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1.  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
2.  Influence of chronic barbiturate administration on sleep apnea after hypersomnia presentation: case study. 
When sleepiness is excessive, undesirable, inappropriate or unexplained, it often indicates a clinical disorder that is generically termed hypersomnia. One of the leading causes of hypersomnia is sleep apnea. We present the case of a 44-year-old woman with a history of bipolar spectrum disorder and epilepsy who initially showed evidence of hypersomnia. The hypersomnia settled with changes to her medication, but the patient was subsequently found to have severe obstructive sleep apnea. The relation between the patient's medication and sleep apnea is discussed, and the possible respiratory-suppressant effects of chronic barbiturate treatment are considered. The role of other evoking factors within the context of this case and the mechanisms by which drug interactions and psychotropic treatment may worsen, obscure or perpetuate sleep apnea are also examined.
PMCID: PMC1407734  PMID: 11022396
3.  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
4.  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
5.  Sleep and psychiatry  
Psychiatric disorders constitute 15.4% of the disease burden in established market economies. Many psychiatric disorders are associated with sleep disturbances, and the relationship is often bidirectional. This paper reviews the prevalence of various psychiatric disorders, their clinical presentation, and their association with sleep disorders. Among the psychiatric disorders reviewed are affective disorders, psychosis, anxiety disorders (including post-traumatic stress disorder), substance abuse disorders, eating disorders, and attention deficit/hyperactivity disorders. The spectrum of associated sleep disorders includes insomnia, hypersomnia, nocturnal panic, sleep paralysis, hypnagogic hallucinations, restless legs/periodic limb movements of sleep, obstructive sleep apnea, and parasomnias. The effects on sleep of various psychotropic medications utilized to treat the above psychiatric disorders are summarized.
PMCID: PMC3181745  PMID: 16416705
sleep disorder; psychiatric disorder; depression; psychosis; anxiety; sleep
6.  Factors associated with psychotropic drug use among community-dwelling older persons: A review of empirical studies 
BMC Nursing  2004;3:3.
Background
In the many descriptive studies on prescribed psychotropic drug use by community-dwelling older persons, several sociodemographic and other factors associated with drug use receive inconsistent support.
Method
Empirical reports with data on at least benzodiazepine or antidepressant drug use in samples of older persons published between 1990 and 2001 (n = 32) were identified from major databases and analyzed to determine which factors are most frequently associated with psychotropic drug use in multivariate analyses. Methodological aspects were also examined.
Results
Most reports used probability samples of users and non-users and employed cross-sectional designs. Among variables considered in 5 or more reports, race, proximity to health centers, medical consultations, sleep complaints, and health perception were virtually always associated to drug use. Gender, mental health, and physical health status were associated in about two-thirds of reports. Associations with age, marital status, medication coverage, socioeconomic status, and social support were usually not observed.
Conclusions
The large variety of methods to operationalize drug use, mental health status, and social support probably affected the magnitude of observed relationships. Employing longitudinal designs and distinguishing short-term from long-term use, focusing on samples of drug users exclusively, defining drug use and drug classes more uniformly, and utilizing measures of psychological well-being rather than only of distress, might clarify the nature of observed associations and the direction of causality. Few studies tested specific hypotheses. Most studies focused on individual characteristics of respondents, neglecting the potential contribution of health care professionals to the phenomenon of psychotropic drug use among seniors.
doi:10.1186/1472-6955-3-3
PMCID: PMC514897  PMID: 15310409
7.  Who seeks primary care for sleep, anxiety and depressive disorders from physicians prescribing homeopathic and other complementary medicine? Results from the EPI3 population survey 
BMJ Open  2012;2(6):e001498.
Objectives
To describe and compare patients seeking treatment for sleep, anxiety and depressive disorders (SADD) from physicians in general practice (GPs) with three different practice preferences: strictly conventional medicine (GP-CM), mixed complementary and conventional medicine (GP-Mx) and certified homeopathic physicians (GP-Ho).
Design and setting
The EPI3 survey was a nationwide, observational study of a representative sample of GPs and their patients, conducted in France between March 2007 and July 2008.
Participants
1572 patients diagnosed with SADD.
Primary and secondary outcomes
The patients’ attitude towards complementary and alternative medicine; psychotropic drug utilisation.
Results
Compared to patients attending GP-CM, GP-Ho patients had healthier lifestyles while GP-Mx patients showed similar profiles. Psychotropic drugs were more likely to be prescribed by GP-CM (64%) than GP-Mx (55.4%) and GP-Ho (31.2%). The three groups of patients shared similar SADD severity.
Conclusion
Our results showed that patients with SADD, while differing principally in their sociodemographic profiles and conventional psychotropic prescriptions, were actually rather similar regarding the severity of SADD in terms of comorbidities and quality of life. This information may help to better plan resource allocation and management of these common health problems in primary care.
doi:10.1136/bmjopen-2012-001498
PMCID: PMC3532988  PMID: 23180389
Epidemiology
8.  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
9.  CIRCADIAN RHYTHM DISTURBANCES IN DEPRESSION 
Human psychopharmacology  2008;23(7):571-585.
Objective
The aim of this article is to review progress in understanding the mechanisms that underlie circadian and sleep rhythms, and their role in the pathogenesis and treatment of depression.
Methods
Literature was selected principally by Medline searches, and additional reports were identified based on ongoing research activities in the authors’ laboratory.
Results
Many physiological processes show circadian rhythms of activity. Sleep and waking are the most obvious circadian rhythms in mammals. There is considerable evidence that circadian and sleep disturbances are important in the pathophysiology of mood disorders. Depressed patients often show altered circadian rhythms, sleep disturbances, and diurnal mood variation. Chronotherapies, including bright light exposure, sleep deprivation, and social rhythm therapies, may be useful adjuncts in non-seasonal and seasonal depression. Antidepressant drugs have marked effects on circadian processes and sleep.
Conclusions
Recent progress in understanding chronobiological and sleep regulation mechanisms may provide novel insights and avenues into the development of new pharmacological and behavioral treatment strategies for mood disorders.
doi:10.1002/hup.964
PMCID: PMC2612129  PMID: 18680211
circadian rhythms; sleep; sleep disturbances depression; chronotherapy; melatonin
10.  The search for new off-label indications for antidepressant, antianxiety, antipsychotic and anticonvulsant drugs 
Most drugs are prescribed for several illnesses, but it took several years for psychotropic drugs to have multiple clinical indications. Our search for serotonergic drugs in affective illnesses and related disorders led to new off-label indications for fluoxetine, sertraline, tryptophan, clonazepam, alprazolam, tomoxetine, buproprion, duloxetine, risperidone and gabapentin. Various clinical trial designs were used for these proof-of-concept studies. Novel therapeutic uses of benzodiazepines, such as in panic disorder and mania, were found with the introduction of 2 high-potency benzodiazepines, clonazepam and alprazolam, which were thought to have serotonergic properties. Our initial clinical trials of fluoxetine and sertraline led to their approved indications in the treatment of obsessive–compulsive disorder, and our trials of gabapentin led to new indications in anxiety disorders (generalized anxiety, panic attack and social phobia) and sleep disorders (insomnia).
PMCID: PMC1449873  PMID: 16699602
anticonvulsants; antidepressive agents; antipsychotic agents; anti-anxiety agents; depressive disorder, major; off-label indications; schizophrenia
11.  Controlled comparison of the characteristics of patients with panic disorder. 
BACKGROUND. Increased general practice attendance rates have been associated with the diagnosis of mental illness but panic disorder has not been specifically investigated in this respect. In addition, studies have failed adequately to assess type and frequency of secondary care referral and patterns of psychotropic prescription in patients with panic disorder in relation to matched controls. AIM. This study set out to compare subjects with panic disorder with age and sex matched controls on measures of general practice consultation rate; psychotropic and non-psychotropic drug use; referral to secondary care, laboratory and radiological tests and hospital admissions; history of illness and complaints; and psychiatric comorbidity. METHOD. The study was carried out in nine practices in the Forth Valley area. One hundred patients with panic disorder, previously diagnosed using DSM III-R criteria, were identified and matched by age and sex with controls. Data were collected by review of general practice case notes. RESULTS. Subjects with panic disorder had significantly higher rates of general practice consultation over the 10 year period prior to DSM III-R diagnosis of panic disorder than controls. Subjects with panic disorder had also been prescribed a significantly greater number of psychotropic and non-psychotropic medications over this period, had had more secondary care investigations and had higher rates of mainly minor illness and related complaints than controls. High comorbidity of panic disorder with depression which had been diagnosed over the 10 year period prior to DSM III-R diagnosis of panic disorder was found. CONCLUSION. The results of this study describe a population of subjects with panic disorder who are long-term heavy users of primary care services. The results also suggest an association between panic disorder and both minor illness and psychiatric comorbidity over the 10 year period prior to DSM III-R diagnosis of panic disorder.
PMCID: PMC1238951  PMID: 8068393
12.  Psychotropic Medication Use Among Medicaid-Enrolled Children With Autism Spectrum Disorders 
Pediatrics  2008;121(3):e441-e448.
OBJECTIVE
The objective of this study was to provide national estimates of psychotropic medication use among Medicaid-enrolled children with autism spectrum disorders and to examine child and health system characteristics associated with psychotropic medication use.
METHODS
This cross-sectional study used Medicaid claims for calendar year 2001 from all 50 states and Washington, DC, to examine 60 641 children with an autism spectrum disorder diagnosis. Logistic regression with random effects was used to examine the child, county, and state factors associated with psychotropic medication use.
RESULTS
Of the sample, 56% used at least 1 psychotropic medication, 20% of whom were prescribed ≥3 medications concurrently. Use was common even in children aged 0 to 2 years (18%) and 3 to 5 years (32%). Neuroleptic drugs were the most common psychotropic class (31%), followed by antidepressants (25%) and stimulants (22%). In adjusted analyses, male, older, and white children; those who were in foster care or in the Medicaid disability category; those who received additional psychiatric diagnoses; and those who used more autism spectrum disorder services were more likely to have used psychotropic drugs. Children who had a diagnosis of autistic disorder or who lived in counties with a lower percentage of white residents or greater urban density were less likely to use such medications.
CONCLUSIONS
Psychotropic medication use is common among even very young children with autism spectrum disorders. Factors unrelated to clinical presentation seem highly associated with prescribing practices. Given the limited evidence base, there is an urgent need to assess the risks, benefits, and costs of medication use and understand the local and national policies that affect medication use.
doi:10.1542/peds.2007-0984
PMCID: PMC2861431  PMID: 18310165
autistic disorder; Asperger disorder; psychotropic drugs; pharmacoepidemiology; physician practice patterns; Medicaid
13.  Assessing Sleep in Opioid Dependence: A Comparison of Subjective Ratings, Sleep Diaries, and Home Polysomnography in Methadone Maintenance Patients 
Drug and alcohol dependence  2010;113(2-3):245-248.
Objectives
Comparisons of subjective and objective sleep measures have shown discrepancies between reported sleep and polysomnography (PSG) in non-drug dependent individuals with and without insomnia. Sleep may affect behavioral and physiologic aspects of drug abuse and dependence; patients in methadone maintenance therapy (MMT) for opioid dependence frequently report sleep problems. Whether subjective sleep reflects objective sleep in MMT patients is unknown. We undertook these analyses to establish the correlations among subjective and objective sleep measures in MMT patients.
Methods
We compared one week of daily sleep diaries, one night of home PSG, a questionnaire completed the morning after PSG, and the Pittsburgh Sleep Quality Inventory (PSQI) as well as demographics and drug use measures in 62 MMT patients with disturbed sleep (PSQI score > 5).
Results
Subjective and objective sleep durations were similar in this sample; average sleep times for the diary, morning questionnaire, and PSG were 340, 323, and 332 minutes, respectively. Average diary sleep time, subjective ratings of feeling rested, and PSG sleep efficiency were correlated significantly with PSQI score. Age was inversely correlated with PSG sleep time. Participants whose urine toxicology showed benzodiazapine use reported significantly longer sleep times on the morning questionnaire.
Conclusions
Objective sleep measures confirm subjective measures in MMT patients with disturbed sleep. The high prevalence of sleep complaints in this population likely reflects pathology rather than sleep misperception. Both objective and subjective measures are useful in research and clinical settings for assessing sleep in opioid-dependent patients.
doi:10.1016/j.drugalcdep.2010.08.007
PMCID: PMC3025068  PMID: 20850231
methadone; opioid dependence; sleep; polysomnography; PSQI; sleep diaries
14.  Delayed sleep phase syndrome in adolescents: prevalence and correlates in a large population based study 
BMC Public Health  2013;13:1163.
Background
The aims of this study were to estimate the prevalence of Delayed Sleep Phase Syndrome (DSPS) in adolescence, and to examine the association to insomnia and school non-attendance.
Methods
Data stem from a large population based study in Hordaland County in Norway conducted in 2012, the ung@hordaland study. In all, 10,220 adolescents aged 16–18 years (54% girls) provided self-reported data on a range of sleep parameters: DSPS was defined according to the International Classification of Sleep Disorders, Revised (ICSD-R) criteria, while insomnia was defined according to the Quantitative Criteria for Insomnia. Other sleep parameters included time in bed, sleep duration, sleep efficiency, oversleeping, sleep onset latency, wake after sleep onset, subjective sleep need, sleep deficiency, sleepiness and tiredness. Sleep data were calculated separately for weekdays and weekends. Data on school non-attendance were provided by official registers.
Results
The prevalence of DSPS was 3.3%, and significantly higher among girls (3.7%) than boys (2.7%). There was a strong overlap between DSPS and insomnia, with more than half of the adolescents with DSPS also meeting the criteria for insomnia (53.8% for boys and 57.1% for girls). Adolescents with DSPS had significantly higher odds ratios (OR) of non-attendance at school. After adjusting for sociodeographical factors, insomnia and depression, the adjusted ORs for days of non-attendance were OR = 3.22 (95% CI: 1.94-5.34) for boys and OR = 1.87 (95% CI: 1.25-2.80) for girls. A similar effect was found for hours of non-attendance for boys, with an adjusted OR = 3.05 (95% CI: 1.89-4.92). The effect for girls was no longer significant after full adjustment (OR =1.48 [95% CI: 0.94-2.32]).
Conclusions
This is one of the first studies to estimate the prevalence of DSPS in adolescents. The high prevalence of DSPS, and overlap with insomnia, in combination with the odds of school non-attendance, suggest that a broad and thorough clinical approach is warranted when adolescents present with symptoms of DSPS.
doi:10.1186/1471-2458-13-1163
PMCID: PMC3878844  PMID: 24330358
Delayes sleep phase syndrome; Sleep; Prevalence; Correlates; Epidemiology
15.  A Clinical Approach to Circadian Rhythm Sleep Disorders 
Sleep medicine  2007;8(6):566-577.
Circadian rhythm sleep disorders are characterized by complaints of insomnia and excessive sleepiness that are primarily due to alterations in the internal circadian timing system or a misalignment between the timing of sleep and the 24-hour social and physical environment. In addition to physiological and environmental factors, maladaptive behaviors often play an important role in the development of many of the circadian rhythm sleep disorders. This review will focus on the clinical approach to the diagnosis and management of the various circadian rhythm sleep disorders, including delayed sleep phase disorder, advanced sleep phase disorder, non-entrained type, irregular sleep-wake rhythm, shift work sleep disorder and jet lag disorder. Diagnostic tools such as sleep diaries and wrist activity monitoring are often useful in confirming the diagnosis. Because behavioral and environmental factors often are involved in the development of these conditions, a multimodal approach is usually necessary. Interventions include sleep hygiene education, timed exposure to bright light as well as avoidance of bright light at the wrong time of the day and pharmacologic approaches, such as melatonin. However, it should be noted that the use of melatonin is not an FDA-approved indication for the treatment of circadian rhythm sleep disorders.
doi:10.1016/j.sleep.2006.11.017
PMCID: PMC2679862  PMID: 17395535
Circadian Rhythm Sleep Disorders; Delayed Sleep Phase Disorder; Advanced Sleep Phase Disorder; Non 24-hr Sleep Wake Syndrome; Irregular Sleep Wake Rhythm; Shift Work Disorder; Jet Lag Syndrome
16.  Psychotropic medication in the French child and adolescent population: prevalence estimation from health insurance data and national self-report survey data 
BMC Psychiatry  2009;9:72.
Background
The aim of this work is to estimate the French frequencies of dispensed psychotropic prescriptions in children and adolescents. Prevalence estimations of dispensed prescriptions are compared to the frequencies of use of psychotropic reported by 17 year-old adolescents.
Methods
Prescription data is derived from national health insurance databases. Frequencies of dispensed prescriptions are extrapolated to estimate a range for the 2004 national rates. Self-report data is derived from the 2003 and 2005 ESCAPAD study, an epidemiological study based on a questionnaire focused on health and drug consumption.
Results
The prevalence estimation shows that the prevalence of prescription of a psychotropic medication to young persons between 3 and 18 years is about 2.2%.
In 2005, the self-report study (ESCAPAD) shows that 14.9% of 17 year-old adolescents took medication for "nerves" or "to sleep" during the previous 12 months. The same study in 2003 also shows that 62.3% of adolescents aged 17 and 18 reporting psychotropic use, took the medication for anxiety and 56.8% to sleep. Only 49.7% of these medications are suggested by a doctor.
Conclusion
This study underlines a similar range of prevalence of psychotropic prescriptions in France to that observed in other European countries. Nevertheless, the proportion of antipsychotics and benzodiazepines seems to be higher, whereas the proportion of methylphenidate is lower.
Secondly, a disparity between the prevalence of dispensed prescriptions and the self-report of actual use of psychotropics has been highlighted by the ESCAPAD study which shows that these treatments are widely used as "self-medication".
doi:10.1186/1471-244X-9-72
PMCID: PMC2781809  PMID: 19919701
17.  Endogenous GABA levels in the pontine reticular formation are greater during wakefulness than during REM sleep 
Studies using drugs that increase or decrease GABAergic transmission suggest that GABA in the pontine reticular formation (PRF) promotes wakefulness and inhibits rapid eye movement (REM) sleep. Cholinergic transmission in the PRF promotes REM sleep, and levels of endogenous acetylcholine (ACh) in the PRF are significantly greater during REM sleep than during wakefulness or non-REM (NREM) sleep. No previous studies have determined whether levels of endogenous GABA in the PRF vary as a function of sleep and wakefulness. This study tested the hypothesis that GABA levels in cat PRF are greatest during wakefulness and lowest during REM sleep. Extracellular GABA levels were measured during wakefulness, NREM sleep, REM sleep, and the REM sleep-like state (REMNeo) caused by microinjecting neostigmine into the PRF. GABA levels varied significantly as a function of sleep and wakefulness, and decreased significantly below waking levels during REM sleep (−42%) and REMNeo (−63%). The decrease in GABA levels during NREM sleep (22% below waking levels) was not statistically significant. Compared to NREM sleep, GABA levels decreased significantly during REM sleep (−27%) and REMNeo (−52%). Comparisons of REM sleep and REMNeo revealed no differences in GABA levels or cortical EEG power. GABA levels did not vary significantly as a function of dialysis site within the PRF. The inverse relationship between changes in PRF levels of GABA and ACh during REM sleep indicates that low GABAergic tone combined with high cholinergic tone in the PRF contributes to the generation of REM sleep.
doi:10.1523/JNEUROSCI.5674-10.2011
PMCID: PMC3073841  PMID: 21325533
sedative-hypnotics; microdialysis; EEG; general anesthesia
18.  Aging and Sleep: Physiology and Pathophysiology 
Aging effects on sleep are important to consider for the practicing pulmonologist due to the increase in prevalence of major respiratory disorders as well as the normal changes that occur in sleep patterns with aging. Typically, aging is associated with decreases in the amount of slow wave sleep and increases in stage 1 and 2 non–rapid eye movement sleep, often attributed to an increased number of spontaneous arousals that occur in the elderly. Elderly individuals tend to go to sleep earlier in the evening and wake earlier due to a phase advance in their normal circadian sleep cycle. Furthermore the development of sleep-related respiratory disorders such as obstructive sleep apnea (OSA) and central sleep apnea or Cheyne-Stokes respiration (CSA-CSR) associated with congestive heart failure (CHF) occur with increasing prevalence in the elderly. The development of such disorders is often of major concern because they are associated with systemic hypertension and cardiovascular disease, metabolic disorders such as diabetes, and impaired neurocognition. The present review reflects the current understanding of the normal changes in sleep patterns and sleep needs with advancing age, in addition to the effect that aging has on the predisposition to and consequences of OSA and CSA-CSR associated with CHF.
doi:10.1055/s-0030-1265902
PMCID: PMC3500384  PMID: 20941662
Aging; sleep patterns; sleep apnea; congestive heart failure
19.  Sleepiness, Quality of Life, and Sleep Maintenance in REM versus non-REM Sleep-disordered Breathing 
Rationale: The impact of REM-predominant sleep-disordered breathing (SDB) on sleepiness, quality of life (QOL), and sleep maintenance is uncertain.
Objective: To evaluate the association of SDB during REM sleep with daytime sleepiness, health-related QOL, and difficulty maintaining sleep, in comparison to their association with SDB during non-REM sleep in a community-based cohort.
Methods: Cross-sectional analysis of 5,649 Sleep Heart Health Study participants (mean age 62.5 [SD = 10.9], 52.6% women, 22.6% ethnic minorities). SDB during REM and non-REM sleep was quantified using polysomnographically derived apnea-hypopnea index in REM (AHIREM) and non-REM (AHINREM) sleep. Sleepiness, sleep maintenance, and QOL were respectively quantified using the Epworth Sleepiness Scale (ESS), the Sleep Heart Health Study Sleep Habit Questionnaire, and the physical and mental composites scales of the Medical Outcomes Study Short Form (SF)-36.
Measurements and Main Results: AHIREM was not associated with the ESS scores or the physical and mental components scales scores of the SF-36 after adjusting for demographics, body mass index, and AHINREM. AHIREM was not associated with frequent difficulty maintaining sleep or early awakening from sleep. AHINREM was associated with the ESS score (β = 0.25; 95% confidence interval [CI], 0.16 to 0.34) and the physical (β = −0.12; 95% CI, −0.42 to −0.01) and mental (β = −0.20; 95% CI, −0.20 to −0.01) components scores of the SF-36 adjusting for demographics, body mass index, and AHIREM.
Conclusions: In a community-based sample of middle-aged and older adults, REM-predominant SDB is not independently associated with daytime sleepiness, impaired health-related QOL, or self-reported sleep disruption.
doi:10.1164/rccm.200908-1304OC
PMCID: PMC3269234  PMID: 20093641
epidemiology; sleep apnea syndromes; sleep, REM; hypersomnia
20.  Brains, Bones, and Aging: Psychotropic medications and bone health among older adults 
Current osteoporosis reports  2012;10(4):303-311.
Psychotropic drugs are a crucial element of treatment for psychiatric disorders; however there is an established association between many classes of psychotropic medications and fracture risk among older adults, and growing evidence that some classes of medications may also impact bone mineral density (BMD). In this paper we review recent epidemiologic research on the association between psychotropic medications and osteoporosis, and discuss current controversies and unresolved issues surrounding this relationship. Key areas in need of focused inquiry include resolving whether the apparent association between psychotropic medications and BMD is due to confounding by indication, whether this relationship differs for men and women, and whether the implications of these medications for bone health vary over the life course. Clinical research to delineate the risk/benefit ratio of psychotropic medications for older adults, particularly those who are at high risk for fracture, is also needed to facilitate prescribing decisions between patients and physicians.
doi:10.1007/s11914-012-0121-4
PMCID: PMC3508080  PMID: 23001917
Epidemiology; aging; psychiatry; polypharmacy; medications; osteoporosis
21.  Sleep Architecture as Correlate and Predictor of Symptoms and Impairment in Inter-episode Bipolar Disorder: Taking on the Challenge of Medication Effects 
Journal of sleep research  2010;19(4):516-524.
This study was designed to clarify the association between inter-episode bipolar disorder and sleep architecture. Participants completed a baseline symptom and sleep assessment and, 3 months later, an assessment of symptoms and impairment. The effects of psychiatric medications on sleep architecture were also considered. Participants included 22 adults with bipolar I or II (inter-episode) and 22 non-psychiatric controls. The sleep assessment was conducted at the Sleep and Psychological Disorders Laboratory at the University of California, Berkeley. Follow-up assessments 3 months later were conducted over the phone. Results indicate that, at the sleep assessment, bipolar participants exhibited greater REM density than control participants with no other group differences in sleep architecture. Sleep architecture was not correlated with concurrent mood symptoms in either group. In the bipolar group, duration of the first REM period and Slow Wave Sleep (SWS) amount were positively correlated with manic symptoms and impairment at 3 months, while REM density was positively correlated with depressive symptoms and impairment at 3 months. The amount of Stage 2 sleep was negatively correlated with manic symptoms and impairment at 3 months. In contrast, for the control group, REM density was negatively correlated with impairment at 3 months. SWS and Stage 2 sleep were not correlated with symptoms or impairment. Study findings suggest that inter-episode REM sleep, SWS and Stage 2 sleep are correlated with future manic and depressive symptoms and impairment in bipolar disorder. This is consistent with the proposition that sleep architecture may be a mechanism of illness maintenance in bipolar disorder.
doi:10.1111/j.1365-2869.2010.00826.x
PMCID: PMC2965266  PMID: 20408930
Sleep architecture; Bipolar Disorder; REM; Slow Wave Sleep; Stage 2 Sleep
22.  Role of Abca7 in Mouse Behaviours Relevant to Neurodegenerative Diseases 
PLoS ONE  2012;7(9):e45959.
ATP-binding cassette transporters of the subfamily A (ABCA) are responsible for the translocation of lipids including cholesterol, which is crucial for neurological function. Recent studies suggest that the ABC transporter ABCA7 may play a role in the development of brain disorders such as schizophrenia and Alzheimer’s disease. However, Abca7’s role in cognition and other behaviours has not been investigated. Therefore, we characterised homozygous Abca7 knockout mice in a battery of tests for baseline behaviours (i.e. physical exam, baseline locomotion and anxiety) and behaviours relevant to schizophrenia (i.e. prepulse inhibition and locomotor response to psychotropic drugs) and Alzheimer’s disease (i.e. cognitive domains). Knockout mice had normal motor functions and sensory abilities and performed the same as wild type-like animals in anxiety tasks. Short-term spatial memory and fear-associated learning was also intact in Abca7 knockout mice. However, male knockout mice exhibited significantly impaired novel object recognition memory. Task acquisition was unaffected in the cheeseboard task. Female mice exhibited impaired spatial reference memory. This phenomenon was more pronounced in female Abca7 null mice. Acoustic startle response, sensorimotor gating and baseline locomotion was unaltered in Abca7 knockout mice. Female knockouts showed a moderately increased motor response to MK-801 than control mice. In conclusion, Abca7 appears to play only a minor role in behavioural domains with a subtle sex-specific impact on particular cognitive domains.
doi:10.1371/journal.pone.0045959
PMCID: PMC3454356  PMID: 23029339
23.  Sleep apnea in young abstinent recreational MDMA (“ecstasy”) consumers  
Neurology  2009;73(23):2011-2017.
Background:
Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a popular recreational drug of abuse and a selective brain serotonin neurotoxin. Functional consequences of MDMA neurotoxicity have defied ready characterization. Obstructive sleep apnea (OSA) is a common form of sleep-disordered breathing in which brain serotonin dysfunction may play a role. The present study sought to determine whether abstinent recreational MDMA users have an increased prevalence of OSA.
Methods:
We studied 71 medically healthy recreational MDMA users and 62 control subjects using all-night sleep polysomnography in a controlled inpatient research setting. Rates of apneas, hypopneas, and apnea hypopnea indices were compared in the 2 groups, controlling for body mass index, age, race, and gender.
Results:
Recreational MDMA users who had been drug free for at least 2 weeks had significantly increased rates of obstructive sleep apnea and hypopnea compared with controls. The odds ratio (95% confidence interval) for sleep apnea (mild, moderate, and severe combined) in MDMA users during non-REM sleep was 8.5 (2.4–30.4), which was greater than that associated with obesity [6.9 (1.7–28.2)]. Severity of OSA was significantly related to lifetime MDMA exposure.
Conclusions:
These findings suggest that prior recreational methylenedioxymethamphetamine use increases the risk for obstructive sleep apnea and lend support to the notion that brain serotonin neuronal dysfunction plays a role in the pathophysiology of sleep apnea.
GLOSSARY
= apnea hypopnea index;
= body mass index;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= methylenedioxymethamphetamine;
= non-REM;
= odds ratio;
= obstructive sleep apnea;
= polysomnography;
= Scheduled Diagnostic Interview for DSM-IV;
= sleep-disordered breathing.
doi:10.1212/WNL.0b013e3181c51a62
PMCID: PMC2790228  PMID: 19955499
24.  Development and Initial Validation of the Iowa Sleep Disturbances Inventory (ISDI) 
Assessment  2010;17(4):423-439.
The Iowa Sleep Disturbances Inventory (ISDI) is a new measure of self-reported sleep difficulties, which was designed to help facilitate research on the overlap of sleep disturbances and psychopathology. This instrument was developed in 2 large student samples using principal factor analyses; the psychometric properties of the scales then were examined in 3 additional samples (students, psychiatric patients, sleep disorder patients). The ISDI consists of 11 specific scales (Nightmares, Initial Insomnia, Fatigue, Fragmented Sleep, Nonrestorative Sleep, Anxiety at Night, Light Sleep, Movement at Night, Sensations at Night, Excessive Sleep, Irregular Schedule) and 1 general scale (Daytime Disturbances). The structure of the ISDI generalizes across both patient and non-patient samples. In addition, the ISDI scales are internally consistent, show good retest reliability, demonstrate convergent and discriminant validity with widely used measures of sleep disturbances, and display criterion validity in relation to psychiatric patient status and specific symptoms of depression and anxiety.
doi:10.1177/1073191110362864
PMCID: PMC3126861  PMID: 20484713
sleep; scale development; factor analysis; major depression; anxiety disorders
25.  Sleep Phenotyping in a Mouse Model of Extreme Trait Anxiety 
PLoS ONE  2012;7(7):e40625.
Background
There is accumulating evidence that anxiety impairs sleep. However, due to high sleep variability in anxiety disorders, it has been difficult to state particular changes in sleep parameters caused by anxiety. Sleep profiling in an animal model with extremely high vs. low levels of trait anxiety might serve to further define sleep patterns associated with this psychopathology.
Methodology/Principal Findings
Sleep-wake behavior in mouse lines with high (HAB), low (LAB) and normal (NAB) anxiety-related behaviors was monitored for 24 h during baseline and recovery after 6 h sleep deprivation (SD). The amounts of each vigilance state, sleep architecture, and EEG spectral variations were compared between the mouse lines. In comparison to NAB mice, HAB mice slept more and exhibited consistently increased delta power during non-rapid eye movement (NREM) sleep. Their sleep patterns were characterized by heavy fragmentation, reduced maintenance of wakefulness, and frequent intrusions of rapid eye movement (REM) sleep. In contrast, LAB mice showed a robust sleep-wake rhythm with remarkably prolonged sleep latency and a long, persistent period of wakefulness. In addition, the accumulation of delta power after SD was impaired in the LAB line, as compared to HAB mice.
Conclusions/Significance
Sleep-wake patterns were significantly different between HAB and LAB mice, indicating that the genetic predisposition to extremes in trait anxiety leaves a biological scar on sleep quality. The enhanced sleep demand observed in HAB mice, with a strong drive toward REM sleep, may resemble a unique phenotype reflecting not only elevated anxiety but also a depression-like attribute.
doi:10.1371/journal.pone.0040625
PMCID: PMC3394752  PMID: 22808211

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