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Thomas Roth - One of the best experts on this subject based on the ideXlab platform.
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esmirtazapine in non elderly adult patients with Primary Insomnia efficacy and safety from a randomized 6 week sleep laboratory trial
Sleep Medicine, 2015Co-Authors: Neely Ivgymay, Andrew D. Krystal, Frank Ruwe, Thomas RothAbstract:Abstract Objective Esmirtazapine (Org 50081), a medication that binds with high affinity to serotonin 5-HT 2A and histamine-1 receptors, was evaluated as a potential treatment for Insomnia. Methods Adults with Primary Insomnia were treated with esmirtazapine (3.0 or 4.5 mg) or placebo in this 6-week, double-blind, randomized, polysomnography (PSG) study. The end points included wake time after sleep onset (WASO) (Primary), latency to persistent sleep, and total sleep time. Patient-reported parameters were also evaluated, including sleep quality and satisfaction with sleep duration. Residual daytime effects and rebound Insomnia (sleep parameters during the single-blind placebo run-out week after treatment ended) were also assessed. Results Overall, 419 patients were randomized and 366 (87%) completed treatment. The median decrease in PSG WASO (double-blind average) was 20.5 min for placebo, and 52.0 min and 53.6 min for the 3.0- and 4.5-mg esmirtazapine groups, respectively (P Conclusions Six weeks of treatment with esmirtazapine was associated with consistent improvements in objective and patient-reported parameters of sleep onset, maintenance, and duration. It was generally well tolerated, and residual daytime effects were minimal and no rebound Insomnia was observed.
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efficacy of eight months of nightly zolpidem a prospective placebo controlled study
Sleep, 2012Co-Authors: Surilla Randall, Timothy Roehrs, Thomas RothAbstract:Study objectives To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic Primary Insomnia using polysomnography. Design Randomized, double-blind, placebo-controlled clinical trial. Setting Sleep disorders and research center. Participants Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for Primary Insomnia. Interventions Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. Measurements and results Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. Conclusions In adults with Primary Insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. Clinical trial information ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525.
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efficacy and safety of doxepin 6 mg in a four week outpatient trial of elderly adults with chronic Primary Insomnia
Sleep Medicine, 2012Co-Authors: Alan Lankford, Heith H Durrence, Elizabeth Ludington, Roberta L Rogowski, Beal Essink, Thomas RothAbstract:Abstract Introduction The efficacy and safety of doxepin (DXP), a histamine H 1 receptor antagonist, was evaluated in elderly adults with sleep maintenance Insomnia. Methods This was a randomized, double-blind, placebo-controlled outpatient trial. Elderly adults meeting DSM-IV-TR criteria for Primary Insomnia were randomized to four weeks of nightly treatment with either DXP 6mg ( N =130) or placebo (PBO; N =124). Efficacy was assessed using patient self-report instruments and clinician ratings. Patient-reported endpoints included subjective total sleep time (sTST), subjective wake after sleep onset (sWASO), latency to sleep onset (LSO), sleep quality, and a Patient Global Impression scale (PGI). The Primary endpoint was sTST at week 1. Results DXP 6mg produced significantly more sTST and less sWASO at week 1 (both p -values p -values p Conclusions In elderly adults with Insomnia, DXP 6mg produced significant improvements in sleep maintenance, sleep duration, and sleep quality endpoints that were sustained throughout the trial. These data suggest that DXP 6mg is effective for treating sleep maintenance Insomnia and is well-tolerated in elderly adults with chronic Primary Insomnia.
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efficacy and safety of doxepin 3 and 6 mg in a 35 day sleep laboratory trial in adults with chronic Primary Insomnia
Sleep, 2011Co-Authors: Andrew D. Krystal, Alan Lankford, Heith H Durrence, Elizabeth Ludington, Philip Jochelson, Roberta L Rogowski, Thomas RothAbstract:Study objectives To evaluate the efficacy and safety of doxepin (DXP) 3 mg and 6 mg in adults diagnosed with Primary Insomnia. Design and methods The study was a randomized, double-blind, parallel-group, placebo-controlled trial. Patients meeting DSM-IV-TR criteria for Primary Insomnia were randomized to 35 days of nightly treatment with DXP 3 mg (n=75), DXP 6 mg (n=73), or placebo (PBO; n=73), followed by 2 nights of single-blind PBO to evaluate discontinuation (DC) effects. Efficacy was assessed using polysomnography (PSG) and patient reports. Efficacy data were examined for Night (N) 1, N15, and N29. Safety assessments were conducted throughout the study. Results Compared with PBO, DXP 3 and 6 mg significantly improved wake time after sleep onset (WASO) on N1 (3 mg and 6 mg; P Conclusions Five weeks of nightly administration of DXP 3 mg and 6 mg to adults with chronic Primary Insomnia resulted in significant and sustained improvements in sleep maintenance and early morning awakenings (with the exception of SE in the final quarter of the night on N29 for 3 mg [P=0.0691]). These sleep improvements were not accompanied by next-day residual effects or followed by rebound Insomnia or withdrawal effects upon discontinuation. These findings confirm the unique profile of sleep maintenance efficacy and safety of DXP observed in prior studies.
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efficacy and safety of doxepin 1 mg and 3 mg in a 12 week sleep laboratory and outpatient trial of elderly subjects with chronic Primary Insomnia
Sleep, 2010Co-Authors: Andrew D. Krystal, Heith H Durrence, Elizabeth Ludington, Philip Jochelson, Roberta L Rogowski, Martin B Scharf, Thomas RothAbstract:Insomnia IS DEFINED AS DIFFICULTY INITIATING SLEEP, MAINTAINING SLEEP, AND/OR NONRESTORATIVE SLEEP ACCOMPANIED BY DAYTIME impairments.1 Although, not found in all studies, many investigations have found that the risk of Insomnia increases with age.2–6 Insomnia has also been reported to be more severe in the elderly.2 Older adults with Insomnia awaken more frequently and spend a greater percentage of their nights awake than do non-elderly adults with Insomnia.2 While Insomnia is associated with decreased quality of life and impairment in function in general, there are some concerning consequences that are specific to the elderly, including increased risk of falls and nursing home placement.7–9 The greater severity and consequences of Insomnia in older adults speak to the need for developing effective Insomnia treatments for this population. Unfortunately, fewer studies of pharmacologic Insomnia therapy have been conducted in this population relative to younger adults.10 In this regard, data are notably lacking on the benefit of Insomnia treatment in the elderly. Evidence to support extended treatment is especially important for older adults as they appear to be more susceptible to developing chronic Insomnia.6,11,12 In a study of elderly general practice patients, 57% met diagnostic criteria for Insomnia, with 80% of these patients reporting Insomnia duration of greater than 1 year.13 However, there is a corresponding increase in the duration of pharmacotherapy for Insomnia with age,14–16 and there are no studies which provide an indication of the safety or efficacy of this practice for any agents.10 Indeed, there have been only 3 large, double-blind, placebo-controlled published trials evaluating the efficacy of any Insomnia agent for more than 5 weeks, and none of these trials were conducted in the elderly.17–19 Although the present study does not fully address this deficiency, it is of importance as it is the longest PSG trial of the efficacy and safety of Insomnia pharmacotherapy in the elderly. The inclusion of PSG outcome assessment addresses concerns related to the adequacy of blinding and the effects of differential dropout that have been raised because of the lack of objective outcome measures in prior pharmacotherapy trials purporting to establish the sustained efficacy of Insomnia medications.20 This study was carried out using doxepin, which has particular promise as a treatment for elderly Insomnia patients. This agent appears to be a selective histamine antagonist (primarily at the H1 receptor) at low doses and has been found to have significant efficacy for improving sleep in doses as low as 1 mg, 3 mg, and 6 mg, with minimal adverse effects in 2 previous clinical trials of patients with Primary Insomnia.21,22 Data from these trials represent the only evidence of an Insomnia therapy having a therapeutic effect on sleep maintenance in the last third of the night, while manifesting no evidence of morning impairment in careful assessments of next-day effects.21,22 It is important to note that sleep maintenance problems and sleep difficulties in the latter part of the night are especially common in the elderly. Difficulty maintaining sleep is reported by one-third of older adults and is the most frequent sleep complaint in the elderly.2,6 At the same time, one-fourth of elderly Insomnia patients report waking too early with difficulty returning to sleep (early morning awakenings).6 The current study assesses the efficacy and safety of doxepin at doses of 1 mg and 3 mg in a 12-week trial of elderly subjects with chronic Insomnia.
Andrew D. Krystal - One of the best experts on this subject based on the ideXlab platform.
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esmirtazapine in non elderly adult patients with Primary Insomnia efficacy and safety from a randomized 6 week sleep laboratory trial
Sleep Medicine, 2015Co-Authors: Neely Ivgymay, Andrew D. Krystal, Frank Ruwe, Thomas RothAbstract:Abstract Objective Esmirtazapine (Org 50081), a medication that binds with high affinity to serotonin 5-HT 2A and histamine-1 receptors, was evaluated as a potential treatment for Insomnia. Methods Adults with Primary Insomnia were treated with esmirtazapine (3.0 or 4.5 mg) or placebo in this 6-week, double-blind, randomized, polysomnography (PSG) study. The end points included wake time after sleep onset (WASO) (Primary), latency to persistent sleep, and total sleep time. Patient-reported parameters were also evaluated, including sleep quality and satisfaction with sleep duration. Residual daytime effects and rebound Insomnia (sleep parameters during the single-blind placebo run-out week after treatment ended) were also assessed. Results Overall, 419 patients were randomized and 366 (87%) completed treatment. The median decrease in PSG WASO (double-blind average) was 20.5 min for placebo, and 52.0 min and 53.6 min for the 3.0- and 4.5-mg esmirtazapine groups, respectively (P Conclusions Six weeks of treatment with esmirtazapine was associated with consistent improvements in objective and patient-reported parameters of sleep onset, maintenance, and duration. It was generally well tolerated, and residual daytime effects were minimal and no rebound Insomnia was observed.
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eszopiclone treatment for Insomnia effect size comparisons in patients with Primary Insomnia and Insomnia with medical and psychiatric comorbidity
The Primary Care Companion To The Journal of Clinical Psychiatry, 2012Co-Authors: Andrew D. Krystal, Vaughn W Mccall, Maurizio Fava, Hadine Joffe, Claudio N Soares, Holly Huang, Todd Grinell, Jacqueline Zummo, William Spalding, Randall MarshallAbstract:Objective: The purpose of this post hoc analysis was to compare the treatment effect size of eszopiclone 3 mg for Insomnia in patients with a diagnosis of Primary Insomnia and in several of the psychiatric and medical conditions that are most commonly comorbid with Insomnia. Method: Data were analyzed from 5 large, multicenter, randomized, double-blind, placebo-controlled studies of adult outpatients of at least 1 month duration published between 2006 and 2009. Diary-derived indices of sleep and daytime functioning and the Insomnia Severity Index were compared for patients with Primary Insomnia (DSM-IV-TR criteria, n = 828) and for those with Insomnia comorbid with major depressive disorder (MDD, DSM-IV-TR criteria, n = 545), generalized anxiety disorder (GAD, DSM-IV-TR criteria, n = 595), perimenopause/postmenopause (Stages of Reproductive Aging Workshop criteria, n = 410), and rheumatoid arthritis (American College of Rheumatology criteria, n = 153). Cohen d effect sizes were calculated for each individual study as the between-treatment difference score divided by the pooled standard deviation. Results: Effect sizes ranged from 0.40 to 0.69 (small–medium) as early as week 1 and were maintained at 0.26–0.63 at week 4 for sleep latency, wake time after sleep onset, and total sleep time. Sleep latency and total sleep time effect sizes increased from week 1 to week 4 in the Primary Insomnia group. At week 4, effect sizes on all 3 parameters and the Insomnia Severity Index tended to be highest for the Primary Insomnia patients and tended to be lowest for patients with comorbid GAD and MDD. The effect sizes for daytime functioning were small for all Insomnia patient groups. Conclusions: Eszopiclone 3 mg is an effective treatment for Insomnia across 5 clinically diverse patient populations; however, magnitude of effect is mediated by underlying comorbidity and their treatments, with largest measures of effect seen in Primary Insomnia and lowest in MDD and GAD. These consistent results, and the fact that clinical trials were conducted in patients being treated as appropriate for their comorbid clinical conditions, support the results’ real-world generalizability and utility to clinical practice.
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efficacy and safety of doxepin 3 and 6 mg in a 35 day sleep laboratory trial in adults with chronic Primary Insomnia
Sleep, 2011Co-Authors: Andrew D. Krystal, Alan Lankford, Heith H Durrence, Elizabeth Ludington, Philip Jochelson, Roberta L Rogowski, Thomas RothAbstract:Study objectives To evaluate the efficacy and safety of doxepin (DXP) 3 mg and 6 mg in adults diagnosed with Primary Insomnia. Design and methods The study was a randomized, double-blind, parallel-group, placebo-controlled trial. Patients meeting DSM-IV-TR criteria for Primary Insomnia were randomized to 35 days of nightly treatment with DXP 3 mg (n=75), DXP 6 mg (n=73), or placebo (PBO; n=73), followed by 2 nights of single-blind PBO to evaluate discontinuation (DC) effects. Efficacy was assessed using polysomnography (PSG) and patient reports. Efficacy data were examined for Night (N) 1, N15, and N29. Safety assessments were conducted throughout the study. Results Compared with PBO, DXP 3 and 6 mg significantly improved wake time after sleep onset (WASO) on N1 (3 mg and 6 mg; P Conclusions Five weeks of nightly administration of DXP 3 mg and 6 mg to adults with chronic Primary Insomnia resulted in significant and sustained improvements in sleep maintenance and early morning awakenings (with the exception of SE in the final quarter of the night on N29 for 3 mg [P=0.0691]). These sleep improvements were not accompanied by next-day residual effects or followed by rebound Insomnia or withdrawal effects upon discontinuation. These findings confirm the unique profile of sleep maintenance efficacy and safety of DXP observed in prior studies.
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efficacy and safety of doxepin 1 mg and 3 mg in a 12 week sleep laboratory and outpatient trial of elderly subjects with chronic Primary Insomnia
Sleep, 2010Co-Authors: Andrew D. Krystal, Heith H Durrence, Elizabeth Ludington, Philip Jochelson, Roberta L Rogowski, Martin B Scharf, Thomas RothAbstract:Insomnia IS DEFINED AS DIFFICULTY INITIATING SLEEP, MAINTAINING SLEEP, AND/OR NONRESTORATIVE SLEEP ACCOMPANIED BY DAYTIME impairments.1 Although, not found in all studies, many investigations have found that the risk of Insomnia increases with age.2–6 Insomnia has also been reported to be more severe in the elderly.2 Older adults with Insomnia awaken more frequently and spend a greater percentage of their nights awake than do non-elderly adults with Insomnia.2 While Insomnia is associated with decreased quality of life and impairment in function in general, there are some concerning consequences that are specific to the elderly, including increased risk of falls and nursing home placement.7–9 The greater severity and consequences of Insomnia in older adults speak to the need for developing effective Insomnia treatments for this population. Unfortunately, fewer studies of pharmacologic Insomnia therapy have been conducted in this population relative to younger adults.10 In this regard, data are notably lacking on the benefit of Insomnia treatment in the elderly. Evidence to support extended treatment is especially important for older adults as they appear to be more susceptible to developing chronic Insomnia.6,11,12 In a study of elderly general practice patients, 57% met diagnostic criteria for Insomnia, with 80% of these patients reporting Insomnia duration of greater than 1 year.13 However, there is a corresponding increase in the duration of pharmacotherapy for Insomnia with age,14–16 and there are no studies which provide an indication of the safety or efficacy of this practice for any agents.10 Indeed, there have been only 3 large, double-blind, placebo-controlled published trials evaluating the efficacy of any Insomnia agent for more than 5 weeks, and none of these trials were conducted in the elderly.17–19 Although the present study does not fully address this deficiency, it is of importance as it is the longest PSG trial of the efficacy and safety of Insomnia pharmacotherapy in the elderly. The inclusion of PSG outcome assessment addresses concerns related to the adequacy of blinding and the effects of differential dropout that have been raised because of the lack of objective outcome measures in prior pharmacotherapy trials purporting to establish the sustained efficacy of Insomnia medications.20 This study was carried out using doxepin, which has particular promise as a treatment for elderly Insomnia patients. This agent appears to be a selective histamine antagonist (primarily at the H1 receptor) at low doses and has been found to have significant efficacy for improving sleep in doses as low as 1 mg, 3 mg, and 6 mg, with minimal adverse effects in 2 previous clinical trials of patients with Primary Insomnia.21,22 Data from these trials represent the only evidence of an Insomnia therapy having a therapeutic effect on sleep maintenance in the last third of the night, while manifesting no evidence of morning impairment in careful assessments of next-day effects.21,22 It is important to note that sleep maintenance problems and sleep difficulties in the latter part of the night are especially common in the elderly. Difficulty maintaining sleep is reported by one-third of older adults and is the most frequent sleep complaint in the elderly.2,6 At the same time, one-fourth of elderly Insomnia patients report waking too early with difficulty returning to sleep (early morning awakenings).6 The current study assesses the efficacy and safety of doxepin at doses of 1 mg and 3 mg in a 12-week trial of elderly subjects with chronic Insomnia.
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psychomotor performance deficits and their relation to prior nights sleep among individuals with Primary Insomnia
Sleep, 2008Co-Authors: Jack D Edinger, Melanie K Means, Colleen E Carney, Andrew D. KrystalAbstract:Primary Insomnia (PI) IS A PREVALENT AND SERIOUS HEALTH CONCERN CHARACTERIZED BY COMPLAINTS OF CHRONIC NOCTURNAL SLEEP disturbance and associated daytime impairment occurring in the absence of any contributory medical or psychiatric condition. Current evidence suggests that 1% to 2%1,2 of the general population and approximately 20%3,4 of patients encountered in clinical settings suffer for this form of sleep difficulty. Since PI persists in the absence of medical/psychiatric causes, there is, perhaps, a temptation to minimize the seriousness of this condition. However, epidemiologic studies show PI substantially increases health care utilization/costs and absenteeism from work among affected individuals.3,5,6 Also, numerous studies have shown that PI dramatically increases risks for depressive illness even after other significant predictors are statistically controlled.7–9 In addition, PI contributes to reduced productivity, work-related accidents, increased alcohol consumption, serious falls among the elderly, and a general sense of being in poor health.10–14 Anecdotal observations suggest that PI sufferers are well aware of their day-to-day impairment. Indeed, clinical observations suggest such patients commonly view themselves as sleepy, fatigued, cognitively impaired, and generally not as “mentally sharp” as they recall themselves to be prior to the onset of their sleep difficulties. Despite such common reports, laboratory-based studies conducted with PI sufferers have shown that the daytime deficits of such individuals are rather elusive and difficult to document phenomena. In fact, in a recent summary prepared for the 2005 NIH State-of-the-Science Conference on the Manifestations and Management of Chronic Insomnia in Adults, Bonnet15 noted that studies of daytime psychomotor deficits among PI sufferers have produced significant findings at no better than chance levels. Given such mixed findings, some researchers have attributed PI sufferers' diurnal complaints to such traits as their dysfunctional beliefs about the impact of Insomnia on functioning16 or excessive self-focus17 rather than to any “real” or measurable daytime impairment. Evidence17–20 suggests these traits are indeed pronounced among PI sufferers, yet it is not clear that such individuals are devoid of diurnal psychomotor deficits. A review of the previous investigations of PI sufferers' performance deficits shows these studies generally included small and/or poorly characterized samples or employed a limited range of psychomotor performance measures. As a consequence, methodological limitations (e.g., limited statistical power, mixed Insomnia samples, insensitive psychomotor tests) may, at least in part, explain the mixed results in this literature. Given the above-noted long-term morbidity associated with PI, it seems likely that individuals with this condition should show measurable day-to-day impairments as well. Thus, the current study was conducted to compare the diurnal psychomotor performances of well-characterized PI sufferers and non-complaining normal sleepers in a large study sample tested with a range of simple and complex psychomotor reaction time tasks. We predicted that our PI sufferers would perform significantly worse than the normal sleepers on performance measures, and group differences would be most obvious on more complex tasks. In addition to testing this hypothesis, we examined the association between the observed daytime performance deficits and both subjective and objective sleep measures derived from nights preceding our daytime testing.
James K Walsh - One of the best experts on this subject based on the ideXlab platform.
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dual orexin receptor antagonist almorexant in elderly patients with Primary Insomnia a randomized controlled study
Sleep, 2017Co-Authors: Marzia Cavallaro, Gary Zammit, Jed Black, Raymond Cluydts, Pascal Charef, Fabrice Kramer, James K WalshAbstract:Objective Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with Primary chronic Insomnia. Methods Patients aged ≥65 years with Primary Insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The Primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also assessed. Results 112 patients were randomized (mean [SD] age 72.1 [5.0] years; 69.9% female). Significant, dose-related improvements (reductions) in mean WASO were observed with almorexant. Least-squares mean (95% CI) treatment effects in the almorexant 200, 100, 50, and 25 mg dose groups versus placebo were -46.5 minutes (-53.0, -39.9; p < .0001), -31.4 minutes (-38.0, -24.9; p < .0001), -19.2 minutes (-25.7, -12.6; p < .0001), and -10.4 minutes (-17.0, -3.9; p = .0018), respectively. Mean total sleep time was significantly increased with each almorexant dose (mean increases versus placebo ranged 55.1-14.3 minutes; p < .0001 for each dose). Latency to persistent sleep was statistically significantly reduced only with almorexant 200 mg versus placebo (mean [95% CI] treatment effect -10.2 minutes, [-15.4, -5.0]; p = .0001). No unexpected safety concerns were identified. Adverse events were similar between all almorexant dose groups and placebo. Conclusions Two-night oral administration of almorexant was effective and well tolerated in treating Primary Insomnia in elderly patients.
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efficacy and safety of zolpidem extended release in elderly Primary Insomnia patients
American Journal of Geriatric Psychiatry, 2008Co-Authors: James K Walsh, Christina Soubrane, Thomas RothAbstract:Objectives To evaluate the clinical efficacy and safety of zolpidem extended release for the treatment of Primary Insomnia in elderly patients. Methods A randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 205 (117 women, 88 men; mean age 70.2 ± 4.5 years) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–defined Primary Insomnia patients were randomized to 3 weeks of nightly treatment with either zolpidem extended release 6.25 mg or placebo; 198 patients completed the study. Results Relative to placebo, zolpidem extended release 6.25 mg significantly decreased wake time after sleep onset during the first six hours of the night, as measured by polysomnogram (PSG). PSG latency to persistent sleep was reduced and PSG total sleep time was increased, both at nights 1/2 and 15/16. Patient self-report measures were significantly better with zolpidem extended-release 6.25 mg than with placebo throughout treatment. Some PSG measures indicated a worsening of sleep for a single night after abrupt discontinuation of zolpidem extended release. No next-morning residual effects were observed. The overall incidence and nature of adverse events was comparable between the two groups. Conclusions Zolpidem extended release 6.25 mg improved both sleep maintenance and sleep induction in elderly Primary Insomnia patients during three weeks of administration.
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efficacy and safety of zolpidem mr a double blind placebo controlled study in adults with Primary Insomnia
Sleep Medicine, 2006Co-Authors: Thomas Roth, Christina Soubrane, Laurence Titeux, James K WalshAbstract:Abstract Background and purpose To evaluate the clinical efficacy and safety of modified-release zolpidem (zolpidem-MR 12.5 mg) for the treatment of Primary Insomnia in adults. Patients and methods Two hundred and twelve (123 women, 89 men; mean age 44.3±SD 3.0 years), Diagnostic and Statistical Manual of Mental Disorders—4th Edition (DSM-IV)-defined Primary Insomnia patients were randomized in a double-blind, placebo-controlled, parallel-group study. The study was completed by 192 patients. Patients received 3 weeks of nightly treatment with either zolpidem-MR 12.5 mg or placebo, preceded and followed by two nights of single-blind placebo. The main outcome measures were mean polysomnographic (PSG) sleep parameters of nights 1/2 and nights 15/16 of double-blind treatment and daily subjective sleep estimates from sleep questionnaires to assess efficacy, and PSG parameters of nights 22 and 23 of single-blind placebo substitution to assess the effect of drug discontinuation. Results Relative to placebo, zolpidem-MR 12.5 mg improved sleep maintenance by significantly reducing PSG wake time after sleep onset (WASO) during the first 6 h of sleep as well as the number of awakenings. Consistent with the effects of standard zolpidem, zolpidem-MR also significantly reduced latency to persistent sleep, and significantly increased sleep efficiency, both at the beginning and after 2 weeks of double-blind treatment. There was no evidence of next-day residual effects as measured objectively by psychometric tests. Rebound Insomnia on the first night after abrupt discontinuation resolved the following night. Overall, zolpidem-MR was well tolerated. Conclusions Zolpidem-MR 12.5 mg is effective and safe in treating Primary Insomnia in adults and improves sleep maintenance, induction and duration of sleep.
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an evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic Primary Insomnia
Sleep Medicine, 2005Co-Authors: Thomas Roth, Thomas Wessel, James K Walsh, Andrew D. Krystal, Timothy RoehrsAbstract:Abstract Background and purpose A double-blind placebo-controlled study of eszopiclone found significant, sustained improvement in sleep and daytime function. The 6-month open-label extension phase is described herein. Patients and methods Adults (21–64) with Primary Insomnia who reported sleep duration 30 min/night were included. Patient-reported endpoints included sleep and daytime function. Safety and compliance were assessed at monthly clinic visits. The final double-blind month was used as the baseline for efficacy analyses of the open-label period. Results Patients who were initially randomized to double-blind placebo and then switched to open-label eszopiclone ( n =111) significantly reported the following: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline ( P ≤0.0001 all monthly endpoints). There was no evidence of tolerance on any measure in either group. These subjects ( n =360) sustained the double-blind treatment gains for all sleep and daytime parameters, with further significant improvement in a number of measures. Eszopiclone was well tolerated in both groups; unpleasant taste was the only undesirable effect reported by >5% of patients. Conclusions The significant improvements in sleep and daytime function were evident in those switched from double-blind placebo to 6 months of open-label eszopiclone therapy and were sustained during the 6 months of open-label treatment for those receiving prior double-blind eszopiclone. During 12 months of nightly treatment, eszopiclone 3 mg was well tolerated; tolerance was not observed.
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long term non nightly administration of zolpidem in the treatment of patients with Primary Insomnia
The Journal of Clinical Psychiatry, 2004Co-Authors: Michael L Perlis, Vaughn W Mccall, Andrew D. Krystal, James K WalshAbstract:INTRODUCTION While it is common practice that hypnotics are used on a non-nightly basis, few investigations have been undertaken to evaluate the efficacy of the intermittent dosing strategy. The present study was designed to further evaluate this issue within a large scale, double-blind, placebo-controlled, long-term trial. METHOD Patients who met DSM-IV criteria for Primary Insomnia participated in the study from January 2000 through October 2001. Patients were randomly assigned to 1 of 2 treatment groups (zolpidem 10 mg or placebo) for a period of 12 weeks. Ten pills were provided in foil packs on an every-other-week basis, and patients were instructed to take no fewer than 3 and no more than 5 pills per week. Sleep was evaluated daily with sleep diaries. Pill use was recorded in the sleep diaries. RESULTS 199 patients (mean +/- SD age = 41.0 +/- 12.8 years; 71% female) were randomly assigned to treatment. On mean, patients receiving zolpidem exhibited (vs. baseline) a 42% decrease in sleep latency, a 52% reduction in number of awakenings, a 55% decrease in wake time after sleep onset, and a 27% increase in total sleep time. These positive clinical gains did not diminish with time and were not associated with dose escalation. There was also no evidence of rebound Insomnia. CONCLUSIONS Over a period of 12 weeks of intermittent treatment with zolpidem, sleep continuity was significantly improved, the clinical gains were sustained, and there was no evidence of subjective rebound Insomnia between doses or increases in the amount of medication used during the study interval.
Milton K Erman - One of the best experts on this subject based on the ideXlab platform.
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apd125 a selective serotonin 5 ht2a receptor inverse agonist significantly improves sleep maintenance in Primary Insomnia
Sleep, 2008Co-Authors: Russell Rosenberg, David Seiden, Milton K Erman, Steven Hull, Howard Schwartz, Christen M Anderson, Warren Prosser, William R Shanahan, Matilde Sanchez, Emil ChuangAbstract:THE PREVALENCE OF Insomnia COMPLAINTS IN DEVELOPED COUNTRIES IS ESTIMATED TO BE 25% TO 35% IN SEVERAL GENERAL POPULATION SURVEYS1–3 and includes 30 to 45 million Americans who have a diagnosis of Insomnia.4 The DSM-IV defines Insomnia as difficulty initiating or maintaining sleep or nonrestorative sleep associated with significant distress or impairment in social, occupational, or other important areas of functioning.5 The majority of drugs approved to treat Insomnia exert their effects by activating benzodiazepine receptors located on gamma amino butyric acid (GABA)A receptor complexes, leading to increased inhibition of several pathways involved in sleep-wake regulation, which in turn causes drowsiness and facilitates sleep.6–8 These benzodiazepine receptor agonists (BzRAs) are effective in promoting sleep, and those with longer half-lives are also effective in maintaining sleep.9,10 However, BzRAs are associated with central nervous system side effects and possible dependency in at-risk populations.11–16 As a result, much recent research has focused on developing safer sleep agents2,17,18; some of the newer agents under evaluation are designed to increase slow wave sleep (SWS) in an effort to improve sleep quality and maintenance. The serotonergic pathway is one of the key pathways that contribute to wakefulness.19–21 Some atypical selective serotonin reuptake inhibitors have been shown to increase SWS, particularly those that bind to the serotonin (5-HT) 2A receptor.20,22,23 Importantly, it has been suggested that increasing SWS and reducing arousals and stage shifts may improve sleep maintenance.20,24–26 APD125, a potent and selective inverse agonist for 5-HT2A receptors, belongs to a new class of compounds under investigation for the treatment of Insomnia. Inverse agonists differ from neutral antagonists, which affect only ligand-dependent receptor activation and have no effect on constitutive receptor signaling. The potential benefit of an inverse agonist is that, unlike a ligand-dependent neutral agonist, it can block receptor activity in the presence or absence of the native ligand.27–28 In previous phase 1 clinical trials, APD125 significantly improved polysomnographic (PSG) parameters of sleep in normal volunteers in the nap model of transient Insomnia, resulting in increased SWS, decreased number of awakenings (NAW), and decreased arousal index.29 Moreover, APD125 was non-sedating: drowsiness and clinically significant adverse cognitive or psychomotor effects were not observed by Leeds psychomotor testing, Bond and Lader visual analog scale, or memory consolidation testing either at Tmax during daytime dosing or in the morning following nighttime dosing. This is in contrast to compounds whose Primary action is on the GABA receptor complexes, where cognitive and psychomotor impairment is observed during peak plasma levels.30 The present study was conducted to test the Primary hypothesis that APD125 reduces wake time after sleep onset (WASO) in subjects with Primary Insomnia as compared to placebo during a 7-day treatment period. Secondarily, effects of APD125 on other parameters of sleep maintenance including SWS and NAW were evaluated. Other objectives were to assess the tolerability and safety of APD125 in a Primary Insomnia population, and to evaluate study drug effects on a panel of other objective and subjective sleep parameters.
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long term efficacy and safety of zolpidem extended release 12 5 mg administered 3 to 7 nights per week for 24 weeks in patients with chronic Primary Insomnia a 6 month randomized double blind placebo controlled parallel group multicenter study
Sleep, 2008Co-Authors: Andrew D. Krystal, Gary Zammit, Milton K Erman, Christina Soubrane, Thomas RothAbstract:Study Objectives: To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic Primary Insomnia.
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long term efficacy and safety of zolpidem extended release 12 5 mg administered 3 to 7 nights per week for 24 weeks in patients with chronic Primary Insomnia a 6 month randomized double blind placebo controlled parallel group multicenter study
Sleep, 2008Co-Authors: Andrew D. Krystal, Gary Zammit, Milton K Erman, Christina Soubrane, Thomas RothAbstract:STUDY OBJECTIVES To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic Primary Insomnia. DESIGN Multicenter, 25-week, phase IIIb, randomized, double-blind, placebo-controlled, parallel-group. SETTING Outpatient; visits every 4 weeks. PATIENTS Aged 18 to 64 years; DSM-IV criteria for chronic Primary Insomnia; > or =3 months of difficulty initiating or maintaining sleep or experiencing nonrestorative sleep. INTERVENTIONS Single-dose zolpidem extended-release 12.5 mg (n = 669) or placebo (n = 349), self-administered from a minimum of 3 nights/week to a maximum of 7 nights/week. MEASUREMENTS AND RESULTS Patient's Global Impression (PGI) and Clinical Global Impression-Improvement (CGI-I) were assessed every 4 weeks up to week 24. Patient Morning Questionnaire (PMQ), recorded daily, assessed subjective sleep measures-sleep onset latency (SOL), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and quality of sleep (QOS)-and next-day functioning. At week 12, PGI, Item 1 (aid to sleep), the Primary endpoint, was scored as favorable (i.e., "helped me sleep") by 89.8% of zolpidem patients vs. 51.4% of placebo patients (P < 0.0001, based on rank score) and at week 24 by 92.3% of zolpidem extended-release patients vs. 59.7% of placebo patients. Zolpidem extended-release also was statistically significantly superior to placebo at every time point for PGI (Items 1-4) and CGI-I (P < 0.0001, rank score), TST, WASO, QOS (P < 0.0001), and SOL (P < or = 0.0014); NAW (Months 2-6; P < 0.0001). Sustained improvement (P < 0.0001, all time points) was observed in morning sleepiness and ability to concentrate (P = 0.0014, month 6) with zolpidem extended-release compared with placebo. Most frequent adverse events for zolpidem extended-release were headache, anxiety and somnolence. No rebound effect was observed during the first 3 nights of discontinuation. CONCLUSIONS These findings establish the efficacy of 3 to 7 nights per week dosing of zolpidem extended-release 12.5 mg for up to 6 months. Treatment provided sustained and significant improvements in sleep onset and maintenance and also improved next-day concentration and morning sleepiness.
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evaluation of the efficacy and safety of ramelteon in subjects with chronic Insomnia
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2007Co-Authors: Gary Zammit, Stephen Sainati, Sherry Wangweigand, Jeffrey Zhang, Milton K Erman, Thomas RothAbstract:Objective: To evaluate efficacy and safety of ramelteon (MT1/MT2-receptor agonist) in subjects with chronic Primary Insomnia.
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an efficacy safety and dose response study of ramelteon in patients with chronic Primary Insomnia
Sleep Medicine, 2006Co-Authors: Milton K Erman, Gary Zammit, David Seiden, Stephen Sainati, Jeffrey ZhangAbstract:Abstract Background and purpose To evaluate the efficacy, safety, and dose response of Ramelteon, a novel highly selective MT 1 /MT 2 receptor agonist, in patients with chronic Primary Insomnia. Patients and methods A randomized, multicenter, double-blind, placebo-controlled, five-period crossover study design was performed. A total of 107 patients, aged 18–64 years, were randomized into a dosing sequence that included 4, 8, 16, and 32mg of ramelteon and placebo. Patients received all five treatments, with a 5- to 12-day washout period between treatments, and served as their own controls. Medication was administered 30min before habitual bedtime and polysomnographic monitoring. Next-day residual effects were assessed with two visual analog scales (mood and feeling), digit symbol substitution test (DSST), word-list memory tests (immediate recall and delayed recall), and a post-sleep questionnaire that ascertained patients' alertness and ability to concentrate. Results All tested doses of ramelteon resulted in statistically significant reductions in latency to persistent sleep (LPS) and increases in total sleep time (TST). No next-day residual effects were apparent at any dose, as compared with placebo. There were no differences in the number or type of adverse events between any active treatment and placebo group. The most commonly reported adverse events were headache, somnolence, and sore throat. Conclusions Ramelteon demonstrated a statistically significant reduction in LPS and a statistically significant increase in TST, with no apparent next-day residual effects, in patients with chronic Primary Insomnia.
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dual orexin receptor antagonist almorexant in elderly patients with Primary Insomnia a randomized controlled study
Sleep, 2017Co-Authors: Marzia Cavallaro, Gary Zammit, Jed Black, Raymond Cluydts, Pascal Charef, Fabrice Kramer, James K WalshAbstract:Objective Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with Primary chronic Insomnia. Methods Patients aged ≥65 years with Primary Insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The Primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also assessed. Results 112 patients were randomized (mean [SD] age 72.1 [5.0] years; 69.9% female). Significant, dose-related improvements (reductions) in mean WASO were observed with almorexant. Least-squares mean (95% CI) treatment effects in the almorexant 200, 100, 50, and 25 mg dose groups versus placebo were -46.5 minutes (-53.0, -39.9; p < .0001), -31.4 minutes (-38.0, -24.9; p < .0001), -19.2 minutes (-25.7, -12.6; p < .0001), and -10.4 minutes (-17.0, -3.9; p = .0018), respectively. Mean total sleep time was significantly increased with each almorexant dose (mean increases versus placebo ranged 55.1-14.3 minutes; p < .0001 for each dose). Latency to persistent sleep was statistically significantly reduced only with almorexant 200 mg versus placebo (mean [95% CI] treatment effect -10.2 minutes, [-15.4, -5.0]; p = .0001). No unexpected safety concerns were identified. Adverse events were similar between all almorexant dose groups and placebo. Conclusions Two-night oral administration of almorexant was effective and well tolerated in treating Primary Insomnia in elderly patients.
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safety and subjective sleep effects of ramelteon administration in adults and older adults with chronic Primary Insomnia a 1 year open label study
The Journal of Clinical Psychiatry, 2009Co-Authors: Gary S. Richardson, Gary Zammit, Sherry Wangweigand, Jeffrey ZhangAbstract:Objective: To evaluate the long-term safety and subjective sleep effects of ramelteon in adults with chronic Insomnia. Method: Subjects with Primary Insomnia (DSM-IV-TR criteria) for ≥ 3 months received ramelteon nightly for 1 year; a 3-day placebo run out followed. Subjects aged ≥ 65 years received open-label ramelteon 8 mg (N = 248); those aged 18 to 64 years received ramelteon 16 mg (N = 965). Subjects completed sleep diaries and returned to the clinic at week 1 and at months 1, 2, 3, 4, 6, 8, 10, and 12 for safety assessments and investigator-performed Clinical Global Impressions. The study was conducted from February 2003 through September 2004. Results: There were no noteworthy changes in vital signs, physical examinations, clinical chemistry, hematology, or urinalysis values and no electrocardiogram changes to suggest adverse cardiac effects. Endocrine values remained within normal range throughout treatment. Consistent statistically significant (p ≤.05) decreases in free thyroxine (in adults) and free testosterone (in older men) were detected. Duration of menses increased by approximately 1 day. A total of 40.8% of subjects reported at least 1 adverse event possibly associated with ramelteon use. The adverse events reported varied considerably, the incidence of individual adverse events was low, and the frequencies of adverse events were similar at months 6 and 12. In both groups, subjective sleep latency and total sleep time improved by month 1 and was sustained during the 1-year period. At 6 months and 1 year, Clinical Global Impressions indices were improved. During placebo run out, subjective sleep latency did increase but did not return to baseline. Conclusion: Year-long administration of ramelteon was well tolerated. Ramelteon was associated with sustained improvements in subjective sleep latency, subjective total sleep time, and Clinical Global Impressions.
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long term efficacy and safety of zolpidem extended release 12 5 mg administered 3 to 7 nights per week for 24 weeks in patients with chronic Primary Insomnia a 6 month randomized double blind placebo controlled parallel group multicenter study
Sleep, 2008Co-Authors: Andrew D. Krystal, Gary Zammit, Milton K Erman, Christina Soubrane, Thomas RothAbstract:Study Objectives: To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic Primary Insomnia.
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long term efficacy and safety of zolpidem extended release 12 5 mg administered 3 to 7 nights per week for 24 weeks in patients with chronic Primary Insomnia a 6 month randomized double blind placebo controlled parallel group multicenter study
Sleep, 2008Co-Authors: Andrew D. Krystal, Gary Zammit, Milton K Erman, Christina Soubrane, Thomas RothAbstract:STUDY OBJECTIVES To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic Primary Insomnia. DESIGN Multicenter, 25-week, phase IIIb, randomized, double-blind, placebo-controlled, parallel-group. SETTING Outpatient; visits every 4 weeks. PATIENTS Aged 18 to 64 years; DSM-IV criteria for chronic Primary Insomnia; > or =3 months of difficulty initiating or maintaining sleep or experiencing nonrestorative sleep. INTERVENTIONS Single-dose zolpidem extended-release 12.5 mg (n = 669) or placebo (n = 349), self-administered from a minimum of 3 nights/week to a maximum of 7 nights/week. MEASUREMENTS AND RESULTS Patient's Global Impression (PGI) and Clinical Global Impression-Improvement (CGI-I) were assessed every 4 weeks up to week 24. Patient Morning Questionnaire (PMQ), recorded daily, assessed subjective sleep measures-sleep onset latency (SOL), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and quality of sleep (QOS)-and next-day functioning. At week 12, PGI, Item 1 (aid to sleep), the Primary endpoint, was scored as favorable (i.e., "helped me sleep") by 89.8% of zolpidem patients vs. 51.4% of placebo patients (P < 0.0001, based on rank score) and at week 24 by 92.3% of zolpidem extended-release patients vs. 59.7% of placebo patients. Zolpidem extended-release also was statistically significantly superior to placebo at every time point for PGI (Items 1-4) and CGI-I (P < 0.0001, rank score), TST, WASO, QOS (P < 0.0001), and SOL (P < or = 0.0014); NAW (Months 2-6; P < 0.0001). Sustained improvement (P < 0.0001, all time points) was observed in morning sleepiness and ability to concentrate (P = 0.0014, month 6) with zolpidem extended-release compared with placebo. Most frequent adverse events for zolpidem extended-release were headache, anxiety and somnolence. No rebound effect was observed during the first 3 nights of discontinuation. CONCLUSIONS These findings establish the efficacy of 3 to 7 nights per week dosing of zolpidem extended-release 12.5 mg for up to 6 months. Treatment provided sustained and significant improvements in sleep onset and maintenance and also improved next-day concentration and morning sleepiness.
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evaluation of the efficacy and safety of ramelteon in subjects with chronic Insomnia
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2007Co-Authors: Gary Zammit, Stephen Sainati, Sherry Wangweigand, Jeffrey Zhang, Milton K Erman, Thomas RothAbstract:Objective: To evaluate efficacy and safety of ramelteon (MT1/MT2-receptor agonist) in subjects with chronic Primary Insomnia.
