Ravi Singareddy

Risk Factors for Incident Chronic Insomnia: A General Population Prospective Study

OBJECTIVE The few population-based, prospective studies that have examined risk factors of incident insomnia were limited by small sample size, short follow-up, and lack of data on medical disorders or polysomnography. We prospectively examined the associations between demographics, behavioral factors, psychiatric and medical disorders, and polysomnography with incident chronic insomnia. METHODS From a random, general population sample of 1741 individuals of the adult Penn State Sleep Cohort, 1395 were followed-up after 7.5 years. Only subjects without chronic insomnia at baseline (n = 1246) were included in this study. Structured medical and psychiatric history, personality testing, and 8-h polysomnography were obtained at baseline. Structured sleep history was obtained at baseline and follow-up. RESULTS Incidence of chronic insomnia was 9.3%, with a higher incidence in women (12.9%) than in men (6.2%). Younger age (20-35 years), non-white ethnicity, and obesity increased the risk of chronic insomnia. Poor sleep and mental health were stronger predictors of incident chronic insomnia compared to physical health. Higher scores in MMPI-2, indicating maladaptive personality traits, and excessive use of coffee at baseline predicted incident chronic insomnia. Polysomnographic variables, such as short sleep duration or sleep apnea, did not predict incident chronic insomnia. CONCLUSION Mental health, poor sleep, and obesity, but not sleep apnea, are significant risk factors for incident chronic insomnia. Focusing on these more vulnerable groups and addressing the modifiable risk factors may help reduce the incident of chronic insomnia, a common and chronic sleep disorder associated with significant medical and psychiatric morbidity and mortality.

Clinical and polysomnographic predictors of the natural history of poor sleep in the general population.

STUDY OBJECTIVES Approximately 8-10% of the general population suffers from chronic insomnia, whereas another 20-30% of the population has insomnia symptoms at any given time (i.e., poor sleep). However, few longitudinal studies have examined risk factors of the natural history of poor sleep, and none have examined the role of polysomnographic (PSG) variables. DESIGN Representative longitudinal study. SETTING Sleep laboratory. PARTICIPANTS From a random, general population sample of 1,741 individuals of the adult Penn State Cohort, 1,395 were followed up after 7.5 yr. MEASUREMENTS Full medical evaluation and 1-night PSG at baseline and telephone interview at follow-up. RESULTS The rate of incident poor sleep was 18.4%. Physical (e.g., obesity, sleep apnea, and ulcer) and mental (e.g., depression) health conditions and behavioral factors (e.g., smoking and alcohol consumption) increased the odds of incident poor sleep as compared to normal sleep. The rates of persistent, remitted, and poor sleepers who developed chronic insomnia were 39%, 44%, and 17%, respectively. Risk factors for persistent poor sleep were physical health conditions combined with psychologic distress. Shorter objective sleep duration and a family history of sleep problems were risk factors for poor sleep evolving into chronic insomnia. CONCLUSIONS Poor sleep appears to be primarily a symptom of physical and mental health conditions, whereas the persistence of poor sleep is associated with psychologic distress. Importantly, sleep apnea appears to be associated with incident poor sleep but not with chronic insomnia. Finally, this study suggests that objective short sleep duration in poor sleepers is a biologic marker of genetic predisposition to chronic insomnia.

Persistent Insomnia: the Role of Objective Short Sleep Duration and Mental Health

STUDY OBJECTIVES Few population-based, longitudinal studies have examined risk factors for persistent insomnia, and the results are inconsistent. Furthermore, none of these studies have examined the role of polysomnographic (PSG) variables such as sleep duration or sleep apnea on the persistence of insomnia. DESIGN Representative longitudinal study. SETTING Sleep laboratory. PARTICIPANTS From a random, general population sample of 1741 individuals of the adult Penn State Cohort, 1395 were followed-up after 7.5 years. MEASUREMENTS Individuals underwent one-night PSG and full medical evaluation at baseline and a telephone interview at follow-up. PSG sleep duration was analyzed as a continuous variable and as a categorical variable: < 6 h sleep (short sleep duration) and ≥ 6 h sleep (longer sleep duration). RESULTS The rates of insomnia persistence, partial remission, and full remission were 44.0%, 30.0%, and 26.0%, respectively. Objective short sleep duration significantly increased the odds of persistent insomnia as compared to normal sleep (OR = 3.19) and to fully remitted insomnia (OR = 4.92). Mental health problems at baseline were strongly associated with persistent insomnia as compared to normal sleep (OR = 9.67) and to a lesser degree compared to fully remitted insomnia (OR = 3.68). Smoking, caffeine, and alcohol consumption and sleep apnea did not predict persistent insomnia. CONCLUSIONS Objective short sleep duration and mental health problems are the strongest predictors of persistent insomnia. These data further support the validity and clinical utility of objective short sleep duration as a novel marker of the biological severity of insomnia.

A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers.

Background and Rationale Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans. Methodology/Principal Findings A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18–30 years old, BMI 18.5–25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged. Conclusions/Significance Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics. Trial Registration ClinicalTrials.gov NCT00741026

Nocturnal sleep panic and depression: Relationship to subjective sleep in panic disorder

BACKGROUND Patients with panic disorder (PD) often complain of sleep disturbances. PD patients have high co-morbid depression and almost 65-70% reports a history of nocturnal panic attacks. It is possible that both nocturnal-sleep panic attacks and depression contribute to sleep disturbances in PD patients. However, the individual and interactive effects of nocturnal-sleep panic attacks and lifetime depression on subjective sleep in PD are unknown. METHODS The National Institute of Mental Health Panic Disorder Questionnaire (NIMH-PQ) was administered to 773 individuals who met DSM-IV criteria for PD. All of these subjects completed queries related to nocturnal-sleep panic attacks, lifetime depression, difficulty sleeping, and sleep duration. RESULTS We examined difficulty in sleeping and sleep duration in four subgroups [PD without nocturnal panic attacks or lifetime depression (NP-D-), PD with nocturnal panic attacks (NP+D-), PD with lifetime depression (NP-D+), and PD with both nocturnal panic attacks and lifetime depression (NP+D+)]. Significantly greater proportions of NP+D+ subjects reported difficulty sleeping compared to other three subgroups. In addition, the NP+D+ patients reported significantly decreased subjective sleep durations compared to the other three subgroups. Using < or = 5h as a criteria for severe sleep restriction, approximately 20% of the NP+D+ patients, compared to 9.2%, 9.6%, and 2.5% in the NP+D-, NP-D+, NP-D- subgroups, respectively, reported sleeping 5h or less. 8.2% of panic disorder patients reported excessive sleeping per sleeping period. CONCLUSIONS A high percentage of panic disorder individuals report subjective sleep disturbances. Not surprisingly, an unusually high prevalence of patients with nocturnal panic attacks or depression have sleep problems and 92.3% of patients with both nocturnal panic attacks and depression report striking extremes in sleep duration or insomnia. Thus, nocturnal-sleep panic attacks and depression are independently as well as interactively associated with increased sleep disturbances in panic disorder. Although these findings are expected, they underscore the importance of assessing sleep functions, including over-sleeping, in panic disorder patients.

Differential effects of hypocretins on noise-alone versus potentiated startle responses.

Hypocretins are recently discovered neuropeptides, synthesized exclusively in the hypothalamus with excitatory efferents to noradrenergic, serotonergic, and GABAergic (gamma-aminobutyric acid) neurons. Hypocretins also increase corticotropin releasing hormone (CRH) secretion. These actions suggest a possible role for hypocretins in the neurobiology of anxiety, fear, or startle mechanisms. We examined the effects of intracerebroventricular (ICV) administration of hypocretin-A and hypocretin-B on behavior in the Startle Potentiated Startle (SPS) paradigm, a repeated measures, non-shock animal model for studying the classically conditioned enhancement of acoustic startle in the rat. SPS has been used to study effects of anxiolytic treatments. Male Sprague-Dawley rats were tested using the SPS paradigm for 3 days (M-W-F). Following training, rats were anesthetized and 26 gauge stainless cannulae were permanently implanted into the lateral ventricle for intracerebroventricular (ICV) infusions. Following 6-9 days of recovery period, the M-W-F SPS testing was resumed. ICV infusion of both Hypocretin-A (1 and 3 nM) and Hypocretin-B (3 and 10 nM) produced significant reduction in Noise Alone Startle amplitude compared to pre-infusion baseline, whereas infusion with vehicle did not affect Noise Alone Startle. The effect of Hypocretin-B was brief (first 10 min post-infusion), whereas the effect of Hypocretin-A persisted across much of the 50 min post-infusion period. Neither Hypocretin-A nor Hypocretin-B significantly altered the magnitude of the SPS response. Contrary to our expectations, hypocretins seems to possess anxiolytic rather than pro-anxiogenic properties, as indicated by decrease in Noise Alone Startle.

Subjective and objective sleep and self-harm behaviors in young children: A general population study

Significant association between sleep disturbances and suicidal ideation and/or attempts is reported in adults and adolescents. However, there is paucity of studies exploring the association between sleep and self-harm behaviors (SHB) in young children and are limited to only subjective sleep measures. We examined the association between SHB and both subjective and objective sleep in a population-based sample of 5-12 yr old. Parents of every student in 3 local school (K-5) districts (n=7312) was sent a screening questionnaire. Randomly selected children from this sample underwent a comprehensive history, physical examination, a 9-h overnight polysomnogram and completed several questionnaires. Among the final sample (n=693), 27 children had SHB with adjusted prevalence of 3%. There was no difference in age, gender, obesity, or socioeconomic status in subjects with or without SHB. Significantly more children with SHB had subjective sleep difficulty and depression. Difficulty maintaining sleep and frequent nightmares were associated with SHB independent of depression or demographics. Polysomnographic %REM-sleep was significantly higher in the SHB group after adjusting for demographics and depression. These data indicate that parent reported sleep disturbances are independently associated with SHB. It is possible that higher REM-sleep is a non-invasive biomarker for risk of self-harm behaviors in young children.

Severe onychophagia and finger mutilation associated with obstructive sleep apnea.

Untreated obstructive sleep apnea (OSA) can lead to important neurobehavioral consequences including cognitive deficits, hyperactivity/inattention, daytime sleepiness, and mood disturbances. Interestingly, the potential role of OSA in the pathogenesis of impulse-control disorders such as nail biting (onychophagia) is currently unknown. We present a case of a man with severe onychophagia and biting-induced finger mutilation that was completely resolved after diagnosis and treatment of severe OSA. Accordingly, this report represents an important clinical observation that suggests a connection between sleep physiology and the neurobiological circuits implicated in the regulation of impulse-control behaviors. Further research in this area may improve our current understanding of the neurobehavioral consequences of untreated OSA.