Associations between sleep complaints, suicidal ideation and depressive symptoms among adolescents and young adults in Greece.

Depression prevalence increases significantly during adolescence/early adulthood. Depression in youth may present suicidal ideation, while suicide represents the leading cause of death in this age group. Moreover, adolescents/young adults frequently report sleep complaints that may partially be due to depressive symptoms. Studies on the associations between depression, sleep complaints and suicidality in this age group are limited. We aimed to examine associations between depressive symptoms, sleep complaints and suicidal ideation in a large (n = 2771), representative sample of adolescents (age: 15-17 years, n = 512) and young adults (age: 18-24 years, n = 2259) from the general population in Greece. A telephone structured questionnaire was administered. Depressive symptoms were assessed using the modified Patient Health-7 questionnaire score, while presence of suicidal ideation and sleep complaints were assessed using the ninth and third question of Patient Health-9 questionnaire, respectively. Mediation logistic regression analysis revealed significant direct paths from depressive symptoms to sleep complaints (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.19-1.24; OR 1.21, 95% CI 1.18-1.24) and suicidal ideation (OR 1.18, 95% CI 1.14-1.22; OR 1.18, 95% CI 1.14-1.22), as well as sleep complaints and suicidal ideation (OR 1.82, 95% CI 1.32-2.50; OR 1.91, 95% CI 1.33-2.76) in the total group and in young adults, respectively, but not among adolescents. Moreover, we detected a significant indirect effect of depressive symptoms on suicidal ideation mediated by sleep complaints (18.8%) in young adults. These findings support the hypothesis that treatment of sleep disturbances among youth with depression may independently further reduce suicidal risk.

Differential effects of earthquakes on patients with bipolar disorder versus schizophrenia: Findings from Crete, Greece, 2008-2010.

Electromagnetic radiation influences in many ways humans and animals, while earthquakes are known to be related with electromagnetic phenomena. We recently showed that large earthquakes reduced admissions of psychiatric patients, whereas small earthquakes were associated with increased number of admissions. Our aim was to examine the effect of seismic-related electromagnetic activity on two chronic and severe psychiatric disorders varying in terms of etiology and treatment, i.e. bipolar disorder and schizophrenia. Retrospective data concerning monthly admission rates of patients diagnosed with schizophrenia or bipolar disorder in the Psychiatric Unit of the University Hospital of Heraklion, Crete, Greece between 2008 and 2010 were analyzed in relation to the number of earthquakes with small (≥2) or larger magnitude in the Crete region in Greece. Results showed a marked reduction of acute admissions during a storm of large earthquakes, which was greater in patients with bipolar disorder (91.2%) than schizophrenia patients (52.4%). In addition there was a significant increase of admissions during a period of frequent small earthquakes, primarily among patients with bipolar disorder. The results suggest that electrostatic fields that accompany large earthquakes may have a protective effect on psychiatric disorders, particularly on bipolar disorder. These findings are consistent with the ameliorating effect of electromagnetic fields used in Electroconvulsive therapy (ECT) and Transcranial Magnetic Stimulation (TMS) in patients with bipolar disorder. Future studies focusing on the underlying mechanisms may lead to more specific treatments of psychiatric disorders.

Childhood obesity, weight loss and developmental trajectories predict the persistence and remission of childhood sleep-disordered breathing.

BACKGROUND: Obesity has been recognized as a risk factor for childhood sleep-disordered breathing (SDB), yet it remains unclear how obesity and weight change predict the course of childhood SDB. OBJECTIVE: The objective of the study is to investigate the role of body weight, upper airway abnormalities and developmental trajectories on the persistence and remission of childhood SDB in the transition to adolescence. METHODS: The Penn State Child Cohort is a representative population sample of 700 children (5-12 years), of whom 421 were followed up as adolescents (12-23 years). Participants underwent a clinical history, physical examination and polysomnography at both time points. RESULTS: Obesity and enlarged tonsils were cross-sectionally associated with childhood SDB. Longitudinally, baseline obesity predicted the persistence of childhood SDB (OR = 3.75, 95% CI = 2.00-7.05), while weight loss predicted its remission (OR = 1.67, 95% CI = 1.11-2.50). Children with enlarged tonsils who remitted from SDB had not experienced significant weight loss and only 4.4% had undergone adeno/tonsillectomy. Body fat distribution/composition at follow-up was similar in those who had remitted from childhood SDB as compared with those who had never experienced SDB, while those who persisted with childhood SDB showed significant android distribution and visceral adiposity at follow-up. CONCLUSIONS: Our data support a causal role for obesity and weight loss in the chronicity and remission, respectively, of childhood SDB in the transition to adolescence and suggest that remission of SDB is related to developmental trajectories of the upper airway in a significant proportion of children. Thus, targeting childhood obesity and weight gain should be a priority in the prevention and treatment of SDB during this critical developmental period.

[A proposal for the implementation of Early Intervention in Psychosis (EIP) services in Greece: If not now, when?]

The disorders of the psychosis spectrum, with the most severe being schizophrenia, are prevalent and have a great impact on the patients' quality of life. The purpose of this article is to highlight the need for a novel national strategic approach to the management of psychotic disorders in accordance with the international principles of early intervention. Even though outpatient treatment is considered adequate, there is an urgent need to adopt an early and more comprehensive and effective intervention strategy for young patients with psychosis and their families whose clinical and personal needs are clearly not met by the existing infrastructure of our mental health services. This can be accomplished by the legislation and implementation within the national health system of EIP services which on the one hand actively engage community organizations with the purpose of early identification of cases, reduction of the duration of untreated psychosis and on the other, offer assertive community-based support and treatment, based on a multi-disciplinary community team model. The effectiveness of early intervention in psychosis is supported by evidence provided by 9 international RCTs. The results of these programs indicate a superior effect in indexes of quality of life, retention in treatment, psychopathology, judicious use of medication and return to work/school as well as the patient's effective recovery. International experience (Denmark, Norway, Australia, UK, USA, Canada and Italy) and the corresponding prevention programs emphasize the effectiveness of EIP services and thus the patients' reintegration. However, in contrast to Northern European countries, Southern European countries have not yet incorporated EIP services in their national health system. From a financial perspective, EIP services seem to be cost-effective for the national health system, since the economic burden is compensated in the long term through their qualitative benefits. In Greece, specialized services for those young afflicted for the first time by the most serious of mental disorders are non-existent and no local information exists for the patient's outcome and social integration after a first psychotic-episode nor for the financial burden, placed on mental health services. Overall, the implementation of EIP services is expected to have long-term benefits for our country's National Health System as well as for the patients and their families.

Neurocognitive and behavioral functioning in adolescents with sleep-disordered breathing: a population-based, dual-energy X-ray absorptiometry study.

BACKGROUND/OBJECTIVES: Sleep-disordered breathing (SDB) has been associated with neurocognitive and behavioral problems in young children; however, this association is less studied in adolescents. Evidence suggests that obesity plays a key role in the development of SDB, although its relative association with neurobehavioral functioning remains unclear. We examined whether SDB and obesity are associated with neurocognitive and behavioral problems in adolescents. SUBJECTS/METHODS: A total of 421 adolescents (17.0±2.2y, 53.9% male) from the Penn State Child Cohort, a general population sample, underwent a 9-h polysomnography, clinical history, physical examination, neurocognitive evaluation and Dual-energy X-ray Absorptiometry (DXA) scan, and completed the Child or Adult Behavior Checklist. Obstructive sleep apnea (OSA) was defined as an apnea-hypopnea index (AHI)⩾2, primary snoring (PS) as AHI<2+snoring and no-SDB as AHI<2 without snoring. Body weight measures included body mass index (BMI) percentile, waist circumference (WC) and DXA-measured total adipose tissue (TAT). RESULTS: WC and TAT were significantly associated with impaired vigilance, processing speed, working memory, and control interference and greater internalizing and externalizing behaviors, while BMI percentile was marginally associated. SDB per se (PS, AHI or OSA) was not significantly associated with impaired neurocognitive outcomes or greater behavioral problems. However, TAT was significantly associated with impaired vigilance and greater internalizing and externalizing behaviors and, to a lesser extent, slower processing speed and greater control interference, only in adolescents with OSA. CONCLUSIONS: Central obesity, an etiopathogenic mechanism of OSA, is more strongly associated with neurocognitive and behavioral problems in adolescents than SDB alone. Deficits in low-order (vigilance) and high-order (executive) functions and behavioral problems observed in adolescents with OSA are primarily associated with increased central adiposity, a finding not entirely captured with less precise measures of obesity. These data support that OSA and its associated neurocognitive and behavioral morbidity are related to underlying metabolic dysfunction as early as adolescence.

Sleep quality is associated with weight loss maintenance status: the MedWeight study.

Sleep duration and quality have been associated with many health outcomes, including weight management. We aimed to investigate the effect of self-reported sleep duration and quality on weight loss maintenance in participants of the MedWeight study, a registry of individuals that lost at least 10% of body weight in the past and either maintained the loss (maintainers: weight maintenance of at least 10% of initial weight loss) or regained it (regainers: weight ≥95% of their maximum body weight). Study participants included 528 volunteers (61% women). Sleep quantity referred to the reported duration of nocturnal sleep, as well as the frequency of mid-day naps during the last month. Sleep quality was assessed through the Athens Insomnia Scale (AIS). Reported sleep quantity was associated with weight maintenance status, but the association became non-significant when the AIS score entered the model. In specific, AIS was inversely associated with the likelihood of being a maintainer (OR=0.89 per AIS unit, 95% CI: 0.81 - 0.98), even after adjusting for potential confounders. Sex-specific analysis revealed that the association between the AIS score and maintenance status was evident in men but not in women. Future studies are needed to confirm these results in other population groups and reveal underlying mechanisms.

The relative association of obstructive sleep apnea, obesity and excessive daytime sleepiness with incident depression: a longitudinal, population-based study.

BACKGROUND: It is postulated that obstructive sleep apnea (OSA) is a risk factor for the development of depression. However, obesity and excessive daytime sleepiness (EDS) are associated with both OSA and depression. The goal of this study was to examine the relative contribution of OSA, obesity and EDS to incident depression. METHODS: A representative random sample of 1137 adults without depression from the Penn State Adult Cohort was followed up after 7.5 years. All subjects underwent a full medical examination and polysomnography at baseline. OSA was defined as an apnea/hypopnea index (AHI) ⩾5, overweight as a body mass index (BMI) of 25-29.9 kg m(-)(2), obesity as a BMI⩾30 kg m(-)(2) and EDS as moderate-to-severe drowsiness/sleepiness and/or irresistible sleep attacks. RESULTS: Overweight, obesity and EDS were associated with incident depression, whereas OSA alone was not. Overweight was associated with incident depression in women, while obesity and EDS were associated with incident depression in both genders. The association of overweight and obesity with incident depression was independent of premorbid emotional distress, while that of EDS was not. The association between BMI and EDS with incident depression was stronger in women 20-40 years old. The severity of EDS predicted incident depression in those with OSA, while AHI or oxygen desaturation did not. CONCLUSIONS: Overweight, obesity and EDS are the main predictors of incident depression. Obesity may be linked to depression through psychobiological mechanisms, while EDS may be an early sign of depression. Obesity should be a target of our preventative strategies for depression.

The structured diagnostic interview for sleep patterns and disorders: rationale and initial evaluation.

OBJECTIVES: We aimed to describe and report the initial validity of a newly developed structured interview for sleep disorders (Diagnostic Interview for Sleep Patterns and Disorders [DISP]) administered by trained lay interviewers. METHODS: A total of 225 patients with various sleep disorders were recruited from two nationally recognized sleep centers in the United States. The International Classification of Sleep Disorders, second edition (ICSD-2) criteria, were used to classify sleep disorders (e.g., delayed sleep phase disorder, hypersomnia, narcolepsy with cataplexy [NC], restless legs syndrome [RLS], periodic limb movement disorder [PLMD], insomnia, rapid eye movement sleep behavior disorder [RBD], and obstructive sleep apnea [OSA]). Interview diagnoses were compared with final diagnoses by sleep specialists (reference diagnosis based on clinical history, examination, and polysomnography [PSG] when indicated). RESULTS: DISP diagnoses had fair to substantial concordance with clinician diagnoses for various sleep disorders, with area under the receiver operator characteristic curves (AUC) ranging from 0.65 to 0.84. Participants classified by the clinician as having a sleep disorder were moderately well-detected (sensitivity ranging from 0.50 for RBD disorder to 0.87 for insomnia). Substantial specificity (>0.8) also was seen for five of the eight sleep disorders (i.e., delayed sleep phase, hypersomnia, NC, PLMD, and RBD). Interviews were more likely than clinicians to detect disorders secondary to the primary sleep problem. CONCLUSIONS: The DISP provides an important tool for the detection of a wide range of sleep disorders in clinical settings and is particularly valuable in the detection of secondary disorders that were not the primary referral diagnosis.

Unveiling the longitudinal association between short sleep duration and the incidence of obesity: the Penn State Cohort.

OBJECTIVE: Several epidemiologic, longitudinal studies have reported that short sleep duration is a risk factor for the incidence of obesity. However, the vast majority of these studies used self-reported measures of sleep duration and did not examine the role of objective short sleep duration, subjective sleep disturbances and emotional stress. DESIGN: Longitudinal, population-based study. SUBJECTS: We studied a random sample of 815 non-obese adults from the Penn State Cohort in the sleep laboratory for one night using polysomnography (PSG) and followed them up for a mean of 7.5 years. Subjective and objective measures of sleep as well as emotional stress were obtained at baseline. Obesity was defined as a body mass index (BMI) ≥30 kg/ m(-2). RESULTS: The incidence of obesity was 15% and it was significantly higher in women and in individuals who reported sleep disturbances, shorter sleep duration and higher emotional stress. Significant mediating effects showed that individuals with subjective sleep disturbances who developed obesity reported the shortest sleep duration and the highest emotional stress, and that subjective sleep disturbances and emotional stress were independent predictors of incident obesity. Further analyses revealed that the association between short sleep duration, subjective sleep disturbances and emotional stress with incident obesity was stronger in young and middle-age adults. Objective short sleep duration was not associated with a significantly increased risk of incident obesity. CONCLUSION: Self-reported short sleep duration in non-obese individuals at risk of developing obesity is a surrogate marker of emotional stress and subjective sleep disturbances. Objective short sleep duration is not associated with a significant increased risk of incident obesity. The detection and treatment of sleep disturbances and emotional stress should become a target of our preventive strategies against obesity.

[Chronic obstructive pulmonary disease: sense of coherence and family support versus anxiety and depression].

Chronic Obstructive Pulmonary Disease (COPD) is mainly related to smoking habit and is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Worldwide and in Greece, COPD constitutes a major epidemiological issue. Incidence of depression and anxiety is high in the COPD population. Most studies on depression and anxiety in COPD deal with factors that are positively correlated with both of these comorbidities. The aim of our study was to assess whether two variables, sense of coherence (SOC) and perception of family support (FS), are negatively correlated with depressive and anxiety symptoms in outpatients with COPD. According to Aaron Antonovsky, sense of coherence refers to the ability of individuals to make sense of and manage events. Studies in other diseases suggest that sense of family support has a significant impact on the course and outcome of the disease, yet a limited number of reports across literature addresses the role of family support in COPD patients. In our present study one hundred twenty two (98 men and 24 women) outpatients with pure COPD were included. Age and years of education were recorded. Severity of COPD was assessed with spirometry before and after bronchodilation. All patients replied to self- administered questionnaires on depression (Beck Depression Inventory, BDI), anxiety (Spielberger State-Trait Anxiety Scale, STAI), family support (Family Support Scale, FSS-13) and sense of coherence (Sense of Coherence Scale, SOC). According to our results the mean BDI depression score was 11.65 (SD 7.35), mean trait anxiety score was 40.69 (SD 11.19), mean SOC score was 54.62 (SD 7.40) and mean FS score was 64.58 (SD 11.63). Women patients had higher anxiety scores and lower sense of family support compared to men. Significant negative correlations were evidenced between depression and sense of coherence as well as between anxiety and family support. Step-wise multiple linear regression analysis verified the results and quantified the aforementioned correlations. Notably, raising scores in sense of family support by one point reduces anxiety scores by 0.14 points, and increasing sense of coherence scores by one point reduces depression scores by 0.21 points. In sum, our study confirms the presence of high levels of anxiety and depressive symptoms in COPD patients, with females being in a more disadvantaged position as they tend to have higher levels of both. Sense of coherence and family support are both protective psychological factors against the risk of developing anxiety and depressive symptoms in these patients.

Selective effects of CPAP on sleep apnoea-associated manifestations.

BACKGROUND: Visceral adiposity and obstructive sleep apnoea (OSA) may be independently associated with daytime sleepiness/low performance, insulin resistance, hypercytokinaemia, and/or hypertension. The objectives of this study are to simultaneously test these associations at baseline and after 3 months of continuous positive airway pressure (CPAP) therapy. MATERIALS AND METHODS: Sixteen obese men with OSA; 13 non-apnoeic, obese controls, and 15 non-obese controls were monitored in the sleep laboratory for four consecutive nights. Objective measures of daytime sleepiness and performance, serial 24 h plasma measures of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), TNF receptor 1 (TNF-r1) and adiponectin, fasting blood glucose and insulin, visceral adiposity and blood pressure were obtained. Sleep apnoeics were re-assessed using the same protocol after 3 months of CPAP. RESULTS: At baseline, IL-6, TNF-r1, and insulin resistance were highest in OSA patients, intermediate in obese controls, and lowest in non-obese controls (P < 0.05). Visceral fat was significantly greater in sleep apnoeics than obese controls and predicted insulin resistance and IL-6 levels, whereas OSA predicted TNF-r1 levels (P < 0.05). CPAP decreased daytime sleepiness and blood pressure (P < 0.05), but did not affect fasting glucose or insulin or around the clock adiponectin, IL-6, TNF-alpha, or TNF-r1 levels. CONCLUSIONS: In obese sleep apnoeics, visceral fat is strongly associated with insulin resistance and inflammation. CPAP decreases sleepiness and moderates hypertension but does not affect visceral adiposity, insulin resistance, hypoadiponectinaemia or hypercytokinaemia, all of which are independent risk factors for cardiovascular disease and diabetes.

Short sleep duration and obesity: the role of emotional stress and sleep disturbances.

OBJECTIVE: Many epidemiologic studies have reported that obesity is associated with short sleep duration. How the degree of obesity or other clinical characteristics of the obese individuals, such as sleep disturbances or emotional stress, define this relation is not known. DESIGN: We studied a random sample of 1300 middle-aged men and women from the Penn State Cohort in the sleep laboratory for one night. Sleep disturbances were recorded as insomnia, excessive daytime sleepiness (EDS) or sleep difficulty. Chronic emotional stress was determined by the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). RESULTS: Obese individuals (body mass index, BMI>30) reported shorter duration of sleep, had a higher incidence of subjective sleep disturbances (47.4 vs 25.5%; P<0.01) and scored higher for chronic emotional stress than nonobese subjects. However, there was no difference in self-reported sleep duration between obese and nonobese individuals without subjective sleep disturbances, while both obese men and women with sleep complaints scored higher in the MMPI-2 compared to obese individuals without sleep complaints. The shortest sleep duration was reported by the obese insomniac patients (5.9 h), followed by obese with EDS (6.3 h) or sleep difficulty (6.6 h). The effect of chronic emotional stress was stronger than that of the BMI on the reported sleep duration, with a synergistic joint effect. The presence of a sleep disturbance was associated with a reduction of reported sleep by 18 min for men and 42 min in women, whereas a 10 kg m(-2) increase of BMI was associated with a 16 and 6 min decrease of sleep in men and women, respectively. Interestingly, there was no association between objective sleep duration and BMI. CONCLUSION: Self-reported short sleep duration in obese individuals may be a surrogate marker of emotional stress and subjective sleep disturbances, whose detection and management should be the focus of our preventive and therapeutic strategies for obesity.

Hypothalamic-pituitary-adrenal axis activity in obese men with and without sleep apnea: effects of continuous positive airway pressure therapy.

CONTEXT: Previous studies on the association between the hypothalamic-pituitary-adrenal axis activity and sleep apnea (SA) and obesity are inconsistent and/or limited. OBJECTIVE: In this study, we evaluated the activity of the hypothalamic-pituitary-adrenal axis in nonpsychologically distressed obese subjects with and without SA and examined the impact of continuous positive airway pressure (CPAP) in SA patients. DESIGN AND PARTICIPANTS: In study I, four-night sleep laboratory recordings and serial 24-h plasma measures of cortisol were obtained in 45 obese men with and without apnea and nonobese controls. Sleep apneic patients were reassessed after 3 months of CPAP use. In study II, 38 obese men with and without sleep apnea and nonobese controls were challenged with ovine CRH administration after four nights in the sleep laboratory. RESULTS: The sleep patterns were similar between obese and nonobese controls. Twenty-four-hour plasma cortisol levels were highest in nonobese controls, intermediate in obese apneic patients, and lowest in obese controls (8.8 +/- 0.4 vs. 8.1 +/- 0.3 vs. 7.5 +/- 0.3 microg/dl, P < 0.05). CPAP tended to reduce cortisol levels in the apneic patients (difference -0.7 +/- .4 microg/dl, P = 0.1). CRH administration resulted in a higher ACTH response in both obese groups, compared with nonobese controls; the three groups were not different in cortisol response. CONCLUSIONS: Nonpsychologically distressed, normally sleeping, obese men had low cortisol secretion. The cortisol secretion was slightly activated by SA and returned to low by CPAP use. The low cortisol secretion in obesity through its inferred hyposecretion of hypothalamic CRH might predispose the obese to sleep apnea.

Daytime napping after a night of sleep loss decreases sleepiness, improves performance, and causes beneficial changes in cortisol and interleukin-6 secretion.

Sleep loss has been associated with increased sleepiness, decreased performance, elevations in inflammatory cytokines, and insulin resistance. Daytime napping has been promoted as a countermeasure to sleep loss. To assess the effects of a 2-h midafternoon nap following a night of sleep loss on postnap sleepiness, performance, cortisol, and IL-6, 41 young healthy individuals (20 men, 21 women) participated in a 7-day sleep deprivation experiment (4 consecutive nights followed by a night of sleep loss and 2 recovery nights). One-half of the subjects were randomly assigned to take a midafternoon nap (1400-1600) the day following the night of total sleep loss. Serial 24-h blood sampling, multiple sleep latency test (MSLT), subjective levels of sleepiness, and psychomotor vigilance task (PVT) were completed on the fourth (predeprivation) and sixth days (postdeprivation). During the nap, subjects had a significant drop in cortisol and IL-6 levels (P < 0.05). After the nap they experienced significantly less sleepiness (MSLT and subjective, P < 0.05) and a smaller improvement on the PVT (P < 0.1). At that time, they had a significant transient increase in their cortisol levels (P < 0.05). In contrast, the levels of IL-6 tended to remain decreased for approximately 8 h (P = 0.1). We conclude that a 2-h midafternoon nap improves alertness, and to a lesser degree performance, and reverses the effects of one night of sleep loss on cortisol and IL-6. The redistribution of cortisol secretion and the prolonged suppression of IL-6 secretion are beneficial, as they improve alertness and performance.

Excessive daytime sleepiness in a general population sample: the role of sleep apnea, age, obesity, diabetes, and depression.

CONTEXT: Excessive daytime sleepiness (EDS) is commonly considered a cardinal sign of sleep apnea; however, the mechanism underlying the association is unclear. OBJECTIVE: The purpose of this study was to assess the association between the complaint of EDS and sleep apnea, considering a wide range of possible risk factors in a population sample. DESIGN AND SETTING: We examined this question in the Penn State cohort (a random sample of 16,583 men and women from central Pennsylvania, ranging in age from 20 to 100 yr). A random subset of this cohort (n = 1,741) was further evaluated for one night in the sleep laboratory. MAIN OUTCOME MEASURE: The main measure was a complaint of EDS. RESULTS: The final logistic regression model indicated depression was the most significant risk factor for EDS followed by body mass index, age, typical sleep duration, diabetes, smoking, and finally sleep apnea. The strength of the association with EDS decreased with increasing age, whereas the association of depression with EDS was stronger in the young. EDS is more prevalent in the young (<30 yr), suggesting the presence of unmet sleep needs and depression, and in the very old (>75 yr), suggesting increasing medical illness and health problems. EDS was associated with a reduced report of typical sleep duration without any association with objective polysomnographic measures. CONCLUSIONS: It appears that the presence of EDS is more strongly associated with depression and metabolic factors than with sleep-disordered breathing or sleep disruption per se. Our findings suggest that patients with a complaint of EDS should be thoroughly assessed for depression and obesity/diabetes independent of whether sleep-disordered breathing is present.

IL-6 and its circadian secretion in humans.

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by numerous types of immune and nonimmune cells and is involved in many pathophysiologic mechanisms in humans. Many studies suggest that IL-6 is a putative 'sleep factor' and its circadian secretion correlates with sleep/sleepiness. IL-6 is elevated in disorders of excessive daytime sleepiness such as narcolepsy and obstructive sleep apnea. It correlates positively with body mass index and may be a mediator of sleepiness in obesity. Also the secretion of this cytokine is stimulated by total acute or partial short-term sleep loss reflecting the increased sleepiness experienced by sleep-deprived individuals. Studies that evaluated the 24-hour secretory pattern of IL-6 in healthy young adults suggest that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 08.00 and 21.00, and two zeniths at about 19.00 and 05.00 h. In contrast, following sleep deprivation or in disorders of sleep disturbance, e.g., insomnia, IL-6 peaks during the day and, based on the level of stress system activity, i.e., cortisol secretion, contributes to either sleepiness and deep sleep (low cortisol) or feelings of tiredness and fatigue and poor sleep (high cortisol). In order to address concerns about the potential impact of differences of IL-6 levels between the beginning and the end of the 24-hour blood-drawing experiment, we proceeded with a cosinor analysis of 'detrended' data in young and old healthy individuals. This new analysis did not affect the biphasic circadian pattern of IL-6 secretion in young adults, while it augmented the flattened circadian pattern in old individuals in whom the difference was greater. Finally, IL-6 appears to be somnogenic in rats and exhibits a diurnal rhythm that follows the sleep/wake cycle in these animals. We conclude that IL-6 is a mediator of sleepiness and its circadian pattern reflects the homeostatic drive for sleep.

Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist.

The proinflammatory cytokines, TNFalpha and IL-6, are elevated in obstructive sleep apnea (OSA) and have been proposed as mediators of excessive daytime sleepiness in humans. We tested the effects of etanercept, a medication that neutralizes TNFalpha and is approved by the FDA for the treatment of rheumatoid arthritis, in eight obese male apneics. These patients participated in a pilot, placebo-controlled, double-blind study during which nighttime polysomnography, multiple sleep latency test, and fasting blood glucose and plasma levels of IL-6, C-reactive protein, insulin, and adiponectin were obtained. There was a significant and marked decrease in sleepiness by etanercept, which increased sleep latency during the multiple sleep latency test by 3.1 +/- 1.0 min (P < 0.05) compared with placebo. Also, the number of apneas/hypopneas per hour was reduced significantly by the drug compared with placebo (52.8 +/- 9.1 vs. 44.3 +/- 10.3; adjusted difference, -8.4 +/- 2.3; P < 0.05). Furthermore, IL-6 levels were significantly decreased after etanercept administration compared with placebo (3.8 +/- 0.9 vs. 1.9 +/- 0.4 pg/ml; adjusted difference, -1.9 +/- 0.5; P < 0.01). However, no differences were observed in etanercept vs. placebo in the levels of fasting blood glucose and plasma C-reactive protein, insulin, and adiponectin. We conclude that neutralizing TNFalpha activity is associated with a significant reduction of objective sleepiness in obese patients with OSA. This effect, which is about 3-fold higher than the reported effects of continuous positive airway pressure on objective sleepiness in patients with OSA (0.9 vs. 3.1 min), suggests that proinflammatory cytokines contribute to the pathogenesis of OSA/sleepiness.

Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines.

Total sleep restriction in humans is associated with increased daytime sleepiness, decreased performance, and hormonal/metabolic disturbances. The effects of mild chronic sleep restriction that mimic real life are not known. To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory. After 1 wk of sleep restriction, although subjects' nighttime sleep was deeper, subjects were significantly sleepier (multiple sleep latency test) and performed worse in four primary variables of psychomotor vigilance test (both P < 0.01). Furthermore, 24-h secretion of IL-6 was increased by 0.8 +/- 0.3 pg/ml (P < 0.05) in both sexes, whereas TNFalpha was increased only in men. Also, the peak cortisol secretion was lower after sleep restriction than at baseline, and this difference was stronger in men (55.18 +/- 24.83 nmol/liter; P < 0.05) than in women (35.87 +/- 24.83 nmol/liter; P < 0.16). We conclude that in young men and women, modest sleep loss is associated with significant sleepiness, impairment of psychomotor performance, and increased secretion of proinflammatory cytokines. Given the potential association of these behavioral and physical alterations with health, well-being, and public safety, the idea that sleep or parts of it are optional should be regarded with caution.

Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance.

Obstructive sleep apnoea (OSA) is a very prevalent disorder particularly amongst middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness'. In 1997, we first reported that the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor-alpha (TNF alpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNF alpha plasma levels and the body mass index (BMI). In subsequent studies, we showed that IL-6, TNF alpha, leptin and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnoea. The association of OSA with insulin resistance and diabetes type 2 has been confirmed since then in several epidemiological and clinical studies. Furthermore, our findings that women with polycystic ovary syndrome (PCOS, a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness support the pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnoea and sleepiness may be manifestations of a serious metabolic disorder, namely the Metabolic or Visceral Obesity Syndrome, include: obesity without sleep apnoea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity and age; and increased prevalence of sleep apnoea in postmenopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA. In conclusion, accumulating evidence provides support to our model of the bi-directional, feedforward, pernicious association between sleep apnoea, sleepiness, inflammation and insulin resistance, all promoting atherosclerosis and cardiovascular disease.