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1.  Exposure to intimate partner violence and parental depression increases risk of ADHD in preschool children 
QUESTION
Question: Does exposure to parental depression or intimate partner violence (IPV) during the first 3 years of life have an effect on a child's subsequent mental health?
People: A total of 2422 children (52% boys, Hispanic/ Latino 45.5%, Black 40.6%, White 10.5%) visiting health centres served by the Child Health Improvement through Computer Automation (CHICA) paediatric primary care system, from birth to age 3 years, and again when aged between 37 and 72 months.
Setting: Four community health centres, Indianapolis, Indiana, USA; November 2004–June 2012.
Risk factors: Exposure to IPV and parental depression within the first 3 years of life. This information was collected using screening questions presented in a prescreener form which parents completed in the clinic waiting rooms. To screen for depression, The Patient Health Questionnaire (PHQ-2) was used until 2010, and then replaced by the anxiety subscale of the Edinburgh Postnatal Depression Scale (EPDS-3). IPV was screened using the questions ‘Has your partner kicked, hit or slapped you?’ and ‘Do you feel safe in your home?’
Outcomes: Child mental health diagnosis or psychotropic drug treatment received between the ages of 3 and 3. Diagnoses were identified using International Classification of Diseases-9 codes for attention deficit hyperactivity disorder (ADHD), disruptive behaviour disorder, depression, anxiety, sleep disturbance or adjustment disorder. Prescription information was taken from the Indiana Network for Patient Care and Regenstriel Medical Record Systems databases.
METHODS
Design: Prospective cohort study.
Follow-up period: Three years.
MAIN RESULTS
Within the first 3 years of the child's life, 1591 (65.7%) of parents reported neither IPV nor depression, 704 (29.1%) reported depression only, 69 (2.8%) reported IPV only and 58 (2.4%) reported IPV as well as depression. Between ages 3 and 6 years, 48 (2%) of children had received psychotropic medication, 80 children (3.3%) were diagnosed with ADHD, 209 (8.7%) with disruptive behaviour disorder, 9 (0.4%) with depression, 17 (0.7%) with anxiety, 7 (0.3%) with sleep disturbance and 41 (1.7%) with adjustment disorder. Prevalence of ADHD was higher in children exposed to parental depression compared with those not exposed (4.5% vs 2.8%, p≤0.03). Psychotropic drug prescriptions were higher in children exposed to parental depression compared with those who were not exposed (2.9% vs 1.6%, p≤0.03). Multivariate regression analysis revealed that increased exposure to IPV as well as depression was associated with increased risk of ADHD diagnosis compared with non-exposure (OR 4.0, 95% CI 1.5 to 10.9; see table). Exposure to parental depression was also associated with increased risk of child psychotropic medication prescription (OR 1.9, 95% CI 1.0 to 3.4). There were no significant associations with exposure to IPV only or with both exposures for any other mental health condition.
CONCLUSIONS
Exposure to parental IPV and parental depression within the first 3 years of life is associated with increased risk of ADHD diagnosis prior to 6 years. Early exposure to parental depression is associated with increased risk of psychotropic medication prescription.
doi:10.1136/eb-2013-101411
PMCID: PMC4081449  PMID: 23868927
2.  Sleep disturbances, psychiatric disorders, and psychotropic drugs 
Brain neurotransmitter dysfunctions involved in the pathophysiological processes of psychiatric disorders are likely to be reflected by concomitant alterations in sleep continuity and architecture. Since the corrective effects of psychotropic drugs on dysfunctional neurotransmission systems can be evidenced through polysomnographic recordings, one may consider sleep as a kind of “window” on the neurobiology of psychiatric disorders. During the last 10 years, major breakthroughs in our understanding of sleep-wake mechanisms have provided some indications on how psychotropic drugs could influence the sleep-wake cycle. In this review, recent inroads into the understanding of sleep regulatory neural mechanisms are introduced and discussed in terms of the effects of psychotropic drugs. The relationship between the patho-physiological process of a disease, its consequence on sleep, and the corrective effect of a psychotropic drug are exemplified by two psychopathological states: substance withdrawal and major depression. One may conclude that polysomnographic recordings are a unique noninvasive tool to analyze brain functioning, and are particularly well suited to evaluating the objective effects of new psychotropic drugs.
PMCID: PMC3181742  PMID: 16416708
sleep disturbance; polysomnography; psychiatric disorder; sleep-wake mechanism; psychotropic drug; rapid eye movement sleep; non-rapid eye movement sleep; neurotransmitter
3.  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
4.  Epidemiology of Psychotropic Drug Use in Rio de Janeiro, Brazil: Gaps in Mental Illness Treatments 
PLoS ONE  2013;8(5):e62270.
Objective
Estimate the prevalence of psychotropic drugs use in the city of Rio de Janeiro, Brazil, and establish its relationship with the presence of mental disorders.
Methods
A probabilistic sample of non-institutionalized individuals, from the general population of Rio de Janeiro (n = 1208;turn out:81%), 15 years or older, who were interviewed using the Composite International Diagnostic Interview 2.1 (depression, anxiety-phobia, OCD\PTSD, alcoholism sections), and asked about their psychotropic use during a 12 and one-month period before the interview. Data were collected between June/2007-February/2008.The prevalence was estimated with a confidence interval of 95%. The associations between psychotropics use and mental disorders were analyzed through a logistic regression model (Odds Ration – OR).
Results
The one-month prevalence of psychotropic drug use was 6.55%, 3.19% for men and 9.13% for women. Antidepressants were the most frequently used drug (2.78%), followed by anorectics (1.65%), tranquilizers (1.61%) and mood stabilizers (1.23%). General practitioners issued the highest number of prescriptions (46.3%), followed by psychiatrists (29.3%); 86.6% of the psychotropic drugs used were paid for by the patient himself. Individuals with increased likelihood of using psychotropic drugs were those that had received a psychiatric diagnosis during a one-month period before the study (OR:3.93), females (OR:1.82), separated/divorced (OR:2.23), of increased age (OR:1.03), with higher income (OR:2.96), and family history of mental disorder (OR:2.59); only 16% of the individuals with a current DSM IV diagnosis were using a psychotropic drug; 17% among individuals with a depression-related diagnosis and 8% with Phobic Anxiety Disorders-related diagnosis used psychotropics.
Conclusion
Approximately 84% of individuals displaying some mental disorder did not use psychotropic drugs, which indicates an important gap between demand and access to treatment. A significant failure is evident in the health system for patients with mental disorders; this could be due to health workers' inability to recognize mental disorders among individuals.
doi:10.1371/journal.pone.0062270
PMCID: PMC3653914  PMID: 23690934
5.  Effectiveness of Physio Acoustic Sound (PAS) therapy in demented nursing home residents with nocturnal restlessness: study protocol for a randomized controlled trial 
Trials  2012;13:34.
Background
Many older people with neuropsychiatric disorders such as Alzheimer's disease and frontotemporal dementia suffer from sleeping problems and often show nocturnal restlessness. Professionals and informal carers face considerable problems in solving these problems. Attempts to diminish these problems with medication in a safe and responsible manner have proven hardly effective or not effective at all. Therefore, nowadays the focus lies more on non-pharmacological solutions, for example by influencing environmental factors. There are indications that treatment with low-frequency acoustic vibrations, that is Physio Acoustic Sound (PAS) therapy, has a positive effect on sleeping problems. Therefore we study the effectiveness of PAS therapy in demented patients with nocturnal restlessness.
Methods
In a randomized clinical trial, 66 nursing home patients will be divided into two groups: an intervention group and a control group. For both groups nocturnal restlessness will be measured with actiwatches during a period of six weeks. In addition, a sleep diary will be filled in.
For the intervention group the baseline will be assessed, in the first two weeks, reflecting the existing situation regarding nocturnal restlessness. In the next two weeks, this group will sleep on a bed identical to their own, but with a mattress containing an in-built PAS device. As soon as the patient is lying in bed, the computer programme inducing the vibrations will be switched on for the duration of 30 min. In the last two weeks, the wash-out period, the measurements of the intervention group are continued, without the PAS intervention.
During the total study period, other relevant data of all the implied patients will be recorded systematically and continuously, for example patient characteristics (data from patient files), the type and seriousness of the dementia, occurrence of neuropsychiatric symptoms during the research period, and the occurrence of intermittent co-morbidity.
Discussion
If PAS therapy turns out to be effective, it can be of added value to the treatment of nocturnal restlessness in demented patients. Non-pharmacological PAS therapy is not only safe and patient-friendly, but it can also be widely used in a simple and relatively inexpensive way, both in institutions such as nursing homes and residential homes for the elderly, and at home. Ultimately, this may lead to a decrease in the frequent and still common use of psychotropic drugs. In addition, care needs of demented patients also may decrease as well as the number of preventable admissions to care institutions.
Trial registration
Netherlands Trial Register (NTR): NTR3242
doi:10.1186/1745-6215-13-34
PMCID: PMC3349520  PMID: 22495093
Dementia; Sleep; Actiwatch; Physio acoustic sound; Nursing home; Nocturnal restlessness
6.  Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care 
Psychopharmacology  2013;231(6):1011-1021.
Rationale
Autism spectrum disorders (ASDs) affect 1 % of children, having significant impact on health and social outcomes. Psychotropic medication use by individuals with ASD in the USA increased over time, and polypharmacy occurred in >50 % of those prescribed. In the UK, no psychotropic drugs are approved in ASDs, and little is known about patterns of pharmacological treatment in the ASD population and associated co-morbidities.
Methods
We used The Health Improvement Network, a nationally representative primary care database, to assess the prevalence of ASD diagnoses, psychotropic drug prescribing and neuropsychiatric co-morbidities of 0–24 year olds between 1992 and 2008.
Results
ASD prevalence increased 65-fold from 0.01 % (1992) to 0.50 % (2008). Psychotropic drugs were prescribed to 29 % (1,619/5,651) of the ASD cohort; the most prescribed drugs were sleep medication (9.7 % of prescribed patients), psychostimulants (7.9 %) and antipsychotics (7.3 %). More patients were given psychostimulants and sleep medications over time from 1.5–6.3 % and 2.2–5.9 % respectively. Thirty-seven per cent of the cohort had ≥1 record of a neuropsychiatric co-morbidity, the most common being developmental difficulties and learning disabilities (12.6 %), behavioural, conduct and personality disorders (11.1 %) and attention deficit hyperactivity disorder (7.5 %).
Conclusions
British physicians are more conservative in prescribing practice than American colleagues. However, use of psychostimulants and antipsychotics is much higher in those with ASD than in the general population. Polypharmacy was seen in 34 % of prescribed patients in 2008. Additional studies examining use, efficacy, and long-term safety of antipsychotics and psychostimulants in autistic individuals are warranted.
doi:10.1007/s00213-013-3140-7
PMCID: PMC3932167  PMID: 23681164
Autistic spectrum disorder; Prevalence; Psychotropic drugs; Primary care; Co-morbidity; Children; Adolescents; Young adults
7.  Sleep disorders in children 
Clinical Evidence  2010;2010:2304.
Introduction
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for dyssomnias in children? What are the effects of treatments for parasomnias in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 28 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihistamines; behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives; benzodiazepines alone; exercise; extinction and graduated extinction; 5-hydroxytryptophan; light therapy; melatonin; safety/protective interventions for parasomnias; scheduled waking (for parasomnias); sleep hygiene; and sleep restriction.
Key Points
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias) or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders. Other risk factors include the child being the first born, having a difficult temperament or having had colic, and increased maternal responsiveness.
There is a paucity of evidence about effective treatments for sleep disorders in children, especially parasomnias, but behavioural interventions may be the best first-line approach.
Extinction and graduated extinction in otherwise healthy children with dyssomnia may improve sleep quality and settling, and reduce the number of tantrums and wakenings compared with no treatment. Extinction and graduated extinction in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder with dyssomnia may be more effective at improving settling, reducing the frequency and duration of night wakings, and improving parental sleep compared with no treatment; however, we don't know whether it is more effective in improving sleep duration.Graduated extinction may be less distressing for parents, and therefore may have better compliance.
Sleep hygiene for dyssomnia in otherwise healthy children may be more effective in reducing the number and duration of bedtime tantrums compared with placebo, but we don’t know if it is more effective at reducing night wakenings, improving sleep latency, improving total sleep duration, or improving maternal mood. Sleep hygiene and graduated extinction seem to be equally effective at reducing bedtime tantrums in otherwise healthy children with dyssomnia.We don't know whether sleep hygiene for dyssomnia in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder is effective.
Melatonin for dyssomnia in otherwise healthy children may be more effective at improving sleep-onset time, total sleep time, and general health compared with placebo. Evidence of improvements in dyssomnia with melatonin is slightly stronger in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder.
Little is known about the long-term effects of melatonin, and the quality of the product purchased could be variable as melatonin is classified as a food supplement.
Antihistamines for dyssomnia may be more effective than placebo at reducing night wakenings and decreasing sleep latency, but we don’t know if they are more effective at increasing sleep duration. The evidence for antihistamines in dyssomnia comes from only one small, short-term study.
We don’t know whether behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives, exercise, light therapy, or sleep restriction are effective in children with dyssomnia.
We don’t know whether antihistamines, behavioural therapy plus benzodiazepines or plus chloral and derivatives, benzodiazepines, 5-hydroxytryptophan, melatonin, safety/protective interventions, scheduled waking, sleep hygiene, or sleep restriction are effective in children with parasomnia.
PMCID: PMC3217667  PMID: 21418676
8.  Treatment resistant adolescent depression with upper airway resistance syndrome treated with rapid palatal expansion: a case report 
Introduction
To the best of our knowledge, this is the first report of a case of treatment-resistant depression in which the patient was evaluated for sleep disordered breathing as the cause and in which rapid palatal expansion to permanently treat the sleep disordered breathing produced a prolonged symptom-free period off medication.
Case presentation
An 18-year-old Caucasian man presented to our sleep disorders center with chronic severe depression that was no longer responsive to medication but that had recently responded to electroconvulsive therapy. Ancillary, persistent symptoms included mild insomnia, moderate to severe fatigue, mild sleepiness and severe anxiety treated with medication. Our patient had no history of snoring or witnessed apnea, but polysomnography was consistent with upper airway resistance syndrome. Although our patient did not have an orthodontic indication for rapid palatal expansion, rapid palatal expansion was performed as a treatment of his upper airway resistance syndrome. Following rapid palatal expansion, our patient experienced a marked improvement of his sleep quality, anxiety, fatigue and sleepiness. His improvement has been maintained off all psychotropic medication and his depression has remained in remission for approximately two years following his electroconvulsive therapy.
Conclusions
This case report introduces the possibility that unrecognized sleep disordered breathing may play a role in adolescent treatment-resistant depression. The symptoms of upper airway resistance syndrome are non-specific enough that every adolescent with depression, even those responding to medication, may have underlying sleep disordered breathing. In such patients, rapid palatal expansion, by widening the upper airway and improving airflow during sleep, may produce a prolonged improvement of symptoms and a tapering of medication. Psychiatrists treating adolescents may benefit from having another treatment option for treatment-resistant depression.
doi:10.1186/1752-1947-6-415
PMCID: PMC3542016  PMID: 23210848
9.  The Effect of Exercise Training on Quality and Quantity of Sleep and Lipid Profile in Renal Transplant Patients: A Randomized Clinical Trial 
Background: Patients undergoing renal transplantation consume immunosuppressive drugs to prevent graft rejection. Cardiovascular complications and reduced quality of sleep are among the side effects of these drugs. Studies have indicated that the use of non-therapeutic methods such as exercise is important to reduce these complications.
Objective: To evaluate the effect of a period of exercise training, as a non-therapeutic method, on quality and quantity of sleep and lipid profile in renal transplant patients.
Methods: 44 renal transplant recipients were selected to participate in the study and randomized into exercise (n=29) and control (n=15) groups. The exercise group participated in a cumulative exercise program 3 days a week for 10 weeks in 60–90-minute exercise sessions. Control group subjects did not participate in any regular exercise activity during this period. Sleep quality of the subjects was evaluated using Pittsburgh Sleep Quality Index (PSQI) questionnaire; the sleep quantity was assessed by recording the duration of convenient nocturnal sleep of the subjects. Physiological sleep-related variables (serum triglyceride [TG], and total, high-density lipoprotein [HDL], and low-density lipoprotein [LDL] cholesterol) were measured before and after 10 weeks of exercise training
Results: In exercise training group, sleep quality of the subjects was improved by 27%; the sleep quantity was increased by 30 minutes (p<0.05). TG, cholesterol and LDL values were significantly (p<0.05) decreased after 10 weeks of exercise training in the exercise group compared to the control group, however, no change was observed in serum HDL level in exercise group compared to the control. There was also a significant (p=0.05) difference in sleep quality and quantity between control and exercise groups. However, there was no correlation between changing quality and quantity of sleep with sleep-related physiological factors.
Conclusion: 10 weeks of exercise activity improved the quality and quantity of sleep as well as a number of sleep-related physiological parameters in renal transplant recipients, and would be an effective approach to treat sleep-related disorders in renal transplant recipients.
PMCID: PMC4243047  PMID: 25426284
Exercise training; Sleep quality; Sleep quantity; Lipid profile; Renal transplantation
10.  Sleep apnoea in patients with quadriplegia. 
Thorax  1995;50(6):613-619.
BACKGROUND--This study was undertaken to establish the prevalence of, and the factors contributing towards, sleep disordered breathing in patients with quadriplegia. METHODS--Forty representative quadriplegic patients (time since injury > 6 months, injury level C8 and above, Frankel category A, B, or C; mean (SE) age 35.0 (1.7) years) had home sleep studies in which EEG, EOG, submental EMG, body movement, nasal airflow, respiratory effort, and pulse oximetry (SpO2) were measured. Patients reporting post traumatic amnesia of > 24 hours, drug or alcohol abuse or other major medical illness were excluded from the study. A questionnaire on medications and sleep was administered and supine blood pressure, awake SpO2, spirometric values, height, and neck circumference were measured. RESULTS--A pattern of sustained hypoventilation was not observed in any of the patients. Sleep apnoeas and hypopnoeas were, however, common. Eleven patients (27.5%) had a respiratory disturbance index (RDI, apnoeas plus hypopnoeas per hour of sleep) of > or = 15, with nadir SpO2 ranging from 49% to 95%. Twelve of the 40 (30%) had an apnoea index (AI) of > or = 5 and, of these, nine (75%) had predominantly obstructive apnoeas-that is, > 80% of apnoeas were obstructive or mixed. This represents a prevalence of sleep disordered breathing more than twice that observed in normal populations. For the study population RDI correlated with systolic and diastolic blood pressure and neck circumference. RDI was higher in patients who slept supine compared with those in other postures. Daytime sleepiness was a common complaint in the study population and sleep architecture was considerably disturbed with decreased REM sleep and increased stage 1 non-REM sleep. CONCLUSIONS--Sleep disordered breathing is common in quadriplegic patients and sleep disturbance is significant. The predominant type of apnoea is obstructive. As with non-quadriplegic patients with sleep apnoea, sleep disordered breathing in quadriplegics is associated with increased neck circumference and the supine sleep posture.
PMCID: PMC1021258  PMID: 7638801
11.  Pharmacological Treatment of Disruptive Behavior in Smith-Magenis Syndrome 
Smith-Magenis syndrome (SMS) is a complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2. Children and adults with SMS appear to have unique neurobehavioral problems that include: sleep disturbance, self-injurious and maladaptive behaviors, stereotypies, and sensory integration disorders. We gathered retrospective psychotropic use information from parents or other caregivers of 62 individuals with SMS who were asked about use of psychotropic medication from a list of commonly used psychiatric medications. For those drugs identified, respondents were asked to rate the experience with the particular medication using a likert-type scale. Drugs were grouped into seven main categories: (1) stimulants; (2) antidepressants; (3) antipsychotics; (4) sleep aides; (5) mood stabilizers; (6) alpha 2 agonists; and (7) benzodiazepines. Relative frequencies, means and standard deviations pertaining to age and medication effect were derived for each medication category. Six of the seven medication categories examined showed no meaningful deviations from the “no change” score. The benzodiazepine group showed a mild detrimental effect. There were no gender differences in efficacy. Use of psychotropic medication started early in life (mean age 5 years), particularly with sleep aides. Although no medication category was identified as efficacious in SMS, all the categories reported herein may be considered as an option for brief symptomatic relief.
doi:10.1002/ajmg.c.30282
PMCID: PMC3022344  PMID: 20981776
Smith-Magenis Syndrome; SMS; treatment; pharmacology; genetics; pharmacogenomics; pharmacogenetics; autism; mental retardation; self-injurious behavior; aggression; sleep; melatonin
12.  Socioeconomic inequalities in access to specialized psychotropic prescribing among older Swedes: a register-based study 
Background: Mental disorders among older adults are mainly treated with psychotropic drugs. Few of these drugs are, however, prescribed by specialized geriatricians or psychiatrists, but rather from general practitioners (GPs). Socioeconomic inequalities in access to specialist prescribing have been found in younger age groups. Hence, we aimed to investigate whether there are socioeconomic differences in access to geriatrician and psychiatrist prescribing of psychotropic drugs among older adults. Methods: By record-linkage of The Swedish Prescribed Drug Register and The Swedish Education Register, we obtained information for persons aged 75–89 years who had filled a prescription for psychotropic drugs (antipsychotics, anxiolytics, hypnotic/sedatives or antidepressants) with information on prescriber specialty from July to October 2005 (n = 221 579). Multinomial regression analysis was used to investigate whether education was associated with geriatrician and psychiatrist prescribing of psychotropic drugs. Results: The vast majority of the psychotropic drugs were prescribed by ‘GPs and other specialists’ (∼95% GPs). Older adults with higher educational level were more likely to be prescribed psychotropic drugs from psychiatrists and geriatricians. However, after adjustment for place of residence, the association between patient’s education and prescription by a geriatrician disappeared, whereas the association with seeing a psychiatrist was only attenuated. Conclusion: Access to specialized prescribing of psychotropics is unequally distributed between socioeconomic groups of older adults in Sweden. This finding was partially confounded by place of residence for geriatrician but not for psychiatrist prescribing. Further research should examine if inequalities in specialized psychotropic prescribing translate into worse outcomes for socioeconomically deprived and non-metropolitan-living older individuals.
doi:10.1093/eurpub/cku058
PMCID: PMC4245009  PMID: 24860048
13.  The Role of Health Systems Factors in Facilitating Access to Psychotropic Medicines: A Cross-Sectional Analysis of the WHO-AIMS in 63 Low- and Middle-Income Countries 
PLoS Medicine  2012;9(1):e1001166.
In a cross-sectional analysis of WHO-AIMS data, Ryan McBain and colleagues investigate the associations between health system components and access to psychotropic drugs in 63 low and middle income countries.
Background
Neuropsychiatric conditions comprise 14% of the global burden of disease and 30% of all noncommunicable disease. Despite the existence of cost-effective interventions, including administration of psychotropic medicines, the number of persons who remain untreated is as high as 85% in low- and middle-income countries (LAMICs). While access to psychotropic medicines varies substantially across countries, no studies to date have empirically investigated potential health systems factors underlying this issue.
Methods and Findings
This study uses a cross-sectional sample of 63 LAMICs and country regions to identify key health systems components associated with access to psychotropic medicines. Data from countries that completed the World Health Organization Assessment Instrument for Mental Health Systems (WHO-AIMS) were included in multiple regression analyses to investigate the role of five major mental health systems domains in shaping medicine availability and affordability. These domains are: mental health legislation, human rights implementations, mental health care financing, human resources, and the role of advocacy groups. Availability of psychotropic medicines was associated with features of all five mental health systems domains. Most notably, within the domain of mental health legislation, a comprehensive national mental health plan was associated with 15% greater availability; and in terms of advocacy groups, the participation of family-based organizations in the development of mental health legislation was associated with 17% greater availability. Only three measures were related with affordability of medicines to consumers: level of human resources, percentage of countries' health budget dedicated to mental health, and availability of mental health care in prisons. Controlling for country development, as measured by the Human Development Index, health systems features were associated with medicine availability but not affordability.
Conclusions
Results suggest that strengthening particular facets of mental health systems might improve availability of psychotropic medicines and that overall country development is associated with affordability.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Mental disorders—conditions that involve impairment of thinking, emotions, and behavior—are extremely common. Worldwide, mental illness affects about 450 million people and accounts for 13.5% of the global burden of disease. About one in four people will have a mental health problem at some time in their life. For some people, this will be a short period of mild depression, anxiety, or stress. For others, it will be a serious, long-lasting condition such as schizophrenia, bipolar disorder, or major depression. People with mental health problems need help and support from professionals and from their friends and families to help them cope with their illness but are often discriminated against, which can make their illness worse. Treatments include counseling and psychotherapy (talking therapies), and psychotropic medicines—drugs that act mainly on the brain. Left untreated, many people with serious mental illnesses commit suicide.
Why Was This Study Done?
About 80% of people with mental illnesses live in low- and middle-income countries (LAMICs) where up to 85% of patients remain untreated. Access to psychotropic medicines, which constitute an essential and cost-effective component in the treatment of mental illnesses, is particularly poor in many LAMICs. To improve this situation, it is necessary to understand what health systems factors limit the availability and affordability of psychotropic drugs; a health system is the sum of all the organizations, institutions, and resources that act together to improve health. In this cross-sectional study, the researchers look for associations between specific health system components and access to psychotropic medicines by analyzing data collected from LAMICs using the World Health Organization's Assessment Instrument for Mental Health Systems (WHO-AIMS). A cross-sectional study analyzes data collected at a single time. WHO-AIMS, which was created to evaluate mental health systems primarily in LAMICs, is a 155-item survey that Ministries of Health and other country-based agencies can use to collect information on mental health indicators.
What Did the Researchers Do and Find?
The researchers used WHO-AIMS data from 63 countries/country regions and multiple regression analysis to evaluate the role of mental health legislation, human rights implementation, mental health care financing, human resources, and advocacy in shaping medicine availability and affordability. For each of these health systems domains, the researchers developed one or more summary measurements. For example, they measured financing as the percentage of government health expenditure directed toward mental health. Availability of psychotropic medicines was defined as the percentage of mental health facilities in which at least one psychotropic medication for each therapeutic category was always available. Affordability was measured by calculating the percentage of daily minimum wage needed to purchase medicine by the average consumer. The availability of psychotropic medicines was related to features of all five mental health systems domains, report the researchers. Notably, having a national mental health plan (part of the legislation domain) and the participation (advocacy) of family-based organizations in mental health legislation formulation were associated with 15% and 17% greater availability of medicines, respectively. By contrast, only the levels of human resources and financing, and the availability of mental health care in prisons (part of the human rights domain) were associated with the affordability of psychotropic medicines. Once overall country development was taken into account, most of the associations between health systems factors and medicine availability remained significant, while the associations between health systems factors and medicine affordability were no longer significant. In part, this was because country development was more strongly associated with affordability and explained most of the relationships: for example, countries with greater overall development have higher expenditures on mental health and greater medicine affordability compared to availability.
What Do These Findings Mean?
These findings indicate that access to psychotropic medicines in LAMICs is related to key components within the mental health systems of these countries but that availability and affordability are affected to different extents by these components. They also show that country development plays a strong role in determining affordability but has less effect on determining availability. Because cross-sectional data were used in this study, these findings only indicate associations; they do not imply causality. They are also limited by the relatively small number of observations included in this study, by the methods used to collect mental health systems data in many LAMICs, and by the possibility that some countries may have reported biased results. Despite these limitations, these findings suggest that strengthening specific mental health system features may be an important way to facilitate access to psychotropic medicines but also highlight the role that country wealth and development play in promoting the treatment of mental disorders.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001166.
The US National Institute of Mental Health provides information on all aspects of mental health (in English and Spanish)
The UK National Health Service Choices website provides information on mental health; its Live Well feature provides practical advice on dealing with mental health problems and personal stories
The UK charity Mind provides further information about mental illness, including personal stories
MedlinePlus provides links to many other sources of information on mental health (in English and Spanish)
Information on WHO-AIMS, including versions of the instrument in several languages, and WHO-AIMS country reports are available
doi:10.1371/journal.pmed.1001166
PMCID: PMC3269418  PMID: 22303288
14.  Factors associated with antidepressant, anxiolytic and hypnotic use over 17 years in a national cohort 
Journal of Affective Disorders  2008;110(3):234-240.
Background
In the general population, most individuals with mental disorders are not treated with psychotropic medications. The objective of this study was to identify factors associated with psychotropic medication use over a 17 year period in a birth cohort.
Method
Members of the 1946 British birth cohort (n = 2928 in 1999) reported psychotropic medication use in 1982 at age 36, in 1989 at age 43, and in 1999 at age 53. At each of the three time points, several factors were investigated for their association with antidepressant, anxiolytic or hypnotic medication use.
Results
After adjusting for severity of symptoms of depression and anxiety, clinical factors such as suicidal ideation, sleep difficulty and poor physical health were strongly associated with antidepressant, anxiolytic or hypnotic medication use in 1982 and 1989, but not in 1999. Non-clinical factors were infrequently associated with antidepressant, anxiolytic or hypnotic medication use in 1982 and 1989 after adjusting for severity of symptoms, however several non-clinical factors were associated with antidepressant, anxiolytic or hypnotic medication use in 1999 including being female (OR = 1.4, 95% CI: 1.0, 1.9), unemployment (OR = 2.9, 95% CI: 2.1, 4.1), living alone (OR = 2.6, 95% CI: 1.7, 3.9), and being divorced, separated or widowed (OR = 1.5, 95% CI: 1.1, 2.3).
Limitations
Data were not available on help-seeking behaviour.
Conclusions
Treatment of mental disorder with psychotropic medications is strongly associated with clinical factors. However, non-clinical factors continue to be significant, and may influence both treatment-seeking and prescribing behaviour.
doi:10.1016/j.jad.2008.01.021
PMCID: PMC3500680  PMID: 18295901
Antidepressants; Anxiolytics; Hypnotics; Treatment; Depression; Anxiety
15.  The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease 
Brain  2013;136(7):2120-2129.
In Parkinson’s disease, rapid eye movement sleep behaviour disorder is an early non-dopaminergic syndrome with nocturnal violence and increased muscle tone during rapid eye movement sleep that can precede Parkinsonism by several years. The neuronal origin of rapid eye movement sleep behaviour disorder in Parkinson’s disease is not precisely known; however, the locus subcoeruleus in the brainstem has been implicated as this structure blocks muscle tone during normal rapid eye movement sleep in animal models and can be damaged in Parkinson’s disease. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex in patients with Parkinson’s disease using combined neuromelanin-sensitive, structural and diffusion magnetic resonance imaging approaches. We compared 24 patients with Parkinson’s disease and rapid eye movement sleep behaviour disorder, 12 patients without rapid eye movement sleep behaviour disorder and 19 age- and gender-matched healthy volunteers. All subjects underwent clinical examination and characterization of rapid eye movement sleep using video-polysomnography and multimodal imaging at 3 T. Using neuromelanin-sensitive imaging, reduced signal intensity was evident in the locus coeruleus/subcoeruleus area in patients with Parkinson’s disease that was more marked in patients with than those without rapid eye movement sleep behaviour disorder. Reduced signal intensity correlated with the percentage of abnormally increased muscle tone during rapid eye movement sleep. The results confirmed that this complex is affected in Parkinson’s disease and showed a gradual relationship between damage to this structure, presumably the locus subcoeruleus, and abnormal muscle tone during rapid eye movement sleep, which is the cardinal marker of rapid eye movement sleep behaviour disorder. In longitudinal studies, the technique may also provide early markers of non-dopaminergic Parkinson’s disease pathology to predict the occurrence of Parkinson’s disease.
doi:10.1093/brain/awt152
PMCID: PMC3692035  PMID: 23801736
MRI; RBD; diffusion imaging; neuromelanin-sensitive imaging; VBM
16.  Characterization of Sleep in Zebrafish and Insomnia in Hypocretin Receptor Mutants 
PLoS Biology  2007;5(10):e277.
Sleep is a fundamental biological process conserved across the animal kingdom. The study of how sleep regulatory networks are conserved is needed to better understand sleep across evolution. We present a detailed description of a sleep state in adult zebrafish characterized by reversible periods of immobility, increased arousal threshold, and place preference. Rest deprivation using gentle electrical stimulation is followed by a sleep rebound, indicating homeostatic regulation. In contrast to mammals and similarly to birds, light suppresses sleep in zebrafish, with no evidence for a sleep rebound. We also identify a null mutation in the sole receptor for the wake-promoting neuropeptide hypocretin (orexin) in zebrafish. Fish lacking this receptor demonstrate short and fragmented sleep in the dark, in striking contrast to the excessive sleepiness and cataplexy of narcolepsy in mammals. Consistent with this observation, we find that the hypocretin receptor does not colocalize with known major wake-promoting monoaminergic and cholinergic cell groups in the zebrafish. Instead, it colocalizes with large populations of GABAergic neurons, including a subpopulation of Adra2a-positive GABAergic cells in the anterior hypothalamic area, neurons that could assume a sleep modulatory role. Our study validates the use of zebrafish for the study of sleep and indicates molecular diversity in sleep regulatory networks across vertebrates.
Author Summary
Sleep disorders are common and poorly understood. Further, how and why the brain generates sleep is the object of intense speculations. In this study, we demonstrate that a bony fish used for genetic studies sleeps and that a molecule, hypocretin, involved in causing narcolepsy, is conserved. In humans, narcolepsy is a sleep disorder associated with sleepiness, abnormal dreaming, and paralysis and insomnia. We generated a mutant fish in which the hypocretin system was disrupted. Intriguingly, this fish sleep mutant does not display sleepiness or paralysis but has a 30% reduction of its sleep time at night and a 60% decrease in sleep bout length compared with non-mutant fish. We also studied the relationships between the hypocretin system and other sleep regulatory brain systems in zebrafish and found differences in expression patterns in the brain that may explain the differences in behavior. Our study illustrates how a sleep regulatory system may have evolved across vertebrate phylogeny. Zebrafish, a powerful genetic model that has the advantage of transparency to study neuronal networks in vivo, can be used to study sleep.
Zebrafish sleep, and have the receptor for the wake-inducing molecule hypocretin. While mutation in this receptor causes narcolepsy in mammals, in fish, sleep is fragmented, demonstrating differences in sleep control in vertebrates.
doi:10.1371/journal.pbio.0050277
PMCID: PMC2020497  PMID: 17941721
17.  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
18.  Obstructive Sleep Apnea is More Common than Central Sleep Apnea in Methadone Maintenance Patients with Subjective Sleep Complaints 
Drug and alcohol dependence  2010;108(1-2):77-83.
Objectives
Opioid-dependent patients treated with methadone have subjective sleep complaints and disrupted sleep on polysomnography (PSG). Previous studies of sleep-disordered breathing (SDB) in this population have focused on central sleep apnea (CSA). Our objectives were to: (1) characterize obstructive sleep apnea (OSA) and CSA in patients in methadone maintenance treatment (MMT) for opioid dependence; (2) examine factors associated with SDB in this population; and (3) investigate whether SDB was related to severity of subjective sleep complaints in MMT patients with subjective sleep disturbances.
Methods
We analyzed OSA and CSA from one night of home PSG in 71 patients who were in MMT for at least 3 months and had a Pittsburgh Sleep Quality Inventory (PSQI) score > 5.
Results
OSA (defined as obstructive apnea-hypoponea index (OAHI) ≥ 5) was observed in 35.2% of our sample. OSA was associated with higher body mass index, longer duration in MMT, and non-Caucasian race. CSA (defined as central apnea index (CAI) ≥ 5) was observed in 14.1% of the sample. CSA was not associated with methadone dose or concomitant drug use. Subjective sleep disturbance measured with the PSQI was not related to OSA or CSA.
Conclusions
SDB was common in this sample of MMT patients and OSA was more common than CSA. Given the lack of association between presence of SDB and severity of subjective sleep difficulties, factors other than sleep apnea must account for complaints of disturbed sleep in this population.
doi:10.1016/j.drugalcdep.2009.11.019
PMCID: PMC2859844  PMID: 20079978
methadone; opiate dependence; sleep; sleep apnea; central sleep apnea; obstructive sleep apnea; sleep-disordered breathing
19.  Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 
PLoS Medicine  2009;6(8):e1000132.
In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.
Background
Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
Methods and Findings
We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
Conclusions
Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing 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. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.
Why Was This Study Done?
Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.
What Did the Researchers Do and Find?
At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.
What Do These Findings Mean?
These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000132.
The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)
The UK National Heath Service also provides information for patients about sleep apnea
MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)
More information on the Sleep Heart Health Study is available
doi:10.1371/journal.pmed.1000132
PMCID: PMC2722083  PMID: 19688045
20.  Sleep apnoea 
Clinical Evidence  2009;2009:2301.
Introduction
Sleep apnoea is the popular term for obstructive sleep apnoea-hypopnoea syndrome (OSAHS). OSAHS is abnormal breathing during sleep that causes recurrent arousals, sleep fragmentation, excessive daytime sleepiness, and nocturnal hypoxaemia. Apnoea may be "central", in which there is cessation of inspiratory effort, or "obstructive", in which inspiratory efforts continue but are ineffective because of upper airway obstruction. OSAHS affects up to 4% of men and 2% of women in the USA, with obesity being a major determinant.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment for severe obstructive sleep apnoea-hypopnoea syndrome? What are the effects of treatment for non-severe obstructive sleep apnoea-hypopnoea syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 43 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: nasal continuous positive airway pressure (CPAP); measures aimed at improving compliance with CPAP; oral appliances; and weight loss.
Key Points
Sleep apnoea is the popular term for obstructive sleep apnoea-hypopnoea syndrome (OSAHS). OSAHS is abnormal breathing during sleep that causes recurrent arousals, sleep fragmentation, daytime sleepiness, and nocturnal hypoxaemia. Apnoea may be "central", in which there is cessation of inspiratory effort, or "obstructive", in which inspiratory efforts continue but are ineffective because of upper airway obstruction.OSAHS affects up to 4% of men and 2% of women in the USA, with obesity being a major determinant.
In people with severe OSAHS, nasal CPAP has been shown to reduce daytime sleepiness compared with control treatments. Although effective, it can be difficult getting people to comply with the prescribed CPAP regimen. Compliance seems no better with variations of CPAP, such as automatically titrated CPAP, bi-level positive airway pressure, patient-titrated CPAP, or CPAP plus humidification. We don't know whether educational or psychological interventions may improve compliance with CPAP.
Oral appliances that produce anterior advancement of the mandible seem to be effective in improving sleep-disordered breathing in people with OSAHS (either severe or non-severe). Oral appliances are probably not as effective as CPAP, and we don't know how well they work in the long term.
We found no sufficient evidence judging the effectiveness of weight loss on OSAHS (either severe or non-severe), although there is consensus that advice about weight reduction is an important component of management of OSAHS.
Nasal CPAP also seems beneficial to people suffering from non-severe OSAHS. Nasal CPAP is less acceptable in people with non-severe OSAHS, and we don't know whether measures aimed at improving compliance effectively increase usage.
PMCID: PMC2907765  PMID: 21726484
21.  Snoring and breathing pauses during sleep: telephone interview survey of a United Kingdom population sample. 
BMJ : British Medical Journal  1997;314(7084):860-863.
OBJECTIVES: To determine the prevalence of snoring, breathing pauses during sleep, and obstructive sleep apnoea syndrome and determine the relation between these events and sociodemographic variables, other health problems, driving accidents, and consumption of healthcare resources. DESIGN: Telephone interview survey directed by a previously validated computerised system (Sleep-Eval). SETTING: United Kingdom. SUBJECTS: 2894 women and 2078 men aged 15-100 years who formed a representative sample of the non-institutionalised population. MAIN OUTCOME MEASURES: Interview responses. RESULTS: Forty per cent of the population reported snoring regularly and 3.8% reported breathing pauses during sleep. Regular snoring was significantly associated with male sex, age 25 or more, obesity, daytime sleepiness or naps, night time awakenings, consuming large amounts of caffeine, and smoking. Breathing pauses during sleep were significantly associated with obstructive airways or thyroid disease, male sex, age 35-44 years, consumption of anxiety reducing drugs, complaints of non-restorative sleep, and consultation with a doctor in the past year. The two breathing symptoms were also significantly associated with drowsiness while driving. Based on minimal criteria of the International classification of Sleep Disorders (1990), 1.9% of the sample had obstructive sleep apnoea syndrome. In the 35-64 year age group 1.5% of women (95% confidence interval 0.8% to 2.2%) and 3.5% of men (2.4% to 4.6%) had obstructive sleep apnoea syndrome. CONCLUSIONS: Disordered breathing during sleep is widely underdiagnosed in the United Kingdom. The condition is linked to increased use of medical resources and a greater risk of daytime sleepiness, which augments the risk of accidents. Doctors should ask patients and bed partners regularly about snoring and breathing pauses during sleep.
PMCID: PMC2126255  PMID: 9093095
22.  Socioeconomic determinants of psychotropic drug utilisation among elderly: a national population-based cross-sectional study 
BMC Public Health  2010;10:118.
Background
Psychotropic drugs are commonly utilised among the elderly. This study aimed to analyse whether two socioeconomic determinants - income and marital status - are associated with differences in utilisation of psychotropic drugs and potentially inappropriate psychotropic drugs among elderly in Sweden.
Methods
All individuals aged 75 years and older who had purchased a psychotropic drug in Sweden during 2006 were included (68.7% women, n = 384712). Data was collected from national individual-based registers. Outcome measures were utilisation of three or more psychotropic drugs and utilisation of potentially inappropriate psychotropic drugs, as classified by the Swedish National Board of Health and Welfare.
Results
Individuals with low income were more likely to utilise three or more psychotropic drugs compared to those with high income; adjusted odds ratio (aOR) 1.12 (95% confidence interval [CI] 1.10-1.14). The non-married had a higher probability for utilising three or more psychotropic drugs compared to the married (aOR 1.22; CI 1.20-1.25). The highest probability was observed among the divorced and the never married. Potentially inappropriate psychotropic drugs were more common among individuals with low compared to high income (aOR 1.14; CI 1.13-1.16). Compared to the married, potentially inappropriate psychotropic drug utilisation occurred more commonly among the non-married (aOR 1.08; CI 1.06-1.10). The never married and the divorced had the highest probability.
Conclusions
There was an association between socioeconomic determinants and psychotropic drug utilisation. The probability for utilising potentially inappropriate psychotropics was higher among individuals with low income and among the non-married.
doi:10.1186/1471-2458-10-118
PMCID: PMC2845562  PMID: 20214796
23.  Insomnia (primary) in older people 
Clinical Evidence  2011;2011:2302.
Introduction
Up to 40% of older adults have insomnia, with difficulty getting to sleep, early waking, or feeling unrefreshed on waking. The prevalence of insomnia increases with age. Other risk factors include psychological factors, stress, daytime napping, and hyperarousal.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug treatments for insomnia in older people? What are the effects of drug treatments for insomnia in older people? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antidepressants, benzodiazepines, cognitive behavioural therapy (CBT), diphenhydramine, exercise programmes, timed exposure to bright light, zaleplon, zolpidem, and zopiclone.
Key Points
Up to 40% of older adults have insomnia, with difficulty getting to sleep, early waking, or feeling unrefreshed on waking. The prevalence of insomnia increases with age. Other risk factors include medical and psychiatric illnesses, psychological factors, stress, daytime napping, and hyperarousal.Primary insomnia is a chronic and relapsing condition that may increase the risks of accidents.Primary insomnia is chronic insomnia without specific underlying medical, psychiatric, or other sleep disorders. This review only covers primary insomnia in people aged 60 years and over.
Cognitive behavioural therapy (CBT) improves sleep compared with no treatment.
Exercise may improve symptoms compared with no treatment, but evidence is weak.
We don't know whether timed exposure to bright light can improve sleep quality compared with no treatment.
Zaleplon, zolpidem, and zopiclone may improve sleep latency in older people, although long-term effects are unknown, and they may cause adverse effects. Zolpidem and zopiclone may also increase sleep duration and improve sleep quality compared with placebo in the short term.Zaleplon has not been shown to decrease the number of awakenings, and it may cause rebound insomnia after discontinuation of treatment.
Benzodiazepines may improve sleep outcomes compared with placebo or other treatments, but they may cause adverse effects. We don't know what the long-term effects of benzodiazepines are.Benzodiazepines can cause impairment of memory, cognitive function, and psychological function, and rebound insomnia. They may increase the risks of accidents, falls, and hip fractures in older people.
We don't know whether diphenhydramine improves sleep quality in older people.
We don't know whether antidepressants improve sleep outcomes in older people with primary insomnia, as we found no RCTs.
PMCID: PMC3275108  PMID: 22030082
24.  Sleep Disorders in Parkinsonian Macaques: Effects of l-Dopa Treatment and Pedunculopontine Nucleus Lesion 
The Journal of Neuroscience  2014;34(27):9124-9133.
Patients with Parkinson's disease (PD) display significant sleep disturbances and daytime sleepiness. Dopaminergic treatment dramatically improves PD motor symptoms, but its action on sleep remains controversial, suggesting a causal role of nondopaminergic lesions in these symptoms. Because the pedunculopontine nucleus (PPN) regulates sleep and arousal, and in view of the loss of its cholinergic neurons in PD, the PPN could be involved in these sleep disorders. The aims of this study were as follows: (1) to characterize sleep disorders in a monkey model of PD; (2) to investigate whether l-dopa treatment alleviates sleep disorders; and (3) to determine whether a cholinergic PPN lesion would add specific sleep alterations. To this end, long-term continuous electroencephalographic monitoring of vigilance states was performed in macaques, using an implanted miniaturized telemetry device. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment induced sleep disorders that comprised sleep episodes during daytime and sleep fragmentation and a reduction of sleep efficiency at nighttime. It also induced a reduction in time spent in rapid eye movement (REM) sleep and slow-wave sleep and an increase in muscle tone during REM and non-REM sleep episodes and in the number of awakenings and movements. l-Dopa treatment resulted in a partial but significant improvement of almost all sleep parameters. PPN lesion induced a transient decrease in REM sleep and in slow-wave sleep followed by a slight improvement of sleep quality. Our data demonstrate the efficacy of l-dopa treatment in improving sleep disorders in parkinsonian monkeys, and that adding a cholinergic PPN lesion improves sleep quality after transient sleep impairment.
doi:10.1523/JNEUROSCI.0181-14.2014
PMCID: PMC4078088  PMID: 24990932
cholinergic neurons; l-dopa; macaques; Parkinson's disease; pedunculopontine nucleus; sleep disorders
25.  Sleep disturbances in drug naïve Parkinson's disease (PD) patients and effect of levodopa on sleep 
Context:
Parkinson's disease (PD) is associated with sleep disturbances, attributed to the neurodegenerative process and therapeutic drugs. Studies have found levodopa to increase wakefulness in some patients while increasing sleepiness in others.
Aims:
To confirm sleep disturbances in drug naïve PD patients and understand the impact of levodopa on their sleep.
Materials and Methods:
Twenty-three drug naïve PD patients and 31 age-gender matched controls were compared using the Parkinson's Disease Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS). A polysomnogram objectively compared sleep quality. Of the 23 patients, the 12 initiated on levodopa were reassessed subjectively and through polysomnography after 2 months of therapy.
Statistical Analysis:
Data was expressed as mean ± standard deviation, median, and range. Continuous variables were analyzed by Student's T test for normally distributed data and Mann–Whitney U test for skewed data. Discrete variables were compared by Chi Square tests (Pearson Chi square Test or Fisher's Exact Test). Wilcoxon signed ranks test was applied in the analysis of paired data pre- and post-levodopa. A P value < 0.05 was considered as statistically significant. Statistical analysis of the data was done using the Statistical Package for the Social Sciences (SPSS) version 12.
Results:
Drug naïve PD patients had lower PDSS scores than controls. The sleep architecture changes observed on polysomnogram were reduced NREM Stage III and REM sleep and increased sleep latency and wake after sleep onset time. Following levodopa, improved sleep efficiency with reduced sleep latency and wake after sleep onset time was noted, coupled with improved PDSS scores. However, NREM Stage III and REM sleep duration did not increase.
Discussion:
PD patients take longer to fall asleep and have difficulty in sleep maintenance. Sleep maintenance is affected by nocturia, REM behavioral disorder, nocturnal cramps, akinesia, and tremors, as observed in PDSS scores. Levodopa improves sleep efficiency by improving motor scores without altering sleep architecture.
Conclusions:
Poor sleep quality and sleep architecture changes occur secondary to the neurodegenerative process in PD patients. Though levodopa improves sleep quality by reducing rigidity and tremor, it does not reverse sleep architecture changes.
doi:10.4103/0972-2327.144016
PMCID: PMC4251015  PMID: 25506163
Levodopa on Parkinson's disease sleep; levodopa on sleep; sleep in Parkinson's disease

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