Thomas Pollmächer

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.

Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients

Body weight gain frequently occurs during drug treatment of psychiatric disorders and is often accompanied by increased appetite or food craving. While occurrence and time course of this side effect are difficult to predict, it ultimately results in obesity and the morbidity associated therewith in a substantial part of patients, often causing them to discontinue treatment even if it is effective. This paper reviews the available epidemiological data on the frequency and extent of weight gain associated with antidepressant, mood-stabilizing, and antipsychotic treatment. Possible underlying pathomechanisms are discussed with special attention to central nervous control of appetite including the role of leptin and the tumor necrosis factor system. Metabolic alterations induced by drug treatment such as type 2 diabetes mellitus and the metabolic syndrome are also considered. Weight gain appears to be most prominent in patients treated with some of the second generation antipsychotic drugs and with some mood stabilizers. Marked weight gain also frequently occurs during treatment with most tricyclic antidepressants, while conventional antipsychotics typically induce only slight to moderate weight gain. Serotonin reuptake inhibitors may induce weight loss during the first few weeks, but some of them induce weight gain during long-term treatment. Several antidepressant and antipsychotic drugs are identified which reliably do not cause weight gain or even reduce weight. Based on these insights, countermeasures to manage drug-induced weight gain are suggested.

Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy

We are writing in response to a recent article by Nishino and colleagues, who reported low cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels in parallel with an increased body mass index (BMI) in narcoleptic patients. These findings confirmed earlier preliminary results of studies by this group and of others. Moreover, Nishino and colleagues reported that narcoleptic patients display increased CSF levels of leptin, a fat cell–derived hormone signaling to the brain the size of the adipose tissue. This finding was in contrast to an earlier study of leptin levels in narcoleptic patients published by our group in 2000, which was not mentioned by Nishino and colleagues in their article. In our study, we did not find a significant difference in CSF leptin levels between a group of patients with narcolepsy and control patients. However, we had controlled for the most important factors influencing leptin levels, ie, BMI and gender. Nishino and colleagues took into account neither the increased BMI of their narcoleptic patients nor the higher percentage of females in this group (50.0% compared with 38.2% in the control group) when analyzing the leptin levels. Because both an increased BMI and female gender go along with substantially increased leptin production, it is not justified to conclude from the data presented by Nishino and colleagues that there is an increased disease-related production of leptin in narcolepsy. In contrast, the results of our group suggest that, albeit not in the CSF, narcoleptic patients display considerably reduced leptin levels in plasma. Although this finding deserves independent confirmation, it suggests that the deficiency in hypocretins associated with narcolepsy might be accompanied by a more complex alteration of the regulation of body weight, also involving altered leptin production in the adipose tissue. After this letter was accepted for publication, we found that in a recent study, Kok and colleagues (J Clin Endocrinol Metab 2002;87:805–809) replicated our finding of reduced leptin plasma levels in patients with narcolepsy. Moreover, they reported a reduced amplitude of the circadian rhythm of the levels of this peptide.

Illness, Cytokines, and Depression

Abstract: Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double‐blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus‐induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS‐induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS‐induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive‐like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS‐induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF‐α mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness‐associated depression.

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.

EFNS guidelines on management of narcolepsy.

Management of narcolepsy with or without cataplexy relies on several classes of drugs, namely stimulants for excessive daytime sleepiness and irresistible episodes of sleep, antidepressants for cataplexy and hypnosedative drugs for disturbed nocturnal sleep. In addition, behavioral measures can be of notable value. Guidelines on the management of narcolepsy have already been published. However contemporary guidelines are necessary given the growing use of modafinil to treat excessive daytime sleepiness in Europe within the last 5–10 years, and the decreasing need for amphetamines and amphetamine‐like stimulants; the extensive use of new antidepressants in the treatment of cataplexy, apart from consistent randomized placebo‐controlled clinical trials; and the present re‐emergence of gamma‐hydroxybutyrate under the name sodium oxybate, as a treatment of all major symptoms of narcolepsy. A task force composed of the leading specialists of narcolepsy in Europe has been appointed. This task force conducted an extensive review of pharmacological and behavioral trials available in the literature. All trials were analyzed according to their class evidence. Recommendations concerning the treatment of each single symptom of narcolepsy as well as general recommendations were made. Modafinil is the first‐line pharmacological treatment of excessive daytime sleepiness and irresistible episodes of sleep in association with behavioral measures. However, based on several large randomized controlled trials showing the activity of sodium oxybate, not only on cataplexy but also on excessive daytime sleepiness and irresistible episodes of sleep, there is a growing practice in the USA to use it for the later indications. Given the availability of modafinil and methylphenidate, and the forseen registration of sodium oxybate for narcolepsy (including excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep) in Europe, the place of other compounds will become fairly limited. Since its recent registration cataplexy sodium oxybate has now become the first‐line treatment of cataplexy. Second‐line treatments are antidepressants, either tricyclics or newer antidepressants, the later being increasingly used these past years despite few or no randomized placebo‐controlled clinical trials. As for disturbed nocturnal sleep the best option is still hypnotics until sodium oxybate is registered for narcolepsy. The treatments used for narcolepsy, either pharmacological or behavioral, are diverse. However the quality of the published clinical evidences supporting them varies widely and studies comparing the efficacy of different substances are lacking. Several treatments are used on an empirical basis, specially antidepressants for cataplexy, due to the fact that these medications are already used widely in depressed patients, leaving little motivation from the manufacturers to investigate efficacy in relatively rare indications. Others, in particular the more recently developed substances, such as modafinil or sodium oxybate, are evaluated in large randomized placebo‐controlled trials. Our objective was to reinforce the use of those drugs evaluated in randomized placebo‐controlled trials and to reach a consensus, as much as possible, on the use of other available medications.

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.

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.

Altered Processing of Acoustic Stimuli during Sleep: Reduced Auditory Activation and Visual Deactivation Detected by a Combined fMRI/EEG Study

Although there is evidence that acoustic stimuli are processed differently during sleep and wakefulness, little is known about the underlying neuronal mechanisms. In the present study, the processing of an acoustic stimulus was investigated during different non rapid eye movement (NREM) sleep stages using a combined EEG/fMRI approach in healthy human volunteers: A text stimulus was presented to sleep-deprived subjects prior to and after the onset of sleep, and single-slice silent fMRI were acquired. We found significantly different blood oxygenation level-dependent (BOLD) contrast responses during sleep compared to wakefulness. During NREM sleep stages 1 and 2 and during slow wave sleep (SWS) we observed reduced activation in the auditory cortex and a pronounced negative signal in the visual cortex and precuneus. Acoustic stimulation during sleep was accompanied by an increase in EEG frequency components in the low delta frequency range. Provided that neurovascular coupling is not altered during sleep, the negative transmodal BOLD response which is most pronounced during NREM sleep stages 1 and 2 reflects a deactivation predominantly in the visual cortex suggesting that this decrease in neuronal activity protects the brain from the arousing effects of external stimulation during sleep not only in the primary targeted sensory cortex but also in other brain regions.