Janet Mullington

Cardiovascular, Inflammatory, and Metabolic Consequences of Sleep Deprivation

That insufficient sleep is associated with poor attention and performance deficits is becoming widely recognized. Fewer people are aware that chronic sleep complaints in epidemiologic studies have also been associated with an increase in overall mortality and morbidity. This article summarizes findings of known effects of insufficient sleep on cardiovascular risk factors including blood pressure, glucose metabolism, hormonal regulation, and inflammation with particular emphasis on experimental sleep loss, using models of total and partial sleep deprivation, in healthy individuals who normally sleep in the range of 7 to 8 hours and have no sleep disorders. These studies show that insufficient sleep alters established cardiovascular risk factors in a direction that is known to increase the risk of cardiac morbidity.

Sustained sleep restriction reduces emotional and physical well-being.

Abstract Background: Chronic insufficient sleep is a common finding in many pain‐related and other medical diseases and is frequently experienced in the general population. Prolonged curtailment of nocturnal sleep has been studied for its adverse effect on cognitive functioning and subjective tiredness, but relatively little is known about its effect on mood and physical symptoms. Objective: In order to test whether sleep restriction to 50% of the habitual time over 12 days affects diurnal and day‐to‐day variation of subjective ratings of mood and physical symptoms, 108 adjectives and statements were self‐rated using visual analog scales every 2 h during the waking period. Design: Randomized, 16‐day controlled in‐laboratory study. Setting: General Clinical Research Center (GCRC). Participants: Forty healthy subjects aged 21–40 years (14 females, 26 males). Intervention: Subjects were randomized to either 4 h of sleep per night (11pm–3am, N=22) or 8 h of sleep per night (11pm–7am, N=18) for 12 consecutive days. Main Outcome Measure: Changes in the factor‐derived variables optimism‐sociability, tiredness‐fatigue, anger‐aggression, bodily discomfort, and items constituting bodily discomfort were compared between groups. Results: Optimism‐sociability progressively declined over consecutive days of sleep restriction by 15%. Bodily discomfort showed a slight, but significant interindividual increase of 3% across days of sleep restriction due to significant increases of generalized body pain, back pain, and stomach pain. Optimism‐sociability and tiredness‐fatigue showed diurnal variations with a quadratic function period within each day in both conditions. Conclusion: The data suggest that chronic insufficient sleep may contribute to the onset and amplification of pain and affect health by compromising optimistic outlook and psychosocial functioning.

Sleep Loss Reduces Diurnal Rhythm Amplitude of Leptin in Healthy Men

The aim of the current study was to investigate the effects of sleep loss on the diurnal rhythm of circulating leptin levels. An indwelling forearm catheter was used to sample blood at 90‐min intervals for a total of 120 h, which included 88 h of sustained sleeplessness, in 10 healthy men. The diurnal amplitude of leptin was reduced during total sleep deprivation and returned toward normal during the period of recovery sleep. This finding provides evidence that sleep influences the nocturnal leptin profile, and may have implications for the understanding of the role of sleep in metabolic regulation and the aetiologies of obesity and the night eating syndrome.

Effects of clozapine on plasma cytokine and soluble cytokine receptor levels

The antipsychotic drug clozapine frequently induces fever during the first weeks of administration. In addition, it has been shown that clozapine increases plasma soluble interleukin-2 receptor (sIL-2r) levels as early as 1 week after treatment is started. These findings suggest that clozapine has immunomodulatory effects. To investigate this issue in more detail, we assessed the time course of rectal temperature, blood cell counts, and cytokine and soluble cytokine receptor plasma levels during 6 weeks of clozapine treatment in 27 schizophrenic patients. Clozapine increased the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, and sIL-2r. These increases were independent of prior or concurrent medication and did also occur in patients who did not experience clozapine-induced fever. However, increases in TNF-alpha and sIL-2r levels were more pronounced in patients with clozapine-induced fever who showed in addition increased plasma IL-6 levels and granulocyte counts. Plasma IL-1 receptor antagonist levels and monocyte and lymphocyte counts were not affected by clozapine treatment. It is concluded that clozapine has consistent in vivo immunomodulatory effects. The results presented suggest that clozapine-induced fever is mediated by pyrogenic cytokines.

Sleep Loss and Inflammation

Controlled, experimental studies on the effects of acute sleep loss in humans have shown that mediators of inflammation are altered by sleep loss. Elevations in these mediators have been found to occur in healthy, rigorously screened individuals undergoing experimental vigils of more than 24h, and have also been seen in response to various durations of sleep restricted to between 25 and 50% of a normal 8h sleep amount. While these altered profiles represent small changes, such sub-clinical shifts in basal inflammatory cytokines are known to be associated with the future development of metabolic syndrome disease in healthy, asymptomatic individuals. Although the mechanism of this altered inflammatory status in humans undergoing experimental sleep loss is unknown, it is likely that autonomic activation and metabolic changes play key roles.

Short-Term Exenatide Treatment Leads to Significant Weight Loss in a Subset of Obese Women Without Diabetes

OBJECTIVE To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women. RESEARCH DESIGN AND METHODS Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m2) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight. RESULTS Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (−7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (−2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss. CONCLUSIONS Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.

Mediators of inflammation and their interaction with sleep: relevance for chronic fatigue syndrome and related conditions.

Abstract: In humans, activation of the primary host defense system leads to increased or decreased NREM sleep quality, depending on the degree of early immune activation. Modest elevations of certain inflammatory cytokines are found during experimental sleep loss in humans and, in addition, relatively small elevations of cytokines are seen following commencement of pharmacological treatments with clozapine, a CNS active antipsychotic agent, known to have immunomodulatory properties. Cytokines such as TNF‐α, its soluble receptors, and IL‐6, present in the periphery and the CNS, comprise a link between peripheral immune stimulation and CNS‐mediated behaviors and experiences such as sleep, sleepiness, and fatigue. The debilitating fatigue experienced in chronic fatigue syndrome and related diseases may also be related to altered cytokine profiles.

Activation of the prostaglandin system in response to sleep loss in healthy humans: potential mediator of increased spontaneous pain.

ABSTRACT Insufficient duration of sleep is a highly prevalent behavioral pattern in society that has been shown to cause an increase in spontaneous pain and sensitivity to noxious stimuli. Prostaglandins (PGs), in particular PGE2, are key mediators of inflammation and pain, and we investigated whether PGE2 is a potential mediator in sleep‐loss‐induced changes in nociceptive processing. Twenty‐four participants (7 females, age 35.1 ± 7.1 years) stayed for 7 days in the Clinical Research Center. After two baseline days, participants were randomly assigned to either 3 days of 88 h of sleep deprivation (TSD, N = 15) or 8 h of sleep per night (N = 9), followed by a night of recovery sleep. Participants rated the intensity of various pain‐related symptoms every 2 h across waking periods on computerized visual analog scales. PGE2 was measured in 24‐h‐urine collections during baseline and third sleep deprivation day. Spontaneous pain, including headache, muscle pain, stomach pain, generalized body pain, and physical discomfort significantly increased by 5–14 units on a 100‐unit scale during TSD, compared to the sleep condition. Urinary PGE2 metabolite significantly increased by about 30% in TSD over sleep condition. TSD‐induced increase in spontaneous pain, in particular headache and muscle pain, was significantly correlated with increase in PGE2 metabolite. Activation of the PGE2 system appears to be a potential mediator of increased spontaneous pain in response to insufficient sleep.

Pain Sensitivity and Modulation in Primary Insomnia

Sleep of good quantity and quality is considered a biologically important resource necessary to maintain homeostasis of pain‐regulatory processes. To assess the role of chronic sleep disturbances in pain processing, we conducted laboratory pain testing in subjects with primary insomnia.

Effects of clozapine on sleep : A longitudinal study

Polysomnographic studies on the effects of clozapine, an atypical antipsychotic agent with strong sedative properties, on night sleep report inconsistent results. Most of these studies did not include baseline recordings and were not controlled for clozapine-induced fever, which is known to alter nocturnal sleep. We conducted a 2-week longitudinal polysomnographic investigation in 10 long-term drug-free schizophrenic patients prior to and at the end of the first and second weeks of clozapine treatment. Rectal temperature was measured daily and patients with fever (> 37.9 degrees C) were excluded. Clozapine significantly improved sleep continuity. In addition, non-rapid eye movement (NREM) sleep and in particular stage 2 sleep increased significantly, while the amounts of stage 4 and slow-wave sleep decreased significantly. Clozapine increased significantly REM density, but it did not affect the amount of REM sleep. We conclude that in patients who do not experience clozapine-induced fever, clozapine has strong sleep consolidating effects resulting from an increase in stage 2 NREM sleep.