Monika Haack

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.

Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: Effects of confounding factors and diagnosis.

It has been hypothesized that the immune system plays a pathogenetic role in psychiatric disorders, in particular in major depression and schizophrenia. This hypothesis is supported by a number of reports on altered circulating levels and in vitro production of cytokines in these disorders. However, the respective evidence is not consistent. This may be in part due to an incomplete control for numerous confounding influences in earlier studies. We investigated the plasma levels of cytokines and soluble cytokine receptors in psychiatric patients (N = 361) upon hospital admission and compared the results to those obtained in healthy controls (N = 64). By multiple regression analysis we found that circulating levels of interleukin-1 receptor antagonist (IL-1Ra), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R p55, sTNF-R p75) and IL-6 were significantly affected by age, the body mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-alpha, sTNF-R p75, IL-6) or benzodiazepines (TNF-alpha, sTNF-R p75). Taking all these confounding factors into account, we found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75 and IL-6, whereas levels of TNF-alpha and sTNF-R p55 in major depression and sTNF-R p55 in schizophrenia were slightly decreased compared to healthy controls. We conclude that, if confounding factors are carefully taken into account, plasma levels of the above mentioned cytokines and cytokine receptors yield little, if any, evidence for immunopathology in schizophrenia or major depression.

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.

Low levels of circulating inflammatory cytokines: Do they affect human brain functions?

Animal studies provide consistent evidence for the pivotal role of inflammatory cytokines in inducing sickness behavior during systemic infection and inflammation. Because depression in humans shows a considerable symptomatic overlap with sickness behavior, it has been hypothesized that cytokines are also involved in affective disorders. This view is supported by studies showing that therapeutic administration of inflammatory cytokines can induce typical major depression and by evidence that stimulated cytokine-release during experimental endotoxemia provokes transient deterioration in mood and memory. However, in these conditions, similar to the animal models of acute infections, huge amounts of cytokines produced in the periphery act on the brain. In contrast, during most clinical conditions where depression might involve cytokine actions, such as chronic infection and inflammation, only low amounts of cytokines are circulating. The present paper addresses the question whether and how low amounts of circulating cytokines act on the human brain. Evidence is presented that very low amounts of circulating cytokines are likely to influence brain functions, even under baseline conditions. It is also likely that low levels of cytokines affect the same brain function as high levels do. However, it is uncertain whether these effects go in the same direction. NonREM sleep, for example, is promoted by a slight increase in cytokine levels, but suppressed by prominent increases. Because no comparable data are available for mood and other brain functions, the answer to the question whether and how low circulating amounts of cytokines affect mood depends on further experimental studies.

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.

Effects of antipsychotic drugs on cytokine networks

It has been known since the 1950s that phenothiazines have immunomodulatory effects. This review summarizes recent evidence suggesting that antipsychotic drugs, in particular chlorpromazine and the atypical compound clozapine, influence the production of cytokines. Cytokines, organized in networks of related peptides with pleiotropic functions, are pivotal humoral mediators of infection and inflammation, and they play an important role in hematopoiesis and autoimmunity. Therefore, the effects of antipsychotic drugs on cytokine networks are important for the understanding of immune-mediated side effects of these drugs, e.g. agranulocytosis. In addition, modulation of cytokine production by antipsychotic agents suggests that these drugs might be useful for the treatment of diseases which primarily involve the immune system. Moreover, because cytokines are known to have numerous effects on the CNS, they may mediate effects of antipsychotic drugs on brain functions. Finally, the influence of antipsychotic drugs on cytokine networks is an important confounding factor in studies investigating disease-related immunopathology in psychiatric disorders. This review provides a synopsis of the data published on these topics and outlines future research perspectives.

Low leptin levels but normal body mass indices in patients with depression or schizophrenia.

Appetite, food intake and weight are frequently altered in psychiatric disorders such as major depression and schizophrenia. The few studies investigating weight and the body mass index (BMI) have yielded variable results. Leptin, a fat cell-derived hormone signalling to the brain the size of the adipose tissue, plays a pivotal role in the regulation of weight and food intake. Moreover, leptin is involved in the control of other behaviors and in brain development. There is almost no information about the amounts of circulating leptin in major depression or schizophrenia. We investigated the BMI and plasma leptin levels in patients with major depression (n = 62), schizophrenia (n = 42), and in healthy controls (n = 64). Mean BMIs did not differ between groups. However, leptin levels were significantly lower in both patient groups compared to healthy controls. Moreover, patients suffering from schizophrenia showed significantly lower leptin levels than depressed patients. Decreased leptin levels were independent of psychotropic medication. We conclude that depression and schizophrenia go along with decreased systemic leptin concentrations that cannot be explained by medication or an altered BMI. Hence, leptin might play an important pathophysiological role in these psychiatric disorders that deserves further scientific attention.

Effects of Antidepressants on Weight and on the Plasma Levels of Leptin, TNF-α and Soluble TNF Receptors: A Longitudinal Study in Patients Treated with Amitriptyline or Paroxetine

Leptin, tumor necrosis factor-α (TNF-α), and soluble TNF receptors are involved in weight regulation. Antipsychotic agents, such as clozapine, induce weight gain and increase circulating levels of these cytokines. To assess whether obesity-inducing antidepressants have a similar effect, we measured plasma cytokine levels in depressive inpatients during the first six weeks of treatment with tricyclic agents (amitriptyline or nortriptyline, n = 12), with paroxetine (n = 10), or without medication (n = 14). There was an increase in the body mass index at week 6 of treatment with the tricyclics, which was preceded by a significant increase in soluble TNF receptor p75 plasma levels. Circulating levels of leptin were not affected. Paroxetine and drug-free treatment did not affect any of these parameters. We conclude that weight gain induced by psychotropic agents may occur without increased circulating levels of leptin. However, activation of the TNF-α system might be an early and sensitive marker of ensuing weight gain.

Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients

Deficient orexin signaling has been shown to cause narcolepsy-like conditions in animals. In human narcolepsy, CSF levels of orexin A (hypocretin-1) were reported to be low in most cases. The authors measured CSF and plasma orexin A levels in patients with narcolepsy and in controls. Confirming earlier studies, they found CSF orexin A levels to be extremely low in patients with narcolepsy. However, plasma orexin A levels did not differ from those observed in controls. These results suggest that orexin deficiency in patients with narcolepsy is a phenomena restricted to the CNS.

Diurnal variations of interleukin-6 plasma levels are confounded by blood drawing procedures

Recent findings suggest that inflammatory cytokines are involved in sleep regulation. In part, this idea is based on studies showing that systemic levels of interleukin-6 (IL-6) are affected by sleep and sleep deprivation. However, intravenous (IV) catheters used for repetitive blood sampling were reported to increase local IL-6 production, which might confound sleep-dependent or circadian changes in the plasma concentrations of this cytokine. To further examine the effects of blood drawing procedures on IL-6 plasma levels, 12 healthy young male subjects participated in a 24-h cross-over study protocol involving sleep and sleep deprivation. Blood was collected half-hourly through an IV line and one additional sample was taken by a simple needle stick from the contralateral arm in parallel to the last sample from the catheter. Difficulties in blood sampling, the plasma levels of IL-6, cortisol and subjective sleepiness were quantified. In samples from the IV line there was a linear increase in IL-6 levels in both conditions, whereas the amount of IL-6 detected in the needle stick sample at the end did not differ from baseline. IL-6 levels were significantly higher in samples rated as difficult and those difficulties were more frequent during sleep compared to nocturnal wakefulness. IL-6 levels did not correlate to variations in sleepiness or cortisol levels. We conclude that variations in IL-6 plasma levels measured in samples from an IV catheter are caused, at least in part, by changes in local cytokine production rather than by physiological changes in circulating IL-6 levels.