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0323 Natural Evolution of Insomnia in Major Depressive Disorders
Introduction Insomnia is a fairly common sleep disturbance affecting nearly one third of the general population. Although its predictive value for major depressive disorder (MDD) has been well documented, little is known about its role in the appearance of a first episode or in the recurrence. In this study, we examine the predictive value of insomnia symptoms in the incidence and recurrence of MDD. Methods In this longitudinal study, 2 interview waves were conducted between 2002 and 2015. The initial interviews (wave 1 [W1]) were carried out with 12,218 individuals aged ≥18 years from the general population in 8 US states. At follow-up 3 years later (wave 2 [W2]), 10,931 of the initial participants agreed to be interviewed again. Data were analyzed for the individuals who participated in both interviews (N=10,931). A diagnosis of MDD was made according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Insomnia symptoms were defined according to DSM-5 criteria A, C, and D for insomnia disorder. Results The 12-month prevalence of MDD was 9.5% (95% CI, 9.0%-10.0%) and 12.1% (95% CI, 11.5%-12.7%) in W1 and W2, respectively. Over the course of the study, 2.6% of participants experienced recurrence of depression (95% CI, 2.3%-2.9%). After adjusting for age, gender, race, and body mass index, participant characteristics in W1 that predicted recurrent MDD in W2 included early morning awakenings (EMA) (relative risk [RR], 3.2; 95% CI, 2.3-4.4), being dissatisfied with one’s sleep (RR, 2.8; 95% CI, 2.1-3.7), nocturnal awakenings (RR, 2.4; 95% CI, 1.8-3.2), and difficulty initiating sleep (DIS) (RR, 2.0; 95% CI, 1.5-2.9). MDD incidence was predicted by DIS (RR, 3.8; 95% CI, 2.5-5.9), being dissatisfied with one’s sleep (RR, 2.1; 95% CI, 1,4-3.2), and EMA (RR, 2.0; 95% CI, 1.2-3,2) at W1. Conclusion Insomnia symptoms appear to play an important part in predicting both the development of a first depressive episode as well as the recurrence of depression. Support (if any) Data analysis study were funded by Takeda Pharmaceutical Company.
Journal Article
0345 BZRA Hypnotic Receptor Specificity and Ability to Discontinue Chronic Hypnotic Use
Introduction Clinicians prescribing hypnotics remain concerned regarding the inability to discontinue hypnotics after chronic use. In a controlled prospective study using self-administration choice procedures we tested whether BZRA hypnotic receptor specificity is predictive of discontinuation difficulty in a clinical trial in which insomnia subjects are instructed to stop taking their study medication after 6 months of nightly use. Methods DSM-V diagnosed insomnia subjects, aged 23-61 yrs, (n=41, 36 females), with no other sleep disorders, unstable medical or psychiatric diseases or drug dependency completed the trial. Following a screening polysomnogram and MSLT, participants were randomized to zolpidem XR 12.5 mg (n=16), eszopiclone 3 mg (n=11), or placebo (n=14) nightly for 6 months. After 6 months, nightly use, over a 2-week choice period, they were instructed to discontinue hypnotic use, but if necessary, to self-administer either 1, 2, or 3 capsules of their assigned “blinded” medication (zolpidem XR 6.25 mg, 6.25 mg, placebo; eszopiclone 2 mg, 1 mg, placebo as capsules 1, 2 and 3 respectively; or 3 placebos). Results Over the 14 nights 21 subjects took zero (51%) capsules; among the 20 taking capsules the median total number chosen over the two weeks was 3. Most took one capsule per night; 6 took > 1 capsule on a given night. Overall, the number of capsules taken declined from week 1 to 2 (p< .001). The eszopiclone group took a greater number of capsules than the placebo group (p<.005), with the zolpidem group between. The eszopiclone group also showed a trend (p<.07) to fail to reduce use from week 1 to 2. Conclusion The majority (51%) of the participants discontinued 6-month nightly hypnotic use and among those taking capsules the rate declined from week 1 to 2. The non-hypnotic receptor specific eszopiclone group took a greater number of capsules than the placebo group. This is the first demonstration of differential abuse liability among BzRA hypnotics. Support (if any) NIDA, grant#: R01DA038177 awarded to Dr. Roehrs.
Journal Article
0407 Impact of Lemborexant on Daytime Ratings of Sleepiness/Alertness in Subjects with Insomnia Disorder and Baseline Sleepiness
Introduction Since the use of sleep-promoting drugs can also lead to residual morning sleepiness, it is important to determine if a new hypnotic is associated with such a carryover effect of treatment. To this end, an assessment of sleepiness/alertness was included in lemborexant (LEM) phase 3 studies. LEM is a competitive dual orexin receptor antagonist approved in several countries for the treatment of adults with insomnia. This post-hoc analysis of Study 304 (E2006-G000-304; NCT02783729) assessed the impact of LEM on morning sleepiness/alertness in subjects who reported at least mild/moderate morning sleepiness at baseline. Methods Study 304 was a randomized controlled study in adults ≥55y with insomnia disorder (N=1006). Subjects received bedtime doses of placebo (PBO), LEM 5mg (LEM5), LEM 10mg (LEM10), or zolpidem tartrate extended release 6.25 mg (not reported here) for 1 month. A daily Sleep Diary assessed morning sleepiness, within 90 min of waketime, with the question “How alert/sleepy do you feel this morning?” rated from 1 (extremely sleepy) to 9 (extremely alert). Scores were averaged over 7-day periods for baseline (single-blind run-in) and first and last 7 days of treatment. Chi-square tests were used to compare the shift from sleepy (≤3) to more alert (>3) between PBO and treatment groups. Results At baseline, 59/203 (29.1%), 66/261 (25.3%), and 79/265 (29.8%) of the PBO, LEM5, and LEM10 subjects reported a score ≤3, indicating at least mild/moderate morning sleepiness. At the end of 1 month of treatment, 37/57 (64.9%) of the PBO subjects rated themselves as less sleepy and more alert (>3), compared with 50/64 (78.1%; P=0.11) LEM5- and 58/76 (76.3%; P=0.15) LEM10-treated subjects. Conclusion In this study, ~28% of subjects reported morning sleepiness at baseline. More subjects who reported sleepiness at baseline and received LEM reported improved morning alertness during the last week of treatment compared with PBO subjects. These data are concordant with previous findings of a lack of effect of LEM on tasks requiring alertness in the morning. Support (if any) Eisai Inc.
Journal Article
0350 Daridorexant in patients with insomnia disorder: number needed to treat, number needed to harm & likelihood to be helped or harmed
Introduction Patients with insomnia disorder have difficulty initiating or maintaining sleep and have impaired daytime functioning. Daridorexant is a dual orexin receptor antagonist approved for the treatment of insomnia. This analysis reports the number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH) with daridorexant 25 mg or 50 mg versus placebo over 3 months. Methods Phase 3 data from one of two pivotal trials (N=930: randomized 1:1:1 to daridorexant 25 mg, 50 mg, or placebo) were used to calculate NNT, NNH, and LHH. For the NNT analysis, wakefulness after sleep onset, latency to persistent sleep, self-reported total sleep time, the Insomnia Daytime Symptoms and Impacts Questionnaire, and the Insomnia Severity Index were explored. NNT was assessed using a range of clinically meaningful thresholds (CMTs), from minimal clinical improvement (MiCI) to marked clinical improvement. NNH analysis was performed on adverse events (AEs) occurring in >1% of participants in any treatment arm. LHH values were calculated for all NNT outcomes using the NNH estimates for somnolence and fatigue AEs. Results At Month 1 and 3, NNT values at MiCI thresholds for daridorexant 50 mg ranged from 5–9 and 6–12, respectively, and were all statistically significantly different versus placebo, indicating a good therapeutic response. Daridorexant 50 mg had at least one NNT < 10 for CMTs across all outcomes. NNTs at MiCI thresholds for daridorexant 25 mg ranged between 7–328 and 8–1666. NNH values for daridorexant 25 and 50 mg were negative or not significantly different from placebo, confirming a good tolerability profile. For a somnolence AE, LHH values ranged from 83.3–200 for daridorexant 50 mg versus placebo. For a fatigue AE, LHH ranged from 4.3–10.2. Conclusion Daridorexant 25 mg and 50 mg both have a positive benefit-risk ratio compared with placebo over 3 months. Furthermore, daridorexant 50 mg showed ‘good’ NNT values (i.e. NNT < 10) over all efficacy endpoints in relation to the CMTs. NNH results confirmed the good tolerability profile of both doses. Support (if any) Funded by Idorsia Pharmaceutical Ltd.
Journal Article
0319 Evaluating Illness Severity from Acute to Chronic Insomnia: Is the First the Worst?
Introduction The Spielman 3P and Perlis 4P models represent illness severity over the course of insomnia disorder. The 3P model suggests that illness severity is worst when subjects experience acute illness (as compared to the subchronic and chronic phases of the disorder). The 4P model suggests that illness severity crescendos with chronicity. The present analysis uses an archival data set to assess illness severity with new onset illness (i.e.,from Good Sleep [GS] to Acute Insomnia [AI] and from AI to Chronic Insomnia [CI]). Illness severity is quantified in terms of Total Wake Time (TWT). Number of affected days/week is a tabulation of nights/week with clinical insomnia symptoms. Methods Subjects were recruited as GSs(N=911), followed up to 1-year with digital sleep diaries, and were classified as GS, AI, or CI based on standardized criteria. Data for CI subjects were anchored to the 1st of 14 days with insomnia so that day-to-day TWT, SL, WASO, and EMA were represented for ~100 days prior-to-and-following AI onset. A similar graphic (+/-Acute onset) was constructed for number of days per week with insomnia. GS data were matched to CI subjects dates (i.e., the data were temporally tethered). Segmented linear mixed regression models were applied to examine the change in slopes in the AI-to-CI period compared to GS and AI period. Results 883 subjects remained as GSs (Mage=53.1±10.8years;35.1%female;83.0%white), while 28 indi-viduals transitioned to AI and then CI (Mage=53.6±12.6years;39.3%female;89.3%white). Average TWT rose over the course of the first 2 weeks from the AI onset(b=1.6,SE=0.52minutes,p=0.002) and then was stable for 3 months(b=-0.004,SE=0.03,p=0.91). This worsening of sleep continuity was almost entirely related to increased WASO. Average number of affected days was found to be stable from AI to CI (b=0.002,SE=0.002,p=0.20). That is, while there was week-to-week variability in the number of days affected, no linear trend was evident. Conclusion These data suggest that, in our sample of CIs with primarily middle insomnia, the average severity and number of affected days was worst with the onset of AI (worst is first) and stable thereafter. Whether this temporal trend applies equally to new onset Initial and Late insomnia remains to be determined. Analyses ongoing. Support (if any) R01AG041783
Journal Article