Citations

Abstract Purpose To evaluate the correlation between occupational burnout and depression, frequency with which they coexist, how often 1 condition may be present in the absence of the other, and their association with suicidal ideation. Method The authors conducted a secondary analysis of cross-sectional national surveys of practicing U.S. physicians (conducted October 19, 2023, to March 3, 2024) and residents/fellows (“trainees”; conducted November 30, 2023, to January 2, 2024). They measured correlation between emotional exhaustion (EE) and depersonalization (DP) scores using the Maslach Burnout Inventory and depression T-scores using the National Institutes of Health Patient Reported Outcomes Measurement Information System Depression scale. Results A total of 5993 practicing physicians and 2676 trainees were included in the analysis. The pooled R2 value between EE and depression scores for physicians and trainees was 0.42 (P < .001) and between DP and depression scores was 0.28 (P < .001). Among the 4087 practicing physicians with normal depression scores, 1201 (29.4%) had high EE and/or high DP. Among the 1601 trainees with normal depression scores, 485 (30.3%) had high EE and/or high DP. On multivariable logistic regression adjusting for age, gender, relationship status, and work hours, each 1-point increase in depression T-score was associated with 15% higher odds of suicidal ideation among practicing physicians (OR 1.15; 95% CI, 1.13–1.17; P < .001) and trainees (OR 1.15, 95% CI, 1.13–1.17; P < .001). No statistically significant association between EE or DP scores and suicidal ideation was observed. Conclusions Occupational burnout and depression are correlated but distinct constructs with distinct outcomes. Less than half the variation in burnout is explained by depression (and vice versa). Population health approaches to improve physician well-being should address both conditions. Organizational efforts should go beyond providing support for individuals experiencing distress and also address the work environment factors that contribute to it.

Abstract Introduction Narcolepsy type 2 (NT2) is characterized by excessive daytime sleepiness, heterogeneous symptom severity, and typically normal endogenous orexin levels. The Vibrance-2 phase 2 study evaluated alixorexton, a selective orexin 2 receptor agonist, in patients with NT2. Methods Vibrance-2 was a placebo-controlled, dose-ranging phase 2 study. After a 2-week washout from current narcolepsy medications, adults with NT2 meeting ICSD-3-TR diagnostic criteria were randomized 1:1:1:1 to receive placebo or alixorexton once daily at doses of 10, 14, or 18mg for 8 weeks, followed by an optional 5-week open-label extension. Dual primary endpoints were the change from baseline to week 8 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT) and on the Epworth Sleepiness Scale (ESS). Safety evaluation included treatment-emergent adverse events (TEAEs). P-values were adjusted for multiplicity. Results Ninety-three patients were randomized to placebo (n=24) or alixorexton (10mg, n=23; 14mg, n=22; 18mg, n=24); 90 completed double-blind treatment. At baseline, patients had severe symptoms (MWT: 5.6 minutes; ESS: 17.4). The study met its dual primary endpoints. At week 8, MSL on MWT increased 9.3, 6.7, and 6.7 minutes at 10, 14, and 18mg, respectively, from baseline versus placebo, with statistically significant differences observed for the 14 and 18mg doses (adjusted p< 0.05). ESS improved by -2.1, -3.2, and -3.6 points from baseline versus placebo at week 8 for the 10, 14, and 18mg groups, respectively, with statistical significance observed for the 18mg dose (adjusted p< 0.05), where more than 70% of patients achieved normalization. TEAEs in 10% of all alixorexton-treated patients through week 8 were pollakiuria, insomnia, micturition urgency, dizziness, and headache. Most TEAEs were mild-to-moderate with no serious TEAEs. Conclusion Vibrance-2 was the first large clinical trial in patients with NT2 to demonstrate positive results with an orexin 2 receptor agonist. Alixorexton resulted in statistically significant and clinically meaningful improvements in wakefulness and daytime sleepiness at Week 8 and was generally well tolerated. These results support phase 3 clinical development of alixorexton as a treatment for NT2. Support (if any) Alkermes, Inc.

Abstract Introduction Patients with Parkinson’s disease commonly underreport sleep symptoms, but the extent to which such mismatch may be present in people with isolated RBD (iRBD) is unknown. We evaluated how the patient–bedpartner (PT–BP) mismatch in night-time and daytime sleep complaints relates to cognition, apathy, dopaminergic degeneration, and cortical structure in iRBD. Methods We retrospectively analyzed 425 iRBD participants (2018–2025) from the North American Prodromal Synucleinopathy (NAPS) Consortium with clinicodemographic data, dopamine transporter (DAT) imaging, and magnetic resonance imaging. Using Scales for Outcomes in Parkinson’s Disease (SCOPA)-Sleep, PT–BP mismatch was classified into overestimator (PT>BP), concordant (PT=BP), and underestimator (PT< BP) groups, separately for complaints during night and day. Outcomes included cognition (CDR-Sum of Boxes [CDR-SB], CDR-global, and individual subdomain tests), pareidolia, apathy, subregional DAT uptake, and cortical thickness. Group differences were tested with analysis of covariance adjusting for age, sex, disease duration, education, clinician-rated OSA treatment inadequacy, and the corresponding patient-reported SCOPA-Sleep domain (night or day), and estimated total intracranial volume for cortical thickness; pairwise tests used Bonferroni correction. Results The PT–BP mismatch was common (night – overestimator 127/425, 29.9% and underestimator 116/425, 27.3%; day – overestimator 77/425, 18.1% and underestimator 134/425, 31.5%). For night-time mismatch, underestimators showed lower CDR-SB and lower CDR-global than overestimators. In addition, underestimators exhibited more illusory responses, fewer correct noise rejections, and fewer total correct responses than overestimator and concordant groups. For daytime mismatch, CDR-SB was lower in underestimators versus overestimators; CDR-global was lower in underestimators and concordant participants versus overestimators. No significant associations were found for apathy. Subregional DAT uptake did not differ by mismatch group. Cortical thickness analyses revealed thinner right transverse gyrus in underestimator and concordant groups compared to the overestimator group and thinner left superior temporal gyrus in underestimator group compared to overestimator group, for night-time mismatch only. Conclusion The PT–BP subjective sleep mismatch can be used as a clinical marker associated with overall cognitive decline and cortical thinning in auditory and language processing areas, which may underlie impairment in perceptual interpretation and hallucination proneness. Further research is warranted to seek longitudinal change and phenoconversion in mismatch groups. Support (if any) #U19-AG071754 (NAPS Consortium)

Abstract Introduction Low-sodium oxybate (LXB; Xywav®), the only FDA-approved treatment for idiopathic hypersomnia in adults, was evaluated in the phase 4, open-label DUET study (NCT05875974). This post-hoc analysis evaluated subgroups of participants with idiopathic hypersomnia stratified by patient-reported ideal nighttime sleep duration (with [>9 hours] and without [≤9 hours] long sleep need [LSN]), based on Idiopathic Hypersomnia Severity Scale (IHSS) Item 1. Methods DUET included screening, 8-day baseline (BL), 2−8-week LXB dose titration/optimization, 2-week stable-dose, 8-day end-of-treatment (EOT), and 2-week safety follow-up periods. Outcomes were Epworth Sleepiness Scale (ESS), IHSS, polysomnographic total sleep time (TST), and Patient Global Impression of Severity (PGI-S) and Change (PGI-C). Least squares mean (LSM) changes (BL-to-EOT) were BL-adjusted; P values are nominal. Treatment-emergent adverse events (TEAEs) were assessed by subgroup. Results Of 46 enrolled participants with idiopathic hypersomnia, 45 had BL IHSS data; 24 reported LSN (>9 hours) and 21 reported no LSN (≤9 hours). Most (LSN/without LSN) were female (100%/61.9%) and White (91.7%/76.2%), with mean±SD age 36.8±11.1/38.6±12.1 years; 20/24 and 19/21 completed the study. BL mean±SE (LSN/without LSN) ESS scores were 16.8±0.5/16.1±0.7; LSM changes (95% CI): LSN −9.5 (−11.5, −7.6; P< 0.0001; n=20), without LSN −7.4 (−9.4, −5.4; P< 0.0001; n=19). BL mean±SE (LSN/without LSN) IHSS total scores were 35.7±1.3/30.5±1.8; LSM changes (95% CI): LSN −18.3 (−22.4, −14.1; P< 0.0001; n=19), without LSN −12.5 (−16.9, −8.0; P< 0.0001; n=17). BL mean±SE (LSN/without LSN) IHSS long sleep/sleep inertia component scores were 12.5±0.6/9.2±0.6; LSM changes (95% CI): LSN −5.5 (−6.8, −4.1; P< 0.0001; n=19), without LSN −4.0 (−5.4, −2.5; P< 0.0001; n=17). BL mean±SE (LSN/without LSN) polysomnographic TSTs were 490.0±26.0/442.7± 24.7 minutes; LSM changes (95% CI): LSN −53.1 (−92.5, −13.7; P=0.0097; n=20), without LSN −59.4 (−99.8, −18.9; P=0.0052; n=19). On the PGI-C, most participants (LSN/without LSN) endorsed improved overall disease (100%/88.2%; n=19/n=17) at EOT. TEAEs were reported in 79.2% (LSN) and 66.7% (without LSN); most (LSN/without LSN) were mild (45.8%/42.9%) or moderate (33.3%/23.8%) in severity; 1 (without LSN) was serious (unrelated to study drug). Conclusion Participants with or without LSN (>9 hours or ≤9 hours, respectively) taking LXB showed improvements in multiple idiopathic hypersomnia symptoms and reduced TST. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Clinical hypnosis is among the limited treatment options currently available to mitigate the symptom burden associated with parasomnias; however, there is scant literature regarding its effectiveness. We conducted a retrospective cohort study to examine the efficacy of clinical hypnosis in treating parasomnias. Methods We included all adult patients with research authorization on file who were referred for clinical hypnosis for the management of parasomnias at the Mayo Clinic Center for Sleep Medicine. Data on demographics, type and frequency of parasomnia(s), number of hypnosis sessions, concurrent medication(s), and polysomnographic variables were extracted. Information about the efficacy of treatment, including patient reports of change in intensity and frequency was extracted where available. A Clinical Global Impression-Improvement (CGI-I) score was assigned based on review of the follow up note. Results A total of 134 patients received clinical hypnosis. A majority of the sample was female (65.67%) with a median age of 41.5 years. The most common indications were non-rapid eye movement (REM) parasomnia (33), REM sleep behavior disorder (27), nightmare disorder (24), parasomnia overlap disorder (11), and sleep-related eating disorder (8). Follow up data were available on 76 patients (56.71%). Of these, a total of 47/76 (61.84%) reported subjective improvement in parasomnias following hypnosis. The median CGI-I score was 3.07±1.22; a total of 23/76 (30.26%) reported substantial improvement and 19/76 (25.0%) reported some impovement based on the CGI scores. Conclusion A majority of patients reported improvement in symptoms. Clinical hypnosis was effective for both non-REM and REM parasomnias. Given its relative safety and minimal potential adverse effects, clinical hypnosis remains an effective first-line treatment option for parasomnias. Support (if any)

Abstract Introduction Daily fluctuations in sleep disturbances have been shown to shape pain experiences among individuals with chronic pain. Additional biobehavioral factors, such as abuse history, depression, current and long-term anxiety, opioid use, physical functioning, and fatigue, may also affect daily pain outcomes. Yet the extent to which these factors collectively contribute to daily pain intensity and unpleasantness remains insufficiently understood. Methods Using baseline data from the SPINII randomized controlled trial (R01NR017168; McCrae, PI), women with insomnia and fibromyalgia (N = 294, x- age = 40) completed 14 days of sleep diaries assessing sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and pain intensity and unpleasantness (0–100). Additional predictors included abuse history, Beck Depression Inventory (BDI), State–Trait Anxiety Inventory (STAI), and PROMIS-57 physical functioning and social functioning. Linear mixed models examined the effects of sleep and related factors on daily pain. Results Significant predictors of pain intensity included higher between-person SOL (b = 0.08, p < .001) and WASO (b = 0.08, p < .001), lower between-person TST (b = -0.10, p < .001), lower within-person TST (b = −0.03, p < .001), opioid use (b = 2.84, p = .029), poorer physical functioning (b = −0.35, p = .008), and higher depression scores (b = 0.20, p = .046). Pain unpleasantness showed nearly identical patterns, with only physical functioning becoming non-significant. Random intercepts and residual variance values were significant in both models (p < .001), indicating within- and between-person variation in pain. ICCs of .80-.85 revealed that the majority of variance was between-person, while non-significant autocorrelations (p > .05) indicated minimal day-to-day carryover effects beyond stable individual differences. Conclusion Overall sleep quality and emotional health shape pain experience more strongly than daily fluctuations. Although TST offers some next-day relief, chronic contributors are more relevant to daily pain. Effects were largely consistent; between- and within-person TST showed strong effects, and depression had a slightly larger effect on pain unpleasantness than pain sensitivity, reinforcing a multidimensional biopsychosocial pain process. These findings highlight the need for integrated interventions that strengthen sleep, emotional well-being, and physical functioning. Support (if any) NIDA

Abstract Introduction Central sleep apnea (CSA) may occur as an adverse effect of sodium oxybates, a medication commonly used to treat narcolepsy with cataplexy. Management is challenging, as sodium oxybates remain essential for symptom control in many patients, yet untreated CSA poses substantial respiratory risk. We present a rare case of sodium-oxybate–associated CSA successfully treated with adaptive servo ventilation (ASV), representing, to our knowledge, the first documented use of ASV for this indication. Methods A 49-year-old woman with longstanding narcolepsy with cataplexy presented with worsening daytime sleepiness despite stable use of sodium oxybate. She had been receiving a very high dose prescribed by an outside provider (6.75 g twice nightly), exceeding the recommended maximum of 4.5 g twice nightly, and her dose was subsequently adjusted to 4.5 g twice nightly. An in-lab polysomnogram revealed moderate central sleep apnea (AHI 21; RDI 23) with predominantly central events. Because the patient did not wish to wean or discontinue sodium oxybate—reporting that it remained the only therapy that consistently improved her sleep and cataplexy—adaptive servo ventilation (ASV) titration was pursued as the next step in management. She had previously failed multiple stimulants, wake-promoting agents, and SSRIs due to either limited efficacy or intolerable side effects. Her BMI was 18 kg/m2, she was not taking any CNS depressant medications, and her echocardiogram demonstrated a normal ejection fraction. Results The patient tolerated ASV well. Final settings included an EPAP of 5 cm H₂O with a pressure support range of 3–15 cm H₂O and minimal leak. Her adherence was excellent, with more than 93% of nights exceeding four hours of use. Residual AHI improved to 4.6 events per hour, accompanied by noticeable improvement in daytime alertness. She continued sodium oxybate without any respiratory complications. Conclusion ASV may be an effective and well-tolerated therapy for sodium-oxybate–induced CSA in patients who must continue the medication. Sodium oxybate can induce CSA by acting on GABA-B receptors in the Kölliker–Fuse and pre-Bötzinger complex, suppressing respiratory drive and depressing hypoglossal motor output. This case highlights the successful use of ASV in treating CSA secondary to oxybates when the medication cannot be weaned or discontinued. Support (if any)

Abstract Introduction Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia strongly associated with α-synucleinopathies, most commonly Parkinson’s disease (PD). Among Veterans, posttraumatic stress disorder (PTSD) is common and may influence RBD presentation and outcomes. The extent to which PTSD modifies demographic, medical, and mortality profiles in Veterans with RBD, and how these differ from those with RBD and Parkinson’s disease (PD), remains poorly characterized. Methods We conducted a retrospective cohort study using the Veterans Health Administration Corporate Data Warehouse. Veterans with at least one ICD-9 or ICD-10 diagnostic code for RBD were identified between 1999 - 2020 and categorized into three, mutually-exclusive groups based on the presence or absence of co-occurring ICD codes: RBD-only, RBD+PTSD, or RBD+PD. Demographics, comorbidities (Charlson Comorbidity Index [CCI]), and mortality outcomes were compared using logistic regression models adjusted for age, sex, race/ethnicity, BMI, and CCI. Results The cohort included 11,283 Veterans with RBD only, 17,527 with RBD+PTSD, and 5,675 with RBD+PD. Veterans with RBD+PTSD were younger (mean 58.9 ± 14.9 y) and had higher psychiatric comorbidity (94.2%) compared to RBD only (54.2%) or RBD+PD (46.5%). Those with RBD+PD were older (73.6 ± 8.1 y), predominantly male (98.9%), and had the highest neurological comorbidity (92.6%). Unadjusted mortality was lowest in RBD+PTSD (15.3%) and highest in RBD+PD (53.6%). Adjusted models showed reduced mortality risk for RBD+PTSD (aOR 0.73, 95% CI 0.70–0.80, p < 0.001) and increased risk for RBD+PD (aOR 2.43, 95% CI 2.3–2.6, p < 0.001) vs. RBD alone. Higher age, male sex, and greater comorbidity independently predicted mortality. Conclusion In this large national VA cohort, comorbid PTSD and Parkinson’s disease were associated with distinct demographic and clinical profiles among Veterans with RBD. RBD+PTSD was linked to younger age, greater psychiatric burden, and lower mortality. These findings underscore the heterogeneity of RBD in Veterans and support stratified approaches to surveillance for synucleinopathy and trauma-related sleep disturbances. Support (if any) VA CDA # IK2CX002363-01A1 (MJ); NHLBI K25 #1K25HL152006-01 (JR)

Abstract Introduction Once-nightly sodium oxybate (ON-SXB) is approved to treat cataplexy or excessive daytime sleepiness (EDS) in patients ≥7 years of age with narcolepsy. ON-SXB demonstrated significant improvements in both objective (Maintenance of Wakefulness Test) and subjective (Epworth Sleepiness Scale [ESS] score) measurements of sleepiness in the REST-ON trial and via the ESS in the real-world REFRESH study. Assessing ON-SXB ESS data from a specialty pharmacy and outside of clinical studies further informs the generalizability of effectiveness. Methods Demographic and clinical data were collected from Optum Frontier Therapies pharmacy for patients with ≥1 filled ON-SXB prescription, ≥1 ON-SXB-related clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). Participation in ESS assessment was voluntary. ESS scores were assessed for patients who switched from twice-nightly oxybate (TN-OXB) treatment (first ON-SXB prescription filled ≤30 days of last TN-OXB prescription [switch]) and those new to oxybate or with >30 days between TN-OXB and ON-SXB prescription fills (not-on-oxybate) who had ESS data at initial ON-SXB prescription and at each follow-up assessment. Results Of 452 identified patients, 215 had ≥1 follow-up ESS score (switch, n=82 [mean age, 38.4 years; female, 71%]; not-on-oxybate, n=133 [mean age, 40.0 years; female, 71%]). Of patients who had any prior oxybate use (switch, 100%; not-on-oxybate, 46%), the most common prior oxybate was mixed-salt oxybates (switch, 59%; not-on-oxybate, 70%). Stimulants/wake-promoting agents were taken by 51% of switch and 65% of not-on-oxybate patients. Baseline mean (SD) ESS scores were 11.3 (5.5) for switch and 12.5 (5.6) for not-on-oxybate patients; 23% of switch and 38% of not-on-oxybate patients experienced severe EDS. By the first follow-up (median [IQR], 49 [28-94] days), mean (SD) ESS scores were within the normal EDS range with ON-SXB for both subgroups (ie, ESS < 10; switch, 9.7 [5.5]; not-on-oxybate, 9.5 [5.2]); the majority reported normal levels of daytime sleepiness (switch, 56%; not-on-oxybate, 57%). Mean (SD) change in ESS score from baseline to follow-up was -1.6 [4.5] for switch and -3.1 [5.0] for not-on-oxybate groups. Conclusion Patients who initiated ON-SXB experienced improvements in daytime sleepiness regardless of prior TN-OXB use, and many achieved normal levels of daytime sleepiness in ≤2 months of starting ON-SXB. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Zolpidem is a commonly prescribed FDA- approved hypnotic. In 2013, the FDA recommended reducing maximum dosing of zolpidem in female patients due to concern for slower elimination time as compared to their male counterparts. Despite this, none of the FDA warnings or communications cited published studies that support the claim that women are at increased risk of adverse events. Subsequent prescribing data has shifted to reflect FDA recommendations. In this study we examined risks of using above FDA recommended doses in female patients. Methods This is a retrospective chart review including all adult female patients (> 18 years old) evaluated and managed at the Mayo Clinic Center for Sleep Medicine between 1/1/2024 to 12/31/2024. Detailed review of Mayo Clinic’s EMR was accomplished with subjects on zolpidem split into supratherapeutic and non-supratherapeutic dosing groups. Subjects were relegated to the above maximum dose group if they were ever prescribed FDA-defined supratherapeutic dosing (>5 mg IR formulation or >6.25 mg ER formulation) for a >1 week period. Adverse events were defined as: falls, parasomnias, and cognitive impairment determined via ICD-10-CM codes that occurred at any period following zolpidem initiation. We analyzed rates of adverse effects using chi-square test of independence and Fischer’s exact test in patients with or without supratherapeutic dosing. Results 435 female patients met inclusion criteria. Among the demographic characteristics, only weight was associated with receiving a higher dose of zolpidem (P< 0.001). There were similar rates of adverse effects in both dosing groups with 11.4% of female patients on supratherapeutic dosing as compared to 10.9% of female patients on non-supratherapeutic dosing reporting adverse effects (chi-square test of independence (X2=6.5, N=435, p=0.99) or Fischer’s exact test (OR=1.05, p=0.87). Conclusion Overall, there was not a significant difference in rates of adverse events in female patients receiving supratherapeutic vs non-supratherapeutic doses of zolpidem during the time frame described. Further studies are warranted to better elucidate longitudinal risk of adverse effects related to gender-related differences with zolpidem dosing. Support (if any)