0506 Short and Long-Term Effects of Trazodone vs. Cognitive-Behavioral Treatment on EEG Power During NREM Sleep in Chronic Insomnia

Abstract

Results: Compared to PMRT, BBTI resulted in a greater reduction in subjective total sleep time variability (F 1,90 =6.61, p<0.01, partial η 2 =0.13) and a greater increase in interdaily stability (F 1,78 =12.41, p<0.01, partial η 2 =0.25). There was a greater decrease in intradaily variability following PMRT (F 1,78 =27.96, p<0.01, partial η 2 =0.42). Across the entire sample, reductions in subjective wake time variability were associated with improved functioning (F 1,88 =4.43, p=0.04, η 2 =0.05) and reductions in subjective total sleep time variability were associated with improved quality of life (F 1,89 =4.91, p=0.03, partial η 2 =0.05). Conclusion: There was significant improvement in the stability of sleep-wake rhythms following BBTI, suggesting that BBTI not only treats insomnia, but also may stabilize circadian rhythms. Interestingly, PMRT resulted in greater intradaily variability reductions than BBTI. One explanation is that due to BBTI stimulus control guidelines, individuals were getting out of bed in the middle of the night more frequently and thus, these awakenings were better captured by actigraphy. Reductions in wake time and total sleep time variability were associated with improved functioning and quality of life, further demonstrating the importance of stable sleep-wake rhythms. Introduction: Insomnia disorder affects 3-6% of the population and includes functional impairing symptoms for ≥3 months. Current hypnotics have limitations (eg fall risk, dependency, parasomnia, cognitive impairment). In a previous proof-of-concept study, seltorexant, a selective orexin-2 receptor antagonist, dosed at 40mg nightly improved sleep efficiency, latency to persistent sleep (LPS), and wake after sleep onset (WASO) versus placebo. Methods: A multicenter, double-blind, randomized, parallel-group, active-and placebo-controlled, 14-day, dose-finding study (NCT03375203) assessed the efficacy and safety of seltorexant in adult and elderly subjects meeting DSM-5 insomnia disorder criteria. Subjects were randomized (1:1:1:1:1 ratio) to: placebo, seltorexant 5mg, 10mg, 20mg, or zolpidem. Primary endpoint: Based on PSG, dose response in LPS change on Night 1 relative to baseline. Secondary endpoints included change from baseline in: WASO over the first 6 hours (WASO-6) on Night 1, and LPS and WASO-6 on Night 13. Multiple Comparison Procedure-Modeling, ANCOVA and MMRM were used for data analyses. Results: 365 patients were randomized and 347 (95%) completed the double-blind phase with 68% women and median age of 59yr (22 to 84yr). Statistically significant dose-response relationship (p-value <0.001) was observed for LPS at Night 1 (5mg=12%, 10mg=36%, 20mg=49% improvement compared with placebo). Similar findings were observed for WASO-6 and benefits sustained from Night 1 to 13. The 20 mg dose showed greater improvement than zolpidem on LPS at Nights 1 and 13 and on WASO-6 at Night 13. Overall treatment-emergent adverse events rates were comparable in the seltorexant, placebo, and zolpidem treatment groups. Conclusion: Statistically significant and clinically meaningful improvements on LPS & WASO-6 were observed for seltorexant 10 and 20mg dose groups versus placebo. No safety concerns were observed. Seltorexant with its novel mechanism holds potential as a new treatment for insomnia disorder.