The Interaction Between Brain-Derived Neurotrophic Factor Levels and Alcohol Consumption, Sleep Disturbance and Sex-Hormones in Alcohol Use Disorders.

AIMS: Brain-derived neurotrophic factor (BDNF) levels may be associated with alcohol use disorders (AUD) and alcohol consumption, correlate with sleep disturbance and be influenced by sex differences and sex hormones. These associations have not been examined in a single sample accounting for all these factors. METHODS: Data from 190 participants (29.4% female) with AUD were utilized. Sleep quality, craving intensity, depression, anxiety and alcohol consumption were assessed using the Pittsburgh Sleep Quality Index (PSQI), Penn Alcohol Craving Scale (PACS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and Timeline Follow Back for 90 days(TLFB 90). Inventory of Drug Taking Situations (IDTS) assessed the tendency to drink in positive/negative emotional states. Serum BDNF (sBDNF) and plasma sex hormones (estrogen, progesterone, testosterone, FSH and SHBG) were measured. Pearson correlation analyses were used to examine the association between sBDNF and these measures in the entire sample and in men and women separately. Higher order interaction effects between these factors were evaluated for their association with sBDNF using a backward selection model. RESULTS: No significant correlations between sBDNF levels and sex hormones, PSQI, PHQ-9, PACS, IDTS scores and alcohol consumption were found (all P-values > 0.05). sBDNF levels were negatively correlated with GAD-7 scores in men (r = -0.1841; P = 0.03). When considering all quadratic and two-way interactions among PSQI, PHQ-9, GAD-7, mean and max drinks/day, number of drinking days, heavy drinking days, and sex no higher order moderating effects of sBDNF levels were found. CONCLUSION: Our study revealed no significant associations between sBDNF and alcohol measures, sleep, depression and sex hormones suggesting limited utility as a biomarker.

Assessing the quality of publicly available videos on MDMA-assisted psychotherapy for PTSD.

BACKGROUND AND OBJECTIVES: Patients increasingly rely on the Internet for healthcare information. This study aimed to evaluate the quality of videos on 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder (PTSD) on YouTube™. METHODS: YouTube™ was searched for the terms "MDMA" and "PTSD." The 100 most viewed videos were analyzed using three standard quality measures: Global Quality Scores (GQS), JAMA benchmark, and DISCERN. Viewer engagement features and source of upload, video duration, inclusion of patient narrative and/or MD/DO/PhD, the mention of lack of Food and Drug Administration (FDA) approval, side effects, potential for abuse, and use in conjunction with psychotherapy were recorded. RESULTS: The videos were of poor quality (mean GQS: 2.26 ± 0.94/5, JAMA: 1.96 ± 0.45/4, and DISCERN: 29.5 ± 8.2/80). A significant positive association was found between video quality and duration (GQS: r = .5857, p < .0001, JAMA: r = .279, p = .0409, DISCERN: r = .5783, p < .0001). Videos including an MD/DO/PhD had the highest scores (GQS: 2.87/5 [1.22], p = .006, DISCERN: 38.35/80 [13.32], p < .0003). A minority of videos were uploaded by academic institutions (1%); most were from professional organizations (29%). No correlation was found between quality and viewer engagement features-number of views, subscribers, likes/dislikes, or comments. A majority mentioned that MDMA must be used in conjunction with psychotherapy (85%) and is not FDA-approved (82%) for PTSD. Only 32% of videos mentioned risks or potential for abuse. CONCLUSIONS: These findings highlight the need for better quality of online health material and an opportunity for involvement of healthcare professionals in the dissemination of accurate health information via content creation. SCIENTIFIC SIGNIFICANCE: This is the first study to examine publicly available information on the use of MDMA for PTSD.

Increased Patient Safety-Related Incidents Following the Transition into Daylight Savings Time.

BACKGROUND: "Spring forward," the start of daylight savings time (DST), reduces sleep opportunity by an hour. Insufficient sleep in healthcare workers resulting from the spring forward time change could potentially result in an increase in medical errors. OBJECTIVE: We examined the change in reported patient safety-related incidents (SRIs), in the week following the transition into and out of DST over a period of 8 years. DESIGN: Observational study SETTING: A US-based large healthcare organization with sites across multiple states MEASUREMENTS: Voluntarily reported SRIs that occurred 7 days prior to and following the spring and fall time changes for years 2010-2017 were ascertained. SRIs likely resulting from human error were identified separately. The changes in the number of SRIs (either all SRIs or SRIs restricted to those likely resulting from human error) from the week before and after the time change (either spring or fall) were modeled using a negative binomial mixed model with a random effect to correct for non-independent observations in consecutive weeks. RESULTS: Over the 8-year period, we observed 4.2% (95% CI: - 1.1 to 9.7%; p = 0.12) and 8.8% (95% CI: - 2.5 to 21.5%; p = 0.13) increases in overall SRIs in the 7 days following DST when compared with 7 days prior for spring and fall, respectively. By restricting to SRIs likely resulting from human errors, we observed 18.7% (95% CI: 5.6 to 33.6%; p = 0.004) and 4.9% (95% CI: - 1.3 to 11.5%; p = 0.12) increases for spring and fall, respectively. CONCLUSION: Policy makers and healthcare organizations should evaluate delayed start of shifts or other contingency measures to mitigate the increased risk of SRIs during transition to DST in spring.

Postoperative outcomes in patients with treatment-emergent central sleep apnea: a case series.

PURPOSE: Treatment-emergent central sleep apnea (TECSA) is a central sleep-related breathing disorder, characterized by either the persistence or emergence of central sleep apnea during the initiation of positive airway pressure therapy for obstructive sleep apnea. The purpose of this study was to review the perioperative course of patients diagnosed with TECSA. METHODS: We reviewed medical records of patients with TECSA who had a procedure or surgery with general anesthesia between January 1, 2009 and May 1, 2018. We describe postoperative outcomes including respiratory complications, unplanned intensive care unit (ICU) admissions, and other postoperative outcomes. RESULTS: We identified 150 (116 male, 34 female) patients with TECSA. Of these, 39 (26%) had their anesthesia recovery associated with moderate to profound sedation, 22 (14.7%) required unplanned transfer to ICU (8 for hypoxemia). Compared to patients without ICU admissions, patients with unplanned ICU admissions had higher rates of cardiovascular disease, Charlson comorbid scores, and perioperative benzodiazepines. Within the first 30 postoperative days there were 23 (16%) hospital re-admissions, and 7 (4.6%) deaths. CONCLUSION: Patients with TECSA have high rates of postoperative complications, characterized by an increased rate of unplanned intensive care admissions and both high 30-day readmission and mortality rates. When dealing with these patients perioperative physicians should implement an increased level of respiratory monitoring, and early postoperative use of their home prescribed non-invasive ventilation devices.

Primary central sleep apnea and anesthesia: a retrospective case series.

PURPOSE: Primary (idiopathic) central sleep apnea (PCSA) is a rare central sleep-related breathing disorder characterized by increased chemoreceptor sensitivity to partial pressure of carbon dioxide, which manifests as hyperventilation followed by apnea during non-rapid eye movement sleep. The purpose of this retrospective study was to describe the postoperative course of patients who had PCSA and underwent procedures requiring anesthetic management. METHODS: Patients who received a diagnosis of PCSA at our institution and required procedural anesthesia between 1 January 2010 and 1 June 2016 underwent a comprehensive review of their health records with a focus on identifying respiratory complications. RESULTS: Ten patients (nine males, one female) underwent 47 procedures requiring anesthetic management: 20 (43%) under general anesthesia, 25 (53%) with monitored anesthetic care, and two (4%) with regional anesthesia. Procedures were complicated by second-degree heart block in one patient and pneumonia in another two (one had Ivor-Lewis esophagectomy and the other bronchoscopy to evaluate worsening lung infiltration). Hypoxemia (oxyhemoglobin saturation < 90% for three minutes) developed in three patients during anesthesia recovery. One was possibly due to PCSA-a 73-yr-old male with alcoholic cirrhosis who was moderately sedated and hypoxemic after orthopedic surgery; his oxygenation improved with an adaptive servoventilator positive airway pressure device and supplemental oxygen. His underlying medical condition or level of sedation may have contributed to hypoxemia. The other patients became hypoxemic after bronchoscopy. No other cases were complicated by postoperative respiratory compromise. CONCLUSIONS: No major adverse outcomes were related to PCSA postoperatively. Nevertheless, continuation of home positive airway pressure therapy during anesthesia recovery was useful in one patient who had cirrhosis and postoperative hypoxemia.

Sleep, death, and the heart.

Obstructive and central sleep apnea have been associated with increased risk of adverse cardiovascular events and mortality. Sympathetic dysregulation occurring as a result of the respiratory disturbance is thought to play a role in this increased risk. Sleep apnea increases the risk of arrhythmias, myocardial ischemia/infarction, stroke, and heart failure, all of which may increase mortality risk. A higher incidence of nocturnal arrhythmias, cardiac ischemia, and sudden death has been noted in subjects with sleep-disordered breathing (SDB). In this review, the association between SDB and each of these conditions is discussed, as well as the potential mechanisms underlying these risks and the effects of treatment of SDB. Particular emphasis is placed on the relationship between SDB and nocturnal atrial and ventricular arrhythmias, myocardial ischemia/infarction and sudden death.

Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans.

NEW FINDINGS: What is the topic of this review? This review summarizes chemoreflex physiology in health and disease, with specific focus on chemoreflex-mediated pathophysiology in obstructive and central sleep apnoea. What advances does it highlight? Chemoreflex mechanisms are thought to contribute significantly to the pathophysiology and adverse outcomes seen in sleep apnoea. Clinical implications of altered chemoreflex function in sleep apnoea from recent studies in humans, including cardiac arrhythmias, coronary artery disease, systolic/diastolic heart failure and sudden cardiac death are highlighted. Activation of the chemoreflex in response to hypoxaemia results in an increase in sympathetic neural outflow. This process is predominantly mediated by the peripheral chemoreceptors in the carotid bodies and is potentiated by the absence of the sympatho-inhibitory influence of ventilation during apnoea, as is seen in patients with sleep apnoea. In these patients, repetitive nocturnal hypoxaemia and apnoea elicit sympathetic activation, which may persist into wakefulness and is thought to contribute to the development of systemic hypertension and cardiac and vascular dysfunction. Chemoreflex activation could possibly lead to adverse cardiovascular outcomes, such as nocturnal myocardial infarction, systolic and/or diastolic heart failure, cardiac arrhythmias and sudden death in patients with sleep apnoea. This review summarizes chemoreflex physiology in health and disease, with specific focus on chemoreflex-mediated pathophysiology in obstructive and central sleep apnoea. Measurement of the chemoreflex response may serve as a potential avenue for individualized screening for cardiovascular disease. Whether modulation of this response in sleep apnoea may aid in the prevention and treatment of adverse cardiovascular consequences will require further study.

The association between sleep disturbances and alcohol relapse: A 12-month observational cohort study.

BACKGROUND: Sleep disturbances are extremely common in alcohol recovery. Systematic research into the relationship between alcohol relapse and sleep disturbances using validated scales and accounting for potential confounders is lacking. METHODS: Patients admitted to a 1-month residential addiction treatment program were administered the Pittsburg Sleep Quality Index (PSQI) at admission/discharge. In addition, the Alcohol Use Disorders Identification Test (AUDIT), Patient Health Questionnaire-9 (PHQ-9), and Pennsylvania Alcohol Craving Scale (PACS) were administered. Patients were contacted every 3 months over 1 year following discharge. Associations of clinical factors with time until relapse were examined using univariate Cox proportional hazard models. RESULTS: One-hundred and nineteen patients with alcohol use disorders met inclusion criteria (mean age 50.6 ± 13.2 years, 57% male), relapse data were available for 81 patients. Eighty percent of subjects had other psychiatric diagnoses, 66.3% had sleep disturbances at the time of admission, and 57.1% were using hypnotics; 49.1% of patients had sleep disturbances at discharge. Sleep disturbances at admission and discharge were not associated with alcohol relapse at 12 months (OR = 1.00, 95% CI = 0.89-1.13; p = 0.95 and OR = 0.97, 95% CI = 0.86-1.09; p = 0.61). The PSQI sub-scale scores were also not associated with relapse at 12 months. The use of alcohol to help fall asleep (OR = 3.26, 95% CI = 1.33-7.95; p = 0.008), hypnotic use at admission (OR = 4.03, 95% CI = 1.63-9.97; p = 0.002) and age (OR = 1.03, 95% CI = 1.00-1.06; p = 0.035) were associated with relapse over 12 months. CONCLUSION: In patients completing a residential treatment program, sleep disturbances as measured by the PSQI were not associated with alcohol relapse at 12 months. Alcohol use as a hypnotic and hypnotic use at admission were associated with subsequent relapse.

Chemoreflexes, sleep apnea, and sympathetic dysregulation.

Obstructive sleep apnea (OSA) and hypertension are closely linked conditions. Disordered breathing events in OSA are characterized by increasing efforts against an occluded airway while asleep, resulting in a marked sympathetic response. This is predominantly due to hypoxemia activating the chemoreflexes, resulting in reflex increases in sympathetic neural outflow. In addition, apnea - and the consequent lack of inhibition of the sympathetic system that occurs with lung inflation during normal breathing - potentiates central sympathetic outflow. Sympathetic activation persists into the daytime, and is thought to contribute to hypertension and other adverse cardiovascular outcomes. This review discusses chemoreflex physiology and sympathetic modulation during normal sleep, as well as the sympathetic dysregulation seen in OSA, its extension into wakefulness, and changes after treatment. Evidence supporting the role of the peripheral chemoreflex in the sympathetic dysregulation seen in OSA, including in the context of comorbid obesity, metabolic syndrome, and systemic hypertension, is reviewed. Finally, alterations in cardiovascular variability and other potential mechanisms that may play a role in the autonomic imbalance in OSA are also discussed.

Correlates to Improvement in Sleep Duration in Acute Mania and Depression.

Objective: To examine sleep duration at admission and discharge and change in sleep duration during hospitalization in patients experiencing a manic episode and compare these parameters to patients hospitalized for major depressive disorder (MDD) during the same time frame. The correlation between sleep duration parameters in those with mania and MDD with length of hospital stay, after accounting for possible confounders, was also examined.Methods: This retrospective study examined patients admitted to an acute care psychiatric unit from 2018 to 2021 with an episode of mania or MDD. Sleep duration was determined based on nursing observer report.Results: The study included 41 patients with mania (32.9 ± 1.7 years) and 38 patients with MDD (32.7 ± 1.8 years). Mania patients had longer hospitalization and received higher antipsychotic and benzodiazepine doses, but fewer hypnotics (all P < .005). No differences were found in sleep duration at admission (P = .109) and discharge (P = .623) in the mania and MDD groups. Change in sleep duration was 1.14 ± 0.27 and 0.37 ± 0.28 hours (P = .05) in the groups, respectively. In those with mania, sleep duration at admission negatively correlated with length of stay (r = -0.033; P = .03). Sleep duration parameters were not correlated with length of stay in patients with MDD.Conclusion: There was a trend toward greater improvement in sleep duration in inpatients with mania versus MDD. Sleep duration at admission correlated with length of hospitalization in patients with mania. Future studies should examine whether attempts to increase sleep duration can improve patient outcomes.Prim Care Companion CNS Disord 2024;26(1):23m03620. Author affiliations are listed at the end of this article.

Prevalence and associations of multiple hypnotic prescriptions in a clinical sample.

STUDY OBJECTIVES: We examined the prevalence of multiple hypnotic prescriptions and its association with clinical and demographic characteristics from the electronic health record (EHR) in the Mayo Clinic Biobank. METHODS: Adult participants enrolled in the Mayo Clinic Biobank with an EHR number of ≥ 1 year were included (n = 52,940). Clinical and demographic characteristics were compared between participants who were and were not prescribed any hypnotic approved for insomnia by the US Food and Drug Administration and/or trazodone and in those prescribed a single vs multiple (≥ 2) hypnotics. A phenotype-based, phenome-wide association study (PheWAS) examining associations between hypnotic prescriptions and diagnoses across the EHR was performed adjusting for demographic and other confounders. RESULTS: A total of 17,662 (33%) participants were prescribed at least 1 hypnotic and 5,331 (10%) received ≥ 2 hypnotics. Participants who were prescribed a hypnotic were more likely to be older, female, White, with a longer EHR, and a greater number of diagnostic codes (all P < .001). Those with multiple hypnotic prescriptions were more likely to be younger, female, with a longer EHR, and a greater number of diagnostic codes (all P < .001) compared with those prescribed a single hypnotic. The PheWAS revealed that participants with multiple hypnotic prescriptions had higher rates of mood disorders, anxiety disorders, suicidal ideation, restless legs syndrome, and chronic pain (all P < 1 e-10). CONCLUSIONS: Receiving multiple hypnotic prescriptions is common and associated with a greater prevalence of psychiatric, chronic pain, and sleep-related movement disorders. Future studies should examine potential genetic associations with multiple hypnotic prescriptions to personalize treatments for chronic insomnia. CITATION: Kolla BP, Mansukhani MP, Chakravorty S, Frank JA, Coombes BJ. Prevalence and associations of multiple hypnotic prescriptions in a clinical sample. J Clin Sleep Med. 2024;20(5):793-800.

Aging and sex are associated with multiple sleep latency test findings and their relationship with self-reported sleepiness.

The aim of this study was to assess age- and sex-related differences in multiple sleep latency test (MSLT) results and in the performance of the Epworth Sleepiness Scale (ESS) at classifying objective hypersomnia (mean sleep latency (MSL) ≤ 8 min). We studied 480 consecutive adults (39.3 ± 15.3 years old [18-93], 67.7% female) who underwent hypersomnia evaluation. We fit linear regression models to investigate associations between age and sex and sleep latencies (mean and for every nap), after adjusting for total sleep time and sleep efficiency (on polysomnography), and REM-suppressing antidepressant effect. A logistic regression was performed to assess whether age and sex were associated with sleep-onset REM period (SOREMP) occurrence. ROC analysis assessed the diagnostic performance of ESS scores to identify a MSL ≤ 8 min in different age/sex groups. For every 10 years of age, there was 0.41 (95% CI 0.11-0.72, p = 0.008) min reduction in MSL. Objectively (MSL ≤ 8 min) sleepy patients had shortening of latencies in naps 4 and 5 with aging. Female sex was associated with a higher MSL only in patients with MSL > 8 min. A 2.4% reduction in the odds of SOREMP occurrence was observed for every year of age in objectively sleepy patients (p = 0.045). ESS scores had a better diagnostic performance in older (≥ 50 years old) men than younger (< 50 years old) women (p < 0.05). Older patients with objectively confirmed hypersomnia may be sleepier in later naps, possibly due to less restorative naps and/or circadian rhythm factors. Self-reported sleepiness is more predictive of objective sleepiness in older men than younger women.

Correction: Aging and sex are associated with multiple sleep latency test findings and their relationship with self-reported sleepiness.

[This corrects the article DOI: 10.1007/s41105-024-00512-5.].

Are clinical trials for insomnia recruiting real-world patients?

Recent Phase III trials of hypnotic medications that have led to Food and Drug Administration approval have severely restrictive eligibility criteria. One hundred patients referred for insomnia who received a hypnotic medication at a large tertiary referral center were identified. Data were extracted to evaluate whether these patients would be eligible to be included in any of the recent Phase III trials. Of the 100 patients identified, only 3 were eligible. Most were excluded because of a prior or concurrent trial of cognitive behavioral therapy for insomnia. If this criterion were set aside, only 12% would have been eligible to participate. The remaining top reasons for exclusion were medical comorbidities, daytime napping, and sleep apnea. These findings question the generalizability of the regulatory studies and suggest that future trials should enroll patients with less-restrictive criteria to help determine the effectiveness of these medications in real-world settings. CITATION: Golebiowski R, Mansukhani MP, Kolla BP. Are clinical trials for insomnia recruiting real-world patients? J Clin Sleep Med. 2023;19(8):1553-1555.

Prophylactic Use of Ramelteon for Delirium in Hospitalized Patients: A Systematic Review and Meta-Analyses.

BACKGROUND: Small prospective studies, case reports, as well as some randomized placebo-controlled trials and previous meta-analyses have shown that ramelteon, a melatonin agonist, may reduce the risk of developing delirium. OBJECTIVE: The goal of this systemic review and meta-analyses was to assess the current evidence supporting the use of ramelteon in delirium prevention by including data from larger (>100 subjects) and more recent trials since the most recent meta-analyses were published in 2019. There were no exclusions for trial size, age, ramelteon dose, length of treatment, or hospital setting. METHODS: Medline, Embase, PsycINFO, EBM Reviews, Scopus, and Web of Science databases were queried using the search terms delirium (with subterms including prevention and control), ramelteon, Rozerem, or melatonin receptor agonists, for English-language publications until March 16, 2021. Randomized placebo-controlled trials of hospitalized subjects receiving ramelteon for delirium prevention were included. The primary outcome of interest was delirium incidence. Odds ratios of the risk of developing incident delirium and 95% confidence intervals were calculated using a random effects model. RESULTS: A total of 177 articles were identified by the literature search. Five studies (n = 443, 53.7% male) met criteria for inclusion in the final meta-analyses. The meta-analyses of the randomized placebo-controlled trials revealed that ramelteon did not result in a reduction in the risk of incident delirium (n = 443; odds ratio = 0.49; 95% confidence interval = 0.13-1.85). A moderate degree of heterogeneity was noted among the studies (I2 = 53%). CONCLUSIONS: Current evidence suggests that ramelteon is ineffective as a prophylactic drug in reducing the incidence of delirium in hospitalized patients.

Sex-specific associations between daytime sleepiness, chronic diseases and mortality in obstructive sleep apnea.

Objective: Excessive daytime sleepiness (EDS) is common in obstructive sleep apnea (OSA) and has been linked to adverse outcomes, albeit inconsistently. Furthermore, whether the prognostic impact of EDS differs as a function of sex is unclear. We aimed to assess the associations between EDS and chronic diseases and mortality in men and women with OSA. Methods: Newly-diagnosed adult OSA patients who underwent sleep evaluation at Mayo Clinic between November 2009 and April 2017 and completed the Epworth Sleepiness Scale (ESS) for assessment of perceived sleepiness (N = 14,823) were included. Multivariable-adjusted regression models were used to investigate the relationships between sleepiness, with ESS modeled as a binary (ESS > 10) and as a continuous variable, and chronic diseases and all-cause mortality. Results: In cross-sectional analysis, ESS > 10 was independently associated with lower risk of hypertension in male OSA patients (odds ratio [OR], 95% confidence interval [CI]: 0.76, 0.69-0.83) and with higher risk of diabetes mellitus in both OSA men (OR, 1.17, 95% CI 1.05-1.31) and women (OR 1.26, 95% CI 1.10-1.45). Sex-specific curvilinear relations between ESS score and depression and cancer were noted. After a median 6.2 (4.5-8.1) years of follow-up, the hazard ratio for all-cause death in OSA women with ESS > 10 compared to those with ESS ≤ 10 was 1.24 (95% CI 1.05-1.47), after adjusting for demographics, sleep characteristics and comorbidities at baseline. In men, sleepiness was not associated with mortality. Conclusion: The implications of EDS for morbidity and mortality risk in OSA are sex-dependent, with hypersomnolence being independently associated with greater vulnerability to premature death only in female patients. Efforts to mitigate mortality risk and restore daytime vigilance in women with OSA should be prioritized.

Sleep apnea and autonomic dysfunction in patients with dementia.

Sleep apnea is common sleep disorder that is associated with an is an increase in risk of many health conditions, including systemic hypertension, stroke, atrial fibrillation, and heart failure. The predominant underlying pathophysiological mechanism for elevated risk of these conditions in patients with sleep apnea is thought to involve autonomic dysfunction in the form of sympathetic overactivity. Autonomic dysfunction is also associated with several neurodegenerative disorders and sleep apnea, in turn, has been shown to be associated with an increased risk of development of mild cognitive impairment and various types of dementia. Rapid eye movement sleep behavior disorder, which is also associated with an increased risk of alpha synucleiopathy-related dementia, is also linked with autonomic dysfunction. In this article we explore the relationship between sleep apnea, autonomic dysfunction, rapid eye movement sleep behavior disorder and dementia. This article describes the various autonomic dysfunction that are thought to occur in the context of sleep apnea. And illustrate the mechanisms by which sleep apnea, through its impact on autonomic dysfunction could potentially result in dementia. We also review the evidence examining the impact of treatment of sleep apnea on autonomic dysfunction and cognitive outcomes.