Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold

Smales, Erik; Edwards, Bradley A.; DeYoung, Pamela; McSharry, David G.; Wellman, Andrew; Velasquez, Adrian; Owens, Robert L.; Orr, Jeremy E.; Malhotra, Atul

doi:10.1513/annalsats.201408-399oc

Cited by 104 publications

(71 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Respiratory ArTh was measured according to previously reported methods (7)(8)(9)20). Briefly, subjects were instrumented overnight with an epiglottic pressure catheter (model MCP-500; Millar, Houston, TX).…”

Section: Arousal Threshold Measurementsmentioning

confidence: 99%

“…A high loop gain, which is associated with enhanced ventilation responses and sequential excessive blood gas fluctuations, may lead to instability of ventilation during sleep, resulting in an increase in respiratory events (6). Therefore, pharmacologically increasing the arousal threshold (ArTh) and/or decreasing the loop gain may be beneficial for some patients with OSA (7)(8)(9). Some sedative medications have been reported to increase the ArTh and eliminate sleep apnea in patients with low ArTh (7-9); decreasing loop gain by medication or supplemental oxygen might improve sleep apnea severity (10,11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Effect of Donepezil on Arousal Threshold and Apnea–Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study

Owens

Sands

et al. 2016

Annals ATS

Self Cite

View full text Add to dashboard Cite

Rationale: Obstructive sleep apnea (OSA) has multiple pathophysiological causes. A low respiratory arousal threshold (ArTh) and a high loop gain (unstable ventilatory control) can contribute to recurrent respiratory events in patients with OSA. Prior studies have shown that donepezil, an acetylcholinesterase inhibitor, might improve OSA, but the mechanism is unknown.Objectives: To determine whether a single dose of donepezil lowers the apnea-hypopnea index by modulating the ArTh or loop gain. Methods:In this randomized, double-blind, crossover trial, 41 subjects with OSA underwent two polysomnograms with ArTh and loop gain evaluated, during which 10 mg of donepezil or placebo was administered.Measurements and Main Results: Compared with placebo, sleep efficiency (77.2 vs. 71.9%; P = 0.015) and total sleep time decreased with donepezil (372 vs. 351 min; P = 0.004). No differences were found in apnea-hypopnea index (51.8 vs. 50.0 events/h; P = 0.576) or nadir oxygen saturation as determined by pulse oximetry (80.3 vs. 81.1%; P = 0.241) between placebo and donepezil, respectively. ArTh was not significantly changed (-18.9 vs. -18.0 cm H 2 O; P = 0.394) with donepezil. As a whole group, loop gain (ventilatory response to a 1-cycle/min disturbance) did not change significantly (P = 0.089).Conclusions: A single dose of donepezil did not appear to affect the overall severity of OSA in this patient group, and no consistent effects on ArTh or loop gain were observed. Donepezil may have minor effects on sleep architecture.Clinical trial registered with www.clinicaltrials.gov (NCT02264353).

show abstract

Section: Arousal Threshold Measurementsmentioning

confidence: 99%

mentioning

confidence: 99%

The Effect of Donepezil on Arousal Threshold and Apnea–Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study

Owens

Sands

et al. 2016

Annals ATS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Given that V arousal is a composite measure of ventilatory control sensitivity and arousal threshold, a decrease in the former and/or an increase in the latter would result in a beneficial decrease in V arousal in those individuals in whom this factor is significant to their OSA pathogenesis. Interventions targeting ventilatory control sensitivity and/or arousal threshold, e.g., using acetazolamide and eszopiclone respectively 23–25 , were introduced in the previous section and are the subject of recent reviews 26, 27 and other studies, e.g., 28–32 . For this reason, this section will mainly focus on other developments that identify targets of high interest relevant to the second major strategic direction in OSA treatment by pharmacotherapy.…”

Section: Strategic Directions From the Phenotype Model And Identifmentioning

confidence: 99%

“…Protein products of 26/99 genes are targets of 175 FDA approved drugs. Of those drugs trialled for the treatment of OSA, a total of nine act pharmacologically on ten of the targets (a list drugs trialled for the treatment of OSA 28, 38, 44–46 annotated with protein targets 55 is available in Database S1). Importantly, although the identified targets, or combinations thereof, may not ultimately prove effective for OSA pharmacotherapy, our analysis does reveal significant unexplored potential in terms of trialling approved drugs and developing new drugs for differentially expressed targets in the circuitry critical for OSA pathogenesis and that modulate Active V 0 .…”

Section: Mapping Potential Drug Targets In the Circuitry Controllimentioning

confidence: 99%

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

2017

Self Cite

View full text Add to dashboard Cite

There is currently no pharmacotherapy for OSA, but there is no principled a-priori reason why there shouldn’t be one. This review identifies a rational decision-making strategy with the necessary logical underpinnings that any reasonable approach would be expected to navigate to develop a viable pharmacotherapy for OSA. The process first involves phenotyping an individual to quantify and characterize the critical predisposing factor(s) to their OSA pathogenesis and identify, a-priori, if the patient is likely to benefit from a pharmacotherapy that targets those factors. We then identify rational strategies to manipulate those critical predisposing factor(s), and the barriers that have to be overcome for success of any OSA pharmacotherapy. A new analysis then identifies candidate drug targets to manipulate the upper airway motor circuitry for OSA pharmacotherapy. The first conclusion is that there are two general pharmacological approaches for OSA treatment that are of most potential benefit and are practically realistic, one being fairly intuitive but the second perhaps less so. The second conclusion is that after identifying the critical physiological obstacles to OSA pharmacotherapy, there are current therapeutic targets of high interest for future development. The final analysis provides a tabulated resource of “druggable” targets that are relatively restricted to the circuitry controlling the upper airway musculature, with these candidate targets being of high priority for screening and further study. We also emphasize that a pharmacotherapy may not cure OSA per se, but may still be a useful adjunct to improve the effectiveness of, and adherence to, other treatment mainstays.

show abstract

“…It would be more useful in clinical practice if there were features on the conventional PSG or metrics computed from PSG signals which differentiated phenotypes that could guide therapy. Specifically, a high loop gain phenotype may benefit from supplemental oxygen (Wellman et al 2008), acetazolamide (Edwards et al 2012), or hypocapnia minimization strategies, while sedatives could be an option in those who have low arousal thresholds in NREM sleep (Smales et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Distinct polysomnographic and ECG-spectrographic phenotypes embedded within obstructive sleep apnea

Thomas

Shin

Bianchi

et al. 2017

Sleep Science Practice

View full text Add to dashboard Cite

Background: The primary metric extracted from the polysomnogram in patients with sleep apnea is the apnea-hypopnea index (or respiratory disturbance index) and its derivatives. Other phenomena of possible importance such as periods of stable breathing, features suggestive of high respiratory control loop gain, and sleep fragmentation phenotypes are not commonly generated in clinical practice or research. A broader phenotype designation can provide insights into biological processes, and possibly clinical therapy outcome effects. Methods: The dataset used for this study was the archived baseline diagnostic polysomnograms from the Apnea Positive Pressure Long-term Efficacy Study (APPLES). The electrocardiogram (ECG)-derived cardiopulmonary coupling sleep spectrogram was computed from the polysomnogram. Sleep fragmentation phenotypes used thresholds of sleep efficiency (SE) ≤ 70%, non-rapid eye movement (NREM) sleep N1 ≥ 30%, wake after sleep onset (WASO) ≥ 60 min, and high frequency coupling (HFC) on the ECG-spectrogram ≤ 30%. Sleep consolidation phenotypes used thresholds of SE ≥ 90%, WASO ≤ 30 min, HFC ≥ 50% and N1 ≤ 10%. Multiple and logistic regression analysis explored cross-sectional associations with covariates and across phenotype categories. NREM vs. REM dominant apnea categories were identified when the NREM divided by REM respiratory disturbance index (RDI) was > 1. Results: The data was binned first into mild, moderate, severe and extreme categories based on the respiratory disturbance index of < 10, 10-30, 30-60, and greater than 60, per hour of sleep. Using these criteria, 70, 394, 320 and 188 for polysomnogram, and 54, 296, 209 and 112 subjects for ECG-spectrogram analysis groups. All phenotypes were seen at all severity levels. There was a higher correlation of NREM-RDI with the amount of ECG-spectrogram narrow band coupling, vs. REM-RDI, 0.41 vs 0.14, respectively. NREM dominance was associated with male gender and higher mixed/central apnea indices. Absence of the ECG-spectrogram sleep consolidated phenotype was associated with an increased odds of being on antihypertensive medications, OR 2.65 [CI: 1.64-4.26], p = < 0.001. Conclusions: Distinct phenotypes are readily seen at all severities of sleep apnea, and can be identified from conventional polysomnography. The ECG-spectrogram analysis provides further phenotypic differentiation.

show abstract

Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold

Cited by 104 publications

References 33 publications

The Effect of Donepezil on Arousal Threshold and Apnea–Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study

The Effect of Donepezil on Arousal Threshold and Apnea–Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

Distinct polysomnographic and ECG-spectrographic phenotypes embedded within obstructive sleep apnea

Contact Info

Product

Resources

About