with placebo (P = 0.0002) for 40-min data, and 8.9 (6.3) versus 0.4 (4.6) min for 20-min censored data (P < 0.0001). In Study 202, mean changes in MWT sleep latency were 12.8 (10.3) min with JZP-110 versus 2.1 (7.9) min with placebo (P < 0.0001) for 40-min data, and 8.9 (5.5) versus 1.1 (5.6) min for 20-min censored data (P < 0.0001). In Studies 201 and 202, respectively, Cohen's d effect sizes were large and numerically greater for 20-min censored data (1.54 and 1.41) versus 40-min data (1.37 and 1.17).ConclusionsIn patients with narcolepsy, JZP-110 significantly improved the ability to stay awake compared with placebo, with large effect sizes using both the 40-min and 20-min censored MWT data.     

A randomized,double blind,placebo controlled study to evaluate the effects of ashwagandha (Withania somnifera) extract on sleep quality in healthy adults

ObjectiveNon-restorative sleep (NRS) affects 10% people worldwide, leading to poor sleep quality, as well as physical and cognitive fatigue. This is the first human study in which an extract of ashwagandha (Withania somnifera Dunal L.) was evaluated for effects in improving overall sleep quality in subjects with NRS.MethodsIn this randomized, double-blind, placebo-controlled trial, 150 healthy subjects scoring high on non-restorative sleep measures were given 120 mg of standardized ashwagandha extract (Shoden®) once daily for six weeks. Subjects were evaluated using the Restorative Sleep Questionnaire-weekly version and World Health Organization Quality of Life-Bref (WHOQOL) scale. Sleep actigraphy was used to measure the onset of sleep latency, sleep efficiency, total sleep time and wake after sleep onset. Safety of the treatment was determined by testing of vitals, hematology, biochemistry and urinalysis.ResultsA total of 144 subjects completed the study, with no dropouts due to adverse events. A 72% increase in self-reported sleep quality was found for the treatment group, compared with 29% in the placebo group (p < 0.001). Based on activity monitoring data, the treatment group showed significant improvement in sleep efficiency (SE) (p < 0.01), total sleep time (p < 0.001) and sleep latency (p < 0.01) and wake after sleep onset (WASO) (p < 0.05) versus placebo after six weeks. In the ashwagandha group quality of life (QOL) scores showed significant improvement in physical (p < 0.001), psychological (p < 0.001), and environment domains (p < 0.01).ConclusionsSupplementation with the standardized ashwagandha extract for six weeks improved the overall quality of sleep by significantly improving the NRS condition in healthy subjects. No treatment related adverse events were reported in the study.Trial registrationClinical Trials Registry-India (www.ctri.nic.in). Registration number: CTRI/2017/02/007801.     

Modulation of antisaccade costs through manipulation of target-location probability: Only under decisional uncertainty

Latencies of antisaccades made in the direction opposite to a peripheral target are typically slower longer than of prosaccades towards such a target by 50–100 ms. Antisaccades have proved to be an important tool for diagnostic purposes in neurology, psychology and psychiatry, providing invaluable insights into attentional function, decision making and the functionality of eye movement control. Recent findings have suggested, however, that latency differences between pro- and antisaccades can be eliminated by manipulating target-location probabilities. Pro- and antisaccades were equally fast to locations where a target rarely appeared, a finding that may be of promise for more elaborate diagnoses of neurological and psychiatric illness and further understanding of the eye movement system. Here, we tested probability manipulations for a number of different pro- and antisaccade tasks of varied difficulty. Probability only modulated antisaccade costs in a difficult antisaccade task involving decisional uncertainty with low target saliency. For other tasks including standard ones from the literature, target-location probability asymmetries had minimal effects. Probability modulation of antisaccade costs may therefore reflect effects upon decision making rather than saccade generation. This may limit the usefulness of probability manipulations of antisaccades for diagnostic purposes in neurology, psychology and related disciplines.     

EXPERIENCE-DEPENDENT IMMEDIATE EARLY GENE EXPRESSION IN THE ADULT CENTRAL NERVOUS SYSTEM: EVIDENCE FROM ENRICHED-ENVIRONMENT STUDIES

Here I discuss evidence from our group's work that implicates the immediate early genes NGFI-A and arc as possible regulators of neuronal plasticity. The enriched environment (EE) paradigm has been demonstrated to induce neural plasticity in both developing and mature mammals. Others and we have recently demonstrated that adult rats placed within an enriched environment underwent central nervous system-wide increases in the expression levels for the IEGs NGFI-A and arc. The relationships between the altered expression profiles for both genes in response to an EE exposure, and their putative role in orchestrating network restructuring in response to enhanced environmental complexity are discussed