Maria-Antonia Quera-Salva

Women and the Obstructive Sleep Apnea Syndrome

Twenty-seven women referred to a sleep disorders clinic for symptoms of obstructive sleep apnea syndrome (OSAS) during one year were systematically analyzed after polygraphic monitoring of sleep and cephalometric x-ray examination. Our subjects, one-third of whom were premenopausal, comprised approximately 12 percent of the total OSAS population seen. Women with OSAS were compared with 110 OSAS men and with a group of 16 women without OSAS but referred to orthodontists for mild dental malocclusion. Women with OSAS were massively obese, much more so than their male counterparts. There was no significant difference between pre- and postmenopausal women, with the exception of the respiratory disturbance index (RDI), which was lower in the postmenopausal group despite similar morbid obesity (seemingly better tolerated by women with OSAS than by men with the same syndrome) and long mandibular plane-hyoid bone distance. The significantly higher RDI noted in premenopausal women, despite equally massive obesity and upper airway abnormalities, is thought to be related to hormonal status and better arousal response. Chronic obstructive lung disease (COLD) seen in a subgroup of women with OSAS did not differentiate this subgroup from the other OSAS patients when oxygen saturation during sleep, frequency of abnormal respiratory events and sleep variables were considered. Massive obesity is the dominant factor for the appearance of OSAS in women.

Sleep-related respiratory disturbances in patients with Duchenne muscular dystrophy.

Sleep-related respiratory disturbances (SRD) in patients with muscle diseases may have significant clinical implications, because the patients frequently die at night. The aims of the study were to :1) assess the presence and severity of sleep-related respiratory disturbances in patients with Duchenne muscular distrophy (DMD); and 2) investigate the relationship of sleep-related respiratory disturbances to daytime symptoms and pulmonary function. We studied six clinically stable patients with Duchenne muscular dystrophy, mean age (+/- SD) 18 +/- 2 yrs. Vital capacity was 27 +/- 19% of predicted and daytime arterial oxygen tension (PaO2) was 10.9 +/- 1 kPa (range 8.9-12.4 kPa). The presence of daytime somnolence, insomnia, headache, nightmares and/or snoring was recorded. Four patients (67%) showed symptoms that suggest sleep-related respiratory disturbances. At night, the apnoea-hypopnoea index (AHI) was 11 +/- 6. The patients with more symptoms during the daytime had the highest AHI scores. Most of the apnoeas (85%) were central, particularly during rapid eye movement (REM) sleep. Sleep architecture was well-preserved. Arterial desaturation (> 5% below baseline) occurred during 25 +/- 23% of total time. AHI correlated with daytime PaO2, and AHI in REM sleep correlated with age. A stepwise multivariate analysis showed that PaO2 and, to some extent, the degree of airflow obstruction were significantly correlated with AHI. We conclude that sleep-related respiratory disturbance are frequently present in patients with Duchenne muscular dystrophy. Therefore, physicians should look for symptoms related to sleep-related respiratory disturbances in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of agomelatine and escitalopram on nighttime sleep and daytime condition and efficacy in major depressive disorder patients.

Agomelatine, an MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, is known to have beneficial effects on subjective sleep in major depressive disorder patients. This international multicenter, randomized, double-blind study compared the effects of agomelatine (25–50 mg/day) and escitalopram (10–20 mg/day) on sleep polysomnographic parameters in major depressive disorder patients treated up to 24 weeks. A total of 138 outpatients were randomly allocated to agomelatine (n=71) or escitalopram (n=67). Treatment with agomelatine was associated with a reduction in sleep latency from week 2 onward. The difference between treatments was significant on all evaluations. Rapid eye movement latency was increased with escitalopram compared with agomelatine, with significant between-group differences at every visit. Agomelatine preserved the number of sleep cycles, whereas it was decreased with escitalopram with significant between-group differences at every visit. Assessments on visual analogue scales indicated that treatment with agomelatine improved morning condition, and reduced daytime sleepiness compared with escitalopram.17-item Hamilton depression rating scale total score was reduced in both groups, agomelatine was statistically noninferior to escitalopram at 6 weeks. Both treatments were well tolerated. This study showed that the clinical effects of agomelatine on sleep and wake parameters are different from that of escitalopram.

Impact of the novel antidepressant agomelatine on disturbed sleep–wake cycles in depressed patients†

Disturbance of sleep–wake cycles is common in major depressive disorder (MDD), usually as insomnia, but also as hypersomnia or reduced daytime alertness. Agomelatine, an MT1 and MT2 receptor agonist and 5‐HT2C receptor antagonist, represents a novel approach in MDD, with proven antidepressant efficacy and a positive impact on the sleep–wake cycle. We review the effects of agomelatine 25/50 mg/day on objective and subjective measures of the sleep–wake cycle in MDD.

Antidepressant efficacy of agomelatine versus SSRI/SNRI: results from a pooled analysis of head-to-head studies without a placebo control.

Pooled analysis of individual patient data was used to compare the antidepressant efficacy of agomelatine with that of selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). We sought head-to-head, double-blind, randomized studies without a placebo arm using antidepressant doses in the licensed range and primary evaluation on the Hamilton scale (HAM-D17). Six studies were identified versus venlafaxine, sertraline, fluoxetine, paroxetine or escitalopram. Estimates of differences between treatments were calculated on parameters expressed as the last postbaseline value (6, 8 or 12 weeks). A total of 2034 patients were randomized (age 47.6±14.9 years; 73% women; HAM-D17 total score 26.9±3.0). The full analysis set included 1997 patients (1001 agomelatine; 996 SSRI/SNRI). There was a significant difference between HAM-D17 total scores, with a greater reduction with agomelatine than with SSRI/SNRI [E(SE), 0.86 (0.35), 95% confidence interval 0.18–1.53, P=0.013], and better rates of response on the HAM-D17 (P=0.012) and the Clinical Global Impression-Improvement scales (P=0.032). Similar results were found in patients with severe depression. Agomelatine was associated with better tolerability than SSRI/SNRI. Agomelatine has favourable efficacy and tolerability versus a range of SSRIs and SNRIs – including agents considered to have superior efficacy – and may deserve benefit–risk analysis as a first-line treatment of major depressive disorder.

A pooled analysis of six month comparative efficacy and tolerability in four randomized clinical trials: agomelatine versus escitalopram, fluoxetine, and sertraline

OBJECTIVE A pooled-analysis on the long-term outcome in four head-to-head studies: agomelatine versus fluoxetine, sertraline, and (twice) escitalopram. Method A meta-analytic approach was used. Hamilton Depression Rating Scale (HAM-D) scores, response and remission rates, Clinical Global Impression of Improvement (CGI-I) scores, response and remission rates, and completion rates/discontinuation rates due to adverse events were analyzed. RESULTS At the last post-baseline assessment on the 24-week treatment period, the final HAM-D-17 score was significantly lower in patients treated with agomelatine than in patients treated with selective serotonin reuptake inhibitors (SSRIs), as well in the total group of patients with severe depression (P = 0.014 and 0.040, respectively). HAM-D response rates at the end of 24 weeks were significantly higher in patients treated with agomelatine than in patients treated with SSRIs, as well in the total group of patients with severe depression (P = 0.031 and 0.048, respectively). HAM-D remission rates at the end of 24 weeks were numerically but not significantly higher in patients treated with agomelatine than in patients treated with SSRIs. Final CGI-I scores were significantly lower for agomelatine. CGI-I response as well as remission rates were numerically higher in patients treated with agomelatine, without statistical significance. The percentage of patients with at least one emergent adverse event leading to treatment discontinuation was 9.4% in patients treated with SSRIs and 6.6% in patients treated with agomelatine (P = 0.065). CONCLUSION The present pooled analysis shows that, from a clinical point of view, agomelatine is at least as efficacious as the investigated SSRIs with a trend to fewer discontinuations due to adverse events.

Nocturnal oximetry and transcutaneous carbon dioxide in home-ventilated neuromuscular patients.

BACKGROUND: Pulse oximetry alone has been suggested to determine which patients on home mechanical ventilation (MV) require further investigation of nocturnal gas exchange. In patients with neuromuscular diseases, alveolar hypoventilation (AH) is rarely accompanied with ventilation-perfusion ratio heterogeneity, and, therefore, oximetry may be less sensitive for detecting AH than in patients with lung disease. OBJECTIVE: To determine whether pulse oximetry (SpO2) and transcutaneous carbon dioxide (PtcCO2) during the same night were interchangeable or complementary for assessing home MV efficiency in patients with neuromuscular diseases. METHODS: Data were collected retrospectively from the charts of 58 patients with chronic neuromuscular respiratory failure receiving follow-up at a home MV unit. SpO2 and PtcCO2 were recorded during a 1-night hospital stay as part of standard patient care. We compared AH detection rates by PtcCO2, SpO2, and both. RESULTS: AH was detected based on PtcCO2 alone in 24 (41%) patients, and based on SpO2 alone with 3 different cutoffs in 3 (5%), 8 (14%), and 13 (22%) patients, respectively. Using both PtcCO2 and SpO2 showed AH in 25 (43%) patients. CONCLUSIONS: Pulse oximetry alone is not sufficient to exclude AH when assessing home MV efficiency in patients with neuromuscular diseases. Both PtcCO2 and SpO2 should be recorded overnight as the first-line investigation in this population.

Snoring detection during auto-nasal continuous positive airway pressure

A bench study using an artificial lung model was performed to evaluate the snoring detection sensitivity of six (commercially available) auto-nasal continuous positive airway pressure (NCPAP) devices. Snoring was simulated by a loudspeaker connected to the lung model and abruptly activated during 1 s of each inspiratory period to induce pressure oscillation. The oscillation frequencies chosen were 30, 60, 90, and 120 Hz. For each frequency, the amplitude of the pressure oscillation produced by the loudspeaker was adjusted to find the threshold at which the auto-nCPAP devices detected snoring. Differences in pressure-amplitude thresholds of up to three-fold were found across auto-nCPAP devices. A randomized clinical study to compare the effects of the least sensitive (Virtuoso LX; Respironics, Nantes, France) and one of the most sensitive, (Goodknight 418A; Malinckrodt, Nancy, France) devices, in two groups of six patients with obstructive sleep apnoea syndrome was then conducted. Goodknight 418A was more sensitive than Virtuoso LX for detecting snoring (mean±sd 92±11% versus 50±39% respectively, p=0.03). To conclude, striking differences exist between auto-nasal continuous positive airway pressure devices in sensitivity for detecting snoring.

Efficiency of invasive mechanical ventilation during sleep in Duchenne muscular dystrophy

OBJECTIVE Inspiratory unintentional leaks (IULs) during noninvasive ventilation (NIV) adversely affect the sleep and the effectiveness of mechanical ventilation (MV). The aim of this study was to assess the effects of nocturnal IULs in Duchenne muscular dystrophy (DMD) patients with a tracheostomy and uncuffed tube comparatively with NIV patients. METHODS Polysomnography with transcutaneous partial pressure of carbon dioxide (PtcCO(2)) recording and blood gas measurement was performed in 26 stable tracheostomized DMD patients using home MV, among whom 11 were matched with NIV patients. RESULTS IULs occurred during 29.4% [1.7-61.9%] (median [IQR]) of the total sleep time. By univariate regression analysis, the closest correlation with IUL duration was for daytime base excess (r(2)=0.69, P<0.0001), followed by daytime bicarbonate level. In a stepwise multiple regression analysis, only base excess remained significantly correlated. Sleep and respiratory parameters improved in the four patients who agreed to use cuffed tubes. Tracheostomized patients had lower maximal PtcCO(2) (P=0.02) and base excess values (P=0.045) compared to NIV controls. CONCLUSION Tracheostomy does not guarantee that MV is effective during sleep, as IULs may occur, but ensures better nocturnal gas exchanges than NIV. DMD patients should be evaluated using at least blood gas measurement, nocturnal oximetry, and PtcCO(2) monitoring.

Safety profile of tasimelteon, a melatonin MT1 and MT2 receptor agonist: pooled safety analyses from six clinical studies.

Introduction: Tasimelteon, a novel circadian regulator, is the first product for the treatment of Non-24-hour Sleep-Wake Disorder (Non-24) approved by either the FDA or the European Medicines Agency (EMA). Tasimelteon is a potent and specific melatonin (MT1 and MT2) receptor agonist with 2 – 4 times greater affinity for the MT2 receptor. Methods: Safety was assessed in two controlled and two open-label studies in blind individuals with Non-24 and in two controlled studies of primary insomnia. Periodic assessments included collection of adverse events (AEs), laboratory testing, electrocardiograms (ECGs), vital sign monitoring, physical examinations and assessment for the potential for suicide. One study included additional assessments for endocrine function. Results: A total of 184 blind individuals with Non-24 received tasimelteon nightly with a median exposure > 1 year. In placebo-controlled studies, 387 patients with insomnia and 42 patients with Non-24 received tasimelteon nightly for 4 – 26 weeks. The total patient years exposure for the six studies assessed here is 258.64 patient years. Discontinuations due to AEs were similar across treatment groups. Overall in the clinical studies described here, AEs attributable to tasimelteon treatment were headache, diarrhea, dry mouth, alanine aminotransferase increased, somnolence, dizziness and nightmare/abnormal dreams. There were no clinically significant differences in treatment group with ECGs, vital signs, withdrawal, endocrine function and suicidality assessments. Conclusion: Long-term tasimelteon administration was safe and well-tolerated. This is supported by placebo-controlled data in both Non-24 and insomnia patients.