Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy.

BACKGROUND: The neuropeptides hypocretin-1 and -2 (hcrt-1 and -2, also known as orexin A and B) are crucially involved in the regulation of sleep/wake states. On the one hand, the sleep-wake disorder narcolepsy can be caused by an hcrt-1 deficiency. On the other, intracerebral administration of hcrt-1 produces an increase in wakefulness at the expense of REM sleep in normal and narcoleptic animals. In humans intranasal administration has been shown to effectively deliver neuropeptides directly to the central nervous system. We hypothesised that the intranasal application of hcrt-1 increases wakefulness and reduces REM sleep in the natural human hcrt-1 deficiency narcolepsy with cataplexy. METHODS: In this double-blind, random-order crossover, placebo-controlled, within-subject design study we administered human recombinant hcrt-1 (435 nmol) intranasally to eight subjects with narcolepsy with cataplexy before night sleep, followed by standard polysomnography. RESULTS: Although intranasal administration of hcrt-1 had no statistically significant effect on nocturnal wakefulness, we found that it reduced REM sleep quantity, particularly during the second half of the recording. Furthermore, intranasal hcrt-1 had a clear REM sleep stabilising effect and led to significantly reduced direct wake to REM transitions. CONCLUSION: In this pilot study we found, first, evidence that the intranasal administration of hcrt-1 has functional effects on sleep in narcolepsy with cataplexy. Our results may encourage the use of the intranasal approach in further studies on hypocretinergic sleep regulation and might also contribute to the future development of a causal treatment for narcolepsy with cataplexy.

Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia.

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin.

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

[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.

Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine.

Weight gain is a frequent and important side effect of psychopharmacotherapy. Recent studies suggest that the fat-cell-derived hormone leptin and the tumor necrosis factor-alpha (TNF-alpha) cytokine system are pathophysiologically involved. No information is available concerning the influence of the antidepressants mirtazapine and venlafaxine on these immunoendocrine variables. An open-labeled study was performed in 20 patients suffering from major depression treated with either mirtazapine (N = 11) or venlafaxine (N = 9). During 4 weeks, the patients' weight, body mass index (BMI), and plasma levels of leptin, TNF-alpha, sTNF-R p55, and sTNF-R p75 were assessed. Mirtazapine induced a significant increase in weight (mean weight gain: 2.4 kg) that was evident after the first week of treatment. In parallel, the plasma levels of TNF-alpha and both soluble TNF receptors increased. In addition, a slight rise in leptin levels, which occurred slowly and was significant only at the end of the 4 th week of treatment, was observed. Weight decreased slightly but significantly in patients treated with venlafaxine (mean weight loss: 0.4 kg), whereas plasma levels of leptin, TNF-alpha, or soluble TNF receptors did not change significantly. The present results further support the notion that the activation of the TNF-alpha cytokine system is an early, sensitive, and specific marker of weight gain induced by psychotropic agents. In contrast, the effects of such drugs on leptin production seem to be less sensitive with respect to weight gain and more variable.

[Zolpidem: the risk of tolerance and dependence according to case reports, systematic studies and recent molecularbiological data]. / Zolpidem: Zur Entwicklung von Toleranz und Abhängigkeit anhand von Fallberichten, systematischen Studien und aktuellen molekularbiologischen Daten.

Our group as well as about 20 other publications report cases of dependence from zolpidem. Furthermore, there is epidemiological and polysomnographic evidence that there is a risk for tolerance and dependence for zolpidem although lower than in the case of benzodiazepines. Recent molecularbiological findings offer interesting data in this respect. Whereas in the recommended dose range zolpidem almost exclusively binds to the alpha(1) subunit of the GABA(A) receptor associated with sleep promotion, in higher doses it also binds the alpha(2), alpha(3) and alpha(5) subunits typically targeted by benzodiazepines and associated with anxiolytic effects. Moreover, because age, gender and alcohol were shown to significantly affect expression of these subunits in individual brain regions, dosage and duration of treatment with zolpidem as well as age, gender and additional consumption of alcohol, a history of abuse and dependence might play a role in the development of tolerance and dependence in individual patients.

[On the clinical relevance of clozapine-triggered release of cytokines and soluble cytokine-receptors]. / Zur klinischen Relevanz der Wirkung von Clozapin auf die Freisetzung von Zytokinen und löslichen Zytokinrezeptoren.

Cytokines are pivotal mediators of the interaction between immunocompetent cells. Moreover, they mediate the interaction between the immune system and other physiological systems, including the CNS. It has been shown recently that the antipsychotic drug clozapine stimulates in vivo the release of cytokines and soluble cytokine receptors. This holds true for the tumor necrosis factor(TNF)-system, the interleukin(IL)-2-system, IL-6, and granulocyte colony-stimulating factor (G-CSF). The present paper discusses the clinical relevance of these findings for the pathophysiology of clozapine-induced side-effects. It is very probable that TNF-alpha plays an important role in clozapin-induced fever and in the hematopoetic side effects, including agranulocytosis. Moreover, it is likely that TNF-alpha and other cytokines are involved in metabolic (weight gain, diabetes), cardiac (myocarditis), CNS (sedation) and other rare side effects. The mechanisms underlying clozapine-induced immunomodulation are unknown. Hence, further studies are very important to enhance our understanding of clozapins's side effects and to develop strategies for prevention and treatment.

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.

[The physiopathology of weight regulation during treatment with psychotropic drugs]. / Zur Pathophysiologie der Gewichtsregulation im Rahmen der Therapie mit Psychopharmaka.

Weight changes during pharmacological treatment are a well-known phenomenon and they have been an object of research since the 1950's. Weight gain occurs during treatment with drugs of different chemical structures and is an important problem when patients are treated with antidepressants, antipsychotics, or mood stabilizers. The clinical relevance of drug-induced weight changes is due to increased rates of morbidity and reduced treatment compliance. Regarding the underlying causes, the important role of neurotransmitter systems and in particular the blockade of serotonin and histamine receptors has been discussed since decades. Only recently, however, research has been started on the effects of psychotropic agents on major neuroendocrine systems involved in appetite and weight regulation. These studies suggest that the fat-cell derived hormone leptin might play an important role. Leptin signals to the brain the size of the adipose tissue and is probably the most important peripheral signal for the long-term regulation of weight. In addition to the neuroendocrine systems, weight gain induced by psychotropic agents might also involve immune modulators, in particular the proinflammatory cytokine tumor-necrosis-factor-alpha (TNF-alpha) and soluble TNF-receptors. Some psychotropic agents influence the TNF system very rapidly, already prior to any obvious increases in weight. Hence, changes in the TNF-alpha system might be of predictive value for drug-induced weight gain. Strategies to minimize or to counteract weight gain induced by psychotropic agents include psychotherapeutic and pharmacological approaches. Although numerous psychotherapeutic approaches are available, they are only of limited usefulness in severely ill psychiatric patients. Fortunately, a number of promising pharmacological approaches to reduce weight have been introduced into clinical practice during the last years; however, so far there is no knowledge on pharmacodynamic and -kinetic interactions with psychotropic drugs, and there is no clinical data on the usefulness and safety of such drug combinations.

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.

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

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-alpha, 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.

In vitro cytokine secretion in individuals with schizophrenia: results, confounding factors, and implications for further research.

The present paper reviews the results of all publications on in vitro cytokine secretion in patients with schizophrenia, as published by March 2001. The authors supply easy to read tables with respect to the individual cytokines and soluble cytokine receptors investigated, the in vitro methodology used, characterization of the patient samples, and the results on cytokine secretion as stated in these studies. Inconsistent results, e.g., regarding in vitro secretion of IL-2 with 11/18 studies finding decreased secretion, 5/18 finding no change, and 2/18 finding increases, cannot systematically be correlated with any methodological procedures nor any diagnostic subtypes, per se. However, factors such as medication and cigarette smoking are likely to play a role. The authors suggest that more hypothesis-driven research, together with more carefully designed studies, as well as better communication between basic or animal researchers and clinicians might help to answer the question of whether there are meaningful peripheral changes in the immune system related to schizophrenia.

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 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.

A comparison of the effects of clozapine and olanzapine on the EEG in patients with schizophrenia.

Clozapine is known to induce epileptic seizures and changes in EEG-patterns, including slowing and the appearance of epileptiform activity. Olanzapine, a new antipsychotic drug, shares many pharmacological and clinical properties with clozapine. However, in patients treated with olanzapine, no case of seizure induction has been reported so far, and the EEG has not been studied systematically. We examined the EEGs of patients with schizophrenia treated with either olanzapine (N = 9) or clozapine (N = 9) prior to medication and 3 to 7 weeks afterwards. Clozapine induced significant EEG slowing present in 78% of the patients, and definite epileptiform activity appeared in 33%. Olanzapine also induced significant EEG slowing, but less frequently (in 44% of the patients) and less pronounced than clozapine. Olanzapine had no significant effect an epileptiform activity, but in one patient, an isolated sharp/slow-wave complex was observed. These preliminary data suggest that olanzapine induces EEG slowing to a lower extent than clozapine. Olanzapine's possible effect an the seizure threshold deserves further attention.

Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight.

RATIONALE: Clozapine treatment is associated with side-effects such as blood cell dyscrasias and weight gain. Increased plasma levels of the cytokines and soluble cytokine receptors leptin, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, as well as toxic metabolites of clozapine, have been suggested as the basis for these side-effects, OBJECTIVES: This study examined whether the coadministration of the selective serotonine reuptake inhibitor fluvoxamine, which interferes with clozapine's hepatic metabolism, affects the immunomodulation by clozapine and some of its side-effects. METHODS: The following parameters were measured: circulating levels of the cytokines and soluble receptors, plasma concentrations of clozapine and its metabolite N-desmethylclozapine, body weight and blood cell counts in 11 and 12 schizophrenic inpatients on combined and monotherapy, respectively, before and during the first 6 weeks of medication. RESULTS: On the basis of comparable plasma levels of clozapine and N-desmethylclozapine, the coadministration of fluvoxamine 1) attenuated and delayed the clozapine-induced increase in TNF-alpha plasma levels, 2) enhanced and accelerated the clozapine-induced increase in leptin plasma levels without significant effect on clozapine-induced weight gain, and 3) decreased granulocyte counts. CONCLUSIONS: As clozapine, its metabolite N-desmethylclozapine and fluvoxamine are unlikely to make these differences, other metabolites might be responsible. The coadministration of clozapine and fluvoxamine offers the opportunity to investigate further the putative associations between certain metabolites, immunomodulation and these side-effects.

[Thiamine treatment in psychiatry and neurology]. / Die Thiaminbehandlung in der Psychiatrie und Neurologie.

Every physician knows that alcohol dependence, alcohol withdrawal and Wernicke-Korsakow-syndrome require substitution with thiamine, in acute stages even parenterally. This would be trivial if there was not the widespread fear of anaphylactic, even lethal reactions to parenteral thiamine application. The present article reviews the literature published on thiamine since 1936, when the first synthetic, parenteral thiamine preparation became available, and, on this basis, tries to give practical advice and therapeutic regimens for the treatment of thiamine deficiency states. Controlled clinical studies on indications and differential thiamine therapy have not been published. From the data that are available, the following conclusions can be drawn: 1) Acute mortality of Wernicke-Korsakow-syndrome is about 20%. 2) Oral thiamine is safe. 3) The risk for an anaphylactic shock due to parenteral thiamine administration is below 1 to 100,000. 4) Not only alcohol but any condition with either increased metabolic need (pregnancy, consuming diseases) or deficient nutrition (including eating disorders) can lead to thiamine deficiency. Therefore, we suggest: 1) Oral thiamine substitution with at least 50 mg per day and supply of a sufficient and complete diet should be given to any person that might be at risk for thiamine deficiency. 2) Any patient suspicious for acute thiamine deficiency needs to be treated under inpatient conditions and there needs to receive 50 to 100 mg thiamine intravenously 3 to 4 times a day. 3) General practitioners, psychiatrists and neurologists should take care of the oral supplementation of thiamine, sufficient nutrition, and they are the physicians to diagnose early stages of thiamine deficiency.

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.