Low doses of dexamethasone affect immune parameters in the absence of immunological stimulation.

Recent findings suggest an important role of subtle changes in the plasma levels of inflammatory cytokines within the brain-immune interplay. It is unclear how such changes are regulated in the absence of acute inflammatory or infectious stimuli. Endocrine systems are a good candidate, because innate immunity and the hypothalamo-pituitary-adrenal (HPA)-system are closely related: glucocorticoids have immunosuppressive properties and modulate cytokine release from stimulated mononuclear blood cells in vitro and the immune response in vivo, but it still remains unclear, whether they also modulate circulating cytokine levels in the absence of immunological stimuli. We measured the influence of 1.5 or 3.0 mg dexamethasone (DEX) per os at 09:00 or 21:00 hours on body temperature, cortisol plasma levels, differential white blood cell counts, and cytokine plasma levels in 40 healthy male volunteers using a double-blind, placebo-controlled study design. In addition to significant morning-evening differences in tympanic temperature and several immune parameters, we found that DEX-intake significantly increased tympanic temperature, decreased cortisol plasma levels, altered differential white blood cell counts and induced changes in unstimulated plasma cytokine levels. Whereas the levels of TNF-alpha and sTNF-R p75 were reduced, the levels of sTNF-R p55 increased after a transient decrease.

[Chronic pain and depression]. / Chronischer Schmerz und Depression.

Pain and depression are a severe burden on the patient and on the health system. The diseases have many common pathophysiological aspects and a high level of comorbidity. In this article the different diagnostic tools and options for the treatment of pain and depression are described. Prognostic factors for the course of the diseases are given. Documentation of the disease is important for treatment, for questions in the field of healthcare and in order to furnish a medical opinion. Important diagnostic assessments and differential diagnoses are described.

Cytokine-associated emotional and cognitive disturbances in humans.

BACKGROUND: Infectious, autoimmune, and neurodegenerative diseases are associated with profound psychological disturbances. Studies in animals clearly demonstrate that cytokines mediate illness-associated behavioral changes. However, the mechanisms underlying the respective psychological alterations in humans have not been established yet. Therefore, we investigated the effects of low-dose endotoxemia, a well-established and safe model of host-defense activation, on emotional, cognitive, immunological, and endocrine parameters. METHODS: In a double-blind, crossover study, 20 healthy male volunteers completed psychological questionnaires and neuropsychological tests 1, 3, and 9 hours after intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) or saline in 2 experimental sessions. Blood samples were collected hourly, and rectal temperature and heart rate were monitored continuously. RESULTS: Endotoxin had no effects on physical sickness symptoms, blood pressure, or heart rate. Endotoxin caused a mild increase in rectal temperature (0.5 degrees C), and increased the circulating levels of tumor necrosis factor alpha (TNF-alpha), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. After endotoxin administration, the subjects showed a transient significant increase in the levels of anxiety (effect size [ES] = 0.55) and depressed mood (ES = 0.66). Verbal and nonverbal memory functions were significantly decreased (ES = 0.55 to 0.64). Significant positive correlations were found between cytokine secretion and endotoxin-induced anxiety (r = 0.49 to r = 0.60), depressed mood (r = 0.40 to r = 0.75), and decreases in memory performance (r = 0.46 to r = 0.68). CONCLUSIONS: In humans, a mild stimulation of the primary host defense has negative effects on emotional and memory functions, which are probably caused by cytokine release. Hence, cytokines represent a novel target for neuropsychopharmacological research.

Changes in dehydroepiandrosterone (DHEA) and DHEA-sulfate plasma levels during experimental endotoxinemia in healthy volunteers.

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) have immunomodulatory effects in vitro and in vivo. Additionally, their plasma levels are altered during chronic infection and inflammation. However, it remains unknown whether these steroids are involved in early host responses to infection in humans. We examined DHEA and DHEA-S levels during experimental endotoxinemia, a well established pathophysiological model of bacterial infections in humans. Purified Salmonella abortus equi endotoxin (0.2, 0.4, or 0.8 ng/kg body weight) was injected in a single-blind, placebo-controlled experiment to 17 healthy male volunteers. During the following 12 h, rectal temperature and the plasma levels of ACTH, cortisol, DHEA, DHEA-S, interleukin 6, and tumor necrosis factor alpha were determined. Confirming earlier studies, temperature and cytokine levels showed monophasic, dose-dependent increases in response to endotoxin. In contrast, endocrinological effects of endotoxin showed a complex, biphasic pattern: cortisol levels were not affected by 0. 2 ng/kg but significantly increased during the first 6 h following 0. 4 and 0.8 ng/kg endotoxin, whereas ACTH and DHEA levels were significantly enhanced during the first 6 h following 0.8 ng/kg only. ACTH, DHEA, and cortisol secretion was blunted 6-12 h following 0.8 ng/kg. DHEA-S levels were unaffected during the first 6 h following all dosages, but between 6-12 h after injection they were significantly increased following 0.2 ng/kg, unaffected by 0.4 ng/kg, and significantly decreased following 0.8 ng/kg endotoxin. The present results suggest that similarly to glucocorticoids, the adrenal androgens DHEA and DHEA-S play an important role during early host responses to bacterial infections in humans.

Plasma levels of cytokines and soluble cytokine receptors during treatment with haloperidol.

OBJECTIVE: Clozapine increases the levels of cytokines and soluble cytokine receptors. The authors investigated whether haloperidol has similar effects. METHOD: Rectal temperature, white blood cell counts, and plasma levels of cytokines and soluble cytokine receptors were assessed before and during 6 weeks of haloperidol treatment in 10 psychiatric patients. RESULTS: Haloperidol at mean doses of 7.0 mg/day (SD = 3.4), 6.9 mg/day (SD = 3.4), and 5.0 mg/day (SD = 3.1) at the end of the 1st, 2nd, and 6th weeks of treatment, respectively, did not affect rectal temperature, white blood cell counts, or plasma level of interleukin-1 receptor antagonist, interleukin-6, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor p55 or p75, or soluble interleukin-2 receptor. CONCLUSIONS: Haloperidol is unlikely to confound the results of studies investigating disease-related alterations in the levels of a broad range of cytokines and soluble cytokine receptors in schizophrenia.

Body weight and leptin plasma levels during treatment with antipsychotic drugs.

OBJECTIVE: Leptin is produced by fat cells and is presumed to signal the size of the adipose tissue to the brain. The authors investigated whether antipsychotic drugs that often induce weight gain affect circulating levels of leptin. METHOD: Weight, body mass index, and leptin plasma level were measured weekly over 4 weeks in psychiatric inpatients who received clozapine (N = 11), olanzapine (N = 8), haloperidol (N = 13), or no psychopharmacological treatment (N = 12). RESULTS: In patients receiving clozapine or olanzapine, significant increases in weight, body mass index, and leptin level were found, whereas these measures remained stable in patients who received haloperidol or no pharmacological treatment. CONCLUSIONS: Weight gain induced by clozapine or olanzapine appears to be associated with an increase in leptin level that cannot be attributed to dietary changes upon hospitalization.

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.

Effects of antidepressants on weight and on the plasma levels of leptin, TNF-alpha and soluble TNF receptors: A longitudinal study in patients treated with amitriptyline or paroxetine.

Leptin, tumor necrosis factor-alpha (TNF-alpha), 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-alpha system might be an early and sensitive marker of ensuing weight gain.

The endotoxin-induced increase of cytokines is followed by an increase of cortisol relative to dehydroepiandrosterone (DHEA) in healthy male subjects.

Dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) inhibit T-helper lymphocyte type 2 immune reactions and exert anti-inflammatory effects in some chronic inflammatory diseases. Both DHEA and, in particular, DHEAS levels are dramatically decreased in chronic inflammatory diseases whereas cortisol levels remain stable or are elevated. However, the time course of cortisol relative to DHEA production is not known. We tested whether administration of endotoxin to healthy male subjects can induce an early predominance of cortisol relative to DHEA and DHEAS. It is demonstrated that endotoxin induces a dose-dependent increase of cortisol in relation to DHEA (no effect at 0.2 ng endotoxin/kg body weight (b.w.), clear effect at 0.4 and 0.8 ng/kg b.w., p<0.05) and DHEAS (tested at 0.4 ng/kg b.w., P=0.014). The increase of cortisol relative to DHEA appears 4 h after endotoxin injection and 2 h after a strong increase of interleukin (IL)-6 relative to tumour necrosis factor (TNF). In addition, an increase of cortisol relative to 17OH-progesterone was observed. The ratio of serum IL-6/TNF was positively correlated with the ratio of serum cortisol/DHEA (R(Rank)=0.472, P=0.041) and serum cortisol/17OH-progesterone (R(Rank)=0.514, P=0.048). In conclusion, dissociation of cortisol relative to DHEA, DHEAS or 17OH-progesterone appears very early during a systemic inflammatory response which is associated with an increase of IL-6 relative to TNF. As in chronic inflammatory diseases, during an acute inflammatory response with endotoxin, these physiological hormone changes are probably necessary to achieve adequate cortisol levels at the expense of adrenal androgens.

Effects of dexamethasone on cytokine plasma levels and white blood cell counts in depressed patients.

In major depression, alterations of some aspects of the host defense system and the hypothalamo-pituitary-adrenal (HPA) system have been reported. Both systems are closely related, but their interaction in major depression has not yet been explored. Moreover, little is known about the effects of glucocorticoids on the circulating amounts of cytokines in humans in the absence of immunological challenges. Therefore, we investigated the effects of dexamethasone (DEX) in 17 depressed patients who underwent a combined DEX-suppression and corticotropine-releasing-hormone (CRH)-stimulation test on white blood cell counts, and on the plasma levels of granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, and soluble TNF-receptors (sTNF-R) p55 and p75. DEX induced an increase in granulocyte counts, which was positively correlated with increases in the circulating amounts of G-CSF and paralleled by decreased lymphocyte and monocyte counts. Moreover, DEX reduced the plasma levels of IL-6, TNF-alpha and sTNF-R p75. The levels of sTNF-R p55 and IL-10 were not affected. DEX-induced changes in immunological parameters did not differ between patients who had different amounts of HPA-system alteration, and were neither related to the severity of depressive symptomatology or to other clinical features. We conclude that a single oral dose of DEX, even in the absence of infection and inflammation, affects the circulating amounts of cytokines and soluble cytokine receptors, further supporting the pivotal role of these immune-mediators in glucocorticoid-induced immunomodulation. Neuroendocrinological alterations associated with major depression seem to be independent from these processes.

Endotoxin-induced changes in food consumption in healthy volunteers are associated with TNF-alpha and IL-6 secretion.

This study examined the effects of endotoxin administration on food and water consumption in humans, and the associations between these changes and endotoxin-induced secretion of cytokines, cortisol, and fever. Twenty healthy male volunteers received an i.v. injection of Salmonella abortus equi endotoxin (0.8 ng/kg) or saline in two experimental sessions. Blood samples were collected hourly, and rectal temperature was monitored continuously. Food consumption was significantly reduced at 0-4 h and significantly elevated at 4-5 h after the endotoxin injection. Endotoxin administration had no significant effect on water consumption. Endotoxin-induced secretion of TNF-alpha and IL-6 was positively associated with the decrease in food consumption (r=0.61 and 0.68), and negatively associated with the rebound increase in food consumption (r=-0.53 and -0.45). Neither the febrile response, nor the secretion of cortisol was associated with the changes in food consumption. These results suggest that TNF-alpha and IL-6 are involved in endotoxin-induced anorexia in humans.

Experimental immunomodulation, sleep, and sleepiness in humans.

Infection, inflammation, and autoimmune processes are accompanied by serious disturbances of well-being, psychosocial functioning, cognitive performance, and behavior. Here we review those studies that have investigated the effects of experimental immunomodulation on sleep and sleepiness in humans. In most of these studies bacterial endotoxin was injected intravenously to model numerous aspects of infection including the release of inflammatory cytokines. These studies show that human sleep-wake behavior is very sensitive to host defense activation. Small amounts of endotoxin, which affect neither body temperature nor neuroendocrine systems but slightly stimulate the secretion of inflammatory cytokines, promote non-rapid-eye-movement sleep amount and intensity. Febrile host responses, in contrast, go along with prominent sleep disturbances. According to present knowledge tumor necrosis factor-alpha (TNF-alpha) is most probably a key mediator of these effects, although it is likely that disturbed sleep during febrile host responses involves endocrine systems as well. There is preliminary evidence from human studies suggesting that inflammatory cytokines such as TNF-alpha not only mediate altered sleep-wake behavior during infections, but in addition are involved in physiological sleep regulation and in hypnotic effects of established sedating drugs.

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.

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.

[Cytokine network in patients with schizophrenia and its significance for the pathophysiology of the illness]. / Zytokinnetzwerke bei Patienten mit Schizophrenie und ihre Bedeutung für die Pathophysiologie der Erkrankung.

Experimental findings from psychoimmunologic research in humans and epidemiological data suggest that alterations in cytokine networks may induce acute psychopathologic symptoms and may be involved in the pathogenesis and pathophysiology of schizophrenia by influencing brain development. However, there is insufficient evidence from genetic, post-mortem, and cerebrospinal fluid studies to demonstrate this in the CNS of schizophrenic patients. In contrast, there are quite robust findings from peripheral blood that interleukin (IL)-2, IL-6, tumor necrosis factor-alpha, and interferon cytokine systems in patients are regulated differently than in controls. However, these findings are not specific to schizophrenia, they are confounded by numerous intervening variables such as stress, smoking, and medication, and their pathophysiologic relevance for processes in the CNS is undetermined. Therefore, future research on the involvement of cytokines in the pathogenetics, pathophysiology, and treatment of schizophrenia is needed.

Effects of sleep on endotoxin-induced host responses in healthy men.

OBJECTIVE: To examine whether increased sleep during viral or bacterial infections supports host defense mechanisms. METHODS: To test this assumption in humans, healthy male subjects were assigned either to sleep from 2300 to 0700 hours (n = 10) or to stay awake through the night (n = 10). In the sleeping subjects Salmonella abortus equi endotoxin (0.4 ng/kg) or placebo were intravenously injected in balanced order during the first SWS episode. The age-matched, sleep-deprived subjects were injected at the same time point. RESULTS: As expected, endotoxin significantly increased rectal temperature, the plasma levels of cortisol, tumor necrosis factor-alpha (TNF-alpha), the soluble TNF receptors p55 and p75, Interleukin (IL)-6, the IL-1 receptor antagonist (RA), leukocyte, and granulocyte counts in both sleeping and sleep-deprived subjects, whereas lymphocyte and monocyte counts were transiently reduced. Time courses of endotoxin-induced host responses did not differ between the sleep and sleep deprivation groups. Endotoxin did not affect the amount of nocturnal wakefulness, nonrapid-eye-movement (NREM) sleep, or rapid-eye-movement (REM) sleep across the total night compared with placebo, but significantly increased electroencephalogram-arousals (EEG-arousals) in stage 2 and decreased arousals in SWS. In addition, the amount of SWS, spectral EEG-delta and -theta power was increased at the beginning and at the end of the sleep period, respectively, when the degree of immune activation was relatively low. CONCLUSION: The present results support the notion that short-term sleep deprivation is unlikely to harm the immune system as far as unspecific acute responses are concerned. The effects of endotoxin on sleep in this case support prior observations that in humans, enhanced SWS and intensified NREM sleep occur when host defense activation is subtle.

Granulocyte colony-stimulating factor plasma levels during clozapine- and olanzapine-induced granulocytopenia.

OBJECTIVE: Recent case studies suggest that impaired granulopoiesis, well-known to occur during clozapine treatment, may also be observed when olanzapine is administered. The underlying mechanisms are unknown, but haematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF) are likely to be involved. METHOD: We measured the plasma levels of G-CSF and of other cytokines longitudinally in a female patient who developed granulocytopenia twice, first during clozapine treatment and again when olanzapine was administered. RESULTS: G-CSF levels, but not those of other cytokines, closely paralleled granulocyte counts, yielding a significant positive correlation. G-CSF was not detectable in plasma when granulocytopenia occurred. Granulocytopenia resolved spontaneously despite continuing treatment with olanzapine. CONCLUSION: The present case suggests that clozapine and olanzapine both are able to induce transient granulocytopenia through a similar or common mechanism that does not involve a compensatory increase in G-CSF levels.

Effects of an intravenous catheter on the local production of cytokines and soluble cytokine receptors in healthy men.

Like many aspects of physiology, functions of the immune system show considerable diurnal variation. Studies investigating diurnal variations in the circulating amounts of cytokines, in general, used blood samples obtained from an intravenous catheter. The results of such studies may be confounded by an effect of the catheter on local cytokine production. We measured the levels of IL-6, tumour necrosis factor alpha (TNF-alpha) and soluble TNF receptors (sTNF-R) p55 and p75 in 20 healthy men between 09:00 and 19:00 h in plasma samples obtained from an intravenous catheter and in one additional sample obtained by a simple needle stick in the contralateral arm 10 h after baseline. In plasma from the catheter the levels of IL-6 increased significantly over time, TNF-alpha levels slightly decreased and the time courses of TNF receptor levels showed significant trends of a higher order. Control levels of IL-6, TNF-alpha and sTNF-R p75 measured in plasma obtained by needle stick after 10 h did not differ from baseline, and those of sTNF-R p55 were even higher. We conclude that local alterations in the production of cytokines and soluble cytokine receptors induced by an intravenous catheter represent an important confounding factor for studies investigating diurnal variations in immune functions.

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.