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P.5.e.005 A 12-week study of eszopiclone in elderly out-patients with primary insomnia: effects of treatment discontinuation
P.5.e Dementia and neurological disorders – Other (clinical) P.5.e.004 The efficacy of 12 weeks of eszopiclone treatment in elderly patients with primary insomnia: effect on daytime function A. Krystal1 ° , S. Ancoli-Israel2 , W. McCall3 , K. Schaefer4 , 1 Duke University R. Claus5 , R. Rubens4 , T. Roth6 . Medical Center, Psychiatry & Behavioral Sciences, Durham, USA; 2 University of California San Diego, Psychiatry, San Diego, USA; 3 Wake Forest University, Health Sciences‘, Winston-Salem, USA; 4 Sepracor Inc, Medical Affairs, Marlborough, USA; 5 Sepracor Inc, Biostatistics, Marlborough, USA; 6 Henry Ford Health System, Henry Ford Sleep Disorders Center, Detroit, USA Purpose: The prevalence of insomnia is reported to increase with age. Sleep maintenance difficulties in the elderly may lead to daytime fatigue, next-day impairments, and frequent napping. In two studies of elderly patients with chronic primary insomnia, two weeks of nightly treatment with 2 mg eszopiclone (a nonbenzodiazepine cyclopyrrolone) improved patient-reported measures of sleep onset and maintenance, measures of daytime function, and reduced total nap time. However, data on the long-term treatment of chronic insomnia in elderly individuals is limited. The current trial evaluated the effect of 12 weeks of nightly eszopiclone on self-reported daytime function in this elderly population. Methods: Subjects (65−85 years) in this double-blind, placebocontrolled trial met DSM-IV-TR criteria for primary insomnia. Following a one-week single-blind placebo run-in period (“baseline”), subjects were randomized to 12 weeks of nightly eszopiclone 2 mg (n = 194) or placebo (n = 194). Throughout the trial, subjects maintained daily sleep diaries in which they were queried about their daytime functioning (0 [worst]-10 [best] Likert scale). During clinic visit, patients completed the Insomnia Severity Index (ISI), a validated instrument that assesses patient-perceived insomnia severity, quality of life, and impact on daytime function (ISI extended items: rested/refreshed upon awakening, daytime fatigue, and attention/concentration). The ISI was completed at baseline and at three-week intervals during the trial. Changes from baseline in daytime function (daytime alertness, ability to function, ability to concentrate, physical well-being) and total nap time were determined over three-week intervals and for the average over the double-blind period (DB average). Between-group comparisons were performed using an analysis of covariance model with baseline as a covariate. All analyses were based on the lastobservation-carried-forward method. Results: The improvement from baseline in daytime function over 12 weeks was significantly greater for eszopiclone than for placebo (LS Mean differences between the treatments for the DB average [95% CI] for daytime alertness: 0.44 [0.24, 0.64], ability to function: 0.44 [0.20, 0.67], ability to concentrate: 0.44 [0.25, 0.63], and physical well-being: 0.42 [0.23, 0.61]; all p-values <0.0001). Although not significantly different from placebo, mean total nap time decreased by 60.8 minutes in the eszopiclone group and 38.9 minutes in the placebo group over the treatment period (p = 0.08). Significant improvements relative to placebo in all measures of daytime function, and total nap time, were observed at Week 3 (all p-values 0.014). The improvements in daytime function measures were sustained through Week 12 (all p-values 0.0005). The eszopiclone group had significantly improved ISI total scores (change from baseline for the DB average: −5.7; Week 3: 4.9; Week 12: −6.2) relative to the placebo group (3.4, −2.7, −4.1, respectively, all p-values <0.0001). Similar results were observed for the individual ISI extended items that assessed
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the impact of insomnia on daytime functioning (DB average: all p-values 0.034). Conclusions: In the elderly patients with chronic primary insomnia studied in this trial, relative to placebo, nightly eszopiclone treatment for 12 weeks significantly improved patientreported measures of daytime function, and significantly improved insomnia severity and daytime function as assessed by the ISI. Support for this study provided by Sepracor Inc.
P.5.e.005 A 12-week study of eszopiclone in elderly out-patients with primary insomnia: effects of treatment discontinuation A. Krystal1 ° , S. Ancoli-Israel2 , W. McCall3 , K. Schaefer4 , 1 Duke University R. Claus5 , R. Rubens4 , T. Roth6 . Medical Center, Psychiatry & Behavioral Sciences, Durham, USA; 2 University of California at San Diego, Psychiatry, San Diego, USA; 3 Wake Forest University, Health Sciences, WinstonSalem, USA; 4 Sepracor Inc, Medical Affairs, Marlborough, USA; 5 Sepracor Inc, Biostatistics, Marlborough, USA; 6 Henry Ford Health System, Henry Ford Sleep Disorders Center, Detroit, USA Purpose: The prevalence of insomnia is reported to increase with age, and its consequences can be more severe than in the nonelderly. In two previous studies of elderly patients with primary insomnia, two weeks of nightly treatment with 2 mg eszopiclone (a non-benzodiazepine cyclopyrrolone) improved patient reported measures of sleep onset, sleep maintenance, sleep quality, and next-day function. However, these trials did not examine the effects of eszopiclone discontinuation on sleep parameters, and the extent to which hypnotic discontinuation could lead to rebound insomnia (defined as a worsening of sleep relative to pretreatment levels). In the current trial, rebound insomnia following 12 weeks of nightly eszopiclone administration was assessed in elderly outpatients with primary insomnia. Methods: Patients (65−85 years of age; mean age 72 years) in this double-blind, randomized, placebo-controlled trial met DSM-IV-TR criteria for primary insomnia and sleep (total sleep time [TST] 6.5 hours, sleep latency [SL] 30 minutes) during a screening period. Following a one-week single-blind placebo runin period (“baseline”), eligible patients were randomized to 12 weeks of nightly eszopiclone 2 mg (n = 194) or placebo (n = 194). Patients then entered a two-week single-blind placebo run-out period (“run-out”). Rebound was evaluated in patients randomized to treatment who entered the run-out period and took at least one dose of single-blind placebo (“run-out population”, n = 145 in the eszopiclone group, n = 146 in the placebo group). Patientreported sleep measures (TST, SL, and wake time after sleep onset [WASO]) were assessed during the pretreatment baseline period and compared to those obtained on each day of the run-out period. The Wilcoxon signed rank test was used to test for within group changes from baseline. WASO and SL were log-transformed prior to analysis and computation of the change from baseline. Results: On each day of the 14-day run-out period, elderly patients who discontinued from 12 weeks of nightly eszopiclone treatment still had significant improvements in SL, WASO, and TST when compared with baseline (all p-values 0.01, see table). Conclusions: There was no evidence of rebound insomnia in this trial. In these elderly out-patients with primary insomnia, improvement in patient-reported sleep measures associated with 12 weeks of nightly eszopiclone administration was not followed by rebound insomnia after hypnotic discontinuation.
S518 Sleep measures during run-out period* SL (median minutes) Baseline Night 1 Night 2 Night 3 Night 14 WASO (median minutes) Baseline Night 1 Night 2 Night 3 Night 14 TST (median minutes) Baseline Night 1 Night 2 Night 3 Night 14
P.5.f Dementia and neurological disorders – Other (basic) Placebo (n = 146)
Eszopiclone 2 mg (n = 145)
60.0 30.0 30.0 30.0 30.0
60.0 41.5 42.5 30.0 30.0
91.5 60.0 60.0 60.0 47.5
94.4 45.0 30.0 60.0 30.0
300.9 360.0 360.0 360.0 355.0
300.7 350.0 360.0 360.0 375.0
*Patients randomized to treatment who entered the run-out period and took at least one dose of single-blind placebo.
Support for this study provided by Sepracor Inc.
P.5.e.006 Scopolamine: modelling memory and cognitive deficits for clinical trials D.L. Milovan1 ° , M.K. Romach1 , E.M. Sellers1 , M. Miguelez1 , M. Grigorova1 , M. Sokolowska1 . 1 DecisionLine Clinical Research Corporation, Research Consulting, Toronto Ontario, Canada Purpose of the study: Scopolamine acts as a muscarinic acetylcholine antagonist at M1 receptors. As a result of its anticholinergic activity, scopolamine has been associated with reversible memory and attention deficits as well as hallucinogenic effects that mimic those present in dementia and schizophrenia [1]. Blockade of cholinergic activity with scopolamine has been repeatedly demonstrated to affect performance on tests of paired-associated learning, digit span recall, information processing, verbal procedural learning, working and recognition memory [2]. As such, the induction of memory and cognitive deficits following scopolamine challenge has been used as a screen for novel psychoactive drugs targeting cognitive processes. The goal of this study was to formalize the use of specific measures to compare the effects of scopolamine to those of investigational compounds with respect to the reversal of anticholinergic-type cognitive impairments in healthy volunteers. Methods used: The study followed a double-blind, randomized placebo-controlled crossover design. Six healthy, non-smoking subjects (3 males), mean age 21 to 31 years-old completed the study. Subjects received a single dose of scopolamine (0.4 mg) or placebo administered sub-cutaneously. Treatment sessions were separated by no less than 24 hours. Subjects fasted 8 hours before and 2 hours following each dose. Dose selection was based on previous studies in healthy volunteers and epileptic patients. Computerized measures included: Divided Attention (DA); Choice
Reaction Time (CRT); Digit Vigilance (DV); and Sternberg ShortTerm Memory Test (STM). Additionally, several visual analog scales were administered: dry mouth, nausea, restlessness, confusion, and drowsiness. Data were analysed using a mixed effect ANCOVA including time as fixed effect, subject as random effect, and pre-dose baseline value as covariate. Summary of results: Significant differences were present between the scopolamine and placebo conditions on the objective, but not on the subjective measures selected. As compared to placebo, scopolamine was associated with significantly diminished divided attention (lower total percent over the road; fewer correct responses; increased number of errors; P < 0.05), slower choice reaction time (delayed recognition reaction time; delayed motor reaction time; P < 0.05), and poorer short term memory (increased response latency; lower digit detection sensitivity; P < 0.05). Conclusions: Several measures were selected to assess the effect of scopolamine on cognitive abilities. Results showed that the subject performance on the DA, CRT, and STM was significantly reduced in response to a single dose of scopolamine (0.4.mg) and, as such, represent good candidates for comparing the effects of scopolamine to those of novel central nervous systemacting drugs. The subject performance on the DV task was not significantly modulated by the scopolamine challenge. Although not statistically significant, subjects reported increased feelings of restlessness, drowsiness, dry mouth, nausea, and confusion in response to scopolamine. In conclusion, with the exception of the DV task, the selected test battery can be applied as an experimental model of cognitive impairment in dementia and schizophrenia to study the effects of novel investigational compounds with respect to the reversal of anticholinergic-type cognitive impairments. References [1] Sunderland T, Tariot P, Murphy DL, Weingartner H, Mueller EA, Cohen RM, 1985, Scopolamine challenges in Alzheimer’s disease. Psychopharmacology 87(2), 247–249. [2] Wenses KA, Simpson P, Kidd A, 1988, An investigation of the range of cognitive impairments induced by scopolamine 0.6 mg s.c. Hum Psychopharmacol 3, 27−41.
P.5.f Dementia and neurological disorders – Other (basic) P.5.f.001 Dietary restriction effects on age induced changes in APP, PS-1 and ADAM mRNA expression A. Mladenovic Djordjevic1 ° , M. Perovic1 , N. Tanic1 , S. Ruzdijic1 , S. Kanazir1 . 1 Institute for Biological Research “Sinisa Stankovic”, Department for Neurobiology, Belgrade, Serbia The aging brain is associated with a variety of neurodegenerative disorder like Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s disease (HD). On the other hand, numerous studies have shown that restricting food intake in humans and animals can extend the lifespan, and delays and slows down the progression of a variety of age-associated diseases, including neurodegenerative disorders. The aim of this study was to assess the effects of aging and long-term DR on expression of amyloid precursor protein (APP),
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the impact of insomnia on daytime functioning (DB average: all p-values 0.034). Conclusions: In the elderly patients with chronic primary insomnia studied in this trial, relative to placebo, nightly eszopiclone treatment for 12 weeks significantly improved patientreported measures of daytime function, and significantly improved insomnia severity and daytime function as assessed by the ISI. Support for this study provided by Sepracor Inc.
P.5.e.005 A 12-week study of eszopiclone in elderly out-patients with primary insomnia: effects of treatment discontinuation A. Krystal1 ° , S. Ancoli-Israel2 , W. McCall3 , K. Schaefer4 , 1 Duke University R. Claus5 , R. Rubens4 , T. Roth6 . Medical Center, Psychiatry & Behavioral Sciences, Durham, USA; 2 University of California at San Diego, Psychiatry, San Diego, USA; 3 Wake Forest University, Health Sciences, WinstonSalem, USA; 4 Sepracor Inc, Medical Affairs, Marlborough, USA; 5 Sepracor Inc, Biostatistics, Marlborough, USA; 6 Henry Ford Health System, Henry Ford Sleep Disorders Center, Detroit, USA Purpose: The prevalence of insomnia is reported to increase with age, and its consequences can be more severe than in the nonelderly. In two previous studies of elderly patients with primary insomnia, two weeks of nightly treatment with 2 mg eszopiclone (a non-benzodiazepine cyclopyrrolone) improved patient reported measures of sleep onset, sleep maintenance, sleep quality, and next-day function. However, these trials did not examine the effects of eszopiclone discontinuation on sleep parameters, and the extent to which hypnotic discontinuation could lead to rebound insomnia (defined as a worsening of sleep relative to pretreatment levels). In the current trial, rebound insomnia following 12 weeks of nightly eszopiclone administration was assessed in elderly outpatients with primary insomnia. Methods: Patients (65−85 years of age; mean age 72 years) in this double-blind, randomized, placebo-controlled trial met DSM-IV-TR criteria for primary insomnia and sleep (total sleep time [TST] 6.5 hours, sleep latency [SL] 30 minutes) during a screening period. Following a one-week single-blind placebo runin period (“baseline”), eligible patients were randomized to 12 weeks of nightly eszopiclone 2 mg (n = 194) or placebo (n = 194). Patients then entered a two-week single-blind placebo run-out period (“run-out”). Rebound was evaluated in patients randomized to treatment who entered the run-out period and took at least one dose of single-blind placebo (“run-out population”, n = 145 in the eszopiclone group, n = 146 in the placebo group). Patientreported sleep measures (TST, SL, and wake time after sleep onset [WASO]) were assessed during the pretreatment baseline period and compared to those obtained on each day of the run-out period. The Wilcoxon signed rank test was used to test for within group changes from baseline. WASO and SL were log-transformed prior to analysis and computation of the change from baseline. Results: On each day of the 14-day run-out period, elderly patients who discontinued from 12 weeks of nightly eszopiclone treatment still had significant improvements in SL, WASO, and TST when compared with baseline (all p-values 0.01, see table). Conclusions: There was no evidence of rebound insomnia in this trial. In these elderly out-patients with primary insomnia, improvement in patient-reported sleep measures associated with 12 weeks of nightly eszopiclone administration was not followed by rebound insomnia after hypnotic discontinuation.
S518 Sleep measures during run-out period* SL (median minutes) Baseline Night 1 Night 2 Night 3 Night 14 WASO (median minutes) Baseline Night 1 Night 2 Night 3 Night 14 TST (median minutes) Baseline Night 1 Night 2 Night 3 Night 14
P.5.f Dementia and neurological disorders – Other (basic) Placebo (n = 146)
Eszopiclone 2 mg (n = 145)
60.0 30.0 30.0 30.0 30.0
60.0 41.5 42.5 30.0 30.0
91.5 60.0 60.0 60.0 47.5
94.4 45.0 30.0 60.0 30.0
300.9 360.0 360.0 360.0 355.0
300.7 350.0 360.0 360.0 375.0
*Patients randomized to treatment who entered the run-out period and took at least one dose of single-blind placebo.
Support for this study provided by Sepracor Inc.
P.5.e.006 Scopolamine: modelling memory and cognitive deficits for clinical trials D.L. Milovan1 ° , M.K. Romach1 , E.M. Sellers1 , M. Miguelez1 , M. Grigorova1 , M. Sokolowska1 . 1 DecisionLine Clinical Research Corporation, Research Consulting, Toronto Ontario, Canada Purpose of the study: Scopolamine acts as a muscarinic acetylcholine antagonist at M1 receptors. As a result of its anticholinergic activity, scopolamine has been associated with reversible memory and attention deficits as well as hallucinogenic effects that mimic those present in dementia and schizophrenia [1]. Blockade of cholinergic activity with scopolamine has been repeatedly demonstrated to affect performance on tests of paired-associated learning, digit span recall, information processing, verbal procedural learning, working and recognition memory [2]. As such, the induction of memory and cognitive deficits following scopolamine challenge has been used as a screen for novel psychoactive drugs targeting cognitive processes. The goal of this study was to formalize the use of specific measures to compare the effects of scopolamine to those of investigational compounds with respect to the reversal of anticholinergic-type cognitive impairments in healthy volunteers. Methods used: The study followed a double-blind, randomized placebo-controlled crossover design. Six healthy, non-smoking subjects (3 males), mean age 21 to 31 years-old completed the study. Subjects received a single dose of scopolamine (0.4 mg) or placebo administered sub-cutaneously. Treatment sessions were separated by no less than 24 hours. Subjects fasted 8 hours before and 2 hours following each dose. Dose selection was based on previous studies in healthy volunteers and epileptic patients. Computerized measures included: Divided Attention (DA); Choice
Reaction Time (CRT); Digit Vigilance (DV); and Sternberg ShortTerm Memory Test (STM). Additionally, several visual analog scales were administered: dry mouth, nausea, restlessness, confusion, and drowsiness. Data were analysed using a mixed effect ANCOVA including time as fixed effect, subject as random effect, and pre-dose baseline value as covariate. Summary of results: Significant differences were present between the scopolamine and placebo conditions on the objective, but not on the subjective measures selected. As compared to placebo, scopolamine was associated with significantly diminished divided attention (lower total percent over the road; fewer correct responses; increased number of errors; P < 0.05), slower choice reaction time (delayed recognition reaction time; delayed motor reaction time; P < 0.05), and poorer short term memory (increased response latency; lower digit detection sensitivity; P < 0.05). Conclusions: Several measures were selected to assess the effect of scopolamine on cognitive abilities. Results showed that the subject performance on the DA, CRT, and STM was significantly reduced in response to a single dose of scopolamine (0.4.mg) and, as such, represent good candidates for comparing the effects of scopolamine to those of novel central nervous systemacting drugs. The subject performance on the DV task was not significantly modulated by the scopolamine challenge. Although not statistically significant, subjects reported increased feelings of restlessness, drowsiness, dry mouth, nausea, and confusion in response to scopolamine. In conclusion, with the exception of the DV task, the selected test battery can be applied as an experimental model of cognitive impairment in dementia and schizophrenia to study the effects of novel investigational compounds with respect to the reversal of anticholinergic-type cognitive impairments. References [1] Sunderland T, Tariot P, Murphy DL, Weingartner H, Mueller EA, Cohen RM, 1985, Scopolamine challenges in Alzheimer’s disease. Psychopharmacology 87(2), 247–249. [2] Wenses KA, Simpson P, Kidd A, 1988, An investigation of the range of cognitive impairments induced by scopolamine 0.6 mg s.c. Hum Psychopharmacol 3, 27−41.
P.5.f Dementia and neurological disorders – Other (basic) P.5.f.001 Dietary restriction effects on age induced changes in APP, PS-1 and ADAM mRNA expression A. Mladenovic Djordjevic1 ° , M. Perovic1 , N. Tanic1 , S. Ruzdijic1 , S. Kanazir1 . 1 Institute for Biological Research “Sinisa Stankovic”, Department for Neurobiology, Belgrade, Serbia The aging brain is associated with a variety of neurodegenerative disorder like Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s disease (HD). On the other hand, numerous studies have shown that restricting food intake in humans and animals can extend the lifespan, and delays and slows down the progression of a variety of age-associated diseases, including neurodegenerative disorders. The aim of this study was to assess the effects of aging and long-term DR on expression of amyloid precursor protein (APP),