Zolpidem Research Articles

B-295 Sensitive and Rapid Homogeneous Immunoassay for the Detection of Zolpidem and its Major Metabolite in Urine

Abstract Background Zolpidem, a schedule IV controlled substance under the Controlled Substances Act, is commonly known as Ambien and Ambien CR, a prescription only treatment for insomnia. Zolpidem is one of the most common prescribed sleep aids in the U.S. due to its rapid sedative effects. The recommended duration of treatment is between two days and four weeks, as long-term use of zolpidem increases the risk of habit formation. Addiction to zolpidem can cause severe side effects, including memory loss, delusion, and in extreme cases, fatal overdose. From 2005-2010, Zolpidem-related emergency room visits doubled, underscoring the need for accurate testing as zolpidem testing plays an important role in cases of misuse, diversion, and forensics. The sole commercially available homogeneous immunoassay for the detection of zolpidem in urine has a relatively high cutoff at 20 ng/mL and poor cross-reactivity (0.02%) to major metabolite zolpidem 4-carboxylic acid. ARK Diagnostics has developed the ARK™ Zolpidem Assay to detect zolpidem at a cutoff concentration of 10 ng/mL with high cross-reactivity to its metabolite, Zolpidem phenyl 4-carboxylic acid and no cross-reactivity to zaleplon and zopiclone at concentrations below 100,000 ng/mL. Methods The ARK™ Zolpidem Assay is a liquid stable homogeneous enzyme immunoassay, consisting of two reagents, with a cutoff concentration of 10 ng/mL and semi-quantitative range up to 40 ng/mL. Preliminary performance characterization for this assay was evaluated on the Beckman Coulter AU680 Automated Clinical Chemistry Analyzer. Precision, analytical recovery, specificity, Histogram Overlap Analysis of ±50% controls and the cutoff, and method comparison with LC-MS/MS were evaluated. Results In semi-quantitative mode, total precision ranged from 2.6 to 3.1% CV. Spiked recovery of zolpidem ranged from 88.6% (2.5 ng/mL) to 96.8% (10 ng/mL). The major metabolite, zolpidem phenyl-4-carboxylic acid, showed an approximate equivalence to the 10 ng/mL zolpidem cutoff at 30 ng/mL (33.3% cross-reactivity). Histogram overlap analysis showed no overlap between cutoff and control levels. Method correlation with LC-MS/MS using authentic urine samples showed an excellent agreement with a specificity of 100% and sensitivity of 100% (15 positives and 100 negatives). Conclusions The ARK™ Zolpidem Assay measures zolpidem and its major metabolite zolpidem phenyl-4-carboxylic acid in human urine with acceptable performance. The assay is sensitive, rapid, and applicable to a wide range of clinical chemistry analyzers.

Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials.

Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults. Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2-7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance. Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65years. LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65years, supporting LEM as a treatment option for older adults with insomnia. Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017.

Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report

BackgroundZolpidem is a non-benzodiazepine hypnotic widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before.Case presentationA 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril/valsartan 12/13 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no significant change. The night before admission, the patient attempted suicide by overdosing on 40 mg of zolpidem after an argument, which resulted in severe lethargy. Upon admission, his ECG revealed new-onset AF, necessitating immediate cessation of zolpidem. Nine hours into admission, AF spontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that AF was not detected.ConclusionsThis study provides valuable clinical evidence indicating that zolpidem overdose may induce AF in patients with cardiomyopathy. It serves as a critical warning for clinicians when prescribing zolpidem, particularly for patients with existing heart conditions. Further large-scale studies are needed to validate this finding and to explore the mechanisms between zolpidem and AF.

Wastewater-based epidemiology to monitor 68 NPS/conventional drug use in Taipei metropolitan area in Taiwan during and after COVID-19 pandemic

Amidst far-reaching COVID-19 effects and social constraints, this study leveraged wastewater-based epidemiology to track 38 conventional drugs and 30 new psychoactive substances (NPS) in northern Taiwan. Analyzing daily samples from four Taipei wastewater plants between September 2021 and January 2024—encompassing club reopenings, holidays, Lunar New Year, an outbreak, and regular periods—thirty-one drugs were detected, including 5 NPS. Tramadol, zolpidem tartrate, CMA, and MDPV were newly detected in Taiwanese sewage with frequency of 1.4 %− 89.0 %. Conventional drug use typically increased post-pandemic, aside from benzodiazepines and methadone. Methamphetamine showed 100 % frequency, indicating ongoing daily consumption despite COVID-19 measures. Methamphetamine and morphine's consumption dipped then rose around club reopening, hinting at limited access. The consumption trend of methadone appeared to compensate for the use of morphine. Ketamine and NPS demonstrated similar patterns throughout the entire period. NPS as party drugs seemed influenced by an unstable supply chain and complexities in implementation. Benzodiazepines, commonly abused alongside synthetic cathinones in Taiwan exhibited an opposing trend to NPS while aligned with acetaminophen, suggesting elevated stress and anxiety levels during the pandemic. No significant differences were observed in drug consumption between weekdays and weekends, potentially indicating that COVID-19 measures blurred the traditional distinctions between these timeframes. Environmental ImplicationNew psychoactive substances refer to chemically modified variants of controlled drugs designed to mimic the effects of the original drugs while evading modern detection methods, categorizing them as hazardous materials. The study presents a sewage monitoring project conducted from 2021 to 2024, collecting samples from four WWTPs to analyze NPS and conventional drug trends during and after the COVID-19 pandemic. The findings uncovered connections between drug consumption patterns and pandemic-related policies. In light of the persistent drug abuse and their environmental presence, the results bear critical importance for both environmental and public health. We provide a thorough assessment of these relationships and prioritize areas for future research.

Digital cognitive–behavioural therapy application compared with zolpidem for the treatment of insomnia: protocol for an exploratory randomised controlled trial

IntroductionInsomnia is a common health problem and cognitive–behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we developed a digital CBT application...

Powder bed fusion–laser beam (PBF-LB) three-dimensional (3D) printing: Influence of laser hatching distance on the properties of zolpidem tartrate tablets

Laser sintering, known as powder bed fusion–laser beam (PBF-LB), offers promising potential for the fabrication of patient-specific drugs. The aim of this study was to provide an insight into the PBF-LB process with regard to the process parameters, in particular the laser hatching distance, and its influence on the properties of zolpidem tartrate (ZT) tablets. PHARMACOAT® 603 was used as the polymer, while Candurin® Gold Sheen and AEROSIL® 200 were added to facilitate 3D printing. The particle size distribution of the powder blend showed that the layer height should be set to 100 µm, while the laser hatching distance was varied in five different steps (50, 100, 150, 200 and 250 µm), keeping the temperature and laser scanning speed constant. Increasing the laser hatching distance and decreasing the laser energy input led to a decrease in the colour intensity, mass, density and hardness of the ZT tablets, while the disintegration and dissolution rate were faster due to the more fragile bonds between the particles. The laser hatching distance also influenced the ZT dosage, indicating the importance of this process parameter in the production of presonalized drugs. The absence of drug-polymer interactions and the amorphization of the ZT were confirmed.

Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended release for insomnia disorder subtypes

Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended release for insomnia disorder subtypes

Performance Evaluation of Multi-Drug Rapid Test for Rapid Detection of Multiple Drugs and Drug Metabolites in Human Blood Samples

Objective: The Multi-Drug Rapid Test Cassette, developed by Hangzhou AllTest Biotech Co., Ltd, is a rapid chromatographic immunoassay designed for the qualitative detection of multiple drugs and drug metabolites in human whole blood, serum, or plasma. It aims to simultaneously detect various abused substances, including Amphetamine (AMP), Barbiturates (BAR), Benzodiazepines (BZO), Buprenorphine (BUP), Cocaine (COC), Cannabis (THC), Methadone (MTD), Methamphetamine (MET), 3,4-Methylenedioxymethamphetamine (MDMA), Morphine (MOP/OPI), Propoxyphene (PPX), Tricyclic antidepressants (TCA), Oxycodone (OXY), 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), Cotinine (COT), Tramadol (TML), Fentanyl (FYL), 3,4-Methylenedioxy pyrovalerone (MDPV), Synthetic cannabinoids(K2), Phencyclidine(PCP), Ketamine(KET), Lysergic acid diethylamide(LSD), 3,4-Methylenedioxyamphetamine(MDA), Acetaminophen(ACE), Ketamine(CAT), 6-Monoacetylmorphine (6-MAM), Zolpidem (ZOL), AB-PINACA (ABP/K3). Therefore, the present research was done to evaluate the diagnostic performance of this test. Material and Method: In this study, the accuracy, precision, and sensitivity of the drug testing methods were assessed. Approximately 100 specimens of each drug, obtained from previous drug screening tests, were tested. The results were compared to confirmatory analysis using GC/MS, and the accuracy of the testing was determined based on the comparative classification results. The evaluation of precision included measuring the consistency of measurements within a single run, between different runs, and among different operators, using the AllTest multi-drug detection tool across three different hospitals and three different batches. To evaluate the sensitivity of the detection method, various concentrations of drugs were added to a pool of whole blood, serum, or plasma without any drugs. The positive and negative results obtained from the testing were analyzed to assess the method’s ability to detect drugs at different concentrations. Results: In this study, we evaluated the performance of the Multi-Drug Rapid Test Cassette developed by Hangzhou AllTest Biotech Co., Ltd. The results demonstrated excellent performance of the test in terms of accuracy, sensitivity, and precision. Conclusion: The Multi-Drug Rapid Test Cassette developed by Hangzhou AllTest Biotech Co., Ltd exhibited reliable detection of multiple drugs and drug metabolites, providing trustworthy results for drug abuse screening. These findings have significant implications for drug control and monitoring, as well as supporting the broad application of this test in clinical and legal settings.

Transitioning insomnia patients from zolpidem to lemborexant: A multicenter, open-label study evaluating a next-dose transition approach to insomnia pharmacotherapy

ObjectiveFew clinical studies have assessed real-world abrupt transitioning between insomnia medications. This study assessed strategies for directly transitioning patients from zolpidem tartrate (ZOL) immediate/extended release to the dual orexin receptor antagonist, lemborexant (LEM). MethodsThis randomized, open-label, multicenter study (Study 312; E2006-A001-312) enrolled 53 adults age ≥18 years with insomnia disorder and ≥1-month history of intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL use. Subjects recorded their ZOL use in a 3-week Pretreatment Phase, followed by a 2-week Treatment Phase (TRT; Titration) during which ZOL was discontinued. Intermittent ZOL users transitioned to LEM 5 mg (LEM5), Cohort 1, and frequent ZOL users were randomized 1:1 to LEM5, Cohort 2A, or LEM 10 mg (LEM10), Cohort 2B. One dose adjustment was permitted during the TRT. Subjects completing the TRT could continue LEM in the 12-week Extension Phase (EXT). The primary outcome was proportion of subjects who successfully transitioned and remained on LEM at the end of the TRT. ResultsMost subjects (43 [81.1 %]) successfully transitioned to LEM (9 [90 %], 17 [81.0 %], and 17 [77.3 %] in Cohorts 1, 2A, and 2B, respectively). By the end of the EXT, 66.7 % in Cohort 1 and 60.0 % in Cohort 2A up-titrated to LEM10, whereas 41.2 % in Cohort 2B down-titrated to LEM5; 61.0 % were receiving LEM10 at study end. At the end of the TRT, more subjects taking LEM reported that it helped them return to sleep after waking, compared with those taking ZOL (71.7 % vs. 49.1 %). There were no important differences between treatments regarding how subjects reported feeling as they fell asleep. Most of the treatment-emergent adverse events with LEM were mild in severity. ConclusionsMost subjects transitioned successfully to LEM from ZOL (intermittent or frequent use). LEM was well tolerated.

Effective removal of hypnotic drug from the aqueous medium through adsorption on graphene oxide magnetic derivatives

This study evaluated the adsorption of zolpidem (ZPD) on magnetic graphene oxide (GO‧Fe3O4). The graphene oxide-based magnetic adsorbents used to remove zolpidem were synthesized with different amounts of magnetite. The Adsorbents were characterized, confirming the presence of magnetic nanoparticles on the graphene oxide surface. The best magnetic nanoadsorbent was GO‧Fe3O4 1:1, with a removal percentage of 87.07 % at pH 5.0 and 293.15 K. In this sense, zolpidem removal was unrelated to the graphene oxide surface area but to the surface chemistry of the adsorbent. The physical–chemical Interactions between the ZPD molecules and the functional groups of the adsorbent were suggested. ZPD adsorption on GO‧Fe3O4 1:1 was spontaneous and exothermic. The equilibrium and kinetic studies (Sips and Elovich) suggested adsorption in a heterogeneous surface. Furthermore, the adsorbent presented excellent adsorption efficiency even after many regeneration cycles, and magnetic behavior avoids the centrifugation/filtration steps. Until now, no study in the literature reported removing this harmful and widespread hypnotic drug from water contamination, and GO·Fe3O4 1:1 was an efficient nanomaterial to remove ZPD from aqueous solutions.

Does Melatonin Decrease the Use of As-Needed Antipsychotics or Benzodiazepines in Noncritically Ill Hospitalized Patients? A Multicenter Retrospective Cohort Study.

Background: Delirium is a common neuropsychiatric syndrome without an FDA-approved treatment. Commonly used modalities show little improvement in outcomes; therefore, prevention efforts are imperative. Abnormalities in the sleep/wake cycle have been linked to delirium, and melatonin has been proposed to replace the hypothesized low levels of endogenous melatonin and restore sleep/wake cycle synchronization. Objectives: The primary objective of this study was to evaluate the association between melatonin, benzodiazepines (BZDs) or zolpidem (ZLP), and the use of as-needed antipsychotics and BZDs for delirium in noncritically ill adult patients. Methods: This was a multicenter retrospective cohort study of noncritically ill adult patients admitted to two separate health systems from August 2012 to December 2018 receiving either melatonin or nonmelatonin medications (ZLP or BZDs) for sleep. The coprimary endpoint was the proportion of patients receiving a pro re nata (PRN) antipsychotic or BZD 5 days from the patient's first dose of melatonin, BZD, or ZLP. Secondary outcomes included evaluation of the coprimary outcome in patients 65 years of age or older, total number of PRN antipsychotic and BZD doses, and length of stay. Results: Two hundred and twenty-five patients were included in the final analysis. Administration of BZD or ZLP was associated with a higher risk of subsequent BZD administration as compared with melatonin (OR 2.78, 95% CI 1.2-1.87) and ZLP (OR 2.78, 95% CI 1.25-6.17). BZD or ZLP had no impact on PRN antipsychotic use compared with melatonin (OR 1.09, 95% CI 0.51-2.35) and ZLP (OR 1.16, 95% CI 0.56-2.4). Conclusion: Melatonin use was found to be associated with a significant decrease in PRN BZD use in noncritically ill patients hospitalized on general floors; however, there was no observed association with overall PRN antipsychotic use. These results suggest that using melatonin may help decrease utilization of medications commonly used to manage delirium.

Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology.

Type A γ-aminobutyric acid receptors (GABAARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants1-3. However, our understanding of GABAAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits4 and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem(ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone(APG)). Using cryo-electron microscopy (cryo-EM)analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABAARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.

Selective laser sintering (SLS) 3D printing process: Influence of model design on the properties of zolpidem tartrate tablets

Selective laser sintering (SLS) 3D printing process: Influence of model design on the properties of zolpidem tartrate tablets

A randomized controlled study of a psycho-behavioral intervention combined with a non-benzodiazepine to improve perioperative sleep quality in patients undergoing knee arthroplasty.

To clarify the effectiveness and safety of psycho-behavioral intervention combined with a non-benzodiazepine to improve perioperative sleep quality in patients undergoing knee arthroplasty, and also to explore the optimal dosage of non-benzodiazepine (oral zolpidem tartrate) to form a standardized sleep quality management process to promote accelerated recovery of patients. 240 patients undergoing initial unilateral total knee arthroplasty between January and December 2016 were prospectively included and randomly divided into blank control group (group A), psycho-behavioral intervention group (group B), zolpidem tartrate 10 mg group (group C), and psycho-behavioral intervention + zolpidem tartrate 5 mg group (group D). Sleep, pain, psychological, and knee function scores were compared. There were significant differences between the four groups with respect to Pittsburgh sleep quality index scores, sleep efficiency, Epworth Sleepiness Scale scores, inflammatory indices, pain, and enhanced recovery after surgery indices during hospitalization (P < 0.05). Psychological behavioral intervention combined with non-benzodiazepine can improve the perioperative quality of sleep. Compared with drug intervention alone, it reduces the dosage of non-benzodiazepine, alleviates anxiety, improves patient satisfaction, and enhances the quality of life.

Hypnotic prescriptions in Japan may be shifting from benzodiazepine receptor agonists to other types of hypnotics, melatonin receptor agonists, and orexin receptor antagonists.

Hypnotic prescriptions in Japan may be shifting from benzodiazepine receptor agonists to other types of hypnotics, melatonin receptor agonists, and orexin receptor antagonists.

0351 Differential Effect of Lemborexant and Zolpidem on Wake Across the Night in Patients with Insomnia Disorder

Abstract Introduction Insomnia can involve difficulty with falling and/or staying asleep; older adults tend to report more sleep maintenance issues. While zolpidem tartrate extended-release 6.25mg (ZOL) is indicated to treat sleep onset and maintenance, data indicate that ZOL may be less effective in the last 2 hours of the night. It is important to understand the differences between ZOL and lemborexant (LEM), a dual-orexin-receptor-antagonist with the same indication. In Study 304 (E2006-G000-304; NCT02783729), LEM treatment significantly improved objective sleep maintenance (wake after sleep onset [WASO] and WASO in the second half of the night) assessed by polysomnography (PSG) over 1 month compared with placebo (PBO) and ZOL in older adults with insomnia disorder. This post-hoc analysis assessed the effect of LEM and ZOL on wake at each hour (H) of an 8-h sleep period. Methods Study 304 was a randomized, double-blind, PBO- and active-controlled, parallel-group study in adults ≥55y. Subjects (n=1006) received PBO, LEM 5mg (LEM5) or 10mg (LEM10), or ZOL for 1 month. Wake (minutes) was assessed hourly from paired PSGs during single-blind PBO run-in and post-randomization at nights (NT) 1/2 and NT29/30. Change from baseline (CfB) for H1-8 was analyzed using pooled t-tests. Results Between-group baseline wake was similar. On NT1/2 and NT29/30, CfB for LEM10 was significantly greater (less wake) than PBO for all hours except H4 NT29/30. On NT1/2 and NT29/30, CfB for LEM5 was significantly greater than PBO for all hours except H4 NT1/2 and NT29/30 and H8 NT1/2. On NT1/2 and NT29/30, CfB for LEM5 and LEM10 were significantly greater than ZOL during H1,2,7, and 8. CfB for ZOL was not significantly different than PBO except for H2-6 NT1/2 and H3,5,6 NT29/30; CfB for PBO was significantly greater (better) than ZOL during H1 NT29/30. Conclusion LEM improves total sleep time by decreasing wake time throughout the night after sleep onset compared to PBO, and at the beginning/end of the night compared to ZOL. These findings support that ZOL may be less effective in maintaining sleep during the last 2 hours of the night compared with LEM in older subjects, especially those with sleep maintenance difficulties. Support (if any) Eisai Inc.

0354 Effect of Lemborexant on Sleep Architecture in Subjects with Comorbid Insomnia and Mild Obstructive Sleep Apnea from a Ph 3 Trial

Abstract Introduction Many patients with insomnia have co-morbid obstructive sleep apnea (COMISA). Patients with obstructive sleep apnea (OSA) may also have decreased REM-sleep. Lemborexant (LEM) is a dual-orexin-receptor-antagonist approved to treat adults with insomnia. LEM has been demonstrated to increase total sleep, with prominent increases in rapid eye movement (REM). Thus, sleep architecture was analyzed in subjects with insomnia/mild OSA receiving LEM in a phase 3 trial. Methods Study 304 (E2006-G000-304; NCT02783729) was a 1-month, randomized, double-blind, placebo (PBO)-controlled and active-comparator study in adults ≥55y with insomnia disorder. Subjects received PBO, LEM 5mg (LEM5), LEM 10mg (LEM10) or zolpidem tartrate extended-release 6.25mg (ZOL). Least-squares-mean (LSM) duration of each sleep stage (minutes) was compared across treatment groups from pooled data on Nights (NT)1/2 and NT29/30 for ­subjects with mild OSA (apnea hypopnea index ≥5 to &amp;lt; 15). Treatment-emergent adverse events (TEAEs) were recorded. Results The analysis set comprised 409 subjects (LEM5=114/LEM10=105/ZOL=112/PBO=78) with mild OSA. Mean (SD) change from baseline (CFB) in total sleep time was significantly larger (more sleep) in both LEM groups than ZOL or PBO at the post-randomization assessments. CFB for REM sleep was also significantly larger (P&amp;lt; 0.0001) for both LEM vs ZOL/PBO at both assessments, NT1/2: LEM5 21.08 (21.79), LEM10 32.57 (24.34), ZOL 3.06 (23.51), PBO 2.42 (17.51); NT29/20: LEM5 14.49 (18.12), LEM10 24.26 (24.50), ZOL 0.75 (22.32), PBO 2.14 (22.62). Compared with PBO, CFB for total nonREM sleep significantly increased (P&amp;lt; 0.0001) in the LEM groups at both assessments, NT1/2: LEM5 39.64 (34.30), LEM10 44.63 (37.85), ZOL 45.80 (37.43); PBO 7.80 (37.88); NT29/30: LEM5 44.66 (37.77), LEM10 44.08 (39.68), ZOL 36.22 (41.95), PBO 15.33 (36.52). Compared to ZOL, total nonREM sleep in either LEM group was not significantly different on NT1/2, and only LEM5 was significantly different vs ZOL at NT29/30 (P&amp;lt; 0.05). LEM was well-tolerated; most TEAEs were mild/moderate. Conclusion LEM significantly increased total sleep time in subjects with insomnia and mild OSA. The additional sleep was comprised importantly with REM sleep, a sleep stage that may be decreased in patients with OSA. These data support the use of LEM in a population with COMISA. Support (if any) Eisai Inc.

0407 Impact of Lemborexant on Daytime Ratings of Sleepiness/Alertness in Subjects with Insomnia Disorder and Baseline Sleepiness

Abstract Introduction Since the use of sleep-promoting drugs can also lead to residual morning sleepiness, it is important to determine if a new hypnotic is associated with such a carryover effect of treatment. To this end, an assessment of sleepiness/alertness was included in lemborexant (LEM) phase 3 studies. LEM is a competitive dual orexin receptor antagonist approved in several countries for the treatment of adults with insomnia. This post-hoc analysis of Study 304 (E2006-G000-304; NCT02783729) assessed the impact of LEM on morning sleepiness/alertness in subjects who reported at least mild/moderate morning sleepiness at baseline. Methods Study 304 was a randomized controlled study in adults ≥55y with insomnia disorder (N=1006). Subjects received bedtime doses of placebo (PBO), LEM 5mg (LEM5), LEM 10mg (LEM10), or zolpidem tartrate extended release 6.25 mg (not reported here) for 1 month. A daily Sleep Diary assessed morning sleepiness, within 90 min of waketime, with the question “How alert/sleepy do you feel this morning?” rated from 1 (extremely sleepy) to 9 (extremely alert). Scores were averaged over 7-day periods for baseline (single-blind run-in) and first and last 7 days of treatment. Chi-square tests were used to compare the shift from sleepy (≤3) to more alert (&amp;gt;3) between PBO and treatment groups. Results At baseline, 59/203 (29.1%), 66/261 (25.3%), and 79/265 (29.8%) of the PBO, LEM5, and LEM10 subjects reported a score ≤3, indicating at least mild/moderate morning sleepiness. At the end of 1 month of treatment, 37/57 (64.9%) of the PBO subjects rated themselves as less sleepy and more alert (&amp;gt;3), compared with 50/64 (78.1%; P=0.11) LEM5- and 58/76 (76.3%; P=0.15) LEM10-treated subjects. Conclusion In this study, ~28% of subjects reported morning sleepiness at baseline. More subjects who reported sleepiness at baseline and received LEM reported improved morning alertness during the last week of treatment compared with PBO subjects. These data are concordant with previous findings of a lack of effect of LEM on tasks requiring alertness in the morning. Support (if any) Eisai Inc.

Effect of Lemborexant on Sleep Onset and Maintenance in Patients with Comorbid Insomnia Disorder and Mild Obstructive Sleep Apnea (P4-13.001)

<h3>Objective:</h3> Evaluate the effects of lemborexant (LEM), a competitive dual orexin receptor antagonist approved in multiple countries for the treatment of insomnia disorder, in patients with comorbid insomnia and obstructive sleep apnea (COMISA) of mild severity. <h3>Background:</h3> Insomnia and obstructive sleep apnea (OSA) are frequent comorbid sleep disorders. However, commonly prescribed hypnotic drugs may exacerbate pre-existing respiratory dysfunction. <h3>Design/Methods:</h3> Study E2006-G000-304 (Study 304; NCT02783729) was a 1-month, randomized, double-blind, placebo (PBO)-controlled and active-comparator (zolpidem tartrate extended release 6.25mg [ZOL]) study of LEM 5mg (LEM5) and LEM 10mg (LEM10). This post-hoc analysis included subjects age ≥55y with both insomnia disorder and mild OSA (apnea hypopnea index [AHI] ≥5 and &lt;15 events/h of sleep). Sleep onset (latency to persistent sleep [LPS]), sleep efficiency (SE = total sleep time/time in bed), wake after sleep onset (WASO), and WASO in the second half of the night (WASO2H) were assessed at Nights 1/2 (NT1/2) and Nights 29/30 (NT29/30) using polysomnography. <h3>Results:</h3> 40.8% of the population (n=410/1006) had mild OSA, with AHI (mean [SD]) at screening of 9.33 (2.9) events/h; median age 65y, and 83.9% were female. Changes from baseline in SE were larger (increased, indicating improvement) and significantly different for both LEM5 and LEM10 versus PBO and ZOL (P&lt;0.05) on NT1/2 and NT29/30. Compared with PBO, changes from baseline in LPS, WASO, and WASO2H were all larger (decreased, indicating improvement) and significantly different (P&lt;0.005) with LEM5 and LEM10 at both time points. Compared with ZOL, LEM10 produced significantly greater decreases from baseline for LPS, WASO, and WASO2H at NT1/2 and NT29/30 (P&lt;0.01, all assessments); and LEM5 on NT29/30 (P&lt;0.02, all assessments). LEM was well tolerated and consistent with its known safety profile. <h3>Conclusions:</h3> These results demonstrate the effectiveness of LEM versus PBO and ZOL in an older patient population with untreated COMISA of mild severity. <b>Disclosure:</b> Margaret Moline has received personal compensation for serving as an employee of EISAI, INC.. Margaret Moline has received intellectual property interests from a discovery or technology relating to health care. Margaret Moline has received personal compensation in the range of $0-$499 for serving as a review, loan repayment program with NIH. Dr. Cheng has received personal compensation for serving as an employee of Eisai Inc. Dinesh Kumar has received personal compensation for serving as an employee of Eisai. Dr. Ramos has received personal compensation for serving as an employee of Eisai. Dr. Lowe has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai . Dr. Lowe has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz. Dr. Lowe has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Paladin . Dr. Lowe has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sunovion . Dr. Lowe has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Eisai . Dr. Lowe has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sunovion . The institution of Dr. Lowe has received research support from Axsome Therapeutics . The institution of Dr. Lowe has received research support from Boehringer Ingelheim .

Rapid resolution of catatonia secondary to post traumatic stress disorder with secondary psychotic features through scheduled zolpidem tartrate

Catatonia is a complication of numerous psychiatric and medical conditions. The first-line treatment is typically management of the underlying primary condition as well as scheduled benzodiazepines or electroconvulsive therapy. Electroconvulsive therapy and benzodiazepines are not always tolerated or available when treating patients with catatonia. For this reason, other treatment regimens have been trialed in recent years, including the GABA-modulatory Z drugs such as zolpidem. Some alternative treatment modalities have shown great promise. However, which populaces these are most beneficial for is still unclear. In this article, we examine a case report of a woman who suffered from post-traumatic stress disorder with secondary psychotic features who experienced recurrent akinetic catatonia that was refractory to benzodiazepine therapy. She responded rapidly to scheduled zolpidem with minimal side effects. It is our author’s belief that when managing catatonia in patients with post traumatic stress disorder with secondary psychosis, Z drugs may be preferable to benzodiazepines.