Effects of the antipsychotic quetiapine on sleep and breathing: a review of clinical findings and potential mechanisms

OnlinePublQuetiapine is an antipsychotic medication indicated for schizophrenia and bipolar disorder. However, quetiapine also has hypnotic properties and as such is increasingly being prescribed at low doses ‘off-label’ in people with insomnia symptoms. Pharmacologically, in addition to its dopaminergic properties, quetiapine also modulates multiple other transmitter systems involved in sleep/wake modulation and potentially breathing. However, very little is known about the impact of quetiapine on obstructive sleep apnoea (OSA), OSA endotypes including chemosensitivity, and control of breathing. Given that many people with insomnia also have undiagnosed OSA, it is important to understand the effects of quetiapine on OSA and its mechanisms. Accordingly, this concise review covers the existing knowledge on the effects of quetiapine on sleep and breathing. Further, we highlight the pharmacodynamics of quetiapine and its potential to alter key OSA endotypes to provide potential mechanistic insight. Finally, an agenda for future research priorities is proposed to fill the current key knowledge gaps.Cricket Fauska, Tarun Bastiampillai, Robert J. Adams, Gary Wittert, Danny J. Eckert, Kelly A. Loffle

Expression-based strategies for discovery of genes involved in testis and ovary development

In recent years, strategies for gene identification based on differential gene expression have become increasingly popular, due in part to the development of microarray technology. These strategies are particularly well suited to the identification of genes involved in sex determination and gonadal development, which unlike the development of other organ systems, proceeds along two very different alternative courses, depending on the sex of the embryo. We have used a high-throughput, array-based expression screen to identify several genes expressed sex-specifically in developing mouse gonads. One of these, vanin 1, appears to play a role in mediating migration of mesonephric cells into the male genital ridge. Progress in characterizing other genes arising from the screen is discussed

The norepinephrine reuptake inhibitor reboxetine alone reduces obstructive sleep apnea severity: a double-blind, placebo-controlled, randomized crossover trial

Study objectives: Recent findings indicate that noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. However, to date, reductions in obstructive sleep apnea (OSA) severity have only been detected when noradrenergic agents are combined with an antimuscarinic. Accordingly, this study aimed to determine if reboxetine alone and combined with oxybutynin reduces OSA severity. The pathophysiological mechanisms underpinning the effects of these agents were also investigated via endotyping analysis. Methods: Sixteen people (6 women) with OSA completed 3 polysomnograms (∼1-week washout) according to a double-blind, placebo-controlled, three-way crossover design across 2 sites. Single doses of 4 mg reboxetine, placebo, or 4 mg reboxetine + 5 mg oxybutynin were administered before sleep (order randomized). Results: Reboxetine reduced the apnea-hypopnea index (primary outcome) by 5.4 (95% confidence interval -10.4 to -0.3) events/h, P = .03 (-24 ± 27% in men; -0.7 ± 32% in women). Oxybutynin did not cause additional reductions in apnea-hypopnea index. Reboxetine alone reduced the 4% oxygen desaturation index by (mean ± standard deviation) 5.2 ± 7.2 events/h and reboxetine+oxybutynin by 5.1 ± 10.6 events/h vs placebo, P = .02. Nadir oxygen saturation also increased by 7 ± 11% with reboxetine and 5 ± 9% with reboxetine+oxybutynin vs placebo, P = .01. Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control (loop gain). Larger reductions in apnea-hypopnea index with reboxetine in men were associated with higher baseline loop gain. Conclusions: These findings show the first evidence that reboxetine alone reduces OSA severity. The data provide novel insight into the role of norepinephrine reuptake inhibitors on upper airway stability during sleep and are important to inform future pharmacotherapy development for OSA.Thomas J. Altree, Atqiya Aishah, Kelly A. Loffler, Ronald R. Grunstein, Danny J. Ecker

Effects of CPAP treatment on cardiac structure and function in individuals with obstructive sleep apnea and cardiovascular disease: a prospective 6-month randomised control trial

Background: Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular events. The influence of continuous positive airway pressure (CPAP) on cardiac function remains uncertain. Purpose: To prospectively determine the effects of CPAP on cardiovascular function, as measured by cardiac magnetic resonance imaging (CMR) as a sub-study of the international SAVE trial (NCT00738179). Methods: Participants with OSA and established cardiovascular disease were randomized to CPAP treatment plus usual cardiovascular care or Usual Care alone. Primary outcomes were defined as change in ventricular ejection fraction (EF) and stroke volume (SV) between baseline and 6-month follow-up both groups. Secondary outcomes included other ventricular parameters including volumes, mass, and strain, and atrial parameters. Results: 140 participants were included; mean CPAP adherence in those allocated to receive the treatment was 4.31±2.45 hours per night. Most were male (91%) and had moderate-severe OSA with minimal daytime sleepiness. There were no significant differences in left or right ventricular EF between groups after 6 months of treatment. There was an 8.5 mL increase in LV SV (95% CI; [4.3–12.6], p<0.001) and a 7.7 mL increase in RV SV (95% CI; [3.4–12.0], p<0.001) in the CPAP group compared to Usual Care. CPAP also affected left and right ventricular EDV, RV strain, and atrial parameters. Conclusions: In the first prospective CMR imaging study of patients with OSA and cardiovascular disease, CPAP treatment did not change EF after 6 months, but did have significant effects on other parameters of cardiac function.K. Franke, K.A. Loffler, S.J. Nicholls, C.S. Anderson, B.R. Cowan, R.D. McEvoy, A.A. Young, J.W. Verjan

High night-to-night variability in sleep apnea severity is associated with uncontrolled hypertension

Abstract Obstructive sleep apnea (OSA) severity can vary markedly from night-to-night. However, the impact of night-to-night variability in OSA severity on key cardiovascular outcomes such as hypertension is unknown. Thus, the primary aim of this study is to determine the effects of night-to-night variability in OSA severity on hypertension likelihood. This study uses in-home monitoring of 15,526 adults with ~180 nights per participant with an under-mattress sleep sensor device, plus ~30 repeat blood pressure measures. OSA severity is defined from the mean estimated apnea–hypopnoea index (AHI) over the ~6-month recording period for each participant. Night-to-night variability in severity is determined from the standard deviation of the estimated AHI across recording nights. Uncontrolled hypertension is defined as mean systolic blood pressure ≥140 mmHg and/or mean diastolic blood pressure ≥90 mmHg. Regression analyses are performed adjusted for age, sex, and body mass index. A total of 12,287 participants (12% female) are included in the analyses. Participants in the highest night-to-night variability quartile within each OSA severity category, have a 50–70% increase in uncontrolled hypertension likelihood versus the lowest variability quartile, independent of OSA severity. This study demonstrates that high night-to-night variability in OSA severity is a predictor of uncontrolled hypertension, independent of OSA severity. These findings have important implications for the identification of which OSA patients are most at risk of cardiovascular harm.Bastien Lechat, Kelly A. Loffler, Amy C. Reynolds, Ganesh Naik, Andrew Vakulin, Garry Jennings, Pierre Escourrou, R. Doug McEvoy, Robert J. Adams, Peter G. Catcheside, and Danny J. Ecker

One Month Dosing of Atomoxetine plus Oxybutynin in Obstructive Sleep Apnea: A Randomized, Placebo-controlled Trial.

RATIONALE: The combination of noradrenergic and anti-muscarinic agents has recently been shown to improve upper-airway function and reduce obstructive sleep apnea (OSA) severity in short-term (≤1 week) proof-of-concept studies. OBJECTIVE: To determine the safety, tolerability, and potential efficacy of longer-term use of different doses of the noradrenergic agent atomoxetine combined with the anti-muscarinic oxybutynin. METHODS: Thirty-nine people with predominantly severe OSA received either 80mg atomoxetine/5mg oxybutynin (ato-oxy), 40/5mg ato-oxy, 40/2.5mg ato-oxy or placebo nightly for 30 days in a double-blind, randomized, parallel design. Participants completed three in-laboratory sleep studies (baseline, night 1, night 30) to assess efficacy. Vital signs and objective measures of alertness and memory were assessed. In men, potential effects on prostate function were assessed using the International Prostate Symptom Score (IPSS) at baseline and night 30. Potential adverse events were assessed during in-lab visits and via weekly phone calls. RESULTS: Side effects were generally mild and consistent with known side-effect profiles of each individual drug (i.e., dose-dependent increases in dry mouth with oxybutynin). Heart rate increased by night 30 in two active drug arms (mean±SD: 8±10 beats/min, p=0.01, 80/5mg; 9±14 beats/min, p=0.02, 40/2.5mg; versus placebo). No clinically relevant changes to blood pressure, IPSS and measures of alertness and memory were observed between conditions. Apnoea-hypopnea index (4% oxygen desaturation: AHI4) and hypoxic burden decreased by ~50% with 80/5mg ato-oxy from baseline but not versus placebo (e.g., AHI3 and AHI4 difference [95%CI] at night 30= -8.2 [-22.5, 6.2] and -8.5 [-18.3, 1.3] events/h, respectively). CONCLUSIONS: 1 month of nightly noradrenergic and anti-muscarinic combination therapy was generally well-tolerated with a side effect profile consistent with each agent alone and was associated with an ~50% reduction from baseline in a key OSA severity metric, the hypoxic burden with the highest dose combination. These findings highlight the potential to target noradrenergic and anti-muscarinic mechanisms for OSA pharmacotherapy development. CLINICAL TRIAL REGISTRATION: ACTRN12619001153101.Atqiya Aishah, Kelly A. Loffler, Barbara Toson, Sutapa Mukherjee, Robert J. Adams, Thomas J. Altree, Henry W. Ainge-Allen, Brendon J. Yee, Ronald R. Grunstein, Jayne C. Carberry, and Danny J. Ecker

Sleep duration and risk of cardiovascular events: the SAVE study

BACKGROUND AND AIM:Controversy exists regarding cardiovascular risk in relation to sleep duration. We determined sleep duration and major recurrent cardiovascular event associations in patients with obstructive sleep apnoea and established cardiovascular disease. METHODS:Secondary analyses of the international, multicenter, Sleep Apnea Cardiovascular Endpoints trial. Sleep duration was estimated from overnight home oximetry (ApneaLink monitor) used for obstructive sleep apnoea diagnosis. Cox proportional hazards models were used to determine associations of categorized sleep duration (8 h) and major cardiovascular outcomes: primary composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and any hospitalization for unstable angina, heart failure, or transient ischemic attack; secondary composite of cardiac and cerebral (stroke/transient ischemic attack) events. RESULTS:Oximetry-derived sleep duration estimates were available in 2687 participants (mean 61.2 years, 80.9% males) who experienced a total of 436 cardiovascular events over a mean follow-up of 3.7 years. Compared to the reference category, sleep duration was not associated with risk of the primary composite cardiovascular outcome (adjusted hazard ratio (HR) 1.00, 95% confidence interval 0.76-1.33, and HR 1.22, 95% confidence interval 0.98-1.52, for sleep duration 8 h, respectively). However, long sleep was associated with increased cerebral events (HR 1.67, 95% confidence interval 1.17-2.39; P = 0.005) and stroke alone (HR 1.79, 95% confidence interval 1.22-2.63; P = 0.003). CONCLUSIONS:Long sleep duration is associated with an increased risk of stroke but not cardiac events in obstructive sleep apnoea patients with existing cardiovascular disease. CLINICAL TRIAL REGISTRATION:The trial is registered at ClinicalTrials.gov (NCT00738179).Jingwei Li, Danni Zheng, Kelly A Loffler, Xia Wang, R Doug McEvoy, Richard J Woodman ... et al. (for the SAVE Investigators

All-Cause Mortality in People with Co-Occurring Insomnia Symptoms and Sleep Apnea: Analysis of the Wisconsin Sleep Cohort

Purpose: Insomnia symptoms and sleep apnea frequently co-occur and are associated with worse sleep, daytime function, mental health and quality of life, compared to either insomnia or obstructive sleep apnea (OSA) alone. This study aimed to investigate the association of symptoms of co-morbid insomnia and sleep apnea (COMISA) with all-cause mortality. Patients and Methods: Wisconsin Sleep Cohort data were analysed to assess potential associations between COMISA symptoms and all-cause mortality. Nocturnal insomnia symptoms were defined as difficulties initiating sleep, maintaining sleep, and/or early morning awakenings “often” or “almost always”, and/or regular sedative-hypnotic medicine use. OSA was defined as an apneahypopnea index ≥5/hr sleep. Participants were classified as having neither insomnia symptoms nor OSA, insomnia symptoms alone, OSA alone, or COMISA symptoms. Associations between the four groups and all-cause mortality over 20 years of follow-up were examined via multivariable adjusted Cox regression models. Results: Among 1115 adult participants (mean ± SD age 55 ± 8 years, 53% males), 19.1% had COMISA symptoms. After controlling for sociodemographic and behavioral factors, COMISA symptoms were associated with an increased risk of all-cause mortality compared to no insomnia symptoms or OSA (HR [95% CI]; 1.71 [1.00–2.93]). OSA alone (0.91 [0.53, 1.57]) and insomnia symptoms alone (1.04 [0.55, 1.97]) were not associated with increased mortality risk. Conclusion: Co-morbid insomnia symptoms and sleep apnea is associated with increased all-cause mortality risk. Future research should investigate mechanisms underpinning COMISA and the effectiveness of different treatment approaches to reduce mortality risk for this common condition.Bastien Lechat, Kelly A Loffler, Douglas M Wallace, Amy Reynolds, Sarah L Appleton, Hannah Scott, Andrew Vakulin, Nicole Lovato, Robert Adams, Danny J Eckert, Peter G Catcheside, Alexander Sweetma

Multinight prevalence, variability, and diagnostic misclassification of obstructive sleep apnea

Rationale: Recent studies suggest that obstructive sleep apnea (OSA) severity can vary markedly from night to night, which may have important implications for diagnosis and management. Objectives: This study aimed to assess OSA prevalence from multinight in-home recordings and the impact of night-to-night variability in OSA severity on diagnostic classification in a large, global, nonrandomly selected community sample from a consumer database of people that purchased a novel, validated, under-mattress sleep analyzer. Methods: A total of 67,278 individuals aged between 18 and 90 years underwent in-home nightly monitoring over an average of approximately 170 nights per participant between July 2020 and March 2021. OSA was defined as a nightly mean apnea-hypopnea index (AHI) of more than 15 events/h. Outcomes were multinight global prevalence and likelihood of OSA misclassification from a single night's AHI value. Measurements and Main Results: More than 11.6 million nights of data were collected and analyzed. OSA global prevalence was 22.6% (95% confidence interval, 20.9-24.3%). The likelihood of misdiagnosis in people with OSA based on a single night ranged between approximately 20% and 50%. Misdiagnosis error rates decreased with increased monitoring nights (e.g., 1-night F1-score = 0.77 vs. 0.94 for 14 nights) and remained stable after 14 nights of monitoring. Conclusions: Multinight in-home monitoring using novel, noninvasive under-mattress sensor technology indicates a global prevalence of moderate to severe OSA of approximately 20%, and that approximately 20% of people diagnosed with a single-night study may be misclassified. These findings highlight the need to consider night-to-night variation in OSA diagnosis and management.Bastien Lechat, Ganesh Naik, Amy Reynolds, Atqiya Aishah, Hannah Scott, Kelly A. Loffler, Andrew Vakulin, Pierre Escourrou, R. Doug McEvoy, Robert J. Adams, Peter G. Catcheside, and Danny J. Ecker

Spectroscopic Study of Human Teeth and Blood from Visible to Terahertz Frequencies for Clinical Diagnosis of Dental Pulp Vitality

Transmission spectra of wet human teeth and dentin slices, together with blood of different flow rates were investigated. The measurements carried out over a wide spectral range, from visible light down to terahertz radiation. The results make it possible to find the optimum light frequency for an all-optical determination of pulpal blood flow and, consequently, for clinically diagnosis of tooth vitality