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1.  Polysomnography in Patients With Obstructive Sleep Apnea 
Executive Summary
Objective
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario.
Clinical Need: Target Population and Condition
Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies.
The Technology Being Reviewed
There is no ‘gold standard’ for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs.
In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as “The Sleep Book.” The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered.
Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective.
Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value.
At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments.
Methods
Review Strategy
There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature.
To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed.
Diffusion of Sleep Laboratories
To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases.
Summary of Findings
Literature Review
A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study.
Prevalence
Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men.
Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups.
Diagnostic Value of Polysomnography
It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined.
Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population.
Obstructive Sleep Apnea and Obesity
Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m2) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals.
Obstructive Sleep Apnea and Cardiovascular Diseases
Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values.
A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m2; range = 32.30–68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension.
Health Technology Assessments, Guidelines, and Recommendations
In April 2005, the Centers for Medicare and Medicaid Services (CMS) in the United States published its decision and review regarding in-home and in-lab sleep studies for the diagnosis and treatment of OSA with CPAP. In order to cover CPAP, CMS requires that a diagnosis of OSA be established using PSG in a sleep laboratory. After reviewing the literature, CMS concluded that the evidence was not adequate to determine that unattended portable sleep study was reasonable and necessary in the diagnosis of OSA.
In May 2005, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) published a review of guidelines for referral of patients to sleep laboratories. The review included 37 guidelines and associated reviews that covered 18 applications of sleep laboratory studies. The CCOHTA reported that the level of evidence for many applications was of limited quality, that some cited studies were not relevant to the recommendations made, that many recommendations reflect consensus positions only, and that there was a need for more good quality studies of many sleep laboratory applications.
Diffusion
As of the time of writing, there are 97 licensed sleep laboratories in Ontario. In 2000, the number of sleep studies performed in Ontario was 376/100,000 people. There was a steady rise in sleep studies in the following years such that in 2004, 769 sleep studies per 100,000 people were performed, for a total of 96,134 sleep studies. Based on prevalence estimates of the Wisconsin Sleep Cohort Study, it was estimated that 927,105 people aged 30 to 60 years have sleep-disordered breathing. Thus, there may be a 10-fold rise in the rate of sleep tests in the next few years.
Economic Analysis
In 2004, approximately 96,000 sleep studies were conducted in Ontario at a total cost of ~$47 million (Cdn). Since obesity is associated with sleep disordered breathing, MAS compared the costs of sleep studies to the cost of bariatric surgery. The cost of bariatric surgery is $17,350 per patient. In 2004, Ontario spent $4.7 million per year for 270 patients to undergo bariatric surgery in the province, and $8.2 million for 225 patients to seek out-of-country treatment. Using a Markov model, it was concluded that shifting costs from sleep studies to bariatric surgery would benefit more patients with OSA and may also prevent health consequences related to diabetes, hypertension, and hyperlipidemia. It is estimated that the annual cost of treating comorbid conditions in morbidly obese patients often exceeds $10,000 per patient. Thus, the downstream cost savings could be substantial.
Considerations for Policy Development
Weight loss is associated with a decrease in OSA severity. Treating and preventing obesity would also substantially reduce the economic burden associated with diabetes, hypertension, hyperlipidemia, and OSA. Promotion of healthy weights may be achieved by a multisectorial approach as recommended by the Chief Medical Officer of Health for Ontario. Bariatric surgery has the potential to help morbidly obese individuals (BMI > 35 kg/m2 with an accompanying comorbid condition, or BMI > 40 kg/m2) lose weight. In January 2005, MAS completed an assessment of bariatric surgery, based on which OHTAC recommended an improvement in access to these surgeries for morbidly obese patients in Ontario.
Habitual snorers with excessive daytime sleepiness have a high pretest probability of having OSA. These patients could be offered a therapeutic trial of CPAP to diagnose OSA, rather than a PSG. A majority of these patients are also obese and may benefit from weight loss. Individualized weight loss programs should, therefore, be offered and patients who are morbidly obese should be offered bariatric surgery.
That said, and in view of the still evolving understanding of the causes, consequences and optimal treatment of OSA, further research is warranted to identify which patients should be screened for OSA.
PMCID: PMC3379160  PMID: 23074483
2.  Sleep disturbances in an arctic population: The Tromsø Study 
Background
Prevalence estimates for insomnia range from 10 to 50% in the adult general population. Sleep disturbances cause great impairment in quality of life, which might even rival or exceed the impairment in other chronic medical disorders. The economic implications and use of health-care services related to chronic insomnia represent a clinical concern as well as a pronounced public health problem. Hypnotics are frequently prescribed for insomnia, but alcohol and over-the-counter sleep aids seem to be more widely used by insomniacs than prescription medications. Despite the complex relationship between insomnia and physical and mental health factors, the condition appears to be underrecognized and undertreated by health care providers, probably due to the generally limited knowledge of the causes and natural development of insomnia.
Methods/Design
The Tromsø Study is an ongoing population-based cohort study with five previous health studies undertaken between 1974 and 2001. This protocol outlines a planned study within the sixth Tromsø Study (Tromsø VI), aiming at; 1) describing sleep patterns in a community-based sample representative of the general population of northern Norway, and 2) examining outcome variables of sleep disturbances against possible explanatory and confounding variables, both within a cross-sectional approach, as well as retrospectively in a longitudinal study – exploring sleep patterns in subjects who have attended two or more of the previous Tromsø studies between 1974 and 2009. First, we plan to perform a simple screening in order to identify those participants with probable sleep disturbances, and secondly to investigate these sleep disturbances further, using an extensive sleep-questionnaire. We will also collect biological explanatory variables, i.e. blood samples, weight, height and blood pressure. We plan to merge data on an individual level from the Tromsø VI Study with data from the Norwegian Prescription Database (NorPD), which is a national registry including data for all prescription drugs issued at Norwegian pharmacies. Participants with sleep disturbances will be compared with pair-matched controls without sleep disturbances.
Discussion
Despite ongoing research, many challenges remain in the characterization of sleep disturbances and its correlates. Future mapping of the biological dimensions, natural history, as well as the behavioral and drug-related aspects of sleep disturbances in a representative population samples is clearly needed.
doi:10.1186/1472-6963-8-117
PMCID: PMC2424044  PMID: 18510767
3.  An assessment of quality of sleep and the use of drugs with sedating properties in hospitalized adult patients 
Background
Hospitalization can significantly disrupt sleeping patterns. In consideration of the previous reports of insomnia and apparent widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted a study to assess quality of sleep and hypnotic drug use in our acute care adult patient population. The primary objectives of this study were to assess sleep disturbance and its determinants including the use of drugs with sedating properties.
Methods
This single-centre prospective study involved an assessment of sleep quality for consenting patients admitted to the general medicine and family practice units of an acute care Canadian hospital. A validated Verran and Snyder-Halpern (VSH) Sleep Scale measuring sleep disturbance, sleep effectiveness, and sleep supplementation was completed daily by patients and scores were compared to population statistics. Patients were also asked to identify factors influencing sleep while in hospital, and sedating drug use prior to and during hospitalization was also assessed.
Results
During the 70-day study period, 100 patients completed at least one sleep questionnaire. There was a relatively even distribution of males versus females, most patients were in their 8th decade of life, retired, and suffered from multiple chronic diseases. The median self-reported pre-admission sleep duration for participants was 8 hours and our review of PharmaNetR profiles revealed that 35 (35%) patients had received a dispensed prescription for a hypnotic or antidepressant drug in the 3-month period prior to admission. Benzodiazepines were the most common sedating drugs prescribed. Over 300 sleep disturbance, effective and supplementation scores were completed. Sleep disturbance scores across all study days ranged 16–681, sleep effectiveness scores ranged 54–402, while sleep supplementation scores ranged between 0–358. Patients tended to have worse sleep scores as compared to healthy non-hospitalized US adults in all three scales. When compared to US non-hospitalized adults with insomnia, our patients demonstrated sleep disturbance and supplementation scores that were similar on Day 1, but lower (i.e. improved) on Day 3, while sleep effectiveness were higher (i.e. better) on both days. There was an association between sleep disturbance scores and the number of chronic diseases, the presence of pain, the use of bedtime tricyclic antidepressants, and the number of chronic diseases without pain. There was also an association between sleep effectiveness scores and the length of hospitalization, the in hospital use of bedtime sedatives and the presence of pain. Finally, an association was identified between sleep supplementation scores and the in hospital use of bedtime sedatives (tricyclic antidepressants and loxapine), and age. Twenty-nine (29%) patients received a prescription for a hypnotic drug while in hospital, with no evidence of pre-admission hypnotic use. The majority of these patients were prescribed zopiclone, lorazepam or another benzodiazepine.
Conclusions
The results of this study reveal that quality of sleep is a problem that affects hospitalized adult medical service patients and a relatively high percentage of these patients are being prescribed a hypnotic prior to and during hospitalization.
doi:10.1186/1477-7525-2-17
PMCID: PMC521202  PMID: 15040803
4.  Hypnotics' association with mortality or cancer: a matched cohort study 
BMJ Open  2012;2(1):e000850.
Objectives
An estimated 6%–10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality.
Setting
A large integrated health system in the USA.
Design
Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis.
Subjects
Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007.
Main outcome measures
Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity.
Results
As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4–18, 18–132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose–response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease.
Conclusions
Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.
Article summary
Article focus
Estimate the mortality risks associated with specific currently popular hypnotics in a matched cohort design, using proportional hazards regression models.
Estimate the cancer risks associated with specific currently popular hypnotics.
Explore what risk associated with hypnotics can be attributed to confounders and comorbidity.
Key messages
Patients receiving prescriptions for zolpidem, temazepam and other hypnotics suffered over four times the mortality as the matched hypnotic-free control patients.
Even patients prescribed fewer than 18 hypnotic doses per year experienced increased mortality, with greater mortality associated with greater dosage prescribed.
Among patients prescribed hypnotics, cancer incidence was increased for several specific types of cancer, with an overall cancer increase of 35% among those prescribed high doses.
Strengths and limitations of this study
Design strengths included matching patient and control cohorts by age, gender and smoking. Through stratified statistical analyses, patients using hypnotics were matched with controls diagnosed with the exactly the same combination of 12 categories of comorbidity in up to 116 strata.
The major limitation was that residual confounding could not be fully excluded, due to possible biases affecting which patients were prescribed hypnotics and due to possible imbalances in surveillance.
Cohort studies demonstrating association do not necessarily imply causality, but the preferable randomised controlled trial method for assessing hypnotic risks may be impractical due to ethical and funding limitations.
doi:10.1136/bmjopen-2012-000850
PMCID: PMC3293137  PMID: 22371848
5.  Obstructive Sleep Apnea and Risk of Cardiovascular Events and All-Cause Mortality: A Decade-Long Historical Cohort Study 
PLoS Medicine  2014;11(2):e1001599.
Tetyana Kendzerska and colleagues explore the association between physiological measures of obstructive sleep apnea other than the apnea-hypopnea index and the risk of cardiovascular events.
Please see later in the article for the Editors' Summary
Background
Obstructive sleep apnea (OSA) has been reported to be a risk factor for cardiovascular (CV) disease. Although the apnea-hypopnea index (AHI) is the most commonly used measure of OSA, other less well studied OSA-related variables may be more pathophysiologically relevant and offer better prediction. The objective of this study was to evaluate the relationship between OSA-related variables and risk of CV events.
Methods and Findings
A historical cohort study was conducted using clinical database and health administrative data. Adults referred for suspected OSA who underwent diagnostic polysomnography at the sleep laboratory at St Michael's Hospital (Toronto, Canada) between 1994 and 2010 were followed through provincial health administrative data (Ontario, Canada) until May 2011 to examine the occurrence of a composite outcome (myocardial infarction, stroke, congestive heart failure, revascularization procedures, or death from any cause). Cox regression models were used to investigate the association between baseline OSA-related variables and composite outcome controlling for traditional risk factors. The results were expressed as hazard ratios (HRs) and 95% CIs; for continuous variables, HRs compare the 75th and 25th percentiles. Over a median follow-up of 68 months, 1,172 (11.5%) of 10,149 participants experienced our composite outcome. In a fully adjusted model, other than AHI OSA-related variables were significant independent predictors: time spent with oxygen saturation <90% (9 minutes versus 0; HR = 1.50, 95% CI 1.25–1.79), sleep time (4.9 versus 6.4 hours; HR = 1.20, 95% CI 1.12–1.27), awakenings (35 versus 18; HR = 1.06, 95% CI 1.02–1.10), periodic leg movements (13 versus 0/hour; HR = 1.05, 95% CI 1.03–1.07), heart rate (70 versus 56 beats per minute [bpm]; HR = 1.28, 95% CI 1.19–1.37), and daytime sleepiness (HR = 1.13, 95% CI 1.01–1.28).The main study limitation was lack of information about continuous positive airway pressure (CPAP) adherence.
Conclusion
OSA-related factors other than AHI were shown as important predictors of composite CV outcome and should be considered in future studies and clinical practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, particularly among middle-aged and elderly people. It is characterized by apnea—a brief interruption in breathing that lasts at least 10 seconds—and hypopnea—a decrease of more than 50% in the amplitude of breathing that lasts at least 10 seconds or clear but smaller decrease in amplitude associated with either oxygen desaturation or an arousal. Patients with OSA experience numerous episodes of apnea and hypopnea during the night; severe OSA is defined as having 30 or more episodes per hour (an apnea-hypopnea index [AHI] of >30). These breathing interruptions occur when relaxation of the upper airway muscles decreases the airflow, which lowers the amount of oxygen in the blood. As a result, affected individuals frequently wake from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air through a face mask into the airway to keep it open.
Why Was This Study Done?
OSA can be life-threatening. Most directly, daytime sleepiness can cause accidents, but OSA is also associated with an increased risk of developing cardiovascular disease (CVD, disease that affects the heart and the circulation). To date, studies that have investigated the association between OSA and the risk of myocardial infarction (heart attack), congestive heart failure, stroke, and other CVDs have used the AHI to diagnose and categorize the severity of OSA. However, by focussing on AHI, clinicians and researchers may be missing opportunities to improve their ability to predict which patients are at the highest risk of CVD. In this historical cohort study, the researchers investigate the association between other OSA-related variables (for example, blood oxygen saturation and sleep fragmentation) and the risk of cardiovascular events and all-cause mortality (death). A historical cohort study examines the medical records of groups of individuals who have different characteristics at baseline for the subsequent occurrence of specific outcomes.
What Did the Researchers Do and Find?
The researchers used administrative data (including hospitalization records and physicians' claims for services supplied to patients) to follow up adults referred for suspected OSA who underwent diagnostic polysomnography (a sleep study) at a single Canadian hospital between 1994 and 2010. A database of the polysomnography results provided information on OSA-related variables for all the study participants. Over an average follow-up of about 6 years, 11.5% of the 10,149 participants were hospitalized for a myocardial infarction, stroke, or congestive heart failure, underwent a revascularization procedure (an intervention that restores the blood supply to an organ or tissue after CVD has blocked a blood vessel), or had died from any cause. After adjusting for multiple established risk factors for CVD such as smoking and age in Cox regression models (a statistical approach that examines associations between patient variables and outcomes), several OSA-related variables (but not AHI) were significant predictors of CVD. The strongest OSA-related predictor of cardiovascular events or all-cause mortality was total sleep time spent with oxygen saturation below 90%, which increased the risk of a cardiovascular event or death by 50%. Other statistically significant OSA-related predictors (predictors that were unlikely to be associated with the outcome through chance) of cardiovascular events or death included total sleep time, number of awakenings, frequency of periodic leg movements, heart rate, and daytime sleepiness.
What Do These Findings Mean?
These findings indicate that OSA-related factors other than AHI are important predictors of the composite outcome of a cardiovascular event or all-cause mortality. Indeed, although AHI was significantly associated with the researchers' composite outcome in an analysis that did not consider other established risk factors for CVD (“confounders”), the association became non-significant after controlling for potential confounders. The accuracy of these findings, which need to be confirmed in other settings, is likely to be limited by the lack of information available about the use of CPAP by study participants and by the lack of adjustment for some important confounders. Importantly, however, these findings suggest that OSA-related factors other than AHI should be considered as predictors of CVD in future studies and in clinical practice.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001599.
The US National Heart Lung and Blood Institute has information (including several videos) about obstructive sleep apnea (in English and Spanish), sleep studies, heart disease, and other cardiovascular diseases (some information in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about sleep apnea and about cardiovascular disease
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and health-care professionals, including personal stories about the condition
The MedlinePlus encyclopedia has pages on obstructive sleep apnea and on polysomnography; MedlinePlus provides links to further information and advice about obstructive sleep apnea, heart diseases, and vascular diseases (in English and Spanish)
doi:10.1371/journal.pmed.1001599
PMCID: PMC3913558  PMID: 24503600
6.  Impact of sleep disturbance on patients in treatment for mental disorders 
BMC Psychiatry  2012;12:179.
Background
In clinical practice, sleep disturbance is often regarded as an epiphenomenon of the primary mental disorder. The aim of this study was to test if sleep disturbance, independently of primary mental disorders, is associated with current clinical state and benefit from treatment in a sample representative of public mental health care clinics.
Method
2246 patients receiving treatment for mental disorders in eight public mental health care centers in Norway were evaluated in a cross-sectional study using patient and clinician reported measures. Patients reported quality of life, symptom severity, and benefit from treatment. Clinicians reported disorder severity, level of functioning, symptom severity and benefit from treatment. The hypothesis was tested using multiple hierarchical regression analyses.
Results
Sleep disturbance was, adjusted for age, gender, time in treatment, type of care, and the presence of any primary mental disorder, associated with lower quality of life, higher symptom severity, higher disorder severity, lower levels of functioning, and less benefit from treatment.
Conclusion
Sleep disturbance ought to be considered a stand-alone therapeutic entity rather than an epiphenomenon of existing diagnoses for patients receiving treatment in mental health care.
doi:10.1186/1471-244X-12-179
PMCID: PMC3505143  PMID: 23107000
7.  Sleep–wake disturbances in cancer patients: narrative review of literature focusing on improving quality of life outcomes 
Purpose
Evidence suggests a high prevalence of sleep–wake disturbances in patients with cancer, occurring at diagnosis, during treatment, and continuing to survivorship. Yet associations between sleep–wake disturbances and the impact on quality of life outcomes is less clear. The purpose of this narrative review of the literature is to evaluate sleep–wake disturbances in patients with cancer, to describe the influence of poor sleep on quality of life as an outcome, and to evaluate the evidence to recommend future interventions.
Framework and methods
This review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach. Four databases (CINAHL, MEDLINE, PsycINFO, and Embase) were searched using terms “cancer OR neoplasm”, “sleep, sleep disturbance, sleep disorders or insomnia”, and “quality of life”; the search included all years, English language, and peer-reviewed articles on research studies. Studies included measurements of sleep and quality of life in cancer patients at a minimum of two time points and demonstrated relationships between sleep and quality of life. Data were collected on date, patient demographics, cancer type and treatment, timeframe, design, measurement, variables, and results.
Results
This narrative review demonstrates that sleep–wake disturbance is a major problem/symptom in patients with cancer. Of the 18 studies included, measurement of sleep-related variables included objective and subjective measures; however, direct measurement of the associations between sleep and quality of life was not common. Cognitive behavioral therapy for insomnia and mind–body interventions demonstrated feasibility when implemented into cancer care settings. In addition, the majority of interventions exhibited moderate effectiveness in improving sleep–wake disturbance and quality of life outcomes.
Conclusion
The studies predominantly reported that poor sleep negatively impacts quality of life. The intervention studies included nonpharmacologic interventions such as cognitive behavioral treatment and mind–body and exercise interventions with moderate-to-high levels of evidence for improvement in sleep measures and quality of life.
doi:10.2147/NSS.S34846
PMCID: PMC4103930  PMID: 25050080
sleep–wake disturbance; quality of life; cancer; cognitive behavioral therapy; mind-body interventions; insomnia
8.  Utility of self-reported sleep disturbances as a marker for major depressive disorder (MDD): Findings from the World Mental Health Japan Survey 2002–2006 
Psychiatry research  2012;198(1):146-153.
Although major depressive disorder (MDD) is a serious common disease, many depressive patients attend primary care complaining sleep disturbances and remain undiagnosed. The purpose of this study was to investigate the utility of self-reported sleep disturbances as a marker for MDD. This study investigated the association between 12-month prevalence of self-reported sleep disturbances and MDD using data from a cross-sectional survey in Japan. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver operating characteristic curve (AUC) of self-reported sleep disturbances as a marker for MDD were 58.9%, 73.4%, 6.9%, 98.1%, and 0.66, respectively. Self-reported sleep disturbances showed highest utility for the youngest group. Among four types of sleep disturbances, problem of daytime sleepiness was most useful as a marker for MDD. Combined with at least moderate role impairment, self-reported sleep disturbances became more informative with higher specificity (99.6%) and PPV (80.0%) as a marker for MDD. Self-reported sleep disturbances cannot be a marker for MDD in isolation. Comorbid role impairment increases probability of MDD. Clinicians should be cautious about young people who have sleep disturbances. Daytime sleepiness should be included in the question asking about sleep disturbances.
doi:10.1016/j.psychres.2011.10.001
PMCID: PMC3740201  PMID: 22377572
sleep disturbance; major depression; diagnostic tool
9.  Effectiveness and cost-effectiveness of an educational intervention for practice teams to deliver problem focused therapy for insomnia: rationale and design of a pilot cluster randomised trial 
BMC Family Practice  2009;10:9.
Background
Sleep problems are common, affecting over a third of adults in the United Kingdom and leading to reduced productivity and impaired health-related quality of life. Many of those whose lives are affected seek medical help from primary care. Drug treatment is ineffective long term. Psychological methods for managing sleep problems, including cognitive behavioural therapy for insomnia (CBTi) have been shown to be effective and cost effective but have not been widely implemented or evaluated in a general practice setting where they are most likely to be needed and most appropriately delivered. This paper outlines the protocol for a pilot study designed to evaluate the effectiveness and cost-effectiveness of an educational intervention for general practitioners, primary care nurses and other members of the primary care team to deliver problem focused therapy to adult patients presenting with sleep problems due to lifestyle causes, pain or mild to moderate depression or anxiety.
Methods and design
This will be a pilot cluster randomised controlled trial of a complex intervention. General practices will be randomised to an educational intervention for problem focused therapy which includes a consultation approach comprising careful assessment (using assessment of secondary causes, sleep diaries and severity) and use of modified CBTi for insomnia in the consultation compared with usual care (general advice on sleep hygiene and pharmacotherapy with hypnotic drugs). Clinicians randomised to the intervention will receive an educational intervention (2 × 2 hours) to implement a complex intervention of problem focused therapy. Clinicians randomised to the control group will receive reinforcement of usual care with sleep hygiene advice. Outcomes will be assessed via self-completion questionnaires and telephone interviews of patients and staff as well as clinical records for interventions and prescribing.
Discussion
Previous studies in adults have shown that psychological treatments for insomnia administered by specialist nurses to groups of patients can be effective within a primary care setting. This will be a pilot study to determine whether an educational intervention aimed at primary care teams to deliver problem focused therapy for insomnia can improve sleep management and outcomes for individual adult patients presenting to general practice. The study will also test procedures and collect information in preparation for a larger definitive cluster-randomised trial. The study is funded by The Health Foundation.
Trial Registration
ClinicalTrials.gov ID ISRCTN55001433 –
doi:10.1186/1471-2296-10-9
PMCID: PMC2636763  PMID: 19171070
10.  Insomnia is a frequent finding in adults with Asperger syndrome 
BMC Psychiatry  2003;3:12.
Background
Asperger syndrome (AS) is a neurodevelopmental disorder belonging to autism spectrum disorders with prevalence rate of 0,35% in school-age children. It has been most extensively studied in childhood while there is scarcity of reports concerning adulthood of AS subjects despite the lifelong nature of this syndrome. In children with Asperger syndrome the initiation and continuity of sleep is disturbed because of the neuropsychiatric deficits inherent of AS. It is probable that sleep difficulties are present in adulthood as well. Our hypothesis was that adults with AS suffer from difficulty in initiating and maintaining sleep and nonrestorative sleep (insomnia).
Methods
20 AS without medication were compared with 10 healthy controls devoid of neuropsychiatric anamnesis. Clinical examination, blood test battery and head MRI excluded confounding somatic illnesses. Structured psychiatric interview for axis-I and axis-II disorders were given to both groups as well as Beck Depression Inventory and Wechsler adult intelligence scale, revised version.
Sleep quality was assessed with sleep questionnaire, sleep diary during 6 consecutive days and description of possible sleep problems by the participants own words was requested.
Results
compared with controls and with normative values of good sleep, AS adults had frequent insomnia. In sleep questionnaire 90% (18/20), in sleep diary 75% (15/20) and in free description 85% (17/20) displayed insomnia. There was a substantial psychiatric comorbidity with only 4 AS subject devoid of other axis-I or axis-II disorders besides AS. Also these persons displayed insomnia. It can be noted that the distribution of psychiatric diagnoses in AS subjects was virtually similar to that found among patient with chronic insomnia.
Conclusions
the neuropsychiatric deficits inherent of AS predispose both to insomnia and to anxiety and mood disorders. Therefore a careful assessment of sleep quality should be an integral part of the treatment plan in these individuals. Conversely, when assessing adults with chronic insomnia the possibility of autism spectrum disorders as one of the potential causes of this condition should be kept in mind.
doi:10.1186/1471-244X-3-12
PMCID: PMC270035  PMID: 14563215
Asperger; sleep; insomnia
11.  Evaluation and Management of Sleep Disturbance During the Menopause Transition 
Seminars in reproductive medicine  2010;28(5):404-421.
Sleep disturbances in midlife women are common and have been associated with the menopause transition itself, symptoms of hot flashes, anxiety and depressive disorders, aging, primary sleep disorders (i.e., obstructive sleep apnea, periodic limb movement disorder), comorbid medical conditions and medications, as well as with psychosocial and behavioral factors. Because there are several common sources of sleep problems in midlife women, the cause of an individual woman's sleep disturbance may be multifactorial. Effective behavioral and pharmacological therapies are available to treat sleep disturbances of different etiologies. This review provides an overview of different types of sleep disturbance occurring in midlife women and presents data supporting the use of hormone therapy, hypnotic agents, and behavioral strategies to treat sleep problems in this population. The review aims to equip clinicians evaluating menopause-age women with the knowledge and evaluation tools to diagnose, engage sleep experts where appropriate, and treat sleep disturbance in this population. Sleep disorders in midlife women should be treated because substantial improvements in quality of life and health outcomes are achievable.
doi:10.1055/s-0030-1262900
PMCID: PMC3736837  PMID: 20845239
12.  Insomnia in Older Veterans: Prevalence, Self-Rated Health, and Talking to a Doctor About Sleep Problems 
Objectives
To determine insomnia prevalence and variations in prevalence with age among older Veterans and examine the relationships among insomnia, self-rated health, and talking to a doctor about sleep problems.
Design
A cross-sectional postal survey. Setting: VA Greater Los Angeles Healthcare System - Sepulveda Ambulatory Care Center (SACC) Participants: Veterans over age 60, who received outpatient care at SACC in the prior 12 months and resided within 25 miles of SACC (n=9080) Interventions: None
Measures
Data were collected from a postal survey, which included items addressing the diagnostic criteria for insomnia (difficultly falling or staying asleep, early awakening, insufficient/non-restorative sleep, daytime symptoms, duration of sleep problems) plus demographics, self-rated health, and whether the Veteran had previously talked to a doctor about sleep problems.
Results
Of 9080 surveys 4758 were returned. Of responders 51.5% met International Classification of Sleep Disorders (ICSD) insomnia diagnostic criteria. An unadjusted logistic regression model showed that individuals in the 60–65 year age bin were at the highest risk for insomnia, with the odds of having insomnia decreasing with each successively older age group (all P<.05). Veterans with poor self-rated health had higher insomnia prevalence, more daytime symptoms of insomnia, and reported fewer hours of sleep compared to Veterans with good self-rated health. In a regression model, poorer self-rated health, meeting insomnia criteria, younger age, and more daytime symptoms were significant independent predictors of discussing sleep problems with a doctor.
Conclusion
Older Veterans had high rates of insomnia, but contrary to most prior work, insomnia became less prevalent as age increased. Greater efforts are needed to help older Veterans recognize and disclose sleep problems, and doctors should routinely screen for insomnia and account for comorbidities when treating insomnia patients.
PMCID: PMC3764564
13.  Chronic Insomnia and Its Negative Consequences for Health and Functioning of Adolescents: A 12-Month Prospective Study 
Purpose
To estimate prevalence and chronicity of insomnia and the impact of chronic insomnia on health and functioning of adolescents.
Methods
Data were collected from 4175 youths 11–17 at baseline and 3134 a year later sampled from managed care groups in a large metropolitan area. Insomnia was assessed by youth reported DSM-IV symptom criteria. Outcomes are three measures of somatic health, three measures of mental health, two measures of substance use, three measures of interpersonal problems, and three of daily activities.
Results
Over one-fourth reported one or more symptoms of insomnia at baseline and about 5% met diagnostic criteria for insomnia. Almost 46% of those who reported 1 or more symptoms of insomnia in Wave 1 continued to be cases at Wave 2 and 24% met DSM-IV symptom criteria for chronic insomnia (cases in Wave 1 were also cases in Wave 2). Multivariate analyses found chronic insomnia increased subsequent risk for somatic health problems, interpersonal problems, psychological problems, and daily activities. Significant odds (p<.05) ranged from 1.6 to 5.6 for poor outcomes. These results are the first reported on chronic insomnia among youths and corroborate, using prospective data, previous findings on correlates of disturbed sleep based on cross-sectional studies.
Conclusions
Insomnia is both common and chronic among adolescents. The data indicate that the burden of insomnia is comparable to that of other psychiatric disorders such as mood, anxiety, disruptive and substance use disorders. Chronic insomnia severely impacts future health and functioning of youths. Those with chronic insomnia are more likely to seek medical care. These data suggest primary care settings might provide a venue for screening and early intervention for adolescent insomnia.
doi:10.1016/j.jadohealth.2007.09.016
PMCID: PMC2488408  PMID: 18295138
insomnia; prevalence; persistence; outcomes; adolescents
14.  The association between sleep disturbances and suicidal behaviors in patients with psychiatric diagnoses: a systematic review and meta-analysis 
Systematic Reviews  2014;3:18.
Background
Identifying patients with increased risk of suicidal behaviors is a constant challenge and concern for clinicians caring for patients with psychiatric conditions. We conducted a systematic review to assess the association between suicidal behaviors and sleep disturbances in psychiatric patients.
Methods
A systematic literature search of Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycInfo, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials, and Scopus was conducted using earliest inclusive dates to 28 June 2013. Eligible studies were comparative observational studies that reported sleep disturbances in psychiatric patients and the outcome of interest (any type of suicidal behaviors). Pairs of reviewers extracted descriptive data, study quality, and outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were pooled across studies using the random-effects model. Newcastle-Ottawa scale was used to critically appraise study quality.
Results
Nineteen studies met the inclusion criteria. Compared to those without sleep disturbances, patients with psychiatric diagnoses and co-morbid sleep disturbances were significantly more likely to report suicidal behaviors (OR = 1.99, 95% CI 1.72, 2.30, P <0.001). The association was also demonstrated across several psychiatric conditions including depression (OR = 3.05, 95% CI 2.07, 4.48, P <0.001), post-traumatic stress disorder (PTSD) (OR = 2.56, 95% CI 1.91, 3.43, P <0.001), panic disorder (OR = 3.22, 95% CI 1.09, 9.45, P = 0.03), and schizophrenia (OR = 12.66, 95% CI 1.40, 114.44, P = 0.02). In subgroup analysis based on the type of sleep disorder, we also found suicidal behavior to be significantly associated with the presence of insomnia, parasomnias, and sleep-related breathing disorders, but not hypersomnias.
Conclusions
This systematic review and meta-analysis suggests that in patients with psychiatric diagnoses, sleep disturbances are associated with the increased risk of suicidal behaviors.
doi:10.1186/2046-4053-3-18
PMCID: PMC3945796  PMID: 24568642
Sleep disturbances; Suicidal behaviors; Systematic reviews; Meta-analysis
15.  Self-reported sleep disturbances in renal transplant recipients 
BMC Nephrology  2013;14:220.
Background
Poor sleep quality (SQ) and daytime sleepiness (DS) are common in renal transplant (RTx) recipients; however, related data are rare. This study describes the prevalence and frequency of self-reported sleep disturbances in RTx recipients.
Methods
This cross-sectional study included 249 RTx recipients transplanted at three Swiss transplant centers. All had reported poor SQ and / or DS in a previous study. With the Survey of Sleep (SOS) self-report questionnaire, we screened for sleep and health habits, sleep history, main sleep problems and sleep-related disturbances. To determine a basis for preliminary sleep diagnoses according to the International Classification of Sleep Disorders (ICSD), 164 subjects were interviewed (48 in person, 116 via telephone and 85 refused). Descriptive statistics were used to analyze the data and to determine the frequencies and prevalences of specific sleep disorders.
Results
The sample had a mean age of 59.1 ± 11.6 years (60.2% male); mean time since Tx was 11.1 ± 7.0 years. The most frequent sleep problem was difficulty staying asleep (49.4%), followed by problems falling asleep (32.1%). The most prevalent sleep disturbance was the need to urinate (62.9%), and 27% reported reduced daytime functionality. Interview data showed that most suffered from the first ICSD category: insomnias.
Conclusion
Though often disregarded in RTx recipients, sleep is an essential factor of wellbeing. Our findings show high prevalences and incidences of insomnias, with negative impacts on daytime functionality. This indicates a need for further research on the clinical consequences of sleep disturbances and the benefits of insomnia treatment in RTx recipients.
doi:10.1186/1471-2369-14-220
PMCID: PMC3852502  PMID: 24112372
Renal transplantation; Sleep disturbances; Sleep quality; Daytime sleepiness
16.  Using difficulty resuming sleep to define nocturnal awakenings 
Sleep medicine  2010;11(3):236-241.
Objective
Nocturnal awakenings are one of the most prevalent sleep disturbances in the general population. Little is known, however, about the frequency of these episodes and how difficulty resuming sleep once awakened affects subjective sleep quality and quantity. Method: This is a cross-sectional telephone study with a representative sample consisting of 8,937 non-institutionalized individuals aged 18 or over living in Texas, New York and California. The interviews included questions on sleeping habits, health, sleep and mental disorders. Nocturnal awakenings were evaluated according to their frequency per week and per night, as well as their duration.
Results
A total of 35.5% of the sample reported awakening at least 3 nights per week. Of this 35.5%, 43% (15.2% of the total sample) reported difficulty resuming sleep once awakened. More than 80% of subjects with insomnia symptoms (difficulty initiating or maintaining sleep or non-restorative sleep) also had nocturnal awakenings. Difficulty resuming sleep was associated with subjective shorter sleep duration, poorer sleep quality, greater daytime impairment, greater consultations for sleep disturbances and greater likelihood of receiving a sleep medication.
Conclusions
Nocturnal awakenings disrupt the sleep of about one-third of the general population. Using difficulty resuming sleep identifies individuals with significant daytime impairment who are most likely to seek medical help for their sleep disturbances. In the absence of other insomnia symptoms, nocturnal awakenings alone are unlikely to be associated with daytime impairments.
doi:10.1016/j.sleep.2009.11.004
PMCID: PMC2830306  PMID: 20075004
17.  Midlife insomnia and subsequent mortality: the Hordaland health study 
BMC Public Health  2014;14:720.
Background
Previous research suggests a possible link between insomnia and mortality, but findings are mixed and well-controlled studies are lacking. The aim of the current study was to examine the effect of insomnia in middle age on all-cause mortality.
Methods
Using a cohort design with 13-15 years follow-up, mortality registry data were linked to health information obtained during 1997-99, as part of the community-based Hordaland Health Study (HUSK), in Western Norway. 6,236 participants aged 40–45 provided baseline information on self- reported insomnia using the Karolinska Sleep Questionnaire Scale (defined according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), sociodemographic factors, health behaviors, shift/night-work, obstructive sleep apnea symptoms, sleep duration, sleep medication use, anxiety, depression, as well as a range of somatic diagnoses and symptoms. Height, weight and blood pressure were measured. Information on mortality was obtained from the Norwegian Cause of Death Registry.
Results
Insomnia was reported by 5.6% (349/6236) at baseline and a significant predictor of all-cause-mortality (hazard ratio [HR] = 2.74 [95% CI:1.75-4.30]). Adjusting for all confounders did not attenuate the effect (HR = 3.34 [95% CI:1.67-6.69]). Stratifying by gender, the effect was especially strong in men (HR = 4.72 [95% CI:2.48-9.03]); but also significant in women (adjusted HR = 1.96 [95% CI:1.04-3.67]). The mortality risk among participants with both insomnia and short sleep duration (<6.5 hours) was particularly high, whereas insomnia in combination with normal/greater sleep duration was not associated with mortality.
Conclusions
Insomnia was associated with a three-fold risk of mortality over 13-15 years follow-up. The risk appeared even higher in males or when insomnia was combined with short sleep duration, although such unadjusted subgroup analyses should be interpreted with caution. Establishing prevention strategies and low-threshold interventions should consequently be a prioritized task for public health policy.
doi:10.1186/1471-2458-14-720
PMCID: PMC4223526  PMID: 25024049
Insomnia; Risk factor; Mortality; Sleep duration; Sleep medication
18.  Major depressive disorder and sleep disturbance in patients with chronic pain 
BACKGROUND
Disturbed sleep is a common problem in both chronic pain and major depressive disorder (MDD). Moreover, many patients with chronic pain are depressed.
OBJECTIVES:
To examine the effects of depression on the sleep behaviour of chronic pain patients by comparing patients who did or did not meet diagnostic criteria for MDD.
METHODS:
A total of 60 patients with chronic musculoskeletal pain underwent structured diagnostic interviews for MDD and insomnia, and completed questionnaires assessing pain severity, disability, sleep quality, beliefs and attitudes about sleep, and sleep hygiene. For four consecutive days, they also completed a sleep diary, and reported on sleep hygiene practices and presleep arousal.
RESULTS:
Thirty-three patients (55%) met diagnostic criteria for MDD, most of whom (n=32 [97%]) also fulfilled criteria for insomnia disorder. Insomnia was also common among patients without MDD (21 of 27 [78%]). Participants with MDD had higher self-reports of pain, disability, dysfunctional beliefs about sleep, and, on a prospective basis, greater presleep arousal and poorer sleep hygiene. However, diary assessments of specific sleep parameters (eg, sleep onset latency, total sleep time, sleep efficiency) did not differ between the groups.
DISCUSSION:
Chronic pain patients with comorbid MDD exhibited more dysfunctional beliefs about sleep, poorer sleep hygiene practices and greater presleep arousal; however, diary-recorded sleep characteristics may not differ from those of patients without MDD. Chronic pain itself may disturb sleep so extensively that MDD introduces little additive effect.
CONCLUSION:
MDD in chronic pain may be related to the cognitive and behavioural aspects of insomnia, rather than to an incremental disturbance in the initiation or maintenance of sleep.
PMCID: PMC3938341  PMID: 24367795
Chronic pain; Cognitive-behaviour therapy; Depression; Insomnia; Sleep
19.  Misuse and Dependence on Non-Prescription Codeine Analgesics or Sedative H1 Antihistamines by Adults: A Cross-Sectional Investigation in France 
PLoS ONE  2013;8(10):e76499.
Background
Given the growing worldwide market of non-prescription drugs, monitoring their misuse in the context of self-medication represents a particular challenge in Public Health. The aim of this study was to investigate the prevalence of misuse, abuse, and dependence on non-prescription psychoactive drugs.
Method
During one month, in randomly solicited community pharmacies, an anonymous questionnaire was offered to adults requesting paracetamol (control group), codeine combined with paracetamol in analgesics, or sedative H1 antihistamines. Responses about misuse (drug use not in agreement with the Patient Information Leaflet) abuse (excessive drug use having detrimental consequences), and dependence (established according to questions adapted from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria) on psychoactive drugs were compared to those of the paracetamol control group.
Results
295 patients (mean age 48.5 years, 68.5% of women) having used one of the studied drugs during the previous month were included. Misuse and dependence to codeine analgesics concerned 6.8% and 17.8% of the patients exposed to these drugs, respectively, (n = 118), which was significantly higher than for paracetamol. 19.5% had used codeine analgesics daily for more than six months. Headache was the most frequent reason for persistent daily use. A high prevalence of persistent daily users of sedative H1 antihistamines was also observed. Whereas these drugs are recommended only for short treatment courses of occasional insomnia, 72.2% of the participants having taken doxylamine (n = 36) were daily users, predominantly for more than six months.
Conclusions
Results on misuse and dependence on non-prescription codeine analgesics suggest that chronic pain, in particular chronic cephalalgia, requires better medical care. In addition, as for hypnotics on prescription, persistent use of doxylamine for self-medication is not justified until an acceptable benefit-risk ratio for chronic sleep disturbance is shown by clinical data.
doi:10.1371/journal.pone.0076499
PMCID: PMC3789666  PMID: 24098516
20.  Prevalence of causes of insomnia in primary care: a cross-sectional study 
Background
As a result of a research interest in primary insomnia, the prevalence of other causes of insomnia in primary care must be ascertained. No source was found in the literature. It is also essential to know the epidemiology of the common causes of a condition to make an accurate diagnosis in primary care.
Aim
To determine the prevalence of causes of insomnia in primary care, as part of a method of identifying patients with primary insomnia.
Design and setting
Cross-sectional study in three general practices in Auckland, New Zealand.
Method
Consecutive patients from the waiting room were asked to complete a nine-page questionnaire on possible causes of insomnia.
Results
In total, 1517 patients were approached and 955 completed the nine-page questionnaire (63%). Of the 41% (388) who reported difficulty with sleeping, primary insomnia occurred in 12% (45) of the population (95% confidence interval = 9% to 15%); 50% (195) had depression, 48% (185) had anxiety and 43% (165) had general (physical) health problems. Obstructive sleep apnoea occurred in 9% (34) and delayed sleep phase disorder in 2% (7). Only primary insomnia and delayed sleep phase disorder are mutually exclusive; the others can co-exist.
Conclusion
This is the first description of the prevalence of causes of insomnia in primary care. It is hoped that the focus on primary insomnia will result in more behavioural treatments and lower the use of hypnotics in primary care; it should also assist in the appropriate detection and treatment of other causes of insomnia in primary care.
doi:10.3399/bjgp12X625157
PMCID: PMC3268500  PMID: 22520782
prevalence; primary health care; sleep initiation and maintenance disorders
21.  Quality of sleep and its related risk factors in hospitalized older patients in Kashan’s Hospitals, Iran 2009 
Context:
Sleep is an effective factor in the process recovery from diseases. Many variables affect the sleep quality of hospitalized older patients.
Aim:
This study was conducted to evaluate the quality of sleep and its related risk factors in hospitalized older patients in Kashan’s hospitals, Iran 2009. Settings and design: a cross-sectional study was carried out on a sample of 400 hospitalized older adults in the hospital of Kashan, Iran.
Materials and Methods:
The Farsi Pittsburgh Sleep Quality Index (FPSQI) was used for gathering data. A global sum of 6 or greater indicates a poor quality of sleep. Statistical analysis used: data were analyzed using the Chi-square test, t-test, ANOVA, and binary logistic regression at the multivariate model.
Results:
The overall quality of sleep of the patients in this study was poor. In the final regression model, sex (OR = 0.342), level of education (OR = 0.470), type of ward (OR = 0.592), previous hospitalization experience (OR = 2.336), and use of hypnotics in hospital (OR = 3.633) were the most important predictors of sleep quality. The most prevalent sleep disturbing factors were worries and anxiety, environmental noises and pain. However, the most negative effects on the PSQI mean score were reported to be from dyspnea, environmental lights, and changes in the sleep habits. Quality of sleep also had significant relationship with sleep latency (P = 0.001) and having a respiratory disorder.
Conclusions:
The knowledge of sleep disturbing factors in hospitalized older adults might help in planning preventive strategies to improve quality of sleep.
PMCID: PMC3733285  PMID: 23922581
Aged; hospitalization; insomnia; risk factors
22.  Fatigue and Sleep Disturbance Related to Perceived Stress in Chinese HIV-Positive Individuals: A Mixed Methods Study 
Background
Few studies of HIV+ individuals in China have examined the associations between HIV-related stress with sleep disturbance and fatigue, which are common complaints among people living with HIV/AIDS (PLWHA). We carried out this study to examine the relationships among perceived stress, sleep disturbance, and fatigue in PLWHA in China.
Methods
A mixed methods study design was used during data collection in Shanghai, China, from December 2009 to March 2010. Qualitative in-depth interviews were conducted with 19 HIV+ females. Additionally, cross-sectional audio computer-assisted self-interviews (ACASI) were conducted to collect quantitative data from a convenience sample of 107 HIV+ patients (84% were male) including the following scales: 1) Perceived Stress Scale for PLWHA, 2) General Sleep Disturbance Scale, and 3) Fatigue Scale.
Results
The major themes that emerged from the in-depth interviews were around life stress with HIV, sleep disturbance, and fatigue. Participants presented varying amounts of stress around worrying about whether to disclose their diagnosis and whether they might transmit the disease to their family. In addition, in the cross-sectional data, 40% of the participants reported clinically significant sleep disturbances (GSDS > 3) with an average of 3 nights of disturbed sleep in the past week (M=2.87, SD=1.21) and moderate fatigue severity (M=5.24, SD=2.27). In mediation analyses, the data suggests that the relationship between perceived stress and fatigue was largely (53%) mediated through sleep disturbance.
Conclusions
Chinese PLWHA described how stress had caused them to become sleepless and fatigued. The quantitative data also demonstrated significant levels of sleep disturbance and fatigue, where were due to perceived stress with HIV disease. A systematic self-management intervention to decrease perceived stress should be designed and implemented in mental health resource-limited settings such as China in order to reduce sleep disturbance and fatigue.
doi:10.4172/2155-6113.1000214
PMCID: PMC3840538  PMID: 24288655
China; PLWHA; Perceived stress; Sleep disturbance; Fatigue; Cronbach alpha coefficient
23.  Risk Factors Associated with Sleep Disturbance following Traumatic Brain Injury: Clinical Findings and Questionnaire Based Study 
PLoS ONE  2013;8(10):e76087.
Background
Sleep disturbance is very common following traumatic brain injury (TBI), which may initiate or exacerbate a variety of co-morbidities and negatively impact rehabilitative treatments. To date, there are paradoxical reports regarding the associations between inherent characteristics of TBI and sleep disturbance in TBI population. The current study was designed to explore the relationship between the presence of sleep disturbance and characteristics of TBI and identify the factors which are closely related to the presence of sleep disturbance in TBI population.
Methods
98 TBI patients (72 males, mean age ± SD, 47 ± 13 years, range 18-70) were recruited. Severity of TBI was evaluated based on Glasgow Coma Scale (GCS). All participants performed cranial computed tomography and were examined on self-reported sleep quality, anxiety, and depression.
Results
TBI was mild in 69 (70%), moderate in 15 (15%) and severe in 14 (15%) patients. 37 of 98 patients (38%) reported sleep disturbance following TBI. Insomnia was diagnosed in 28 patients (29%) and post-traumatic hypersomnia in 9 patients (9%). In TBI with insomnia group, 5 patients (18%) complained of difficulty falling asleep only, 8 patients (29%) had difficulty maintaining sleep without difficulty in initial sleep and 15 patients (53%) presented both difficulty falling asleep and difficulty maintaining sleep. Risk factors associated with insomnia were headache and/or dizziness and more symptoms of anxiety and depression rather than GCS. In contrast, GCS was independently associated with the presence of hypersomnia following TBI. Furthermore, there was no evidence of an association between locations of brain injury and the presence of sleep disturbance after TBI.
Conclusion
Our data support and contribute to a growing body of evidence which indicates that TBI patients with insomnia are prone to suffer from concomitant headache and/or dizziness, report more symptoms of anxiety and depression and severe TBI patients are likely to experience hypersomnia.
doi:10.1371/journal.pone.0076087
PMCID: PMC3788026  PMID: 24098425
24.  Prevalence and Factors Associated With Sleep Disturbances Among Early-Treated HIV-Infected Persons 
Persons infected with human immunodeficiency virus (HIV) have a high prevalence of insomnia (46%) and daytime drowsiness (30%). Factors associated with insomnia among patients with HIV infection include depression and increased waist size. Screening for sleep disturbances should be considered among HIV-infected persons.
Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited.
Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank.
Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0–142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4–5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7–.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly.
Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
doi:10.1093/cid/cis192
PMCID: PMC3334363  PMID: 22431801
25.  Allergy: A Risk Factor for Suicide? 
Opinion statement
The rates of depression, anxiety, and sleep disturbance (suicide risk factors) are greater in patients with allergic rhinitis than in the general population. The rate of allergy is also greater in patients with depression. Preliminary data suggest that patients with a history of allergy may have an increased rate of suicide. Clinicians should actively inquire to diagnose allergy in patients with depression and depression in patients with allergy.
Spring peaks of suicide are highly replicated, but their origin is poorly understood. Preliminary epidemiologic data suggest that seasonal spring peaks in aeroallergens are associated with seasonal spring peaks in suicide. Our research in Brown Norway rats demonstrates that sensitization and exposure to aeroallergens induces anxiety-like and aggressive behaviors as well as allergy-related helper T-cell type 2 (Th2) cytokine gene expression in the prefrontal cortex. Thus, it is possible that sensitization and exposure to aeroallergens, which peak in spring, may be conducive to seasonal exacerbation of suicide risk factors such as anxiety, depression, hostility/ aggression, and sleep disturbance. Connecting allergy with suicide and suicide risk factors adds to previous neurologic literature connecting allergy with migraines and seizure disorders.
Our recent report of Th2 (allergy-mediating) cytokine expression in the orbito-frontal cortex of suicide victims should lead to future studies to test the hypothesis that mediators of allergic inflammation in the nasal cavities may result in Th2 cytokine expression in the brain, influencing affect and behavioral modulation.
Certain medications used to treat allergy can exacerbate suicide risk factors, potentially worsening suicide risk and even triggering suicide. Systemic (but not topical) corticosteroids have been associated with manic and depressive episodes and mixed mood states. Recently, the US Food and Drug Administration started investigating the possibility that montelukast may trigger suicide. Although this association requires further exploration and confirmation, clinicians should err on the side of caution, inquiring about past suicide attempts; hopelessness; reasons for living; and suicidal ideation, intent, or plan; and referring the patient to a mental health professional for evaluation if appropriate.
PMCID: PMC2592251  PMID: 18782509

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