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Aims: The aim of this study is to determine the cumulative amount of lemborexant (a competitive dual orexin receptor antagonist approved to treat adults with insomnia) excreted in human breast milk and the relative infant dose (RID) as a proportion of daily maternal dose. Methods: E2006‐A001‐010 was a single‐centre, open‐label study that enrolled lactating women (≥18 years) who breastfed for ≥5 weeks postpartum. After overnight fasting, subjects received a single 10‐mg oral dose of lemborexant. Using a standardized electric pump, milk was sampled before and ≤240 h (10 days) after dosing; combined and total volume were recorded. The cumulative total amount of lemborexant excreted, fraction of dose excreted, daily infant dose and RID were calculated. Lemborexant concentration in human milk was assessed by liquid chromatography with tandem mass spectrometry. Results: Eight subjects completed the study. The mean cumulative total amount of lemborexant reached 0.0174 mg (coefficient of variation [CV] 54.5%; 0.174% of lemborexant 10 mg administered) in breast milk at 240 h (10 days); ~70% of excreted lemborexant accumulated in the first 24 h. For an infant weighing 6 kg, the daily infant dose was 0.00290 mg kg−1 (CV 54.5%) and the RID was 1.96% (CV 63.1%) of daily maternal dose. Mild treatment‐emergent adverse events were reported in 4 subjects; these all resolved by end of study. Conclusion: Trace quantities of lemborexant were found in human breast milk. Lemborexant was well tolerated by healthy lactating women. [ABSTRACT FROM AUTHOR]

To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep outcomes data from a phase 3 trial. The subjects in these post-hoc analyses were randomized to placebo for 6 months (Time Period [TP]1) in Study E2006-G000-303 (SUNRISE-2; NCT02952820). Following placebo exposure, subjects were re-randomized to LEM5 or LEM10 for another 6 months (TP2). Subject-reported sleep outcomes derived from sleep diaries included sleep onset latency (sSOL), wake after sleep onset (sWASO), sleep efficiency (sSE), and total sleep time (sTST). Magnitude and change rate in parameters were assessed for 7 days before/after initial randomization to placebo and 7 days before/after re-randomization to LEM (6 months later). Month 6 placebo non-responders were assessed for LEM response in TP2 using predetermined responder definitions. Safety was monitored throughout the study. Overall, 321 subjects received placebo; 258 re-randomized subjects received LEM5 (n = 133) and LEM10 (n = 125). Subjective sleep outcomes improved during TP1 with approximately 62 subjects (∼20%) exhibiting a sustained placebo response. Upon re-randomization to LEM, all measures showed an additional incremental benefit, most prominently in sSOL and sTST. Among Month 6 placebo non-responders, 11%–15% subsequently responded to LEM as assessed at Month 12. The safety profile was similar between treatment periods and treatment groups. These data suggest that even when insomnia symptoms have improved over time with placebo treatment, additional and sustained clinical gains in sleep outcomes are possible with active treatment using lemborexant. • Placebo responses are seen in randomized clinical trials of hypnotics. • The impact of lemborexant on sleep outcomes after placebo exposure was evaluated. • After some improvement with placebo, lemborexant caused additional sleep gains. [ABSTRACT FROM AUTHOR]

Background: Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. Methods: A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. Results: In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. Conclusions: In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan. [ABSTRACT FROM AUTHOR]

Background: Lemborexant is a dual orexin receptor antagonist approved to treat insomnia in adults in several countries including the USA, Canada, and Japan.Aims: This study was conducted to investigate effects of lemborexant and alcohol coadministration on postural stability, cognitive performance, and the pharmacokinetics, safety, and tolerability of lemborexant.Methods: This was a Phase 1, double-blind, placebo-controlled, four-period crossover study in 32 healthy adults. Individuals were randomized into one of four treatment sequences to receive single doses of placebo, lemborexant 10 mg (LEM10), alcohol (males, 0.7 g/kg; females, 0.6 g/kg), and LEM10 plus alcohol, each separated by a 14-day washout. Postural stability (body sway) was measured by ataxiameter and a cognitive performance assessment battery evaluated four domains of attention and memory.Results: Pharmacodynamic outcomes were analyzed for the 18 participants who completed all four treatments. Change from baseline in body sway showed no significant differences between lemborexant plus alcohol versus alcohol alone. Compared with alcohol alone, coadministration of lemborexant with alcohol showed additive negative effects on cognitive performance domains, corresponding approximately with peak plasma lemborexant concentrations (median = 1.5 h). Cognitive performance was also impaired with lemborexant alone at 0.5 and 2 h in this experimental paradigm with morning dosing. Alcohol increased plasma lemborexant exposure by 70% based on area under the curve to 72 h, and increased peak plasma lemborexant concentrations by 35%. The most commonly reported treatment-emergent adverse event was somnolence.Conclusion: Coadministration of lemborexant with alcohol showed additive negative effects on cognitive measures, but not on postural stability, compared with alcohol alone. Lemborexant exposure was increased with alcohol. Lemborexant alone or with alcohol was well tolerated. Patients are advised not to consume alcohol with lemborexant. [ABSTRACT FROM AUTHOR]

Objective/background: Evaluate changes in insomnia severity in subjects with moderate to severe insomnia (Insomnia Severity Index [ISI] score ≥15) treated for 12 months nightly with lemborexant.Patients/methods: This phase 3 randomized study comprised two 6-month treatment periods. In Period 1, 949 subjects were randomized to placebo, lemborexant 5 mg (LEM5) or 10 mg (LEM10). In Period 2, placebo subjects were rerandomized to LEM5 or LEM10; subjects initially randomized to lemborexant continued their assigned treatment. Insomnia severity was assessed using baseline ISI and 1-, 3-, 6-, 9-, and 12-month post-treatment scores.Results: Mean ISI scores improved significantly across treatment groups and disease severities, with greater decreases from baseline in the LEM5 and LEM10 versus placebo groups at months 1 (-7.1, -7.2, -5.2, respectively), 3 (-8.6, -8.9, -6.1, respectively), and 6 (-9.9, -9.8, -7.2 respectively); ISI score improvements were maintained with LEM5 and LEM10 at months 9 (-11.1 and -11.2, respectively) and 12 (-11.5 and -11.2, respectively). At months 1, 3, and 6, significantly more treatment responders (≥7-point ISI score decrease from baseline) were observed with LEM5 (44%-57%) and LEM10 (44%-52%) versus placebo (30%-41%). At months 1, 3, and 6, more remitters (ISI total score <10 and < 8) were observed with LEM5 (30%-44% and 22%-34%, respectively) and LEM10 (31%-41% and 22%-31%, respectively) versus placebo (18%-28% and 11%-21%, respectively).Conclusions: Lemborexant significantly reduced insomnia severity for 12 months and increased clinically meaningful response and remission rates versus placebo.Clinical Trial Registration: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39. [ABSTRACT FROM AUTHOR]

Most conventional insomnia medications are gamma‐aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long‐term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta‐analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5‐ and 10‐mg lemborexant were superior to 20‐mg suvorexant because of the greater improvement in initiating sleep after 1‐week administration. Furthermore, 5‐mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5‐mg lemborexant as an initial treatment for insomnia, followed by 10‐mg lemborexant or suvorexant. [ABSTRACT FROM AUTHOR]

Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug‐drug interaction study was conducted. This single‐center, open‐label, fixed‐sequence study examined potential drug‐drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18–44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady‐state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment. [ABSTRACT FROM AUTHOR]

Background: Many patients with Alzheimer's disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia.Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior.Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated.Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour.Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances. [ABSTRACT FROM AUTHOR]

Lemborexant is a dual orexin receptor antagonist approved in the United States, Japan, and Canada for the treatment of insomnia in adults. We report effectiveness and safety outcomes in subjects with insomnia who received up to twelve months of continuous lemborexant treatment in Study E2006-G000-303 (Study 303; SUNRISE-2). Study 303 was a twelve-month, global, multicenter, randomized, double-blind, parallel-group, Phase 3 study divided into two treatment periods. In Treatment Period 1 (first six months), subjects (n = 949, Full Analysis Set) were randomized to daily placebo, lemborexant 5 mg (LEM5) or lemborexant 10 mg (LEM10). In Treatment Period 2 (second six months), placebo subjects were rerandomized to LEM5 or LEM10, and subjects randomized to lemborexant continued their assigned treatment (LEM5, n = 251; LEM10, n = 226). Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored. For all sleep parameters, the significant benefits observed with LEM5 and LEM10 versus placebo over six months were maintained at twelve months in subjects who received twelve continuous months of treatment. There was no evidence of rebound insomnia or withdrawal in either lemborexant group following treatment discontinuation. Over twelve months of lemborexant treatment, most TEAEs were mild/moderate; the most common TEAEs were nasopharyngitis, somnolence and headache. LEM5 and LEM10 had significant benefit on sleep onset and sleep maintenance compared with placebo, and importantly, lemborexant effectiveness persisted at twelve months, suggesting that lemborexant may provide long-term benefits for subjects with insomnia. ClinicalTrials.gov , NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39. • Lemborexant is a recently approved treatment for adults with insomnia. • Over 12 months, lemborexant was effective for all sleep parameters assessed. • Lemborexant may provide long-term benefits for adults with insomnia. [ABSTRACT FROM AUTHOR]

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to 'bridge' pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed Cmax was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies. [ABSTRACT FROM AUTHOR]

The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of zolpidem after administration of a buffered zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non-elderly male and female volunteers. Subjects received a single morning dose of ZST (1.0, 1.75, and 3.5 mg) or placebo in a four-way crossover study. In male and female subjects zolpidem PK were linear, with area under the curve (AUC) proportional to dose, and apparent oral clearance and elimination half-life independent of dose. However, AUC averaged 40% to 50% higher in females than in males receiving the same dose. The gender effect was incompletely explained by body weight. In females, ZST produced PD changes consistent with benzodiazepine agonist effects, particularly at the 3.5-mg dose. For several PD variables, PD effects were significantly related to plasma zolpidem concentrations when data were aggregated across subjects. However, there was variability in response among individuals. In males, PD effects of zolpidem seldom differed from placebo regardless of plasma concentration. The findings confirm that zolpidem clearance is lower in females than in males. PD effects of zolpidem from ZST are greater in female subjects, due to a combination of higher plasma concentrations and greater intrinsic sensitivity. [ABSTRACT FROM AUTHOR]

Objective Evaluate potential gender effects on efficacy and safety of a buffered zolpidem sublingual tablet (ZST) formulation. Methods Post hoc analysis of the pivotal sleep laboratory and outpatient studies, per gender. Results In the sleep laboratory study, polysomnography-derived latency to persistent sleep after middle-of-the-night was significantly improved for both genders at both 1.75 mg and 3.5 mg ZST (females: 15.7 and 8.6 min, respectively, vs. 27.7 min [placebo]; males: 19.0 and 12.7 min vs. 29.0 min [placebo]) with no significant gender differences. In the outpatient study, subjective sleep onset latency after middle-of-the-night was significantly shorter for both genders treated with ZST 3.5 mg versus placebo over the 4-week average (females: 37.3 vs. 59.4 min, p < 0.0001; males: 38.6 vs. 55.1 min, p ≤ 0.01). There were no gender differences in subjective sleep onset latency after middle-of-the-night awakening. In the outpatient study, weekly usage of ZST and placebo by both genders declined throughout the study. Morning alertness following dosing nights improved in both genders, although significant only in females. In both studies, there were no gender differences in adverse events. Conclusion(s) Time to return to sleep after middle-of-the-night dosing with ZST improved in both genders, with no gender differences in efficacy and safety. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: A zolpidem sublingual tablet (ZST) formulation was recently approved by the US Food and Drug Administration to treat middle-of-the-night (MOTN) awakening with difficulty returning to sleep. Objective: The aim of this study was to compare the zolpidem pharmacokinetic profiles of 3.5-mg ZST and 10-mg immediate-release (IR) oral zolpidem in healthy female and male adults. Methods: This randomized, open-label crossover study compared the pharmacokinetic profile of ZST with that of IR oral zolpidem in healthy adults. Results: The study enrolled 19 males and 14 females. After 3.5-mg ZST and 10-mg IR, respectively, mean zolpidem plasma concentrations at 15 minutes (22 vs 17 ng/mL, respectively, in females and 18 vs 10 ng/mL in males) and AUCs from zero to 15 minutes (2.3 vs 0.8 ng · h/mL in females and 1.6 vs 0.5 ng · h/mL in males) were substantially greater for ZST, despite the larger absolute IR dose. After 3.5-mg ZST and 10-mg IR, respectively, clearance was lower in females, even after correcting for body weight (2.63 vs 2.88 mL/min/kg in females and 3.63 vs 3.91 mL/min/kg in males). The lag time prior to the start of first-order absorption was notably shorter for ZST than IR in both males (8 vs 21 minutes) and females (5 vs 22 minutes). Both zolpidem formulations were generally well tolerated by both genders. Conclusions: Systemic exposure of zolpidem was higher in females for both formulations. Plasma levels and AUC were higher, and clearance was lower, in females with both zolpidem formulations. The initial rate of absorption was faster, and initial systemic exposure was greater, with ZST compared with oral IR. [ABSTRACT FROM AUTHOR]

Background: Currently approved Alzheimer''s disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor. Objective: The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD. Methods: This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for ≥12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician''s Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatmentemergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements. Results: The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0–138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Δ in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Δ in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs −1.5 [0.88], respectively [P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication. Conclusions: In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205. [Copyright &y& Elsevier]

Lemborexant is a dual orexin receptor antagonist (DORA) approved in multiple countries including the United States, Japan, Canada and Australia for the treatment of adults with insomnia. As required for marketing approval of new compounds with central nervous system activity with sedating effects, the abuse potential of lemborexant was assessed in accordance with regulatory guidelines, which included three nonclinical studies. These assessments comprised physical dependence and drug discrimination studies in rats and a self-administration study in rhesus monkeys. There was no evidence of withdrawal signs following abrupt drug discontinuation, indicating that lemborexant does not induce physical dependence. In the drug discrimination study, lemborexant at doses up to 1000 mg/kg administered orally did not cross-generalize to the zolpidem training stimulus, although another DORA included in the same experiment, suvorexant, showed partial generalization with zolpidem. In rhesus monkeys, lemborexant treatment did not induce any gross behavioral changes, and there was no increase in self-administration rates compared with control, indicative of a lack of reinforcing effects of lemborexant. Collectively, these nonclinical studies support the position that lemborexant, which has been placed in Schedule IV by the United States Drug Enforcement Administration, has a low risk of abuse in humans. • The abuse potential of lemborexant was assessed in three nonclinical studies. • Lemborexant did not have a reinforcing effect or produce physical dependence. • Lemborexant did not cross-generalize to zolpidem in a drug discrimination study. • Lemborexant was negative in all nonclinical studies evaluating abuse potential. [ABSTRACT FROM AUTHOR]

Summary: Background: Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimer''s disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASIL''s early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL. Methods: 168 patients with CADASIL (mean age 54·8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10–27 or a trail making test (TMT) B time score at least 1·5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948. Findings: 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was −0·81 (SE 0·59) in the placebo group and −0·85 (SE 0·57) in the donepezil group (p=0·956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0·023), TMT A time (p=0·015), and EXIT25 (p=0·022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients. Interpretation: Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment. Funding: Eisai Medical Research (Ridgefield Park, NJ, USA). [Copyright &y& Elsevier]

Background: Cholinergic deficits might contribute to vascular cognitive impairment. Trials of cholinesterase inhibitors in patients with vascular dementia are difficult because of heterogeneous disease mechanisms and overlap between vascular and Alzheimer's disease (AD) pathology in the age-group recruited. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a genetic form of subcortical ischaemic vascular dementia. It represents a homogeneous disease process, and because of CADASIL's early onset, comorbid AD pathology is rare. We did a multicentre, 18-week, placebo-controlled, double-blind, randomised parallel-group trial to determine whether the cholinesterase inhibitor donepezil improves cognition in patients with CADASIL.Methods: 168 patients with CADASIL (mean age 54.8 years) were assigned to 10 mg donepezil per day (n=86) or placebo (n=82) by a computer-generated randomisation protocol. Inclusion criteria included a mini-mental state examination (MMSE) score of 10-27 or a trail making test (TMT) B time score at least 1.5 SD below the mean, after adjustment for age and education. The primary endpoint was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Secondary endpoints included scores on the ADAS-cog, MMSE, TMT A time and B time, Stroop, executive interview-25 (EXIT25), CLOX, disability assessment for dementia, and sum of boxes of the clinical dementia rating scale. Analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00103948.Findings: 161 patients were analysed. There was no significant difference between donepezil (n=84) and placebo (n=77) in the primary endpoint. The least-squares mean change from baseline score was -0.81 (SE 0.59) in the placebo group and -0.85 (SE 0.57) in the donepezil group (p=0.956). There was a significant treatment effect favouring donepezil on the following secondary outcomes: TMT B time (p=0.023), TMT A time (p=0.015), and EXIT25 (p=0.022). Ten donepezil-treated patients discontinued treatment due to adverse events compared to seven placebo-treated patients.Interpretation: Donepezil had no effect on the primary endpoint, the V-ADAS-cog score in CADASIL patients with cognitive impairment. Improvements were noted on several measures of executive function, but the clinical relevance of these findings is not clear. Our findings may have implications for future trial design in subcortical vascular cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: 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., Methods: 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., Results: Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. 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 ≥ 65 years., Conclusions: LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia., Trial Registration Numbers and Dates of Registration: 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., (© 2024. The Author(s).)

Background: When considering changing hypnotic pharmacotherapy, lemborexant has attracted attention as a candidate due to its effectiveness and safety profile. However, few studies have investigated switching patterns in clinical practice., Research Design and Methods: We conducted a retrospective cohort study using a nationwide claims database. Patients prescribed a single hypnotic who either subsequently switched to (switching cohort) or were additionally prescribed (add-on cohort) lemborexant between July 2020 and December 2021 were identified. Proportion of successful switching was defined as remaining on lemborexant alone or without any hypnotic at 6 months after lemborexant initiation., Results: The success proportion was 70.1% in the switching cohort ( n  = 4,861) and 38.6% in the add-on cohort ( n  = 9,423). In the add-on cohort, the success proportion was lower in patients with a hypnotic history of ≥180 days (31.4%) and in patients whose prescribed hypnotic was a benzodiazepine or non-benzodiazepine (31.5% and 37.6%, respectively)., Conclusion: The proportion of successful switching was higher in patients who switched to lemborexant than in those who added lemborexant as a concomitant treatment. The lower success proportion in the add-on cohort might be related to clinically more severe insomnia, and/or a concomitant prescription of benzodiazepine or non-benzodiazepine, from which discontinuation may be challenging.

Background: Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5 mg (LEM5) and 10 mg (LEM10) in the subgroup age ≥ 65 years with insomnia., Method: Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18 years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression-Insomnia [PGI-I] questionnaire), and safety were also evaluated., Results: In this subgroup of older adults (≥ 65 years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event., Conclusions: Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65 years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated., Clinical Trials Registration: ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016)., (© 2024. The Author(s).)

Background: The Insomnia Severity Index (ISI) is a widely used measure of insomnia severity. Various ISI research findings suggest different factor solutions and meaningful within-individual change (MWIC) to detect treatment response in patients with insomnia. This study examined an ISI factor solution and psychometric indices to define MWIC in a robust patient sample from clinical trial settings., Methods: We endeavored to improve upon previous validation of ISI by examining structural components of confirmatory factor analysis (CFA) models using two large, placebo-controlled clinical trials of lemborexant for insomnia. Using the best-fitting two-factor solution, we evaluated anchor-based, distribution-based and receiver operating characteristic (ROC) curve methods to derive an estimate of the MWIC., Results: The model structure for the 7-item scale proposed in other research did not fit the observed data from our two lemborexant clinical trials (N = 1956) as well as a two-factor solution based on 6 items did. Using triangulation of anchor-based, distribution-based, and ROC methods, we determined that a 5-point reduction using 6 items best represented a clinically meaningful improvement in individuals with insomnia in our patient sample., Conclusions: A 6-item two-factor scale had better psychometric properties than the 7-item scale in this patient sample. On the 6-item scale, a reduction of 5 points in the ISI total score represented the MWIC. Generalizability of the proposed MWIC may be limited to patient populations with similar demographic and clinical characteristics., (© 2024. The Author(s).)

Study Objectives: To evaluate the respiratory safety of lemborexant among adults and older adults with moderate to severe obstructive sleep apnea (OSA)., Methods: E2006-A001-113 (Study 113; NCT04647383) was a double-blind, two-period crossover, placebo-controlled study in adults (ages ≥ 45 to ≤ 90 years, n = 33) with moderate (apnea-hypopnea index [AHI] score ≥ 15 to < 30 events/h, n = 13) or severe (AHI ≥ 30 events/h, n = 20) OSA. Participants were randomized to lemborexant 10 mg (LEM10) or placebo (PBO) for two treatment periods of 8 nights with a ≥ 14-day washout period. AHI and peripheral oxygen saturation were evaluated after treatment on Day 1 (after a single dose) and Day 8 (after multiple doses)., Results: No significant differences in AHI were observed after single and multiple doses of LEM10 compared with PBO in participants with moderate to severe OSA (least-squares mean: single-dose LEM10, 41.7; PBO, 44.8; multiple-dose LEM10, 44.9; PBO, 45.7). In addition, there were no significant differences between treatments in peripheral oxygen saturation (least-squares mean: single-dose LEM10, 93.0; PBO, 93.1; multiple-dose LEM10, 93.1; PBO, 93.4). Further, there were no significant differences between treatments in percentage of total sleep time with peripheral oxygen saturation < 90%, < 85%, or < 80%. No significant differences were observed between treatments when AHI and peripheral oxygen saturation outcomes were analyzed by OSA severity. Altogether, 6/33 (18.2%) participants receiving LEM10, vs 3/33 (9.1%) PBO, reported treatment-emergent adverse events, mostly mild in severity., Conclusions: LEM10 demonstrated respiratory safety and was well tolerated with single-dose and multiple-dose administration in participants with moderate to severe OSA. This suggests that LEM may be a treatment option for patients with OSA and comorbid insomnia., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: A Study to Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Participants With Moderate to Severe Obstructive Sleep Apnea and in Adult and Elderly Participants With Moderate to Severe Chronic Obstructive Pulmonary Disease; URL: https://clinicaltrials.gov/ct2/show/NCT04647383; Identifier: NCT04647383., Citation: Cheng JY, Lorch D, Lowe AD, et al. A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea. J Clin Sleep Med . 2024;20(1):57-65., (© 2024 American Academy of Sleep Medicine.)

Objective: Few 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)., Methods: This 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., Results: Most 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., Conclusions: Most subjects transitioned successfully to LEM from ZOL (intermittent or frequent use). LEM was well tolerated., Competing Interests: J. Kelly is an employee of Clinilabs Drug Development Corporation and M. Ahmad was an employee of Clinilabs Drug Development Corporation at the time of the study. Clinilabs Drug Development Corporation received grants from Eisai Inc. during the conduct of the study. C.B. Montano is an employee of CT Clinical Research, D. Kumar, C. Perdomo and M. Moline are employees of Eisai Inc. M. Malhotra and J. Amchin were employees of Eisai Inc. at the time of the study. This study was sponsored by Eisai Inc., manufacturer/licensee of LEM. Eisai Inc. was involved in the study design, data collection, data analysis, and preparation of the manuscript., (© 2024 The Authors.)

Objective: Insomnia is common in midlife women. The efficacy and safety of lemborexant (LEM), a competitive dual orexin receptor antagonist, was assessed for 12 months in a subgroup of midlife women (age, 40-58 y) from Study E2006-G000-303 (Study 303; SUNRISE-2)., Methods: This was a randomized, double-blind, placebo (PBO)-controlled (first 6 mo) study of adults with insomnia disorder ( N = 949). During treatment period 1 (TP1), participants received PBO or LEM 5 mg (LEM5) or 10 mg (LEM10). During TP2 (second 6 mo), LEM participants continued their assigned dose; PBO participants were rerandomized to LEM5 or LEM10. Assessments included patient-reported sleep- and fatigue-related measures and treatment-emergent adverse events., Results: The midlife female subgroup comprised 280 of 949 participants (TP1: PBO, n = 90 of 318 [28.3%]; LEM5, n = 82 of 316 [25.9%]; LEM10, n = 108 of 315 [34.3%]). At 6 months, median changes from baseline in subjective sleep-onset latency (in minutes) were -17.9, -20.7, and - 30.4 for PBO, LEM5, and LEM10 (vs PBO: LEM5, P = not significant; LEM10, P = 0.0310). At 6 months, mean changes from baseline in subjective wake after sleep onset (in minutes) were -37.0 (59.6), -50.1 (74.5), and -54.5 (65.4) for PBO, LEM5, and LEM10 (vs PBO: LEM5 and LEM10, P = not significant), with benefits sustained through 12 months. Greater decreases from baseline (improvement) in Insomnia Severity Index total score and Fatigue Severity Scale total score were seen with LEM versus PBO at 6 months; benefits continued through 12 months. Most treatment-emergent adverse events were mild to moderate in severity., Conclusions: Consistent with the total population, subjective sleep parameters improved, and improvement was sustained over time in midlife women. LEM was well tolerated, suggesting that LEM may be a potential treatment option for midlife women with insomnia., Competing Interests: Financial disclosure/conflicts of interest: M.T. has no conflicts of interest. J.Y.C., M.Mol., and E.P. are employees of Eisai Inc. M.Mal. is a former employee of Eisai Inc. J.Y. and K.P. are employees of Eisai Ltd. K.I. and M.N. are employees of Eisai Co, Ltd., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Discontinuing long-term pharmacotherapy for insomnia can result in rebound insomnia or withdrawal symptoms and suboptimal treatment. Post hoc analyses evaluated rebound insomnia and withdrawal symptoms among the subset of subjects from a phase III, 12-month, global, multicenter, randomized, double-blind, parallel-group study who completed 12 or 6 months of active treatment and follow-up period. Study E2006-G000-303 (Study 303) included adults (N = 655) with subjective sleep-onset latency ≥30 min and/or subjective wake-after-sleep onset ≥60 min at least three times weekly during the 4 weeks before enrollment. Subjects were randomized 1:1:1 to lemborexant 5 mg (LEM5) or 10 mg (LEM10) or placebo for 6 months. Thereafter, for an additional 6 months, LEM5- and LEM10-treated subjects continued lemborexant and the placebo group was rerandomized 1:1 to LEM5 or LEM10. Month 12 was followed by abrupt discontinuation and a 2-week end-of-study follow-up. Using daily electronic sleep diaries, patients reported (subjective) sleep end points (sleep-onset latency, wake-after-sleep onset, sleep efficiency, and total sleep time). Withdrawal symptoms were assessed using the Tyrer Benzodiazepine Withdrawal Symptoms Questionnaire (T-BWSQ). Sleep outcome improvements with lemborexant at month 12 were generally maintained throughout the 2-week off-treatment period wherein <20% of subjects experienced significant worsening of insomnia symptoms versus screening. There was no evidence of withdrawal symptoms by T-BWSQ following lemborexant discontinuation. This analysis demonstrates rebound insomnia is unlikely to occur with lemborexant, and its effectiveness is maintained after abrupt discontinuation without placebo replacement following 6-12 months of treatment., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This report describes polysomnography and sleep diary exposure-response analyses from Study E2006-G000-304 (Study 304), a 1-month trial of 5- or 10-mg lemborexant, zolpidem, or placebo; and Study E2006-G000-303 (Study 303), a 6-month trial of 5- or 10-mg lemborexant or placebo. Studies 304 and 303 included 1006 (86%) and 956 (68%) (female) participants, respectively; >40% were ≥65 years, with individual lemborexant exposures derived from a previously described pharmacokinetic model. Linear mixed-effects analyses of polysomnography: latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) quantified the change from baseline given lemborexant exposure, time, and covariates, guided by consensus recommendations regarding clinical significance. A small impact of sex, body weight, and race was predicted for LPS and SE, irrespective of treatment. Effect of age on LPS was small; baseline SE was estimated to be 8% higher for a 50-year-old versus an 80-year-old, decreasing to 6% by 1 month. Baseline WASO was 13 minutes longer for Black versus White subjects, corresponding to a 5-minute lower change from baseline at the end of the study. For subjective end points, the statistically significant covariate effects for age, sex, and race were not deemed therapeutically relevant, likely reflecting physiologic sleep pattern changes across age and study subgroups. Both polysomnography and subjective analyses indicated clinically meaningful differences from baseline for both lemborexant treatments, with effects being greater for 10-mg versus 5-mg lemborexant, while indicating that covariate-specific lemborexant dose adjustments are not warranted., (© 2022, The American College of Clinical Pharmacology.)

Rationale: Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health., Objectives: This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act., Results: LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks., Conclusions: LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling., (© 2023. The Author(s).)

Study Objectives: Patients with chronic insomnia may respond differently to therapeutic modalities. This study examined differences in response of individuals with 2 insomnia phenotypes-short sleep duration (I-SSD; < 6 hours) and normal sleep duration (I-NSD; ≥ 6 hours) determined by polysomnography-to treatment with lemborexant and zolpidem tartrate extended-release 6.25 mg (zolpidem ER), compared with placebo., Methods: Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729) was a global, randomized, double-blind, placebo, and active comparator-controlled, parallel-group study comparing lemborexant 5 and 10 mg in individuals aged ≥ 55 years with insomnia disorder. In this analysis, changes in subjective (self-reported) variables based on sleep diaries and objective variables based on polysomnographs were assessed after 1-month administration of study drugs. Data from participants with I-SSD and I-NSD were compared., Results: In the I-SSD subgroup, both lemborexant doses provided significant benefit for sleep-onset latency (SOL), total sleep time (TST), and wake after sleep onset (WASO) vs placebo; zolpidem ER also provided significant benefit for TST and WASO, but not SOL, on both measures vs placebo. In the I-NSD subgroup, lemborexant and zolpidem ER provided significant benefit for TST and WASO vs placebo objectively but not subjectively; both doses of lemborexant provided significant benefit for SOL vs placebo subjectively, but not objectively., Conclusions: Both drugs, but lemborexant more consistently, showed subjective and objective benefits compared with placebo in participants with insomnia with objective short sleep duration. However, neither lemborexant nor zolpidem provided consistent benefits for participants with normal sleep duration on sleep-onset and sleep maintenance variables., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1); URL: https://clinicaltrials.gov/ct2/show/record/NCT02783729; Identifier: NCT02783729., Citation: Inoue Y, Nishida M, Kubota N, et al. Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings. J Clin Sleep Med . 2023;19(3):519-528., (© 2023 American Academy of Sleep Medicine.)

Background: Lemborexant (LEM) is a dual orexin receptor antagonist approved for the treatment of insomnia in adults in multiple countries including the the United States, Japan, Canada, Australia and several Asian countries., Procedures: This was a randomized, single-dose, single-center, double-blind, active-control, 6-way crossover study to evaluate LEM abuse potential. The study assessed oral doses of LEM 10 mg (LEM10), 20 mg (LEM20), and 30 mg (LEM30) compared with placebo (PBO), zolpidem (ZOL) immediate release 30 mg, and suvorexant (SUV) 40 mg. Subjects were healthy, nondependent, recreational sedative users able to discriminate/like the effects of both SUV and ZOL from PBO during a qualification phase., Results: Abuse potential endpoints were analyzed in qualified subjects who received and completed all treatments (n = 32). On the "at this moment" drug-liking visual analog scale (VAS), mean maximum (peak) effect (primary endpoint) values were 78.4, 80.5, and 83.6 for LEM10, LEM20, and LEM30, respectively, which were all significantly greater than PBO (57.8; all P > 0.05) but not different from SUV (76.1) or ZOL (78.3). Similarly, for secondary endpoints overall drug-liking VAS and take-drug-again VAS, mean maximum (peak) effect values for all LEM doses were significantly greater than PBO ( P > 0.05) but not different compared with ZOL or SUV., Conclusions: For all doses, LEM demonstrated abuse potential versus PBO and appeared to have a similar abuse potential profile to ZOL and SUV in this study population. Lemborexant was well tolerated. Lemborexant has been placed in Schedule IV, the same drug schedule as ZOL and SUV., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose/background: As part of a human abuse potential (HAP) study of lemborexant (LEM), the effects of therapeutic (LEM 10 mg), and supratherapeutic doses of LEM 20 mg and LEM 30 mg on cognition and psychomotor performance were compared with placebo (PBO) and supratherapeutic doses of zolpidem (ZOL) 30 mg and suvorexant (SUV) 40 mg. Subjects (n = 32) were healthy, nondependent, recreational sedative users able to discriminate the effects of both SUV and ZOL from PBO on subjective drug measures., Methods/procedures: The human abuse potential study was a single-dose, randomized, double-blind, PBO-controlled, 6-way crossover study. Eligible subjects admitted to the treatment phase completed the choice reaction test (CRT) and divided attention test. The CRT included measurements of recognition reaction time (RRT) and motor reaction time., Findings/results: Recognition reaction time and mean maximum change from baseline (CFB max ) scores were significantly increased (slower performance) versus PBO for all LEM doses (all P < 0.001), ZOL ( P < 0.001), and SUV ( P = 0.004), and LEM (all doses) was not statistically different from ZOL or SUV. Motor reaction time and mean CFB max versus PBO were significantly increased for all LEM doses (all P < 0.001), and ZOL ( P < 0.001) and SUV ( P < 0.001). All LEM doses showed significantly decreased (better performance) mean CFB max versus ZOL (all P < 0.001), but not SUV. Notably, all cognitive effects in the CRT and divided attention test were limited to the main treatment phase (up to 8 hours postdose)., Implications/conclusions: All active doses of LEM, ZOL, and SUV generally increased reaction time and reduced divided attention capabilities versus PBO. However, at therapeutic/supratherapeutic doses, LEM led to significantly less cognitive impairment than supratherapeutic doses of ZOL in some measures., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Fatigue is a common symptom in patients with insomnia. This analysis evaluated whether treatment of nighttime symptoms of insomnia with a dual orexin receptor antagonist, lemborexant, might also reduce fatigue., Methods: Analyses were conducted of two phase 3 studies of subjects with insomnia disorder. Subjects received placebo, lemborexant 5 mg, or lemborexant 10 mg in the 12-month (6 months placebo-controlled) Study E2006-G000-303 (Study 303: SUNRISE-2) of adults (N = 949; full analysis set [FAS]), and the 1-month, placebo- and active-controlled Study E2006-G000-304 (Study 304; SUNRISE-1) of older adults (females ≥55 years, males ≥65 years) (N = 1006; FAS). Fatigue was assessed using the Fatigue Severity Scale (FSS). Patient-reported sleep onset and maintenance endpoints were analyzed using data from electronic sleep diaries., Results: Lemborexant significantly reduced subject-reported fatigue versus placebo over a 6-month treatment period (FSS total score least-squares mean treatment difference of -2.50 for 5 mg and -2.56 for 10 mg of lemborexant; p < 0.05 for both). This reduction was sustained over 12 months of lemborexant in both the overall population and in subjects with clinically meaningful fatigue (FSS total score ≥36) at baseline. Improvements in fatigue over time positively correlated with improvements in sleep onset and maintenance parameters. Improvements in sleep quality were evident as early as 1 week after lemborexant treatment, whereas longer-term treatment (>1 month) may be needed for improvements in insomnia-related fatigue., Conclusions: In addition to improving sleep onset and sleep maintenance in subjects with insomnia disorder, lemborexant provides further benefit by reducing daytime fatigue., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02952820 and https://clinicaltrials.gov/ct2/show/NCT02783729., Abbreviations: DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ; FSS = Fatigue Severity Scale; ICSD-3 = International Classification of Sleep Disorders, Third Edition ; LSM = least squares mean; sSE = subjective sleep efficiency; sSOL = subjective sleep onset latency; sTST = subjective total sleep time; sWASO = subjective sleep after wake onset.

Study Objectives: Lemborexant (LEM) is a dual orexin receptor antagonist approved for treating adults with insomnia. We analyzed the efficacy (subjective sleep outcomes) and safety of LEM over 12 months in the subgroup of Asian subjects from Study E2006-G000-303 (Study 303)., Methods: Study 303 was a 12-month, randomized, placebo-controlled (first 6 months), double-blind, parallel-group, phase 3 study of adults with insomnia disorder. During the 6-month Period 1, subjects were randomized (1:1:1) to placebo, LEM 5 mg (LEM5), or LEM 10 mg (LEM10); LEM subjects continued treatment in the following 6-month Period 2. Outcome measures included subject-reported (subjective) sleep onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), total sleep time (sTST), Insomnia Severity Index (ISI), and Patient Global Impression-Insomnia version (PGI-I). Treatment-emergent adverse events (TEAEs) were assessed., Results: Overall, 178 Asian subjects (Japanese, n  = 161; Chinese, n  = 4; other Asian, n  = 13) were included. Greater decreases in sSOL and sWASO and increases in sSE and sTST from baseline were observed with LEM vs placebo at 6 months; LEM benefits were sustained through 12 months. Greater decreases in ISI total score were seen with LEM vs placebo at 6 months; improvements from baseline with LEM continued through 12 months. For each PGI-I item, LEM-treated subjects had more positive medication effects than placebo-treated subjects at 6 months; these effects were maintained with LEM in Period 2. TEAEs were generally mild to moderate., Conclusions: LEM improved subjective sleep parameters and was well-tolerated in Asian subjects with insomnia disorder over 12 months., Clinical Trial Registration: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39., Competing Interests: Financial disclosure: AD is an employee of Eisai Singapore Pte Ltd. KP and JY are employees of Eisai Ltd. YI has received grants and/or personal fees from Eisai Inc., Eisai Ltd., Merck Sharp & Dohme, and Takeda in relation to the submitted work; has received grants or personal fees from Alfresa Pharma, Philips, and Koike Medical; and has received funding for clinical trials from Astellas and Janssen outside of the submitted work. KH has received grants/personal fees and consultant/speaker fees from Eisai Inc.; has received funding for clinical trials from Eisai Inc.; and has received personal fees from and Eisai Ltd., and Merck Sharp & Dohme. SCL has received grants/personal fees from Eisai Inc. CHY has no conflict of interests relevant to this study. THL and CLH have received funding for clinical trials from Eisai Inc. and have no conflicts of interests relevant to this study. NK is an employee of Eisai Co., Ltd. MM is an employee of Eisai Inc.; she has been issued a patent and has pending and planned patents broadly related to this work. Nonfinancial disclosure: None. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: https://doi.org/10.1016/j.sleepx.2022.100044., (© 2022 The Authors.)

Study Objectives: Changes to sleep architecture that occur as a result of the normal aging process may also exacerbate insomnia in older individuals. Therefore, this study assessed the impact of lemborexant compared with placebo and zolpidem tartrate extended release on objective sleep architecture parameters, as measured by polysomnography, in older adults (ages ≥ 55 years) with insomnia disorder from a phase 3 study., Methods: Study E2006-G000-304 (SUNRISE 1; NCT02783729) was a global, multicenter, randomized, double-blind, placebo-controlled, active comparator (zolpidem)-controlled, parallel-group study comparing 2 dose levels of lemborexant (5 mg and 10 mg). Sleep architecture was measured using polysomnography. Assessments were collected at baseline during a single-blind placebo run-in and during the first 2 nights and last 2 nights of treatment. Mean values for each sleep stage were based on the 2 consecutive polysomnograms., Results: Treatment with lemborexant resulted in significantly greater increases from baseline in total sleep time compared with both placebo and zolpidem. Significant increases from baseline in rapid eye movement sleep and significant decreases from baseline in latency to rapid eye movement sleep were also observed with lemborexant compared with placebo and zolpidem., Conclusions: These findings suggest that treatment with lemborexant may address some of the alterations in sleep architecture normally observed in older individuals with insomnia., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1); URL: https://clinicaltrials.gov/ct2/show/NCT02783729; Identifier: NCT02783729., (© 2021 American Academy of Sleep Medicine.)

Study Objective: Whether there are racial differences in the efficacy/safety of hypnotics has not been sufficiently investigated. We aimed to evaluate the efficacy/safety of lemborexant 5 mg and lemborexant 10 mg vs placebo once daily in a subset of Japanese patients with insomnia and to compare the results with those of non-Japanese patients., Methods: This subanalysis reports the results of the first 6 months (period 1, placebo-controlled) of SUNRISE 2, a 12-month, global, randomized, double-blind, phase 3 study. Changes in patient-reported sleep onset latency, patient-reported sleep efficiency, and patient-reported wake after sleep onset with lemborexant 5 mg or lemborexant 10 mg vs placebo were evaluated. Treatment-emergent adverse events were evaluated for safety., Results: In total, 949 patients were randomized (Japanese, n = 161; non-Japanese, n = 788). Groups were balanced at baseline except for the male/female ratio (P = .0002) and body mass index (P < .0001) in the Japanese vs non-Japanese subgroups. Overall, the efficacy and safety of lemborexant were similar between subgroups. In the Japanese subgroup, the subjective sleep onset latency change from baseline was significant after 7 nights and 6 months with lemborexant 10 mg vs placebo, the subjective sleep efficiency change from baseline was significant after 7 nights with lemborexant 10 mg vs placebo, and the subjective wake after sleep onset change from baseline was significant at 6 months with lemborexant 5 mg vs placebo. The incidence and severity of treatment-emergent adverse events were consistent between both subgroups., Conclusions: Lemborexant 5 mg and 10 mg improved sleep onset and sleep maintenance over 6 months and was well-tolerated in both the Japanese and non-Japanese patients. The safety profiles of lemborexant 5 mg and 10 mg were consistent between the subgroups., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Long-term Study of Lemborexant in Insomnia Disorder (SUNRISE 2); URL: https://clinicaltrials.gov/ct2/show/NCT02952820; Identifier: NCT02952820; and Registry: ClinicalTrialsRegister.eu; Identifier: 2015-001463-39., (© 2021 American Academy of Sleep Medicine.)

Background and Objective: Lemborexant is a dual orexin receptor antagonist recently approved in the USA, Japan, and Canada for the treatment of adults with insomnia. Because some pharmacotherapy for insomnia causes respiratory depression, this study assessed the effects of lemborexant treatment on respiratory safety parameters., Methods: This single-dose, randomized, double-blind, placebo-controlled, three-period crossover study enrolled healthy adult and elderly subjects (n = 17). Subjects were randomized to one of three treatment sequences, each consisting of three treatment periods in which they received a single dose of placebo, lemborexant 10 mg, or lemborexant 25 mg. Each treatment period was separated by a washout period of at least 14 days. Assessments included pharmacodynamic respiratory parameters (peripheral capillary oxygen saturation (SpO 2 ) and apnea-hypopnea index (AHI)) and safety., Results: There were no significant differences for either dose of lemborexant versus placebo in mean peripheral capillary oxygen saturation (SpO 2 ; least squares mean (LSM) difference (95% confidence interval (CI)): lemborexant 10 mg, -0.36 (-0.78 to 0.07); lemborexant 25 mg, - 0.29 (- 0.72 to 0.14)) or AHI (LSM difference (95% CI): lemborexant 10 mg, 0.52 (- 1.72 to 2.76); lemborexant 25 mg, - 1.16 (- 3.40 to 1.08)) during sleep. Additionally, significant differences were not observed for the percentage of total sleep during which SpO 2 was < 85% (LSM difference (95% CI): lemborexant 10 mg, 0.004 (- 0.058 to 0.067); lemborexant 25 mg, 0.044 (- 0.018 to 0.107)) or < 80% (LSM difference (95% CI): lemborexant 10 mg, 0.001 (- 0.002 to 0.005); lemborexant 25 mg, 0.002 (-0.001 to 0.006)) for either lemborexant dose versus placebo. There was also no significant difference for lemborexant 10 mg versus placebo, for which SpO 2 was < 90% during total sleep time (LSM difference (95% CI): 0.185 (- 0.034 to 0.405))., Conclusion: Overall, lemborexant at recommended doses did not have a negative effect on mean SpO 2 or AHI and was well tolerated in this cohort of healthy subjects.

Disturbed sleep is one of the most common complaints following traumatic brain injury (TBI) and worsens morbidity and long-term sequelae. Further, sleep and TBI share neurophysiologic underpinnings with direct relevance to recovery from TBI. As such, disturbed sleep and clinical sleep disorders represent modifiable treatment targets to improve outcomes in TBI. This paper presents key findings from a national working group on sleep and TBI, with a specific focus on the testing and development of sleep-related therapeutic interventions for mild TBI (mTBI). First, mTBI and sleep physiology are briefly reviewed. Next, essential empirical and clinical questions and knowledge gaps are addressed. Finally, actionable recommendations are offered to guide active and efficient collaboration between academic, industry, and governmental stakeholders.

Study Objectives: Middle-of-the-night (MOTN) awakenings with difficulty returning to sleep are among the most common symptoms of insomnia. Despite the epidemiological studies that have been conducted, there is a lack of data on the impact of MOTN awakenings on health status and socioeconomic indicators in comparison with other insomnia symptoms., Methods: Data were analyzed from the 2011 US National Health and Wellness Survey (adults ≥18 years old; N=60,783), which asked respondents whether they had experienced specific symptoms of insomnia (ie, MOTN awakenings, difficulty falling asleep, waking several times, waking up too early, or poor quality of sleep). Respondents who reported only one insomnia symptom were compared among insomnia subgroups and with no insomnia symptom controls with respect to demographics, health history, and health outcomes (Short Form-12v2, Work Productivity and Activity Impairment questionnaire, and costs). Additional analyses compared respondents with only MOTN awakenings and matched controls on health outcomes., Results: MOTN awakenings without other insomnia symptoms were reported by 3.5% of respondents. Poor quality of sleep was associated with the strongest effects on health status compared with other insomnia symptoms even after adjusting for demographic and health characteristics differences. Differences across insomnia symptoms with respect to cost-related outcomes were generally modest, though all were higher (if not significantly so) than respondents without insomnia. Respondents who experienced only waking several times and only MOTN awakenings had the highest direct costs, while respondents who experienced only poor quality of sleep and only difficulty falling asleep had the highest indirect costs. Respondents with only MOTN awakenings reported significantly worse mental and physical health status and worse health utilities relative to insomnia-free matched controls (all P<0.05). Annual per-employee indirect costs were also significantly higher ($4,328 vs $3,000; P<0.05). Among only MOTN awakenings respondents, 74.6% were considered only symptomatic (ie, they did not report having insomnia or having been diagnosed with insomnia)., Conclusion: These findings collectively highlight the prevalence and socioeconomic impact of specific types of insomnia symptoms, including MOTN awakenings, experienced by adults in the US.

Study Objectives: To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings., Design: Multicenter randomized, double-blind, placebo-controlled, parallel-group., Setting: Outpatient., Patients: There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening)., Interventions: After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures., Results: ZST significantly (P < 0.0001) decreased latency to sleep onset over 4 wk (baseline 68.1 min; ZST 38.2 min) compared with placebo (baseline 69.4 min; placebo 56.4 min). Ratings of morning sleepiness/alertness significantly (P = 0.0041) favored the ZST group on nights medication was taken but not on other nights. Participants in the ZST group took the study drug on 62% of nights during the 4 wk; members of the placebo group took study medication on 64% of nights. Adverse events were generally mild and at the same rate (19.3% of participants) in both groups. There were no treatment-related serious adverse events (SAEs), and one adverse event-related study discontinuation from the placebo group. Dosing/week did not increase across the study., Conclusions: 3.5 mg ZST used as needed significantly reduced latency to return to sleep in comparison with placebo in these patients with insomnia. Sleep quality was improved, and morning sleepiness/alertness scores also improved. ZST was well tolerated. These data demonstrate the utility of a sleep-promoting agent when used as needed in the MOTN., Clinical Trials Registration: NCT00466193: "A Study of Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http://www.clinicaltrials.gov/ct2/show/NCT00466193?spons=%22Transcept+Pharmaceuticals%22&spons&#95;ex=Y&rank=2

Background: Recent pathological studies report vascular pathology in clinically diagnosed Alzheimer's disease (AD) and AD pathology in clinically diagnosed vascular dementia (VaD). We compared magnetic resonance imaging (MRI) measures of vascular brain injury (white matter hyperintensities [WMH] and infarcts) with neurodegenerative measures (medial-temporal atrophy [MTA] and cerebral atrophy [CA]) in clinically diagnosed subjects with either AD or VaD. We then examined relationships among these measures within and between the two groups and their relationship to mental status., Methods: Semi-quantitative MRI measures were derived from blind ratings of MRI scans obtained from participants in a research clinical trial of VaD (N = 694) and a genetic epidemiological study of AD (N = 655)., Results: CA was similar in the two groups, but differences in the mean of MTA and WMH were pronounced. Infarcts were significantly associated with CA in VaD but not in AD; MTA and WMH were associated with CA in both. WMH was associated with MTA in both groups; however, MRI infarcts were associated with MTA in VaD but not with MTA in AD patients. MTA was strongly associated with Mini-Mental State Examination scores in both groups, whereas evidence of a modest association between WMH and Mini-Mental State Examination scores was seen in VaD patients., Conclusions: MRI data from two dementia cohorts with differing dementia etiologies find that the clinical consequences of dementia are most strongly associated with cerebral and medial-temporal atrophy, suggesting that tissue loss is the major substrate of the dementia syndrome., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: The Alzheimer's Disease Assessment Scale Cognitive Behavior Section (ADAS-cog), a measure of cognitive performance, has been used widely in Alzheimer's disease trials. Its key role in clinical trials should be supported by evidence that it is both clinically meaningful and scientifically sound. Its conceptual and neuropsychological underpinnings are well-considered, but its performance as an instrument of measurement has received less attention. Objective To examine the traditional psychometric properties of the ADAS-cog in a large sample of people with Alzheimer's disease., Methods: Data from three clinical trials of donepezil (Aricept) in mild-to-moderate Alzheimer's disease (n=1421; MMSE 10-26) were analysed at both the scale and component level. Five psychometric properties were examined using traditional psychometric methods. These methods of examination underpin upcoming Food and Drug Administration recommendations for patient rating scale evaluation., Results: At the scale-level, criteria tested for data completeness, scaling assumptions (eg, component total correlations: 0.39-0.67), targeting (no floor or ceiling effects), reliability (eg, Cronbach's α: = 0.84; test-retest intraclass correlations: 0.93) and validity (correlation with MMSE: -0.63) were satisfied. At the component level, 7 of 11 ADAS-cog components had substantial ceiling effects (range 40-64%)., Conclusions: Performance was satisfactory at the scale level, but most ADAS-cog components were too easy for many patients in this sample and did not reflect the expected depth and range of cognitive performance. The clinical implication of this finding is that the ADAS-cog's estimate of cognitive ability, and its potential ability to detect differences in cognitive performance under treatment, could be improved. However, because of the limitations of traditional psychometric methods, further evaluations would be desirable using additional rating scale analysis techniques to pinpoint specific improvements.